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Atypical (dysplastic) nevi

Atypical (dysplastic) nevi
Literature review current through: Jan 2024.
This topic last updated: Nov 20, 2023.

INTRODUCTION — Atypical nevi, also known as dysplastic nevi, are benign acquired melanocytic neoplasms characterized by irregular borders, variegated colors, and a diameter usually larger than 5 mm (picture 1A). Although atypical nevi are benign lesions, they are strong phenotypic markers of an increased risk of melanoma, especially in individuals with numerous nevi and/or a family history of melanoma. Infrequently, atypical nevi may develop into melanoma [1].

This topic will discuss the clinical features, diagnosis, and management of atypical nevi. Congenital nevi and common acquired melanocytic nevi are discussed separately. The clinical features and diagnosis of melanoma are also discussed separately. (See "Congenital melanocytic nevi" and "Acquired melanocytic nevi (moles)" and "Melanoma: Clinical features and diagnosis".)

TERMINOLOGY AND HISTORICAL BACKGROUND — In 1992, the National Institutes of Health in the United States issued a consensus statement recommending that the term "dysplastic nevus" be replaced with "atypical nevus" and that, histologically, lesions be diagnosed as "nevi with architectural disorder with a statement as to the presence and degree of melanocytic atypia" [2]. In addition, the panel recommended that the syndrome for melanoma-prone families be referred to as "familial atypical mole melanoma (FAMM) syndrome."

However, the terms "atypical nevi" and "dysplastic nevi" continue to be clinically used interchangeably, although a "dysplastic nevus" refers to a histologic diagnosis [3,4]. Likewise, the term "familial atypical multiple mole melanoma (FAMMM) syndrome" continues to be in use.

Terms that were previously used include:

"B-K mole," "B-K mole syndrome," and "familial atypical multiple mole melanoma (FAMMM) syndrome" were first used in 1978 to describe a cutaneous phenotype characterized by multiple large, atypical moles associated with a family history of melanoma in two or more first-degree relatives [5-7]. The terms "B-K mole" and "B-K mole syndrome" are no longer in common use.

The term "dysplastic nevus syndrome" was introduced at the same time to describe individuals with sporadic (nonfamilial) melanoma who had any number of large, clinically and histologically atypical nevi [8,9].

The term "atypical mole syndrome" was subsequently applied to patients with many nevi (>100), including some larger than 8 mm and with atypical features (table 1) [10].

EPIDEMIOLOGY — The prevalence of any atypical nevi in White populations ranges from 2 to 10 percent [11-14]. In a population-based, German study that included nearly 355,000 participants, the prevalence of clinically atypical nevi was 11.2 percent [15]. Some of the prevalence variation is explained by differences in the diagnostic criteria used. In patients with a personal history of melanoma, the estimated prevalence is approximately 30 to 60 percent [12,16,17]. There are no data on the prevalence of atypical nevi in skin of color populations.

The prevalence of the familial atypical mole melanoma (FAMM) syndrome in the general population is unknown. (See 'FAMM syndrome' below.)

PATHOGENESIS — The development and density of nevi appear to be predominantly under genetic control, with ultraviolet light exposure playing an important modifying role [18-21]. Data suggest that activating mutations of the oncogene BRAF V600E are sufficient for common nevogenesis [22-26]. Data also suggest that syndromic atypical nevi arise de novo rather than from a pre-existing common nevus and have multiple driver mutations, including mutations known to activate mitogen-activated protein kinases (MAPKs) signaling, telomerase reverse transcriptase (TERT) promoter mutations, or hemizygous alterations of CDKN2A [26].

Sporadic atypical nevi acquire somatic mutations, show a higher overall mutation burden than common nevi, and have NRAS or BRAF non-V600E mutations [26,27]. Exome sequencing reveals that atypical nevi harbor a substantially lower mutational load than melanoma and differing ultraviolet signature mutation patterns, with cytosine to thymine transitions (eg, TC>TT) more frequently found in melanoma than in atypical nevi [27]. Recurrent TERT promoter mutations have been found in a significant proportion of atypical nevi [28]. Germline mutations of the melanoma susceptibility genes (CDKN2A, ARF, CDK4, PTEN, BRAF) have not been found in individuals with sporadic atypical mole syndrome [29].

FAMM syndrome — Atypical nevi can occur sporadically or in a familial setting. The familial atypical mole melanoma (FAMM) syndrome, also called familial atypical multiple mole melanoma (FAMMM) syndrome, is an autosomal dominant condition characterized by a high number of common and atypical nevi (>50) and history of melanoma in one or more first- or second-degree relatives [30]. This syndrome is associated with pathogenic variants in the CDKN2A gene with reduced penetrance and variable expressivity. In a study of 385 families with three or more patients with melanoma from the Melanoma Genetics Consortium (GenoMEL), 39 percent of families had CDKN2A variants, ranging from 20 percent (32 of 162) in Australia, 45 percent (29 of 65) in North America, and 57 percent (89 of 157) in Europe [31].

The CDKN2A gene is located on chromosome 9p21.3 and encodes the proteins p14ARF and p16(INK4), which are involved in the regulation of critical cell cycle pathways [30]. Patients harboring the specific CDKN2A variants have an increased risk of early or multiple melanomas and other primary cancers, particularly pancreatic cancer [32,33]. (See "Inherited susceptibility to melanoma".)

HISTOLOGIC FEATURES — Most, but not all, clinically atypical nevi manifest histologic dysplasia, which includes architectural disorder, cytologic atypia, and host response features (eg, lymphocytic, dermal infiltration; concentric, eosinophilic fibrosis; lamellar fibroplasia; and neovascularization) [11,34].

It should be noted that there is a continuum in the features that distinguish an atypical nevus from an in situ melanoma, and the line of demarcation between these diagnoses can be uncertain. Even among experienced pathologists, there is poor intra- and interobserver agreement in the diagnosis of melanocytic neoplasms ranging from moderately dysplastic lesions to melanoma in situ and T1a invasive melanoma [35].

Architectural disorder – Architectural disorder is defined by the combination of the following findings:

Lentiginous, melanocytic hyperplasia with elongation of rete ridges and proliferation of single or nested melanocytes in the basal layer

Peripheral extension of the junctional component beyond the dermal component (shoulder phenomenon)

Nests of melanocytes distributed at the sides of rete or at the suprapapillary dermoepidermal junction

Bridging or fusion of intraepidermal, melanocytic nests across adjacent retia

Cytologic atypia – Cytologic atypia is defined as the presence of a variable proportion of atypical melanocytes and is graded as mild, moderate, or severe. Atypical melanocytes are larger than normal and have large, hyperchromatic nuclei; irregular nuclear shape and nuclear polymorphism; abnormal chromatin pattern; and prominent nucleoli.

There are no universally accepted criteria for the diagnosis or grading of cytologic atypia. Several interobserver agreement studies found a good level of agreement among pathologists on the diagnosis of atypical nevi versus melanoma or benign melanocytic nevi but only a fair agreement in grading cytologic atypia [35-39]. The 2018 World Health Organization (WHO) classification of skin tumors recommends using only two grades of dysplasia [4]:

Low grade – Nuclear size 1 to 1.5 times the nuclear size of resting basal cells, hyperchromasia or dispersed chromatin, prominent nuclear size in a small minority of cells (random atypia), small or absent nucleoli

High grade – Nuclear size ≥1.5 times the nuclear size of resting basal cells; hyperchromasia, coarse granular chromatin, or peripheral condensation; prominent nuclear size in a larger minority of cells; prominent nucleoli

The importance of the atypia grade in the assessment of melanoma risk for individual patients is uncertain. An observational study found a higher risk of melanoma in patients who had nevi with high-grade histologic atypia [40].

CLINICAL PRESENTATION

Age of onset and natural history — Atypical nevi usually first appear during puberty and may develop throughout life. In contrast, acquired common nevi appear after the age of six months, reach a peak count in the third decade, and then slowly regress with age. Atypical nevi arising on the scalp, breasts, or buttocks during childhood may be an early sign of high total body nevus count in adulthood [41-43].

Atypical nevi are dynamic in their clinical appearance. In a prospective study of 593 atypical nevi in 153 patients, 50 percent of nevi changed over an average of 89 months of follow-up, with 15 percent showing more atypical features [16].

Clinical features — Atypical nevi are most often seen on the trunk and extremities, although they can develop anywhere on the body, including the scalp, breasts, buttocks, and genitalia (picture 2A-B) [44]. They rarely develop on the chronically sun-exposed skin of the face or hands [45].

Features that characterize a nevus as clinically atypical include:

Diameter in one dimension >5 mm (picture 1B).

Prominent macular component, sometimes with a papular center ("fried egg" or "target" appearance) (picture 3).

Mammillated (cobblestone) topography (picture 1B).

Asymmetry (one-half of the lesion does not match the other in terms of shape or color).

Notched, irregular, or ill-defined borders fading into surrounding skin (picture 1C).

Variegated color, with areas of pink, tan, brown, or dark brown (picture 1A). Other colors (eg, blue, red, or white) are not usually seen in atypical nevi, and their presence increases the probability that the lesion is a melanoma.

It should be noted that, while these features may also be warning signs for melanoma, atypical nevi are considered benign neoplasms. Progression to melanoma can rarely occur and most often manifests as a new focal area of darker pigmentation or firm elevation (picture 4A-B) [46]. (See 'Are atypical nevi melanoma precursors?' below.)

The 'signature nevus' and the 'ugly duckling' sign — In individuals with multiple nevi, the predominant group of nevi that share similar clinical and dermoscopic features defines the "signature nevus" [47,48]. The identification of nevi that appear different from the signature nevi, called "ugly ducklings" or "outliers," has been suggested as a screening method for the detection of melanoma in patients with many nevi, including those with many atypical nevi [49,50].

Dermoscopic features — On dermoscopic examination, many atypical nevi fall into 1 of 10 benign dermoscopic patterns (figure 1). These patterns, identified by examining large series of histologically confirmed atypical nevi, are based upon structural features and pigment distribution [51,52]. (See "Dermoscopic evaluation of skin lesions", section on 'Other algorithms and methods' and "Dermoscopic evaluation of skin lesions", section on 'Dermoscopy from a management perspective' and "Dermoscopy of pigmented lesions of the palms and soles", section on 'Acquired melanocytic nevi'.)

Reticular diffuse (picture 5)

Reticular patchy (picture 6)

Reticular with central hypopigmentation (picture 7)

Reticular with central hyperpigmentation (picture 8)

Homogeneous (picture 9)

Peripheral reticular with central globules (picture 10)

Peripheral globular (picture 11)

Globular (picture 12)

Two-component pattern (picture 13)

Multicomponent pattern (picture 14)

Atypical nevi that have eccentric peripheral hyperpigmentation or a multicomponent pattern are the most challenging to distinguish from melanoma. For this type of lesion, short-term digital dermoscopic monitoring or biopsy and histologic examination are necessary to exclude melanoma. (See 'Dermoscopic examination and short-term dermoscopic monitoring' below and 'Excisional/complete biopsy' below.)

CLINICAL SIGNIFICANCE

Atypical nevi and melanoma risk — The clinical significance of atypical nevi lies in their association with an increased risk of melanoma [12,53-58]. Individuals with atypical nevi have a 3- to 20-fold higher risk of developing a melanoma than individuals without atypical nevi [55,59-61].

The risk of melanoma increases in a dose-response fashion with the number of clinically atypical nevi and is greatest in individuals with atypical nevi and a personal or family history of melanoma [17,55,59]. In a meta-analysis of observational studies, the relative risk of melanoma associated with atypical nevi was 1.5 (95% CI 1.3-1.6) for the presence of a single atypical nevus and 6.36 (95% CI 3.80-10.33) for five atypical nevi versus none [59].

Are atypical nevi melanoma precursors? — Sporadic dysplastic nevi have been shown to be genetically intermediate between common nevi and melanoma, consistent with the clinical and histopathologic impression (table 2) [28,62]. Driver mutations in BRAF occur in common nevi as well as in dysplastic nevi and melanomas, with the mutation burden increasing from benign through intermediate lesions to melanoma, with a strong ultraviolet mutation signature. Intermediate lesions also have TERT promoter mutations in addition to the initiating BRAF mutation, while biallelic inactivation of CDKN2A marks the transition to invasive melanoma [63].

However, the concept of the dysplastic nevus as a precursor necessary for the development of melanoma has never been proved. The risk of an individual atypical nevus progressing to melanoma is very small, and most of them will never develop a melanoma. Nonetheless, progression can rarely occur and has been documented through sequential photographs and histologic studies [64-66].

The rarity of such an event is supported by the observation that atypical nevi are far more common than melanoma and that more than one-half of the melanomas that occur in patients with atypical nevi develop de novo and not from a precursor atypical nevus [27]. This is also true in patients with multiple atypical nevi. Moreover, studies of nevus-associated melanomas (ie, melanomas that show nevus remnants on histopathology) indicate that they are associated with common nevi or atypical nevi with similar frequency [67].

DIAGNOSIS — The diagnosis of atypical nevus is usually clinical, based upon the finding of a predominantly macular, pigmented lesion that is larger than common melanocytic nevi (>5 mm), with an irregular shape, ill-defined border, and variable color with areas of pink, tan, brown, or dark brown (picture 1A-C). Other colors, such as blue, red, or white, are not usually seen in atypical nevi, and their presence increases the probability that the lesion is a melanoma.

Dermoscopy is not necessary to establish the diagnosis of an atypical nevus when the clinical characteristics are well defined, but for many lesions, dermoscopy can be helpful in clarifying the benign nature of the lesion and distinguishing it from a melanoma, as these nevi share some of the ABCDE (asymmetry, border irregularities, color variegation, diameter ≥6 mm, evolution) clinical features of early melanoma. (See 'Clinical presentation' above and 'Dermoscopic features' above.)

Biopsy is generally not indicated to confirm the diagnosis of an atypical nevus. However, excisional biopsy and histologic confirmation are required for lesions that are clinically and/or dermoscopically suspicious for melanoma. (See 'Excisional/complete biopsy' below.)

DIFFERENTIAL DIAGNOSIS — Atypical nevi should be differentiated from benign and malignant, melanocytic or keratinocytic lesions, including:

Melanoma – Atypical nevi share some of the clinical features of melanoma, such as asymmetry, irregular borders, multiple colors, and diameter >5 mm (picture 1A). Distinguishing atypical nevi from superficial spreading melanoma (picture 15A-D) is clearly a major difficulty in examining a patient with multiple atypical nevi (table 3). Since the clinical features of atypical nevi are in continuum with those of in situ melanoma, the clinician must have a sufficiently low threshold for excision to avoid missing a melanoma.

Clinical findings that raise the suspicion of melanoma include (see "Melanoma: Clinical features and diagnosis"):

Shades of blue-gray, red, or white color, which are unusual in atypical nevi

A lesion that is clinically or dermoscopically different from the predominant nevus pattern in an individual patient (the "ugly duckling" sign)

A history of rapid change (in size, color, or shape) in a pre-existing nevus over months

A newly developed pigmented lesion in an individual older than 40 years

On dermoscopy, melanoma usually deviates from the benign nevus patterns and manifests specific melanoma features. (See "Dermoscopy of pigmented lesions of the palms and soles", section on 'Melanoma' and "Dermoscopic evaluation of skin lesions", section on 'Criteria for melanoma'.)

Any lesions with clinical or dermoscopic features that are suspicious of melanoma should be excised and sent for histologic examination.

Common acquired nevi – Common nevi tend to be ≤5 mm in diameter and symmetric, with a homogeneous surface, even pigmentation, round or oval shape, and a well-demarcated border (table 3 and picture 16A-B). (See "Acquired melanocytic nevi (moles)", section on 'Clinical features'.)

Small congenital nevi – Small (<1.5 cm) congenital nevi (picture 17A-B) are present since birth or the first few months of life. They typically have a regular, sharply demarcated border; tan to black color; and a smooth, pebbly, or verrucous surface (table 3). However, some congenital nevi may have irregular and poorly demarcated borders and very dark or discontinuous pigmentation. These atypical lesions require biopsy and histologic evaluation. (See "Congenital melanocytic nevi", section on 'Clinical presentation'.)

Pigmented basal cell carcinoma – Pigmented basal cell carcinomas may clinically mimic an atypical melanocytic lesion (picture 18). They are more often nodular and may have irregular pigmentation ranging from dark brown to black. Although dermoscopy may be helpful in differentiating pigmented basal cell carcinomas from atypical nevi or melanoma, biopsy and histologic examination are necessary for definitive diagnosis. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Clinical presentation' and "Dermoscopic evaluation of skin lesions", section on 'Criteria for basal cell carcinoma'.)

Seborrheic keratosis – Seborrheic keratoses typically have uniform color ranging from pink to dark brown or black, well-circumscribed borders, a dull surface, and a "stuck on" appearance (picture 19A-C). Dermoscopic examination is useful in differentiating seborrheic keratoses from atypical nevi. (See "Dermoscopic evaluation of skin lesions".)

MANAGEMENT — Patients with atypical nevi are at increased risk of developing melanoma, although the vast majority of atypical nevi have a benign course and do not require surgical removal. Risk assessment, prevention, and early detection of melanoma are key aspects of management in these patients, which may involve:

Assessing the patient's personal and family history of melanoma

Total body skin examination

Use of diagnostic aids, such as dermoscopy and total body photography

Excision and histologic examination of suspicious lesions

Education on skin self-examination and sun protection

Screening of family members

Genetic counseling and testing if appropriate

Lifelong follow-up

Routine ophthalmologic examination for ocular nevi/melanoma may be indicated in patients with atypical nevi or familial atypical mole melanoma (FAMM) syndrome [68-70]. (See 'Ophthalmologic examination' below.)

Assessment of patient and lesion history — Patients with atypical nevi should be questioned about:

Family history of atypical nevi and/or melanoma

Personal history of melanoma

Changes or symptoms related to their nevi

Sun exposure habits

Full-body skin examination — In individuals with atypical nevi, regular skin examination beginning around puberty provides an opportunity for education regarding sun avoidance, the importance of skin self-examinations, and the early warning signs of melanoma.

Skin examination of patients with atypical nevi should include the scalp, buttocks, groin, palms, and soles [71]. Skin examination requires a source of bright light and, ideally, a magnifying lens.

The total number of nevi should be approximated. Nevi should be examined for the ABCDE (asymmetry, border irregularities, color variegation, diameter ≥6 mm, evolution) features of melanoma and for the "ugly duckling" sign. (See "Melanoma: Clinical features and diagnosis", section on 'ABCDE criteria' and "Melanoma: Clinical features and diagnosis", section on 'The 'ugly duckling' sign'.)

Any nevus that is remarkably different from the predominant nevus pattern ("ugly duckling" nevus) should undergo a closer examination (dermoscopy or, if available, reflectance confocal microscopy). Any lesions for which malignancy cannot be reliably excluded should be histologically examined.

Total body photography — The clinical identification of new or changed lesions in patients with numerous nevi can be challenging (picture 20). Sequential total body photography using a baseline total body photography for comparison on each follow-up examination may facilitate the detection of new lesions or changes in pre-existing nevi.

The impact of total body photography on early diagnosis of melanoma and survival in high-risk patients has not been evaluated in randomized trials or large, observational studies. However, several retrospective studies provide evidence that this surveillance technique may be helpful in detecting early melanoma in patients with multiple atypical nevi and decreasing unnecessary biopsies [54,55,72-79].

Dermoscopic examination and short-term dermoscopic monitoring — Dermoscopy should be used by trained physicians in the evaluation of patients with atypical nevi. In two meta-analyses, dermoscopy has been shown to improve the sensitivity and specificity of melanoma diagnosis for clinicians with adequate training [80,81]. Several studies support its usefulness, in conjunction with total body photography and clinical examination, in the early diagnosis of melanoma in patients with atypical nevi [74,76,82-85].

Lesion evaluation – Lesions are evaluated by using one of the several algorithms designed to differentiate benign from suspicious or malignant lesions, including the Menzies method, the ABCD (asymmetry, border sharpness, colors, differential dermoscopic structure) rule of dermoscopy, the seven-point checklist, or pattern analysis. (See "Dermoscopic evaluation of skin lesions", section on 'Other algorithms and methods'.)

Atypical nevi with dermoscopic features that deviate from the benign nevus patterns and are suspicious of melanoma should be biopsied [45].

Short-term dermoscopic monitoring – Short-term monitoring of suspicious lesions by sequential digital dermoscopy may be useful in identifying early melanomas, especially featureless melanomas, on the basis of changes detected in sequential images [86-88]. A reasonable interval for short-term mole monitoring is three months [86,89,90]. Approximately 10 to 20 percent of changing lesions on short-term monitoring have been shown to be melanoma on biopsy [86,91].

Excisional/complete biopsy — Prophylactic excision of atypical nevi is not recommended because the risk of melanoma developing in an individual atypical nevus is extremely low and the majority of melanomas arise de novo [66]. (See 'Are atypical nevi melanoma precursors?' above.)

However, new, changing, or symptomatic lesions that are suspicious of melanoma on clinical and/or dermoscopic examination should be excised and sent for histologic examination.

For clinicians who are proficient in the use of dermoscopy, dermoscopic examination may be helpful in deciding whether an atypical nevus should be biopsied or monitored. (See 'Dermoscopic features' above.)

Regardless of the surgical technique employed (eg, scalpel excision, punch biopsy, or shave/saucerization removal), the lesion should be excised with a 2 to 3 mm margin of normal skin beyond the area of pigmentation [44,45,92,93]. Partial or superficial/tangential shave biopsies are discouraged to avoid sampling error and reduce the risk of nevus recurrence [94]. Persistent or recurrent pigmentation at the biopsy site can be difficult to differentiate from melanoma clinically and histologically [94-96]. (See "Melanoma: Clinical features and diagnosis", section on 'Biopsy'.)

Re-excision — Re-excision of atypical nevi with positive margins on histologic examination is a common practice among dermatologists, although there are no universally accepted guidelines [97,98].

A consensus statement from members of the Pigmented Lesion Subcommittee of the Melanoma Prevention Working Group recommended that mildly dysplastic nevi and moderately dysplastic nevi biopsied with clear histologic margins following initial excisional/complete biopsy do not need re-excision, and mildly dysplastic nevi with positive histologic margins following biopsy without evidence of clinically residual pigmentation may be safely observed [99]. Observation was also deemed a reasonable option for moderately dysplastic nevi with positive histologic margins and no clinically apparent residual pigmentation.

However, patients with atypical nevi showing severe histologic atypia and positive biopsy margins may benefit from re-excision to confirm the diagnosis and exclude melanoma. Conservative re-excision with 2 to 3 mm margins may be sufficient for atypical nevi with severe histologic atypia with or without residual nevus in the initial excision specimen [100].

Observational studies suggest that the risk of melanoma developing at a biopsy site with positive margins is very low and not clearly reduced by re-excision.

A 2018 systematic review including 12 observational studies examined the clinical outcome of atypical nevi that were re-excised (n = 1138) or observed (n = 1535) [101]. The follow-up time was specified in nine studies and ranged from 2 weeks to 30 years. Of 2673 atypical nevi of all grades of histologic atypia, 11 (0.4 percent) developed melanoma at the site of the biopsy, of which five (0.44 percent) were in the re-excision group and six (0.39 percent) were in the observation group.

Of note, the six melanomas that occurred in the observation group were reported in a single study of 474 atypical nevi with positive margins followed for an average of 5.5 years [102]. Five of six melanomas developed in nevi that had undergone only a partial biopsy and had grossly positive margins.

Although the results of this systematic review should be viewed with caution, given the low methodologic quality and the high risk of bias of the included studies, they indicate that the risk of melanoma developing at the site of a biopsied atypical nevus is generally low and possibly not mitigated by re-excision.

In a subsequent multicenter study including 438 patients with 467 moderately dysplastic nevi with positive histologic margins, none of the patients developed a melanoma at the biopsy site after a mean follow-up period of 6.9 years [103]. However, 100 patients (23 percent) developed a melanoma at a separate site, highlighting the importance of ongoing clinical surveillance in patients with atypical nevi. On multivariate analysis, factors independently associated with the development of melanoma were a previous history of melanoma and history of one or more prior biopsied dysplastic nevi (odds ratio [OR] 11.7, 95% CI 5.7-24.1 and OR 2.6, 95% CI 1.2-5.3, respectively).

Patient education — Education on the importance of skin self-examination and sun protection is an integral part of the management of patients with atypical nevi.

Skin self-examination — Regular skin self-examination is recommended for several reasons:

Melanomas are first detected by patients in approximately one-half of cases [104].

Self-examination, particularly when combined with regular clinician examination, may be associated with early diagnosis of thinner melanoma [105,106]. In a multicenter study that included 800 patients diagnosed with melanoma, the habit of performing skin self-examination was associated with a lower risk of having a melanoma >1 mm in thickness (OR 0.65, 95% CI 0.45-0.93) [106].

Patient information on how to perform self-examination and recognize early signs of melanoma is available from several organizations, including:

The American Academy of Dermatology

The Skin Cancer Foundation

The American Cancer Society

The Melanoma Genetics Consortium (GenoMEL)

Educating patients on the identification of clinical outliers ("ugly ducklings") may also be beneficial. In an interobserver agreement study involving dermatologists, nurses, and nonclinicians, the sensitivity and specificity of the ugly duckling sign in the detection of melanoma were 0.85 and 0.83, respectively, among nonclinicians [50].

Sun protection — Sun and tanning bed avoidance and use of protective clothing, sunglasses, and broad-spectrum sunscreens are recommended for individuals with atypical nevi (table 4) [107-112]. (See "Selection of sunscreen and sun-protective measures" and "Primary prevention of melanoma".)

Genetic counseling and testing — Genetic counseling is not indicated for patients with atypical nevi in the absence of a family history suggesting FAMM syndrome [113,114]. (See 'FAMM syndrome' above.)

GenoMEL recommends that deoxyribonucleic acid (DNA) testing for mutations in melanoma susceptibility genes be performed only rarely outside of defined research programs [113]. (See "Inherited susceptibility to melanoma", section on 'CDKN2A gene'.)

Ophthalmologic examination — Routine ophthalmologic examination is indicated in patients with many atypical nevi because they have an increased prevalence of ocular melanocytic nevi and may be at increased risk of developing ocular melanoma [68-70,115-118]. (See "Initial management of uveal and conjunctival melanomas", section on 'Clinical presentation'.)

FOLLOW-UP — The optimal frequency of skin examinations in individuals with atypical nevi has not been determined. Examinations are generally performed at intervals of 3 to 12 months based upon phenotypic characteristics, personal or family history of melanoma, and competence in self-examination [119,120]. High-risk patients should ideally be followed in a pigmented lesion clinic or by a clinician with experience in the diagnosis of melanoma.

Patients with few common nevi and one or few atypical nevi — We suggest annual total body skin examination for patients with few common nevi and one or few atypical nevi without a personal and/or family history of melanoma. The frequency of skin examination may be higher for patients who also have a personal and/or family history of melanoma or lower if the patient is proficient at skin self-examination. (See "Inherited susceptibility to melanoma", section on 'Surveillance in melanoma-prone kindreds'.)

Baseline digital photographs and/or dermoscopic images of single atypical nevi may be useful for comparison at follow-up visits. (See 'Total body photography' above and 'Dermoscopic examination and short-term dermoscopic monitoring' above.)

Patients with numerous common and atypical nevi — Patients with numerous common and atypical nevi have a high risk of developing melanoma. The risk is greatest for patients who also have a personal and/or family history of melanoma and for patients with familial atypical mole melanoma (FAMM) syndrome. These high-risk patients should be ideally followed in a pigmented lesion clinic or by a clinician with experience in the diagnosis of melanoma.

For patients with many atypical nevi and without a personal or family history of melanoma, we suggest total body skin examinations at 6- to 12-month intervals, or earlier if the patient notices any changes in a lesion's size, shape, or color. Follow-up may be annual for patients who are judged competent at self-surveillance.

For patients who have a personal history of melanoma, we suggest follow-up visits at 3- to 12-month intervals, depending on melanoma stage and time elapsed since melanoma diagnosis, or earlier if the patient notices any changes in a lesion's size, shape, or color.

In FAMM kindreds, screening for melanoma should begin around puberty with a baseline total body skin examination. Follow-up examinations are scheduled every six months until the nevus pattern is stable and the patient is judged competent at self-surveillance and then every 3 to 12 months depending on the rate of melanoma development [30,113,121,122].

High-risk patients should be advised to perform regular skin self-examinations. Ideally, a family member, caregiver, or partner should be involved in the examination of areas not accessible to self-examination. (See 'Skin self-examination' above.)

Total body photography and digital dermoscopy may be particularly useful in the management of patients with high mole counts [54,55,72-75]. (See 'Total body photography' above and 'Dermoscopic examination and short-term dermoscopic monitoring' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Atypical nevi".)

SUMMARY AND RECOMMENDATIONS

Definition – Atypical (dysplastic) nevi are benign acquired melanocytic neoplasms that share some of the clinical features of melanoma, such as large diameter, irregular borders, and multiple colors (picture 1A). (See 'Introduction' above and 'Terminology and historical background' above.)

Atypical nevi and risk of melanoma – Individuals with atypical nevi have a 3- to 20-fold higher risk of developing a melanoma than individuals without atypical nevi. The risk of melanoma increases in a dose-response fashion with the number of atypical nevi and is greatest in individuals with atypical nevi and a personal or family history of melanoma. The role of atypical nevi as precursors of melanoma is controversial. Although they share some of the clinical, pathologic, and genetic features of melanoma, most atypical nevi will never progress to melanoma. (See 'Clinical significance' above.)

Clinical features – Atypical nevi are most often seen on the trunk and extremities, although they can develop anywhere on the body, including the scalp, breasts, buttocks, and genitalia (picture 1A, 2A). Clinical features include diameter >5 mm (picture 1B); prominent macular component (picture 3); irregular, ill-defined borders (picture 1C); and variegated color (picture 1A). (See 'Clinical presentation' above.)

Histopathology – Histologically, atypical nevi are characterized by architectural disorder, cytologic atypia, and host response features. (See 'Histologic features' above.)

Diagnosis – The diagnosis of atypical nevus is clinical and based upon the finding of a predominantly macular, pigmented lesion that is >5 mm with an irregular shape, ill-defined border, and variable color (picture 1A-C). Biopsy is not indicated to confirm the presence of histologic dysplasia in the absence of features that suggest melanoma. However, lesions that are suspicious for melanoma on clinical and/or dermoscopic examination should be completely removed and sent for histologic examination for diagnosis confirmation. (See 'Diagnosis' above.)

Management – The management of patients with multiple atypical nevi may include:

Assessment of history (see 'Assessment of patient and lesion history' above)

Total body skin examination (see 'Full-body skin examination' above)

Use of diagnostic aids such as dermoscopy and total body photography (see 'Total body photography' above and 'Dermoscopic examination and short-term dermoscopic monitoring' above)

Excision with 2 to 3 mm margins and histologic examination of suspicious lesions for melanoma (see 'Excisional/complete biopsy' above and "Melanoma: Clinical features and diagnosis", section on 'Biopsy')

Education on skin self-examination and sun protection (see 'Skin self-examination' above and 'Sun protection' above)

Genetic counseling and testing (see 'Genetic counseling and testing' above)

Lifelong follow-up (see 'Follow-up' above)

Frequency of skin examination – We base our frequency of skin examination on the number of atypical nevi and other risk factors.

One or few atypical nevi – For patients with few common nevi and one or a few atypical nevi without a personal and/or family history of melanoma, we suggest annual total body skin examinations.

The frequency of skin examination may be higher (every 3 to 12 months) for patients who have a personal and/or family history of melanoma. (See 'Patients with few common nevi and one or few atypical nevi' above.)

Many atypical nevi – For patients with many atypical nevi and without a personal or family history of melanoma, we suggest total body skin examinations at 6- to 12-month intervals, or earlier if the patient notices any changes in a lesion's size, shape, or color.

For patients with many atypical nevi who also have a personal history of melanoma, we suggest follow-up visits at 3- to 12-month intervals, depending on melanoma stage and time elapsed since melanoma diagnosis, or earlier if the patient notices any changes in a lesion's size, shape, or color.

In familial atypical mole melanoma (FAMM) syndrome kindreds, screening for melanoma should begin at the age of 10. (See 'Patients with numerous common and atypical nevi' above.)

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References

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