Acquired melanocytic nevi (moles)

INTRODUCTION — Acquired melanocytic nevi are benign clonal proliferations of melanocytes that develop after birth. They can be classified as common (banal) or atypical and include several clinicopathologic variants, such as halo nevi, blue nevi, and Spitz nevi [1].

Acquired melanocytic nevi will be reviewed here. Congenital melanocytic nevi and specific types of acquired melanocytic nevi are reviewed separately. Other benign pigmented lesions are also reviewed separately.

●(See "Congenital melanocytic nevi".)

●(See "Atypical (dysplastic) nevi".)

●(See "Spitz nevus and atypical Spitz tumors".)

●(See "BAP1-inactivated melanocytoma".)

●(See "Benign pigmented skin lesions other than melanocytic nevi (moles)".)

CELL OF ORIGIN AND CLASSIFICATION — Melanocytic nevi are benign clonal proliferations of a type of melanocyte known as a "nevus cell." Both melanocytes and nevus cells can produce the pigment melanin. There are two major differences between ordinary melanocytes that reside in the basal layer of the epidermis and nevus cells:

●Nevus cells lack dendritic processes, except for those within blue nevi, and appear as oval or spindle cells.

●Nevus cells cluster as nests within the lower epidermis and/or dermis, whereas epidermal melanocytes are evenly dispersed as single units.

Based on the location of the melanocyte nests (figure 1), nevi are classified into:

●Junctional nevi – The nests of melanocytes are at the dermal-epidermal junction.

●Compound nevi – The nests of melanocytes are at the dermal-epidermal junction and in the dermis.

●Intradermal nevi – The nests of melanocytes are in the dermis. With progressive migration of melanocytes from the dermal-epidermal junction into the dermis, these nevi become more elevated and less pigmented over time.

PREDISPOSING FACTORS — Factors related to the development of nevi (with the exception of blue nevi and perhaps Spitz nevi) include:

●Genetic factors – There is a familial tendency to have a large number of moles. Germline polymorphisms that impact the number, morphology (eg, common versus atypical), and dermoscopic features (eg, globular versus reticular pattern) of nevi have been identified in several genes, including cyclin-dependent kinase inhibitor p16/CDKN2A and cyclin-dependent kinase CDK4, interferon regulatory factor 4 (IRF4), telomerase reverse transcriptase (TERT), and protection of telomeres 1 (POT1) [2,3].

●Sun exposure – The degree of sun exposure during childhood, especially when intense and intermittent, impacts nevus development [4-10]. Although the results of studies evaluating the effects of sunscreen use on the development of nevi are inconsistent, in one randomized controlled study, school-aged children who were supplied with and instructed to use a broad-spectrum sunscreen developed significantly fewer new nevi over a three-year period than controls [11,12]. Secondary environmental factors that influence the development and growth of acquired melanocytic nevi include blistering disorders, lichen sclerosus, chemotherapy, systemic immunosuppression, and endocrine conditions [13].

●Cutaneous phenotype – Higher nevus counts are seen in individuals with lightly pigmented skin [5,9,14-16]. The mean number of nevi in White adolescents is approximately 15 to 80, compared with five or fewer in Black, Asian, or Native American adolescents [10,14,16]. However, individuals with very lightly pigmented skin, especially when accompanied by red hair, also tend to have fewer nevi, but they usually have numerous solar lentigines and freckles [17,18].

●Immunosuppression – Increased nevus counts have been reported in patients taking conventional immunosuppressants as well as biologics over weeks to months after initiating treatment [19,20].

PRINCIPLES OF DIAGNOSIS AND INDICATIONS FOR BIOPSY — The diagnosis of a nevus is typically based upon the clinical and dermoscopic appearance. Clinicians should be able to recognize the different types of nevi and atypical features that raise suspicion of melanoma, such as diameter >6 mm, irregular borders, asymmetry, variable pigmentation, and change in appearance over time. The last is especially important in adults, as clinical changes (eg, enlargement, increased elevation) and consistent dermoscopic changes occur as part of the normal natural history of nevi in children and adolescents [21]. (See 'Natural history' below.)

Patients with nevi showing atypical features should be referred to a dermatologist for further examination and diagnosis. (See "Melanoma: Clinical features and diagnosis".)

●Indications for biopsy – We do not suggest removal of nevi simply to confirm or rule out the presence of architectural disorder histologically. Recognizing the natural history and clinical spectrum of nevi in pediatric patients as well as potentially worrisome findings in this age group can help to avoid unnecessary procedures. Potential indications for biopsy of acquired melanocytic nevi include:

•Nevi on the palms or soles with mottled pigmentation, pigment on the ridges (as opposed to furrows) of skin markings on dermoscopy (picture 1), and >6 mm in diameter. (See "Pathologic characteristics of melanoma", section on 'Acral lentiginous melanoma' and "Dermoscopy of pigmented lesions of the palms and soles".)

•Nevi originating in the nail matrix that present as single bands of dark color or are ≥3 mm wide; the threshold for biopsy is considerably lower in adults than in children. (See "Longitudinal melanonychia", section on 'When to biopsy'.)

•Nevi with marked asymmetry (based on irregular outline and/or color variation), areas of regression (oftentimes gray-blue or white in color), development of areas of pink or red color, or a history of rapid change or symptoms. (See "Melanoma: Clinical features and diagnosis", section on 'Introduction' and "Melanoma: Clinical features and diagnosis", section on 'Management of suspicious lesions'.)

•An atypical nevus that has different clinical characteristics as compared with the remainder of the nevi in a given patient (ie, the "ugly duckling"). (See "Atypical (dysplastic) nevi", section on 'The 'signature nevus' and the 'ugly duckling' sign'.)

•A halo nevus in which the central nevus has atypical or worrisome features. (See 'Halo nevi' below.)

•A cellular blue nevus that has developed a superimposed change (eg, a papulonodule). (See 'Blue nevi' below.)

•A Spitz nevus with atypical clinical features (eg, diameter >1 cm, asymmetry, or ulceration). (See 'Spitz nevi' below and "Spitz nevus and atypical Spitz tumors".)

●Biopsy technique – If a decision to biopsy is made for lesions suspicious for melanoma, the preferred biopsy technique is one that allows histologic examination of the entire lesion. It is important to give the dermatopathologist information (eg, presence of foci of eccentric hyperpigmentation) about any pigmented lesion that has been biopsied. (See "Skin biopsy techniques".)

COMMON ACQUIRED MELANOCYTIC NEVI

Clinical features — Common nevi first appear during childhood, increase in number during adolescence and early adulthood, and then decrease with age. (See 'Natural history' below.)

They appear as brown macules that may become raised over time and tend to be small (≤6 mm in diameter) and symmetric with a homogeneous surface, even pigmentation, round or oval shape, regular outline, and a sharply demarcated border (picture 2). Close inspection sometimes reveals pigmentary stippling or perifollicular hypopigmentation.

Nevi are often concentrated in sun-exposed areas of the trunk or, particularly in females, on the lower extremities [22]. Less commonly, they occur in acral sites, such as the palms, soles, and nail matrix. (See 'Nevi on palms/soles' below and 'Nevi originating from the nail matrix' below.)

As many as one-third of children and adolescents have acquired nevi on the scalp; nevi in this location may be a marker for the development of a greater total number of nevi [23].

Dermoscopic features — Dermoscopic examination of acquired melanocytic nevi in children most often reveals a globular pattern (picture 3), especially in lesions located on the head, neck, or upper trunk. In contrast, a reticular pattern is more common in acquired nevi located on the extremities and in children with more darkly pigmented skin, as well as in nevi that develop during adulthood (picture 4) [24]. (See "Dermoscopic evaluation of skin lesions" and "Dermoscopy of pigmented lesions of the palms and soles".)

The globular pattern is histologically associated with a prominent dermal component with or without large junctional nests, while the reticular pattern corresponds to a prominent junctional component with lentiginous melanocytic hyperplasia with or without small junctional nests.

Genetics — Most common acquired melanocytic nevi harbor somatic BRAF V600E driver mutations with high frequency, while a minority have NRAS mutations [25-28]. Acquired nevi with a dermoscopic globular pattern, which histologically corresponds to a prominent dermal component with or without junctional nests, are more likely to have an underlying somatic BRAF V600E activating mutation than those with a reticular pattern (approximately 90 versus 30 percent) [29].

Nevi located in sun-exposed areas are more likely to have ultraviolet (UV) signature mutations (eg, C>T transitions) compared with nevi in shielded body sites, suggesting a contributing pathogenetic role of UV exposure [30,31]. Other genetic alterations found in acquired melanocytic nevi include defective deoxyribonucleic acid (DNA) mismatch repair mutations and copy number aberrations (eg, loss of heterozygosity) [26].

Natural history — Common acquired melanocytic nevi begin to appear after the first six months of life, increase in number during childhood and adolescence, reach a peak count in the third decade, and then slowly regress with age [14,32]. However, new nevi may also develop in adult individuals [33].

Substantial nevus turnover occurs during the first two decades of life. For example, over a three- to four-year period in early adolescence, the net number of nevi increases by a mean of 40 to 60 percent, and approximately 15 percent of nevi disappear [32,34]. Although a changing nevus may raise concern for melanoma in an adult, enlargement and increased elevation occur as part of the normal natural history of nevi in children and adolescents [21].

The clinical and histologic evolution of individual lesions from junctional to compound to dermal nevi (figure 1) can correspond to this cycle:

●Junctional nevi – Junctional nevi are macular or minimally raised, have preserved skin markings, and range from brown to black in color, sometimes with darker pigmentation in the center than at the edge (picture 5). They can be similar in appearance to simple lentigines. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Simple lentigo'.)

●Compound nevi – Compound nevi are classically pigmented papules, but in some lesions, the degree of elevation is subtle. Their surface can be smooth and dome shaped or papillomatous, and they vary in color from tan to dark brown (picture 6). The more symmetric and uniform in color a compound nevus is, especially when tan to medium brown in color, the less one needs to worry about the lesion.

●Intradermal nevi – Nevus cells residing in the dermis often stop producing melanin. As a result, intradermal nevi are usually skin-colored to tan papules that are dome shaped, papillomatous, or pedunculated with a soft, rubbery texture (picture 7). Occasionally, they have speckles of brown pigmentation, terminal hairs, or pseudohorn cysts (ie, accumulations of keratin within invaginations of hyperplastic epidermis). Pseudohorn cysts occur more frequently in seborrheic keratoses, which typically develop in adults, than in intradermal nevi. (See "Overview of benign lesions of the skin", section on 'Seborrheic keratosis'.)

Management — Most acquired nevi remain benign throughout the lifetime of a person and require no treatment other than longitudinal observation. Because a large number of acquired nevi are a recognized risk factor for melanoma, patients with multiple acquired nevi should be followed with periodic total body skin examinations and counseled regarding sun protection [35]. (See "Melanoma: Epidemiology and risk factors", section on 'Common (typical) nevi' and "Primary prevention of melanoma" and "Melanoma: Clinical features and diagnosis".)

There is no benefit to "prophylactic" removal of nevi, as more than one-half of cutaneous melanomas arise de novo (ie, not in association with a nevus). Nevertheless, when melanocytic nevi are removed, no matter what the reason, the specimens should always be sent for histologic examination.

NEVI OF SPECIAL SITES

Scalp nevi — Acquired scalp nevi are a subset of melanocytic nevi seen more frequently in children and young adults. A scalp nevus can present as a common nevus (flat or raised, symmetric lesion with a smooth surface), as a papillomatous nevus, as a blue nevus, or may show atypical features (eg, asymmetry, irregular border, multiple colors, diameter >6 mm) that raise concern for melanoma [36].

The "eclipse" nevus is a type of compound nevus that often develops on the scalp of children and is characterized by a tan center and brown, oftentimes stellate rim (picture 8A-B). Despite their two colors and irregular borders, eclipse nevi have benign behavior and, in the absence of a superimposed concerning feature, do not need to be biopsied or excised [37]. A variation on this, known as the "cockade" nevus, which has a pigmented center surrounded by a hypopigmented ring inside an outer pigmented border without concerning symptoms or features, also does not need to be biopsied or excised in children or adolescents [37].

Nevi on palms/soles — Nevi on the palms and soles (acral melanocytic nevi) occur in individuals of all ethnic backgrounds but are more common in those with darkly pigmented skin or numerous melanocytic nevi [38-41]. Nevi located on the palms and soles are usually of the junctional or compound type and are typically brown to dark brown in color.

On dermoscopy, they often show linear streaks of darker pigmentation in the furrows of skin markings, the so-called parallel furrow pattern (picture 9), or a regular fibrillar pattern (picture 10). (See "Dermoscopy of pigmented lesions of the palms and soles".)

Referral to a dermatologist is generally warranted when acquired acral nevi have marked asymmetry, mottled pigmentation, or a large size (>6 mm). (See "Pathologic characteristics of melanoma", section on 'Acral lentiginous melanoma'.)

Nevi originating from the nail matrix — Acral nevi or lentigines that involve the nail matrix can present as longitudinal melanonychia, a tan, brown, or black streak caused by increased melanin deposition in the nail plate (picture 11). In individuals with darkly pigmented skin, longitudinal melanonychia is commonly seen in multiple nails due to increased melanin production by normal nail matrix melanocytes (picture 12). Streaks that develop in childhood are usually benign [42]. However, single bands that are dark/irregular in color or wide (≥4 mm), become darker or wider with time, are associated with nail dystrophy, or have extension of pigmentation onto the nail fold or surrounding skin may warrant biopsy of the nail matrix to exclude melanoma [43]. (See "Longitudinal melanonychia".)

ATYPICAL NEVI — Atypical nevi are benign acquired melanocytic nevi clinically characterized by a diameter >5 mm; asymmetry (one-half of the lesion does not match the other in terms of shape or color); irregular or ill-defined borders; and variegated color, with areas of pink, tan, brown, or dark brown (picture 13A-D) [44]. The clinical significance of atypical nevi lies in their association with an increased risk of melanoma. (See "Atypical (dysplastic) nevi", section on 'Clinical significance'.)

Atypical nevi are also commonly referred to as "dysplastic nevi," although this term should be reserved for histologically dysplastic lesions, which according to the World Health Organization (WHO) 2018 classification of skin tumors are lesions that show irregular nests of intraepidermal melanocytes and increased density of non-nested junctional melanocytes with cytologically atypical melanocytes rated as having low- or high-grade dysplasia [44,45].

The clinical and dermoscopic features, diagnosis, differential diagnosis, and management of atypical nevi are discussed in detail separately. (See "Atypical (dysplastic) nevi".)

HALO NEVI

Clinical features — The halo nevus (Sutton's nevus) is a melanocytic nevus surrounded by a round or oval, usually symmetric, halo of depigmentation. This pigment loss often heralds the spontaneous regression of the central nevus via a process thought to involve a T cell-mediated immune response to nevus antigens [46]. The halo phenomenon typically involves common acquired melanocytic nevi but may also be seen with congenital melanocytic nevi, blue nevi, Spitz nevi, and melanoma.

Halo nevi are relatively common in children and young adults and have a higher incidence in patients with an increased number of nevi and/or a personal or family history of vitiligo. The back is the most common location for halo nevi, and multiple lesions are present in approximately one-half of cases [47,48].

Halo nevi are rare in middle-aged and older adults; in the latter population, the possibility of the halo nevi representing an immune reaction to a cutaneous melanoma must be considered.

Dermoscopic features — Globular and homogeneous patterns, or a combination of the two, are typical dermoscopic features of halo nevi, with a minority exhibiting a reticular pattern [49].

Natural history — Over months or even years, halo nevi undergo progressive involution through four recognized clinical stages, ending with total regression of the central nevus [50]:

●Stage I – Pigmented nevus surrounded by a halo of depigmentation (picture 14)

●Stage II – Pink nevus surrounded by a halo of depigmentation (picture 15)

●Stage III – Circular area of depigmentation, with disappearance of the nevus

●Stage IV – Normal-appearing skin after repigmentation of the halo

In some cases, the central nevus may darken rather than lighten, developing hyperpigmentation in a reticular pattern [51]. Hyperkeratotic surface change of the benign central nevus has been reported to occur in some children prior to halo development and also concomitantly with the halo phenomenon [52,53].

Association with melanoma — In adults, halo nevi may rarely represent an immune reaction to a cutaneous melanoma. In a multicenter study that included 879 patients with 888 halo nevi diagnosed at a mean age of 36 years, melanoma occurred in 95 patients [54]. The risk of developing a melanoma in the year after halo nevus diagnosis was 1 percent, similar to that of patients with atypical nevi or a personal or family history of melanoma.

Management — It is important to assess the clinical and dermoscopic features of the central nevus. A biopsy is not indicated if the central nevus is banal in appearance and dermoscopy shows a typical benign pattern [55]. Because children with halo nevi often have an increased number of nevi in general, a total body skin examination should be performed. Referral to a dermatologist may be warranted. (See 'Common acquired melanocytic nevi' above.)

If there are atypical or worrisome features suspicious for melanoma, then a biopsy of the central nevus should be performed. However, there is no reason to excise the halo.

BLUE NEVI

Clinical features — Blue nevi are benign proliferations of dendritic dermal melanocytes that actively produce melanin. The blue color (ceruloderma) is due to the preferential scattering of shorter wavelengths of light by the dermal melanin, a phenomenon known as the Tyndall effect. The sites of predilection of blue nevi (eg, the head and neck, dorsal aspect of the distal extremities, and sacral area) represent locations where active dermal melanocytes are normally still present at the time of birth. (See "Benign pigmented skin lesions other than melanocytic nevi (moles)", section on 'Dermal melanocytoses'.)

Several variants of blue nevi have been described [56]:

●Common blue nevus – The common blue nevus typically presents as a solitary, uniformly blue to blue-black, dome-shaped papule with preserved skin markings that measures <1 cm in diameter. These nevi often arise in adolescence and are most often found on the dorsal surface of the hands and feet (picture 16).

●Cellular blue nevus – The cellular blue nevus tends to be a larger and more elevated nodule or plaque, measuring at least 1 cm in diameter, with a smooth or slightly irregular surface. Cellular blue nevi may be congenital or acquired and are most often located on the scalp, buttocks, sacrum, or face.

●A hypopigmented variant of blue nevus that lacks the characteristic blue color is occasionally observed.

Multiple blue nevi may be a clinical feature of Carney complex, a rare multiple neoplasia syndrome (table 1) [57]. (See "Carney complex".)

Dermoscopic features — On dermoscopy, blue nevi typically appear as homogeneous blue, blue-gray, blue-brown, or blue-black structureless lesions (picture 17).

Genetics — Blue nevi have distinctive genetic alterations compared with common nevi. Most blue nevi have a somatic activating mutation in the GNAQ or GNA11 genes, which encode G-protein alpha-subunits [58]. Occasionally, mutations in KRAS, CYSLTR2, and PLCB4 are also seen [59-61].

Differential diagnosis — The most common entities in the clinical differential diagnosis of a blue nevus include [62-65]:

●Traumatic tattoo

●Pencil-core granuloma (also called graphite foreign body granuloma) from dermal implantation of graphite from a pencil

●Nodular melanoma

●Dermal metastases of melanoma

Management — Small, stable blue nevi require no intervention. However, blue lesions appearing suddenly or undergoing clinical change should be biopsied. Because there are reports of melanoma arising within cellular blue nevi (particularly those located on the scalp), patients with congenital cellular blue nevi that are difficult to monitor due to location (eg, difficult for the patient to monitor on their buttock or difficult to examine on scalp due to hair density) should be referred to a dermatologist for discussion of possible surgical excision [65-67]. (See 'Principles of diagnosis and indications for biopsy' above.)

SPITZ NEVI — Spitz nevi (spindle and epithelioid cell nevi) are benign, usually acquired proliferations of melanocytes with histopathologic features that sometimes overlap with those of melanoma. Spitz nevi often develop during childhood, and they are most commonly located on the face and lower extremities. Lesions tend to exhibit a rapid initial growth phase that can be alarming to patients and their parents/caregivers.

Spitz nevi classically appear as uniformly pink, tan, red or red-brown, dome-shaped papules or nodules (picture 18A-B). They are usually symmetric, well circumscribed, and <1 cm in diameter. Darkly pigmented lesions are occasionally seen, typically exhibiting a symmetric "starburst" dermoscopic pattern with peripheral streaks (picture 19). The pigmented spindle cell nevus of Reed, a variant of the Spitz nevus, characteristically presents in adolescents or young adults as a dark brown to black, thin papule on the thigh (picture 20) [68].

The pathogenesis, clinical presentation, diagnosis, and management of Spitz nevi are discussed in detail separately. (See "Spitz nevus and atypical Spitz tumors" and "Spitz nevus/tumor in children: Diagnosis and management".)

BAP1-INACTIVATED MELANOCYTOMAS — Germline mutations in the BAP1 gene lead to a rare autosomal dominant tumor predisposition syndrome that features atypical melanocytic neoplasms (picture 21A-B) and an increased risk of uveal as well as cutaneous melanoma and other tumors, including mesothelioma and renal cell carcinoma [69]. (See "BAP1-inactivated melanocytoma".)

SUMMARY AND RECOMMENDATIONS

●Definition – Acquired melanocytic nevi are benign proliferations of a type of melanocyte known as a "nevus cell." They include common nevi; atypical nevi; and several additional variants, including halo nevi, blue nevi, and Spitz nevi. (See 'Cell of origin and classification' above.)

●Common nevi – Common (banal) acquired melanocytic nevi tend to be ≤6 mm in diameter and symmetric with a homogeneous surface, even pigmentation, round or oval shape, regular outline, and a sharply demarcated border (picture 2). (See 'Common acquired melanocytic nevi' above.)

●Atypical nevi – Atypical nevi are benign acquired melanocytic nevi that share some of the clinical features of melanoma (ie, asymmetry, border irregularities (picture 13D and picture 13B), color variability, and diameter >6 mm (picture 13C)). (See "Atypical (dysplastic) nevi".)

Multiple atypical nevi are a phenotypic marker of increased risk of melanoma. The risk of melanoma also depends upon the total number of nevi, family and/or personal history of melanoma, and sun exposure history. (See "Melanoma: Epidemiology and risk factors".)

●Halo nevi – Halo nevi are melanocytic nevi surrounded by a round or oval halo of depigmentation (picture 14). The halo phenomenon usually involves common acquired melanocytic nevi but may also be seen with congenital nevi, blue nevi, Spitz nevi, and melanoma. (See 'Halo nevi' above.)

●Blue nevi – Blue nevi are benign proliferations of dendritic dermal melanocytes that actively produce melanin. They typically occur on the head and neck, dorsal aspect of the distal extremities, and sacral area. Multiple blue nevi may indicate a syndrome such as the Carney complex (table 1). (See 'Blue nevi' above.)

●Spitz nevi – Spitz nevi are uniformly pink, tan, red or red-brown, dome-shaped, hairless papules or nodules. They are usually symmetric, well circumscribed, and <1 cm in diameter (picture 18A). (See 'Spitz nevi' above and "Spitz nevus and atypical Spitz tumors".)

●Indication for biopsy – We do not remove nevi simply to confirm or rule out the presence of architectural disorder histologically. However, a biopsy is indicated for lesions with features suspicious for melanoma. (See 'Principles of diagnosis and indications for biopsy' above.)