AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Background

In 1820, Norris proposed an association between nevi and melanoma. He described a family in which 2 members developed melanoma, while other family members had "many moles on various parts of their bodies." However, the exact appearance of these lesions is unknown.

In 1974, Munro¹ 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 (AMs). In 1978 and 1981, Clark et al^{2, 3} described these lesions as dysplastic nevi when they were observed as a familial phenomenon.

AMs and dysplastic nevi are acquired melanocytic lesions of the skin whose clinical and histologic definitions are controversial and still evolving. Numerous definitions and criteria have been proposed, including the use of the term AMs for clinically abnormal nevi and dysplastic nevi for histologically abnormal nevi. 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 some dysplastic features.^{4, 5, 6}

The terms AMs and dysplastic nevi 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 AMs may progress to melanoma, although no single marker has been determined.^{7, 8}

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

The US National Institutes of Health Consensus Conference on the diagnosis and treatment of early melanoma defined a syndrome of familial AM and melanoma (FAMM). The criteria for FAMM syndrome are as follows⁹:

• The occurrence of malignant melanoma in 1 or more first- or second-degree relatives
• 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)

For additional information on malignant melanoma, see Malignant Melanoma.

Pathophysiology

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

Germline mutations in 3 genes, CDK2NA¹⁰ and CDK4,¹¹ mapped to 9p21 and 12q14, and CMM1, mapped to 1p,¹² have been linked to a subset of hereditary melanomas and FAMM syndrome. In addition, somatic mutations in PTEN, BRAF,¹³ and MCR1 (melanocortin-1 receptor)¹⁴ have been associated with melanoma. Unfortunately, studies have found no alterations in these genes in some patients with FAMM syndrome, and the genes thought to be responsible for most familial and sporadic AMs 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. UV light exposure may be required for full expression of FAMM syndrome.

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

Frequency

United States

The prevalence of AMs in white populations has been reported to be as high as 17%.¹⁵ AMs can be inherited or occur sporadically. Familial AMs may be inherited as an autosomal dominant trait. Sporadic lesions are those AMs that occur in patients without a family history of AMs.¹⁶

International

In Australia and New Zealand, the prevalence of AMs has been reported to be 5-10%.¹⁷ In Germany, approximately 2% of 500 white males aged 16-25 years were reported to have AMs on biopsy analysis. Eighteen percent of a population of white adults studied in Sweden were determined to have AMs clinically, although only 8% demonstrated histologic features of AMs. 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.

Mortality/Morbidity

Melanoma can develop from precursor nevi and AMs. While many melanomas arise de novo, superficial spreading melanoma may arise from AMs.¹⁸ 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.¹⁹ Patients with numerous AMs are at a higher risk of developing melanoma than those individuals with only a few AMs. This risk is more pronounced with a family history of melanoma.

• A personal or family history of melanoma is more predictive for the future development of a melanoma than is the number of AMs.
• 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 FAMM, the overall lifetime risk of melanoma has been estimated to be 100%.²⁰
• The risk of melanoma is greater for those individuals who have 1 relative with melanoma than for those with no affected relative. The lifetime risk of melanoma may approach 100% in individuals with AMs who are from families prone to melanoma (ie, families having 2 or more first-degree relatives with melanoma).
• Individuals who have nevi with clinical or histologic characteristics of AMs but no family history of AMs or melanoma might also be at an increased risk for the development of melanoma. Several prospective studies have demonstrated that patients with AMs without an obvious family history of melanoma have an increased risk for the occurrence of melanoma.^{16, 21} However, the relative risks for melanoma are lower than in those individuals with a clear family history of melanoma. Thus, the presence of AMs (sporadic or familial) may identify patients at increased risk for melanoma, much like fair skin or UV exposure.

Race

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

Sex

No sexual predilection is reported for AMs.

Age

In familial AMs, 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.

AMs can develop throughout a person's lifetime. AMs 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.²²

In one study, AMs 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.²³

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

History

A detailed personal and family history should be obtained, with special attention regarding moles and melanomas.

AMs may arise anytime during a patient's lifetime. AM can change over time, and new lesions may develop. Individuals with FAMM may have 1 to several hundred AMs, whereas those with nonfamilial (sporadic) AMs typically have only 1-10 lesions, although they may also present with several hundred lesions.

An individual with AMs who is from a family prone to melanoma has a high lifetime risk of developing a melanoma. Rapid and characteristic changes should prompt consideration for excision/biopsy to rule out melanoma.

Physical

Patients with FAMM syndrome should have a complete cutaneous examination performed at the first office visit and then at least every 12 months for life.

AMs often have a characteristic appearance, although individual lesions may not show all the findings. Typically, they are large pigmented lesions and frequently measure 5-15 mm in diameter. AMs are usually larger than common moles. Borders are usually irregular, notched, and ill defined. Macular and papular areas may be present within a single lesion (also described as a "fried egg" appearance). Color is highly variable and ranges from tan to dark brown to pink.¹⁵

AMs may appear anywhere on the body, but they most frequently occur on the back, the chest, the buttocks, the breasts, and the scalp. Lesions can be found in sun-exposed and sun-protected areas. Patients with FAMM syndrome may have more than 100 lesions, which is far greater than the average number of common moles (<50) in most individuals.

Although the diagnosis of an individual AM may be clinically simple, patients often have many nevi, which may make monitoring complex. An excisional biopsy should be considered in the initial evaluation of AM for histologic confirmation of dysplastic nevi versus melanoma. Shallow scoop saucerizations including at least a 2-mm margin of clinically normal skin surrounding the pigmented lesion can be performed if the lesion is removed entirely and care is taken for adequate depth for accurate staging in melanoma.

Causes

AM may be inherited (FAMM syndrome) or appear sporadically.²⁴ Sun exposure may play a part in the distribution patterns of these nevi, but it is not absolutely necessary because AMs also appear on sun-protected skin. Patients with FAMM syndrome are at an increased risk for the development of melanoma, although the individual risk is variable.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Combined nevus

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Imaging Studies

In general, imaging studies are not necessary.

Dermoscopy (epiluminescence microscopy) can be used to evaluate atypically pigmented lesions. However, clinical use of this method relies on experienced individuals. In trained individuals, dermoscopy can improve accuracy in identifying melanoma verses atypical nevi.²⁵ See Dermoscopy for more information.

Total body photography has been shown to aid in detection of evolving melanomas and encourage patients to do self-skin examinations. This is expensive, requires special equipment and training, and may best be used in a pigmented lesion clinic.²³

Procedures

All patients who have or had an AM should have an examination of the entire cutaneous surface. A recent change in a pigmented lesion should alert the clinician to consider an excision or a biopsy to rule out the development of malignant melanoma.

Histologic Findings

Typical histopathologic features, which are superimposed on those of a typical junctional or compound nevus, include the following (Note: Some clinical AMs are normal histologically):

• An increased number of single melanocytes along the basal layer, with elongation of rete ridges
• Cytologic atypia of melanocytes with enlarged, hyperchromatic nuclei in the junctional component: Atypia is usually confined to the shoulder region of the nevus. Diffuse atypia is more worrisome.
• A horizontal arrangement of melanocytes, which generally vary in shape from round to spindled, although an occasional epithelioid configuration may also be identified
• A tendency for melanocytes to aggregate into variably sized nests, which fuse with adjacent rete ridges to produce bridging
• The presence of lamellar and concentric dermal fibroplasia
• The presence of a lymphocytic infiltrate (patchy or diffuse) in the superficial dermis
• Extension of the junctional component many rete ridges beyond the last dermal nest to produce "shoulders"

The above changes may appear focally in any given lesion, and they may not be evident unless multiple histopathologic sections are studied.

The World Health Organization Melanoma Program has proposed a similar list of characteristics/criteria for dysplastic nevi. Criteria are divided into 2 major and 4 minor criteria. An individual lesion requires 2 major and 2 minor criteria to be classified as a dysplastic nevus.⁵ Currently, most dermatopathologists are not using this classification scheme. However, the establishment of widely accepted criteria may eventually result in the uniform selection of patients for trials and population studies.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical Care

All patients diagnosed with 1 or more AM should undergo a complete cutaneous examination. Patients should be taught self-examination to detect changes in existing moles and to recognize clinical features of melanomas. Several studies have shown that regular cutaneous examinations combined with baseline and serial color photographs of the patient's cutaneous surface ultimately decrease biopsies and lead to earlier diagnoses of melanoma.²³

Patients with AMs should avoid excessive sun exposure and routinely use a broad-spectrum sunscreen with a sun protective factor of 30 or greater.

Surgical Care

Because melanomas may develop de novo on the skin and because the risk of any one AM developing malignant transformation is low, the prophylactic removal of all AMs does not prevent the development of melanoma and is not recommended. Changing lesions and any lesion worrisome for melanoma must be removed.

A narrow-margin excisional biopsy or saucerization may be appropriate and can produce adequate tissue for histologic examination. If a suspicious mole is too large for simple excision and is in either a cosmetically sensitive location or a functionally sensitive location, a limited biopsy may be considered. However, because of sampling error, the diagnosis may be inaccurate.²⁶ To decrease the risk of an inaccurate diagnosis, obtaining more than 1 biopsy specimen should be considered, and each biopsy specimen should be full thickness for optimal microscopic evaluation. A wider excision may be indicated after histologic interpretation of the lesion.

Consultations

AMs are clinically challenging, and clinical experience with pigmented lesions is often necessary for proper diagnosis. Persons with unusual nevi, or many nevi, usually benefit from consultation with a dermatologist.

FOLLOW-UP

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

Patients with AMs should be routinely monitored and have a complete cutaneous examination at least every 12 months. More frequent examinations may be indicated if compounding risk factors exist.²⁷ AMs may change over time; however, melanocytic lesions that develop 1 or more of the following conditions may require immediate excision and histologic examination:

• Sudden enlargement in size
• Development of irregular or notched borders
• Inflammation
• Increase in pigmentation
• Mottling of previously uniform pigment
• Bleeding and/or ulceration
• Symptoms of pain or pruritus

Deterrence/Prevention

Currently, no therapy is available to prevent the development of AMs. Multiple studies are ongoing to evaluate therapies for eradication of atypical nevi and chemoprevention of progression to melanoma. Some of the treatments under study include imiquimod, retinoids, statin medications, and cyclooxygenase inhibitors.^{28, 29}

Because sun exposure and UV light may modify the number, the appearance, and the progression of some cases of AMs, patients are encouraged to avoid the sun and to routinely use a broad-spectrum sunscreen with a sun protection factor of 30 or greater, in addition to avoiding UV tanning beds.

Prognosis

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

Patients with FAMM syndrome are at an increased risk for the development of a melanoma. The cumulative risk of melanoma in patients with FAMM 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 FAMM 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.

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 excellent patient education resources, visit eMedicine's Procedures Center. In addition, see eMedicine's patient education article Mole Removal.

MISCELLANEOUS

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

Concern evolves around a failure to consider the diagnosis of malignant melanoma in a changing pigmented lesion. All melanocytic lesions should be histologically interpreted by an individual with proper training and experience because inaccurate histologic diagnosis may lead to improper management.

Special Concerns

If a patient is diagnosed with FAMM syndrome, recommend that all first-degree relatives be examined. Genetic screening is currently not recommended for patients and families with melanoma or FAMM syndrome outside of the research setting.³⁰

Case reports suggest a possible association between uveal melanoma and patients with FAMM syndrome.³¹ Baseline eye examination may be indicated in the workup of persons with FAMM syndrome.

A subset of FAMM syndrome kindreds will also have hereditary pancreatic cancer (FAMM-PC syndrome), also associated with the CDK2NA mutation, and screening for pancreatic cancer may be advisable in certain patients and families.³²

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• References

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28. Somani N, Martinka M, Crawford RI, Dutz JP, Rivers JK. Treatment of atypical nevi with imiquimod 5% cream. Arch Dermatol. Mar 2007;143(3):379-85. [Medline].
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Article Last Updated: Dec 7, 2007