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Keywords:

  • dermoscopy;
  • genetic;
  • nevi;
  • nevogenesis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Dermoscopic patterns and histopathological correlates of nevi
  5. Age-related nevus pattern
  6. Body-site related dermoscopic patterns of nevi
  7. Skin-type related nevus pattern
  8. A dual concept of nevogenesis
  9. Genetic pathways in melanocytic proliferations
  10. Is there a third pathway to nevi?
  11. Summary and future outlook
  12. References

The evolution of nevi is a complex process involving several constitutional and environmental factors. Although histopathology is the gold standard for the diagnosis and classification of melanocytic nevi, the widespread use of in vivo diagnostic technologies such as dermoscopy and more recently of reflectance confocal microscopy, has enriched profoundly our knowledge regarding the morphological variability of nevi in different stages of their evolution. In addition, significant progress has been made in our understanding of genetic alterations and molecular pathways involved in the formation of melanocytic tumors. All this newly acquired knowledge increasingly questions whether morphologically different nevi are also histiogenetically different. In this article, we intend to extract some of the salient points from published clinical and molecular studies on melanocytic tumors and attempt to assimilate them into an integrative concept of nevogenesis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Dermoscopic patterns and histopathological correlates of nevi
  5. Age-related nevus pattern
  6. Body-site related dermoscopic patterns of nevi
  7. Skin-type related nevus pattern
  8. A dual concept of nevogenesis
  9. Genetic pathways in melanocytic proliferations
  10. Is there a third pathway to nevi?
  11. Summary and future outlook
  12. References

The evolution of melanocytic nevi is a complex, multifactorial process involving both constitutional and environmental factors. While histopathology remains the gold standard for diagnosis of melanocytic lesions (also based on our limited ability to clinically differentiate between various types of nevi), it is a mere cross-sectional view of nevus evolution at one point in time. Dermoscopy is an in vivo technique for assessment of morphological features of nevi; the fact that dermoscopy allows the recognition of features not visible with the clinical eye and that most dermoscopic features are well correlated with histopathological criteria makes dermoscopy a valuable method to observe gross tissue changes over time without need for biopsy.1 Thus, the use of dermoscopy has provided new insights regarding the morphological diversity and evolution patterns of nevi.

Dermoscopic patterns and histopathological correlates of nevi

  1. Top of page
  2. Abstract
  3. Introduction
  4. Dermoscopic patterns and histopathological correlates of nevi
  5. Age-related nevus pattern
  6. Body-site related dermoscopic patterns of nevi
  7. Skin-type related nevus pattern
  8. A dual concept of nevogenesis
  9. Genetic pathways in melanocytic proliferations
  10. Is there a third pathway to nevi?
  11. Summary and future outlook
  12. References

Nevi, with the exception of Spitz and blue nevi, can be categorized by dermoscopy into globular, reticular, structureless brown and mixed patterns. Mixed pattern is defined as a combination of two of the former three patterns and can be further sub-classified according to the location of globules or structureless brown areas into central globules/structureless brown areas and peripheral network (MC) and, central reticular or structureless brown pattern and peripheral globules (MP). The histopathological correlates of different dermoscopic types of nevi are shown in Figure 1.

image

Figure 1.  The four most common dermoscopic types of nevi and their histopathological correlates. Globular/cobblestone and reticular nevi are primary dermal and intraepithelial proliferations, respectively. Nevi with mixed pattern reveal typically a central dermal (globular or structureless brown) and lateral epidermal (more or less evident reticular) component.

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Age-related nevus pattern

  1. Top of page
  2. Abstract
  3. Introduction
  4. Dermoscopic patterns and histopathological correlates of nevi
  5. Age-related nevus pattern
  6. Body-site related dermoscopic patterns of nevi
  7. Skin-type related nevus pattern
  8. A dual concept of nevogenesis
  9. Genetic pathways in melanocytic proliferations
  10. Is there a third pathway to nevi?
  11. Summary and future outlook
  12. References

It is well documented that the number of nevi increases significantly from puberty to midlife and thereafter decreases and previous studies demonstrated significant age-related differences in dermoscopic pattern of nevi (Fig. 2).2–6

image

Figure 2.  Age-related dermoscopic pattern of nevi. Nevi that appear before puberty exhibit a globular pattern on dermoscopy (exception: children with a dark skin type, who are prone to small reticular nevi). Nevi with mixed pattern composed by peripheral globules are most commonly seen around puberty and early adolescence. Most nevi in adults show the reticular pattern and to a lesser extent, the mixed pattern with central globules or structureless pattern. Nevi in late adulthood are typically nodular and reveal the stereotypical appearance of a dermal nevus. Note that a few globular or structureless nevi, clinically characterized by a nodular shape, can be seen in few numbers throughout all ages, supporting to the conception that early onset globular nevi and dermal nevi of late adulthood represent the same spectrum of primary dermal proliferations.

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Body-site related dermoscopic patterns of nevi

  1. Top of page
  2. Abstract
  3. Introduction
  4. Dermoscopic patterns and histopathological correlates of nevi
  5. Age-related nevus pattern
  6. Body-site related dermoscopic patterns of nevi
  7. Skin-type related nevus pattern
  8. A dual concept of nevogenesis
  9. Genetic pathways in melanocytic proliferations
  10. Is there a third pathway to nevi?
  11. Summary and future outlook
  12. References

Clinical and dermoscopic studies suggest that nodular nevi with globular pattern (i.e. dermal nevi) prevail significantly on the head/neck area and upper trunk (shoulders) and are generally larger compared with the smaller, flat, reticular nevi (i.e. mostly intraepithelial nevi), which can be seen in any area of the trunk but are particularly common on the extremities.3,7–9

Skin-type related nevus pattern

  1. Top of page
  2. Abstract
  3. Introduction
  4. Dermoscopic patterns and histopathological correlates of nevi
  5. Age-related nevus pattern
  6. Body-site related dermoscopic patterns of nevi
  7. Skin-type related nevus pattern
  8. A dual concept of nevogenesis
  9. Genetic pathways in melanocytic proliferations
  10. Is there a third pathway to nevi?
  11. Summary and future outlook
  12. References

The dermoscopic patterns of nevi, their size and their histopathological features are also related to an individuals’ pigmentary trait (Fig. 3).3,10

image

Figure 3.  Skin type-related dermoscopic pattern of nevi. Persons with a fair skin reveal typically light brown to orange nevi with mixed pattern, which are usually larger than nevi of dark skin types. Histopathologically, they are compound or dermal nevi. Individuals including children with a dark skin type exhibit smaller, dark brown-black reticular nevi with central hyperpigmentation. They correspond to junctional or lentiginous nevi by histopathology.

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A dual concept of nevogenesis

  1. Top of page
  2. Abstract
  3. Introduction
  4. Dermoscopic patterns and histopathological correlates of nevi
  5. Age-related nevus pattern
  6. Body-site related dermoscopic patterns of nevi
  7. Skin-type related nevus pattern
  8. A dual concept of nevogenesis
  9. Genetic pathways in melanocytic proliferations
  10. Is there a third pathway to nevi?
  11. Summary and future outlook
  12. References

The observations that nevi with globular and reticular dermoscopic patterns display significant age-related differences have led us to propose the hypothesis that nevogenesis occurs by at least two distinct pathways.11,12

One pathway, the constitutional pathway, gives rise to globular nevi with predominantly large dermal nests in childhood. Longitudinal studies show that the majority of these “early onset” nevi maintain their dermoscopic pattern while enlarging proportionally to the child’s growth (Fig. 4).3 In contrast, the acquired pathway of nevogenesis is responsible for the formation of nevi displaying a predominantly reticular pattern. These nevi are hypothesized to derive from epidermal melanocytes, which proliferate in response to factors such as intermitted ultraviolet (UV) light exposure (Fig. 5).

image

Figure 4.  Evolution of nevi with globular/cobblestone pattern. Nevi with globular/cobblestone pattern derive from immature dermal melanoblasts which proliferate during early childhood in the dermis. Once stabilization of growth is reached the nevus will persist and acquires with time the stereotypical appearance of a dermal nevus.

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image

Figure 5.  Evolution of nevi with reticular pattern. Reticular nevi of the junctional or lentiginous type derive from intraepithelial melanocytes, which proliferate and migrate horizontally along the basal layer. After decades, reticular nevi will involute, clinically and dermoscopically showing gradually vanishing pigmentation. The latter may appear through transepidermal elimination of apoptotic cells.

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The divergent pathway in the formation of reticular and globular nevi is also supported by their body-site related differences and which can be well explained by the sequence of melanoblast migration during embryogenesis.9

It has been theorized that melanocytes are derived from neural crest cells, which acquire pigment-producing capabilities/maturation upon migration to the skin.13 The sequence of melanoblast (i.e. immature melanocytes) migration follows thereby an intradermal (6–8th gestational week), intraepithelial (12–13th week), intrafollicular (15–17th week) and a cephalo-caudal and proximal-to-distal progression;14,15,16 namely, melanoblasts arrive at an earlier time in the dermis and the head/neck and back than in the epidermis and the extremities and ventral site.

A perturbation or delay of epidermal chemotactic factors that guide the dermal migration of melanoblasts is therefore more likely to affect melanoblasts destined for the head/neck and dorsal trunk that are programmed to reach the dermis at an earlier time. Such a delay may cause the arrest of melanoblasts in the dermis, resulting in the formation of nevi of the globular type. In contrast, melanoblasts destined for the extremities, which arrive at the dermis at a later time, may be relatively unaffected by a transient delay in the expression of epidermal migratory factors. In such cases, the melanocytes may normally progress into the epidermis, leading to formation of epidermal junctional nevi or lentigo simplex (reticular nevi). If this model proves to be true, the current histopathological conception of “maturation” in dermal nevi would require revision into “immaturation”.

Genetic pathways in melanocytic proliferations

  1. Top of page
  2. Abstract
  3. Introduction
  4. Dermoscopic patterns and histopathological correlates of nevi
  5. Age-related nevus pattern
  6. Body-site related dermoscopic patterns of nevi
  7. Skin-type related nevus pattern
  8. A dual concept of nevogenesis
  9. Genetic pathways in melanocytic proliferations
  10. Is there a third pathway to nevi?
  11. Summary and future outlook
  12. References

Research on the molecular pathways aberrant in nevi and melanoma has furthered our understanding of nevogenesis. Oncogenic BRAF mutations have been detected in the majority of cutaneous melanoma BRAF, but the mutational rate is remarkably reduced in melanomas arising from sites with chronically exposed or restricted sun exposure. This has led to the notion that oncogenic BRAF is an early acq-uired somatic mutation induced by intermittent UV exposure.17,18

Notably, oncogenic BRAF is also common among acquired nevi such as Clark (also called dysplastic) nevi or small nevi with congenital-like features. In contrast, other types of melanocytic nevi including intermediate to large congenital nevi, Spitz nevi and blue nevi display mutations in other genes, including NRAS, HRAS or GNAQ, respectively.17 The fact that these different types of nevi display very different dermoscopic pattern suggests that morphology correlates well with genetics.

Based on these early observations, the following progression model has started to emerge. Intermittent UV exposure induces BRAF mutations in melanocytes, which in turn stimulate melanocytic proliferation forming early neoplastic clones that harbor this mutation. In the absence of additional genetic alterations (i.e. among nevi), these clones enter cell cycle arrest and senescence, attributed to the induction of p16INK4a and acidic β-galactosidase activity.19–21

However, it is interesting to note that the frequency of oncogenic BRAF increases from lentiginous/junctional nevi to compound and dermal nevi.18,22–24 These data challenge the model of a UV-induced somatic mutation as one would expect to find higher rates of BRAF mutations among nevi that are predominantly junctional–lentiginous, because epidermal melanocytes are likely exposed to higher levels of UV than dermal melanocytes. Taken together with studies reporting high rates of BRAF mutations among nevi from sun-protected body areas (e.g. genitalia, mucosa or acral sites) challenge the notion that UV exposure plays an important role in acquisition of BRAF mutations among nevi.25,26

Instead, the question raises whether oncogenic BRAF correlates with different maturation stages of melanoblasts/melanocytes; the mutation being more likely associated with immature, dermal melanoblasts (i.e. globular nevi) with a possibly higher proliferative potential compared with mature epidermal melanocytes. In support of this, globular-dermal and mixed pattern-compound nevi are generally larger than uniform reticular nevi (i.e. junctional or lentiginous nevi).3 This hypothesis does not exclude that intraepithelial melanocytes (reticular nevi) proliferate in response to intermittent UV exposure, but they may follow thereby a different molecular pathway.

Is there a third pathway to nevi?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Dermoscopic patterns and histopathological correlates of nevi
  5. Age-related nevus pattern
  6. Body-site related dermoscopic patterns of nevi
  7. Skin-type related nevus pattern
  8. A dual concept of nevogenesis
  9. Genetic pathways in melanocytic proliferations
  10. Is there a third pathway to nevi?
  11. Summary and future outlook
  12. References

It is our experience that nevi with MP pattern are commonly observable in young adolescents with an above average nevus count.5 These nevi correlate histopathologically and under reflectance confocal microscopy to compound nevi, in which the peripheral brown globules correlate with variable large lateral junctional nests of melanocytes that appear to extend centrifugally by elongation and narrowing of their shape.5,27 After a variable period of time, usually on the magnitude of several months, these nevi stop growing and stabilize, indicating senescence. During this stage, the peripheral globules disappear and these nevi tend to manifest either a reticular pattern or a mixed pattern. After a variable time, but usually around midlife, an increasing number of nevi with mixed pattern will involute. Although it remains to be clarified whether evolving compound nevi with MP pattern originate from melanocytes located at or just beneath the dermoepidermal junction, it is possible that nevus cells are capable of migrating and proliferating in and between both compartments (Fig. 6).27

image

Figure 6.  Evolution of nevi with mixed pattern. Nevi with mixed pattern possibly derive from melanocytes located just beneath or at the dermoepidermal junction, which are capable of migrating and proliferating in and between the dermal and epidermal compartments; in particular, intraepidermal melanocytes form large lateral nests at the junction that extend horizontally towards the periphery until stabilization of growth is achieved. At this stage nevi reveal either an mixed pattern with central globules or structureless or reticular pattern. After a variable time (but usually faster than reticular nevi of the junctional or lentiginous type) they undergo involution characterized by a progressive disappearance of pigmentation that typically starts from the peripheral flat, epidermal component and progresses towards the dermal center of the nevus.

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Besides puberty and adolescence, the MP pattern is also seen among growing nevi during pregnancy or among eruptive nevi during immunosuppression or treatment with α-melanocyte stimulating hormone. These observations suggest a possible role of growth-related hormones in the development of nevi with MP pattern.28–31

In this context, it is interesting that most studies reporting on high-rate BRAF mutations among melanocytic tumors show an association with young age and among growing lesions.18,32–34 This supports the view that BRAF mutations are acquired early in nevogenesis.18,24 More recently, it has been additionally shown that nevi are polyclonal with respect to BRAF mutations.18,24,32,35

These findings are interesting as also nevus count and nevus pattern are age related and may be attributed to different growth phases in the nevus life.

If we consider that the MC and reticular dermoscopic patterns of nevi represent a later phase in the life of a nevus and that MP pattern represents an early stage, it seems reasonable to speculate that the frequency of BRAF mutations in nevi is correlated with the actual growth phase of a given nevus.

In a recent study, we tested the frequency of oncogenic BRAF mutations among different dermoscopic types of nevi classified as globular, MP, MC and reticular and by different detection methods.35

The BRAF mutation frequency varied significantly between the different methods and between the different dermoscopic types of nevi with polyclonal oncogenic BRAF associated at a higher rate with globular nevi (i.e. dermal or compound nevi) and nevi with MP pattern. Interestingly, none of the reticular nevi using the less sensitive method as it has been applied in most previous studies showed BRAF mutations. Based on our findings together with the current knowledge, we proposed a model explaining the role of BRAF in melanocytic nevi (Fig. 7).

image

Figure 7.  Role of oncogenic BRAF mutations in the evolution of nevi. BRAF mutant cells initially drive nevus growth, but after a limited number of cell cycles, an increasing number of cells enter cell cycle arrest, while BRAF wild-type cells maintain the proliferation of the nevus; this equilibrium defines a period of nevus stabilization. At this stage, nevus cells are polyclonal for the mutation. In nevi lacking the later population, involution is clinically evident when most cells enter senescence and loose proliferative capacity.

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Summary and future outlook

  1. Top of page
  2. Abstract
  3. Introduction
  4. Dermoscopic patterns and histopathological correlates of nevi
  5. Age-related nevus pattern
  6. Body-site related dermoscopic patterns of nevi
  7. Skin-type related nevus pattern
  8. A dual concept of nevogenesis
  9. Genetic pathways in melanocytic proliferations
  10. Is there a third pathway to nevi?
  11. Summary and future outlook
  12. References

Without doubt, new imagining technologies such as dermoscopy, digital dermoscopic follow up and reflectance confocal microscopy have allowed intriguing and fascinating new insights into the life of nevi. Future studies analyzing genetic alterations in nevi should consider stratifying them by dermoscopic pattern and growth phase.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Dermoscopic patterns and histopathological correlates of nevi
  5. Age-related nevus pattern
  6. Body-site related dermoscopic patterns of nevi
  7. Skin-type related nevus pattern
  8. A dual concept of nevogenesis
  9. Genetic pathways in melanocytic proliferations
  10. Is there a third pathway to nevi?
  11. Summary and future outlook
  12. References