eMedicine Specialties > Dermatology > Benign Neoplasms

Nevi, Melanocytic

Author: Timothy McCalmont, MD, Director, UCSF Dermatopathology Service, Professor of Clinical Pathology and Dermatology, Departments of Pathology and Dermatology, University of California at San Francisco
Contributor Information and Disclosures

Updated: Oct 3, 2008

Introduction

Background

Melanocytic nevi are benign neoplasms or hamartomas composed of melanocytes, the pigment-producing cells that constitutively colonize the epidermis. Melanocytes are derived from the neural crest and migrate during embryogenesis to selected ectodermal sites (primarily the skin and the CNS), but also to the eyes and the ears. Ectopic melanocytes have been identified at autopsy in the gastrointestinal and genitourinary tracts. Congenital melanocytic nevi are thought to represent an anomaly in embryogenesis and, as such, could be considered, at least in a sense, malformations or hamartomas. In contrast, most acquired melanocytic nevi are considered benign neoplasms. Melanocytic nevi occur in all mammalian species and are especially common in humans, dogs, and horses.

The malignant analogue of a melanocytic nevus is melanoma, a topic discussed independently in Malignant Melanoma. Additionally, the Medscape Skin Cancer Resource Center may be helpful.

Pathophysiology

Melanocytes are present in the basal layer of the epidermis and exhibit a certain degree of territoriality. Non-neoplastic melanocytes typically exhibit contact inhibition to each other, and thus pigment cells are never found as contiguous cells.

Melanocytic nevi represent proliferations of melanocytes that are in contact with each other, forming small collections of cells known as nests. Nevi commonly form during early childhood. Their onset is believed by some to be a response to sun (ultraviolet) exposure. However, a genetic factor is also clearly involved in the development of some types of melanocytic nevi. Some kinships express an autosomal dominant condition (the so-called dysplastic nevus syndrome or the familial multiple mole and melanoma syndrome), in which members have a large number of large nevi, sometimes hundreds, scattered over the integument.

Melanocytic nevi have also been observed to develop rapidly after blistering events (eg, second-degree thermal burns or sunburns, toxic epidermal necrolysis) or in persons with genetic blistering diseases such as epidermolysis bullosa. In such instances, the development of so-called eruptive melanocytic nevi probably is propagated by a traumatic stimulus, with scattering of melanocytic nevus cells over a larger area within a zone of blistering and with the subsequent development of multiple independent nevi within the injured area. Growth factors, such as basic fibroblast growth factor, have been suggested to be released by proliferating keratinocytes and could contribute to stimulation of melanocyte proliferation in this context. In short, the exact etiology behind the development of melanocytic nevi is complex and multifactorial and is incompletely understood.

Acquired melanocytic nevi are benign neoplasms; congenital melanocytic nevi are perhaps best interpreted as genetic malformations. Melanocytes are of neural crest origin, and congenital nevi probably represent an error in the development and migration of these neuroectodermal elements.

Melanocytic nevus cell "rests" can be observed in the capsules of lymph nodes, and they can sometimes be mistaken for metastatic deposits because of their extracutaneous location. These rests are commonly associated with agminated blue or cellular blue nevi or with large congenital nevi. However, with the advent of sentinel node evaluation, nodal rests of melanocytic nevi clearly are not uncommon and can be found in association with a variety of melanocytic and nonmelanocytic lesions. These rests of cells are sometimes referred to as benign metastases because these cell clusters may represent the end result of an intralymphatic migration of benign melanocytes. Note, however, that benign nodal nevi are almost invariably within the capsule, while melanoma metastases are subcapsular.

Frequency

United States

Acquired melanocytic nevi are so common that some authorities believe they cannot be considered a defect or an abnormality. However, despite the high prevalence, melanocytic nevi are nonetheless pathologic in the sense that they represent an aberrant or neoplastic proliferation of cells. Most persons with light skin have at least a few nevi. Melanocytic nevi also occur in dark-skinned individuals, albeit with low prevalence.

International

The international prevalence of melanocytic nevi is believed to be similar to that observed in the United States. The prevalence in ethnic groups with dark skin is lower than that observed in individuals with fair skin. Some individuals of northern European extraction, especially those from northern Germany, Holland, Belgium, and the United Kingdom, not uncommonly have large nevi (>1 cm in largest diameter), often of large number (>50, up to several hundred), with a red-brown color. These nevi have been called atypical moles or dysplastic nevi.

Mortality/Morbidity

Melanocytic nevi are completely benign. However, melanocytic nevi can be found in association with melanoma. The true frequency of transformation of a melanocytic nevus into melanoma is not known, and the estimated prevalence varies widely in published series. In some series, it is quite low, while in others, it is up to 40%. Both acquired and congenital melanocytic nevi hold some risk for the development of melanoma. Congenital nevi hold the greater risk.

Large and giant congenital melanocytic nevi often have both biological and cosmetic implications. Large congenital nevi have a low but real risk for malignant transformation and the development of melanoma. Some authorities believe that melanoma can develop within a giant congenital nevus in up to 5% of cases.

Race

Melanocytic nevi are common lesions in patients with light or fair skin and are less common lesions in dark-skinned individuals. This difference in prevalence is in part attributable to the fact that identifying moles in dark-skinned patients is often difficult, especially if the lesions are macular (flat).

• It has been suggested that melanocytic nevi are in part stimulated by exposure to sunlight.^1,2 If so, then individuals with dark skin might have fewer nevi because of the protective properties of melanin.
• Evidence indicates that broad-spectrum sunscreens attenuate the development/evolution of melanocytic nevi when used in children³ ; therefore, dark-skinned individuals probably have inherent protection against the development of moles because of their cutaneous melanization.

Sex

No clear sex predilection is reported for the development of melanocytic nevi. However, melanocytes have been postulated to exhibit some degree of sex hormone responsiveness. The findings associated with melanocytic nevi during pregnancy support this conclusion. Nevi commonly darken and/or enlarge during pregnancy. Melanocytes have been shown to have cytosolic receptors for estrogens and androgens, and melanogenesis is responsive to these steroid hormones. Some melanomas seem to respond to hormones, an observation that might be explained by these cytosolic receptors.

• Subtle differences may exist in the prevalence of melanocytic nevi between women and men. Judging the incidence and prevalence based on available biopsy data is difficult because women may be more likely to seek medical attention. If sex-specific variations in incidence do exist, the differences may be site specific. For example, specific features are commonly observed in melanocytic nevi that occur within genital skin. These features are noted almost exclusively within biopsy specimens from women.
• From the author's database (at the University of California, San Francisco), data clearly show that biopsies of genital melanocytic nevi are much more commonly performed in women than in men. These data do not unequivocally confirm that the prevalence of genital melanocytic nevi is truly increased in women, although this seems likely.

Age

By definition, congenital melanocytic nevi are present at birth or soon thereafter, although some small congenital nevi are clearly tardive Current opinion holds that some elements of such nevi are present at birth but remain inconspicuous until some later date.

• By definition, acquired melanocytic nevi are not present at birth, and the incidence of melanocytic nevi increases throughout the first 3 decades of life.
• The peak incidence of melanocytic nevi is in the fourth to fifth decades of life, and the incidence with each successive decade decreases, with a low incidence in elder persons.
• Acquired melanocytic nevi have been stated to be absent at birth and at death. Although not entirely true, this concept reflects the fact that acquired nevi develop in increasing numbers throughout childhood and early adulthood and then slowly involute; therefore, melanocytic nevi are inconspicuous during the advanced elder years.

Clinical

History

Melanocytic nevi are common lesions that can be found on the integument of almost all individuals. Some patients present with few lesions, while others have hundreds. The number on a given individual increases in rough proportion to the degree of skin pigmentation.

Nevi can be broadly divided into congenital and acquired types. Determining if a lesion is congenital or acquired is generally easily accomplished by direct query of the patient, although some small congenital melanocytic nevi are tardive and may be perceived by the patient as acquired.

• When evaluating the nature of a melanocytic lesion, a number of attributes must be assessed. Further commentary describing physical attributes can be found in Physical.
  • Whether a lesion has become symptomatic (eg, itchy, painful, irritated, or bleeding) is important.
  • Not all melanocytic nevi that change are malignant, especially if change is noted in a person younger than 40 years. However, change that is perceptible over a short time is an indicator of potential malignancy and designates a lesion deserving of biopsy.
• Acquired melanocytic nevi are typically less than a centimeter in diameter and evenly colored.
• Melanocytic nevi most commonly are tan to brown, but coloration can be variable, ranging from skin-colored (nonpigmented) to jet black.
• Spitz nevi are a distinctive variant of melanocytic nevi. In decades past, these lesions were called juvenile melanomas, but now they are recognized by specific microscopical features and are known to be benign. The outdated designation juvenile melanoma persists in some areas, but the term should be discarded because of the dire prognosis it suggests and its potential for misconstrued implications.
  • Although Spitz nevi tend to manifest as pink papules on the head of a child, they can be clinically indistinguishable from conventional nevi in some instances; they also can be heavily pigmented.
  • Many Spitz nevi exhibit considerable associated vascular ectasia and, thus, display a hemangiomalike clinical appearance.
• Blue nevi are a form of melanocytic nevi that typically is heavily pigmented. Because of the presence of deep pigmentation within a refracting colloidal medium (namely, the skin), the brownish-black pigment present contributes a bluish cast to such lesions, thereby explaining the name. The optical effect that accounts for clinical blueness is known as the Tyndall phenomenon.
  • Not all blue nevi are blue, and some are various shades of gray, brown, or black. The clinical appearance varies depending on the degree of clinical pigmentation. Indeed, some blue nevi may be wholly amelanotic. Because of the fact that the term blue nevus is not always reflective of the true clinical appearance of the lesion, some dermatopathologists name blue nevi based on the cellular morphology present (eg, dendritic melanocytic nevi).
  • Despite their variability in coloration, blue nevi are usually relatively small and reasonably symmetric, as typically is the case in benign lesions. Blue nevi typically occur on the distal extremities or scalp, but they can occur anywhere.

Physical

• Congenital nevi vary considerably in size and are commonly classified as small (<1 cm), intermediate (1-3 cm), or large/giant (>3 cm).
  • Congenital nevi are generally relatively evenly pigmented and tan or brown, especially those that are thin. In some congenital nevi, the cells extend from the level of the epidermis to the subcutaneous fat. These lesions can have an array of colors, and, at times, they cannot be easily distinguished from melanoma based solely on findings from the clinical evaluation.
  • Congenital melanocytic nevi are hamartomalike; that is, they contain a predominance of melanocytes but also seem to have simultaneous accentuation of other cutaneous elements. Thus, an increase in the number of hair follicles, the presence of follicles of increased size, or an increase in other appendages may be observed.
• Conventional or common acquired melanocytic nevi are generally less than 1 cm in diameter and evenly pigmented. Some atypical melanocytic nevi (melanocytic nevus of the so-called Clark or dysplastic type) exceed 1 cm in size, especially those occurring on the trunk.
  • Junctional melanocytic nevi are macular or thinly papular. Junctional lesions typically range from brown to brownish-black. The darker coloration of junctional melanocytic nevi stems from the fact that the surface epidermis is often simultaneously hyperpigmented.
  • Compound and intradermal melanocytic nevi display elevation relative to surrounding uninvolved skin. Compound melanocytic nevi are often lighter in color than junctional nevi and range from tan to light brown. Some compound melanocytic nevi have areas of dark pigmentation, particularly those that have been recently irritated or traumatized. Many wholly intradermal melanocytic nevi display no significant pigmentation.
  • The development of a new area of pigmentation within a long-standing nonpigmented or lightly pigmented compound or intradermal melanocytic nevus is a cause for concern. While pigmentary changes could be due to incidental inflammation or recent irritation or trauma, the possibility of evolving melanoma is also a consideration in the differential diagnosis. Generally, a biopsy for microscopic examination is warranted in this context.
• Dysplastic or atypical nevi (also known as Clark nevi) are acquired variants that are relatively flat, thinly papular, and relatively broad. Often, such lesions exhibit targetlike or fried egg–like morphology, with a central papular zone and a macular surrounding area with differing pigmentation.
  • Clark nevi often occur in a familial fashion. Affected individuals may present with dozens or hundreds of such lesions. Almost invariably, individuals with dysplastic nevi are of northern European ancestry from the United Kingdom, the Netherlands, Germany, or, occasionally, Poland or Russia. Most of these individuals have fair skin and other Celtic features. Some individuals have only a few atypical nevi, and their risk of melanoma may not be much higher than those without such nevi. Persons with large numbers of nevi (>100) have a high lifetime risk of melanoma that approaches unity. Persons with large numbers of nevi and a familial history of melanoma (consisting of >2 members of the primary family with melanoma) have an extremely high risk of developing melanoma and deserve vigilant clinical monitoring.
  • Dysplastic nevi generally grow through lateral extension of the intraepidermal component of the lesion; therefore, these lesions often assume the clinical configuration of a fried egg, with a central papular zone and a surrounding macular area of differing pigmentation. The peripheral border is often perceived as blurred or fuzzy because of this lateral extension of superficial melanocytes.
  • Some authorities have postulated that Clark (dysplastic) nevi are precursors to melanoma. The designation dysplastic was chosen to suggest that these lesions represent an intermediate (unstable) form between conventional nevi and melanoma. Whether or not they are precursor lesions, dysplastic nevi are markers for the risk of melanoma, and many of the melanomas may occur de novo. While the removal of all dysplastic nevi from an individual with melanoma is generally not indicated, removal of highly atypical appearing lesions is reasonable.
• Spitz nevi vary considerably in size, but they generally are smaller than 1 cm in diameter.
  • Many Spitz nevi have a keratosislike quality because of associated epidermal hyperplasia and hyperkeratosis, and some have an angiomalike appearance because of associated vascular ectasia.
  • The degree of pigmentation of Spitz nevi also varies; a heavily pigmented, small, spindle cell variant on the legs of women has been referred to as pigmented spindle cell nevus or Reed nevus because the pigmented spindle cell variant was described by Richard Reed.
• Blue nevi are not always blue, and they are not even always pigmented. The designation blue nevus, although flawed, has been preserved for historical reasons.
  • Blue nevi are sometimes larger than other melanocytic nevi, occasionally measuring 2 cm or greater in diameter. This is particularly true of cellular lesions (cellular blue nevi) that occur at sun-protected sites, such as the buttocks.
  • Blue nevi are often firm because of associated stromal sclerosis, and they often have a nodular quality, a reflection of their deeper position within the skin.
  • Heavily pigmented blue nevi manifest clinically as blue, black, or gray lesions, whereas blue nevi with lesser degrees of pigmentation may be tan or brown or strictly the color of surrounding healthy skin.

Causes

The etiology of melanocytic nevi remains unknown. No established genetic or environmental influences are known to contribute to the development of congenital nevi. The specific genetic factors that contribute to the development of acquired melanocytic nevi also remain unknown. However, reasonably reliable data suggest that the propensity for developing large numbers of nevi (eg, multiple Clark nevi) might be inherited as an autosomal dominant trait.

• Patients with the familial atypical multiple mole and melanoma syndrome (also known as the dysplastic nevus syndrome) develop dozens to hundreds of melanocytic nevi and have an elevated lifetime risk for the development of melanoma. As the name implies, this disorder is believed to have an inherited basis.
• Some evidence suggests that ultraviolet irradiation may trigger the development of acquired melanocytic nevi. The number of melanocytic nevi in childhood is inversely related to the degree of skin pigmentation and is high in children with poor sun tolerance. The mechanism of this induction has not been adequately investigated, but such induction could represent an example of tumor promotion by ultraviolet light.

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