Melanocytic Nevus
Key Points
Melanocytic nevus refers to common moles on the skin and is composed of nests of altered melanocytes
Cutaneous melanocytic lesions are designated by the histopathologic location of melanocyte cells relative to the dermis-epidermis junction
Junctional nevi have nests of nevus cells only at the junction
Intradermal nevi are the most common type in adults and are confined to the dermis
Compound nevi contain nevus cells at the junction and in the dermis
Congenital melanocytic nevi have been associated with mutations in proteins of the MAPK signal transduction pathway, particularly NRAS and BRAF
Congenital melanocytic nevi appear at birth or within the first 6 months of life and as small, flat, smooth to irregular, lightly pigmented lesions
Divided nevi span across the palpebral fissure and lie on adjacent portions of the upper and lower eyelids
Acquired nevi develop later in life and sunlight exposure is a risk factor for their development
Management includes surveillance for changes in size, texture, shape, or color suggestive of malignant transformation
Surgical removal is indicated for cosmetic concerns, or for changes in size, color, or progressive elevation
The prognosis is generally good and the risk of malignant transformation is about 14% during a lifetime
The term “nevus” is used to describe a variety of benign neoplasms or hamartomas composed of melanocytes.1 Melanocytic nevus refers to common moles on the skin. Melanocytes are derived from the neural crest, and during embryogenesis, they migrate to selected ectodermal sites in the skin, meninges, eyes, inner ear, vaginal epithelium, bones, and heart. In the skin, melanocytes normally are located evenly distributed in the basal layer of the epidermis. In melanocytic nevi, nests of altered melanocytes are distributed in the epidermis and/or the dermis. Cutaneous melanocytic lesions are broadly designated by the histopathologic location of melanocyte cells relative to the dermis-epidermis junction. Junctional nevi have nests of nevus cells only at the junction. Dermal nevi have nests of nevus cells only in the dermis, and compound nevi contain nevus cells at the junction and in the dermis.2
Junctional nevi clinically present as flat, well-circumscribed brown to black macules anywhere on the body. They appear during childhood or early adolescence.3 Intradermal nevi are the most common type of melanocytic nevi and are mostly found in adults.3 They show essentially no junctional activity and are confined to the dermis where they are arranged in nests and cords.4 They may show a depigmented halo around the pigmented lesion.3,4 The depigmented halo shows an absence of melanin pigment and melanocytes with inflammatory cells.3 Compound nevi occur more commonly in children and adolescents.3 Clinically, they appear as a pigmented papule or plaque.4
Melanocytic nevi can be congenital, present at birth or shortly thereafter, or they may be acquired. The acquired type usually begins in childhood in the basal epithelium where it presents as a junctional nevus and gradually migrates into the dermis in young adults where it becomes a compound nevus. Later in life, they tend to reside entirely in the dermis as a dermal nevus.5 The average young adult has about 15 cutaneous nevi and the eyelid is occasionally affected.3 The most common types of melanocytic nevi that can affect the eyelids are congenital, acquired, blue nevus, and Spitz nevus.
A congenital melanocytic nevus (CMN) may be defined as a lesion present at birth or within the first 6 months of life. It can be seen on the skin anywhere on the body and is seen in about 1% to 2% of newborn infants.4,6,7 Most are less than 10 mm in diameter, but occasionally they may be large.4 Giant CMN is very rare, occurring in 1/20,000 to 1/500,000 newborns.8 They are an important entity to recognize because potentially they can be associated with complications, such as developmental anomalies, neurocutaneous melanocytosis, melanoma, and psychosocial impairment.9 The most recent consensus classification of CMN is based on several factors including the predicted adult size, the number of satellite lesions, the anatomic location, color heterogeneity, surface rugosity, presence of hypertrichosis, and presence of dermal or subcutaneous nodules.10
On the eyelid, lesions can vary in size, and the intensity of pigmentation can diminish during the first year.11 Congenital melanocytic nevi occurring on the eyelid are uncommon.12 They may be small and isolated only to the eyelid, or they can be large, extending to the adjacent periorbital or facial skin.13,14,15 Large or heavy nevi on the upper eyelid can be associated with mechanical ptosis. On the lower lid, exophytic growth of the nevus may produce a warty excrescence that can cause secondary entropion.12 Growth of eyelashes associated with CMN can be disorderly resulting in corneal abrasion.
For small-sized CMN, the risk of malignant transformation to melanoma is very rare,16 estimated to be less than 1%, and it tends to begin at puberty.8,17 But large and giant melanocytic nevi carry a greater risk during the first 5 years,18 estimated to be 4.6% over 30 years.9,19,20,21 But regardless of size, rapid growth, color change, nodular elevation, pain, or bleeding are worrisome and should prompt immediate evaluation.
Divided congenital nevus of the eyelids, also known as a kissing nevus, split ocular nevus, or panda nevus, was first described in 1919 by Fuchs.22 This is a congenital compound nevus that affects portions of both the upper and lower eyelids. These nevi extend to the eyelid margins so that when the eyelid closes the two nevi touch, or “kiss.”13 Kissing nevi arise during melanocyte migration from the neuroectoderm to the epidermis during the 12th to 14th-week stages of gestation. The nevus forms on the eyelids during the period of eyelid fusion.23,24,25,26 During this period, the nevus is a single lesion overlying the zone of future eyelid separation that begins in the 20th to 24th week of gestation,27,28 dividing the nevus into segments that lie on adjacent portions of the upper and lower eyelids.
Acquired melanocytic nevi (AMN) develop later in childhood, adolescence, or in adults most commonly in the 30 to 40 year age range. The major environmental risk factor for their development is exposure to sunlight.29,30,31,32,33 Other risk factors include fair skin color, red hair, blue eyes, a tendency to freckle, and a propensity to sunburn.33,34
The risk of malignant transformation of AMN has been estimated to be 1 per 2000,35,36,37 but the molecular events responsible for the progression from AMN to melanoma remain unclear. An increased risk for melanoma occurs in patients with more than 50 melanocytic nevi and those with clinically atypical nevi. Additional risk factors include a family history of melanoma, a history of excessive UV light exposure, and lightly pigmented skin with a tendency to burn.38,39 In children with acquired nevi, the lifetime risk of transformation from benign nevus to melanoma is only approximately 1 in 10,000, with more than 50% of melanomas occurring de novo, on previously normal skin.40,41 Children with a history of chemotherapy or other immunosuppressive medications, such as for organ transplantation, are also at increased risk of both irregular moles and melanoma.42,43
Melanocytic lesions of the conjunctiva include nevus, melanosis, intermediate melanocytic proliferations, and malignant melanoma,44,45,46 of which the circumscribed nevus is the most common. They generally become clinically apparent in the first or second decades of life where 58% of cases are seen in pediatric and adolescent patients. Three-fourths of conjunctival nevi are of the compound type, with 24% subepithelial, 3% junctional, and 1% blue nevus.45 Conjunctival nevi present as dwell-defined, variably pigmented, slightly elevated lesions that may become more pigmented over time.45,46 They most commonly are located on the bulbar conjunctiva (60%-83%), followed by the caruncle (12%-29%), and the palpebral conjunctiva (1%-2%), and less than 1% may involve the cornea.44,45,46 Less than 1% may transform into malignant melanoma.45
The common blue nevus is composed of melanocytes in the mid- and upper dermis. It is most common in children and young adults but can occur at any age.3,47 They present most often as small, solitary, pigmented papules, plaques, or nodules with a dark-bluish or blue-black coloration.48,49,50 The bluish color is caused by the Tyndall effect resulting from the scattering of the short-wavelength component of visible light by melanin particles. Blue nevi occur on any part of the body, including on the eyelid and conjunctiva.51,52,53,54,55,56,57,58
The cellular blue nevus is a variant of blue nevus composed of melanocytes with islands of neural crest-derived epithelioid and spindle cells that fail to complete their normal migration to the epithelium.59,60 The most typical sites of occurrence are the dorsal aspects of extremities, scalp, and buttocks. Other locations include male and female genital tract, breast, subungual mucosa, eyelids, orbit, and conjunctiva.61,62,63,64 It is seen in all age groups, but are most common in adults younger than 40 years.65
Spitz nevus, also known as spindle cell nevus, epithelioid cell nevus, and benign juvenile melanoma, is rare and diagnosed in only 0.5% to 1.0% of excised nevi in children.3 Spitz nevi occur on the trunk, extremities, the lower face, and have rarely been described in the eyelid,66,67,68 or the conjunctiva.69,70 It usually appears as a dome-shaped, hairless, small pink to lightly pigmented papule or nodule less than 1 cm in size.4,66 These lesions may appear suddenly and undergo rapid growth, hemorrhage, and change of color or may cause pruritus.71 They are more common in children, but can also be seen in adults. Spitz nevi are rare in black patients and more common in females, especially in patients older than 15 years.72 Nonpigmented lesions predominate in the head and neck and pigmented ones in the lower extremities.66
Etiology and Pathogenesis
Melanocytic nevi are benign clonal proliferations of cells that express a melanocytic phenotype.78 They are a heterogeneous group of neoplasms with varying clinical and molecular features,79 and they share associated mutations with melanomas. Congenital melanocytic nevi (OMIM #137500, 1p13) have been associated with mutations in proteins of the mitogen-activated protein kinase (MAPK) signal transduction pathway, particularly NRAS and BRAF, and a relationship between nevus size and the corresponding genetic mutation has been described.79,80,81,82 Smaller congenital nevi more frequently have a BRAF mutation, but NRAS mutations are more frequently seen in medium and large nevi.79,83,84,85,86 AMN and blue nevi also harbor oncogenic mutations in BRAF and NRAS, but Spitz nevi (OMIM #137550, 11p15) have been
linked to HRAS and BAP1 alterations and kinase fusions.79 Most of the gene alterations associated with melanocytic nevi have also been described in the development of melanoma, but contrary to melanomas, nevi undergo senescence where the initial growth phase is followed by loss of proliferative activity and stabilization of size.79 Therefore, at least some melanocytic nevi are likely benign clonal tumors that temporarily undergo proliferation through BRAF signaling followed by growth arrest.87
linked to HRAS and BAP1 alterations and kinase fusions.79 Most of the gene alterations associated with melanocytic nevi have also been described in the development of melanoma, but contrary to melanomas, nevi undergo senescence where the initial growth phase is followed by loss of proliferative activity and stabilization of size.79 Therefore, at least some melanocytic nevi are likely benign clonal tumors that temporarily undergo proliferation through BRAF signaling followed by growth arrest.87
Clinical Characteristics
Congenital melanocytic nevi appear at birth or within the first 6 months of life. They are generally small, initially flat with smooth to irregular borders, and can be pink, lightly pigmented or more darkly pigmented in shades of tan, brown, or black (Figures 86.1 and 86.2). They usually are not associated with telangiectasia, madarosis, or ulceration, which helps to distinguish them from some common simulating lesions. Most CMN are solitary, but they may be multiple or even confluent.10 They may show heterogeneous pigmentation and sometimes develop coarse dark hair and become more elevated and rugose over time (Figure 86.3).90,91 Rarely they can be flat and diffuse (Figure 86.3D). Occasionally, proliferative nodules may develop within the nevus.92 Small satellite lesions can be present at birth or develop later in infancy or childhood. Occasionally, CMN may regress spontaneously,93 sometimes preceded by the development of a local depigmented halo surrounding the lesion.94
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