Atypical Mole (Clark Nevus or Dysplastic Nevus)

Updated: Apr 04, 2017
  • Author: Manuel Valdebran, MD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Background

Clark nevus (also known as dysplastic nevus) was initially described in melanoma-prone families, implying that it was a premalignant condition.

In 1820, Norris proposed an association between nevi and melanoma. He described a family in which two members developed melanoma, while other members had "many moles on various parts of their bodies."

In 1974, Munro [1] described an association of lesions and a family history of melanoma. These nevi had the clinical and microscopic appearance of what are now called atypical moles. In 1978 and 1981, Clark et al [2, 3] described these lesions as dysplastic nevi when they were observed in a series of family members of whom 36% had melanomas. The dysplastic nevi were characterized clinically by showing variability in size, border, and colors. Histologically, they described mesenchymal changes in the papillary dermis with a lymphocytic infiltrate. Clark described these families as having a “B-K mole syndrome.” [4] Also during 1981, Elder introduced the phrase “dysplastic nevus syndrome” (DNS), describing the presentation of sporadic dysplastic nevi. He divided dysplastic nevi into those showing epithelioid and lentiginous cell dysplasia. He defined cytological features found in dysplastic nevi, including nuclear pleomorphism, hyperchromatism, dusty cytoplasm, prominent nucleoli, and hyperchromasia. [5] Similarly during this time, Lynch et al described a similar nevus phenotype in a melanoma-prone family, coining the phrase, “familial atypical multiple-mole melanoma (FAMMM) syndrome.” [6]

In 1984, Clark introduced five histological criteria for the characterization of a dysplastic nevus. The following features were included in the proposed criteria [3] :

  • Lentiginous melanocytic hyperplasia
  • Melanocytic nuclear atypia
  • Lamellar fibroplasia
  • Concentric eosinophilic fibroplasia
  • Patchy lymphocytic infiltrates

Also in 1984, Reed introduced the concept of grading the dysplasia as mild, moderate, or severe. [7] In the late 1980s, Mihm et al expanded Reed’s concept by describing criteria for the three different grades of dysplasia based on nuclear size, chromatin changes, and cytoplasmic attributes. [8] During the 1980s, Ackerman extensively debated the concept of dysplastic nevi and challenged the hypothesis of this being a precursor to melanoma, emphasizing architectural changes over nuclear atypia for the assessment of melanocytic lesions. [9]

Numerous definitions and criteria have been proposed, including the use of the term atypical moles for clinically suspicious nevi and Clark nevi for those that histologically present with the architectural changes described by Clark. Unfortunately, when clinically abnormal nevi are evaluated histologically, some studies have shown a lack of concordance, with some clinically abnormal nevi having no dysplastic features and some normal-appearing nevi having features of Clark nevi. [10, 11, 12]

The terms atypical mole and Clark nevus continue to be used interchangeably, regardless of clinical or histologic appearance. Modern molecular methods, including genetic markers, cytokines, proliferation indexes, and cyclins, are all undergoing study to help determine which atypical moles may progress to melanoma, although no single marker has been determined. [13, 14, 15, 16]

Atypical moles differ from common acquired melanocytic nevi in several respects, including diameter and lack of pigment uniformity. Confusion exists because some atypical moles cannot be clinically distinguished from melanoma. The clinical and histologic appearances of atypical moles occurring in a familial setting appear to overlap with sporadically occurring atypical moles.

The US National Institutes of Health Consensus Conference on the diagnosis and treatment of early melanoma recommended "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." The panel also created criteria for FAMMM syndrome, which are as follows [17] :

  • The occurrence of malignant melanoma in one or more first- or second-degree relative
  • The presence of numerous (often >50) melanocytic nevi, some of which are clinically atypical
  • Many of the associated nevi showing certain histologic features (see Histologic Findings)

See the images below.

Atypical nevus. The central portion of this mole i Atypical nevus. The central portion of this mole is a complex papule. The periphery of the lesion is macular, indistinct, slightly pink. Courtesy of the National Cancer Institute, via Wikimedia Commons.
Atypical nevus. The delicate, hazy, tan, macular r Atypical nevus. The delicate, hazy, tan, macular rim of this lesion, although not clinically dramatic, represents persistent melanocytic proliferation beyond the lateral limits of the common mole at its center. Courtesy of the National Cancer Institute, via Wikimedia Commons.
This mole has a characteristic “fried-egg” appeara This mole has a characteristic “fried-egg” appearance. The eccentric papule is an ordinary nevus. The diagnostic histologic features are found in the macular portion of the mole, particularly at the shoulder (ie, where the papule meets the macule). Courtesy of the National Cancer Institute, via Wikimedia Commons.

See Mole or Melanoma? Test Yourself With These Suspicious Lesions, a Critical Images slideshow, to help identify various skin lesions.

For additional information on malignant melanoma, see Malignant Melanoma. Additionally, the Medscape Skin Cancer Resource Center and Melanoma Resource Center may be helpful.

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Pathophysiology

Atypical nevi can be inherited or sporadic. Formal genetic analysis has suggested an autosomal dominant mode of inheritance, but genetic studies have not shown consistent data.

Germline mutations in three genes, CDK2NA [18] and CDK4, [19] mapped to 9p21 and 12q14, and CMM1, mapped to 1p, [20] have been linked to a subset of hereditary melanomas and FAMMM syndrome. In addition, somatic mutations in PTEN,BRAF, [21] and MCR1 (melanocortin-1 receptor) [22] have been associated with melanoma, but not in patients with sporadic atypical mole syndrome. [23] Other genomic events such as loss of heterozygosity (LOH) for tumor suppressor genes are also responsible for the progression from atypical nevi to melanoma, [24] and the genes thought to be responsible for most familial and sporadic atypical moles are still unknown.

Ultraviolet (UV) light (UV-A and UV-B) has been proposed as both an initiator and a promoter in the transformation of melanocytes into atypical melanocytes or melanoma. Atypical nevi have a significant lower mutational load compared with melanoma, as well as different UV mutation patterns. [25] The International Agency for Research on Cancer raised the classification of UV-emitting tanning devices from "probable carcinogenic to humans" to "carcinogenic to humans," [26] and a meta-analysis concluded that use of UV tanning beds before age 30 years increases the risk of melanoma by 75%. [27] UV light exposure may be required for full expression of FAMMM syndrome.

Genetics and UV radiation may also result in a variable number and anatomical distribution of melanocytic nevi. Some patients with the atypical mole syndrome have many large and highly atypical nevi, whereas other patients with this syndrome have many nevi but only a few are atypical.

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Epidemiology

Frequency

United States

The prevalence of atypical nevi in white populations has been reported to be as high as 17% but varies depending on the diagnostic criteria used. [28] Atypical moles can be inherited or can occur sporadically. Familial atypical moles may be inherited as an autosomal dominant trait. Sporadic lesions are those atypical moles that occur in patients without a family history of atypical moles. [29]

International

In Australia and New Zealand, the prevalence of atypical nevi has been reported to be 5-10%. [30] In Germany, approximately 2% of 500 white males aged 16-25 years were reported to have atypical nevi on biopsy analysis. Eighteen percent of a population of white adults studied in Sweden were determined to have atypical nevi clinically, although only 8% demonstrated histologic features of atypical nevi. The marked differences in prevalence between different populations may be due to true differences between these populations or they may be related to differing clinical and histologic definitions of this entity.

The prevalence of FAMMM syndrome is unknown, but in a 2007 study of 385 families with a history of melanoma, 39% of families had CDKN2A mutations (strongly associated with FAMMM syndrome), ranging from 20% (32 of 162) in Australia to 45% (29 of 65) in North America to 57% (89 of 157) in Europe. [31]

Race

Individuals at the highest risk of atypical nevi are persons of northern European background (Celtic) with light-colored hair and freckles. Atypical moles are rare in black, Asian, or Middle Eastern populations.

Sex

No sexual predilection is reported for atypical nevi.

Age

In familial atypical moles, lesions begin to develop in childhood, most frequently during the first decade of life. Lesions may not be clinically specific early on, but typical features usually develop by the end of puberty.

Atypical nevi can develop throughout a person's lifetime. Atypical nevi may also change or regress throughout adulthood. New or changing pigmented nevi are common in adults, and new or changing nevi in patients older than 50 years are more likely to be melanoma than in patients younger than 50 years. [32]

In a prospective study of 593 atypical moles in 153 patients, 50% of nevi changed over an average of 89 months, with 15% showing more atypical features. [33] In another study, atypical moles in 51% of adult patients showed evidence of clinical change over time. These facts lead to the clinically challenging situation in adults as how to adequately evaluate (1) a change in a long-standing pigmented lesion or (2) the development of a new and clinically atypical lesion. An excisional biopsy should always be considered if the development of a melanoma is a concern. [34]

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Mortality/Morbidity

Melanoma can develop from precursor nevi and atypical moles. While many melanomas arise de novo, superficial spreading melanoma may arise from atypical moles. [35] The exact risk of an individual nevus transforming into a melanoma is thought to be 1 in 200,000, and cutaneous melanomas are associated with precursor lesions at least 50% of the time in patients younger than 30 years. [36] Patients with numerous atypical moles are at a higher risk of developing melanoma compared with those individuals with only a few atypical moles. In a meta-analysis, the relative risk of melanoma associated with atypical nevi was 1.5 (95% confidence interval [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 when compared with no atypical nevi present. This risk is more pronounced with a family history of melanoma. [37, 38, 39]

A personal or family history of melanoma is more predictive for the future development of a melanoma than is the number of atypical moles.

Among whites in the United States, the lifetime risk of developing a cutaneous melanoma is approximately 0.6%, or 1 in 150 individuals. In some studies of patients with FAMMM, the overall lifetime risk of melanoma has been estimated to be 100%. [40]

The risk of melanoma is greater for those individuals who have one relative with melanoma than for those with no affected relative. The lifetime risk of melanoma may approach 100% in individuals with atypical moles who are from families prone to melanoma (ie, families having two or more first-degree relatives with melanoma).

Individuals who have nevi with clinical or histologic characteristics of atypical moles but no family history of atypical moles or melanoma might also be at an increased risk for the development of melanoma. Several prospective studies have demonstrated that patients with atypical moles without an obvious family history of melanoma have an increased risk for the occurrence of melanoma. [29, 41] However, the relative risks for melanoma are lower than in those individuals with a clear family history of melanoma. Thus, the presence of atypical moles (sporadic or familial) may identify patients at increased risk for melanoma, much like fair skin or UV exposure.

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Prognosis

An individual with an isolated atypical mole has little risk of developing a melanoma and should not be identified as melanoma prone.

Patients with FAMMM syndrome are at an increased risk for the development of a melanoma. The cumulative risk of melanoma in patients with FAMMM syndrome may approach 100%. Furthermore, these patients are at an increased risk for the development of multiple, primary melanomas. The likelihood of a second melanoma developing over the course of 10 years may be as high as 35% in patients with FAMMM syndrome, compared with 17% in controls who had an isolated sporadic melanoma. Melanomas that are detected early and removed quickly, because of proper and routine screening, tend to be thin, allowing for a good prognosis.

If a patient is diagnosed with FAMMM syndrome, recommend that all first-degree relatives be examined. In 2009, the followoing selection criteria for genetic assessment of patients with familial melanoma were proposed to test for the CDK2NA mutation [42] :

  • Individuals with three or more primary invasive melanomas
  • Families with at least one invasive melanoma and two or more cases of melanoma and/or pancreatic cancer among first- or second-degree relatives on the same side of the family

Case reports suggest a possible association between uveal melanoma and patients with FAMMM syndrome. [43] Baseline eye examination may be indicated in the workup of persons with FAMMM syndrome.

A subset of FAMMM syndrome kindred’s also will have hereditary pancreatic cancer (FAMMM-PC syndrome), also associated with the CDK2NA mutation, and screening for pancreatic cancer may be advisable in certain patients and families. [44]

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Patient Education

Patients should be taught self-examination to detect changes in existing moles and to recognize the clinical features of melanoma. Patients should be advised to avoid the sun whenever possible and about adequate sun protection. Patients should be advised to avoid UV tanning beds.

For patient education resources, see the patient education article Mole Removal.

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