Atypical Mole (Clark Nevus or Dysplastic Nevus)

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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] :

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] :

See the images below.



View Image

Atypical nevus. The central portion of this mole is a complex papule. The periphery of the lesion is macular, indistinct, slightly pink. Courtesy of t....



View Image

Atypical nevus. The delicate, hazy, tan, macular rim of this lesion, although not clinically dramatic, represents persistent melanocytic proliferation....



View Image

This mole has a characteristic “fried-egg” appearance. The eccentric papule is an ordinary nevus. The diagnostic histologic features are found in the ....

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.

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.

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]

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.

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] :

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]

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.

History

A detailed personal and family history should be obtained, with special attention regarding moles and melanomas. Other important factors to consider are sun exposure habits and recent changes related to their nevi.

Atypical moles may arise anytime during a patient's lifetime. Atypical moles can change over time, and new lesions may develop. Individuals with familial atypical multiple-mole melanoma (FAMMM) syndrome may have one to several hundred atypical moles, whereas those with nonfamilial (sporadic) atypical moles typically have only 1-10 lesions, although they may also present with several hundred lesions.

An individual with atypical moles 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 Examination

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

Atypical moles 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 and are asymmetric. Atypical moles are usually larger than common moles (>5mm). 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" or “target” appearance). Color is highly variable and ranges from tan to dark brown to pink.[28]

See the images below.



View Image

This mole has a characteristic “fried-egg” appearance. The eccentric papule is an ordinary nevus. The diagnostic histologic features are found in the ....



View Image

Atypical nevus. The delicate, hazy, tan, macular rim of this lesion, although not clinically dramatic, represents persistent melanocytic proliferation....



View Image

Atypical nevus. The central portion of this mole is a complex papule. The periphery of the lesion is macular, indistinct, slightly pink. Courtesy of t....

Atypical nevi may appear anywhere on the body, but they most frequently occur on the back, chest, buttocks, breasts, and scalp. Lesions can be found in sun-exposed and sun-protected areas. Patients with FAMMM 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 atypical mole 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 atypical mole 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.[45]

Causes

Atypical nevi may be inherited (FAMMM syndrome) or appear sporadically.[5] Sun exposure may play a part in the distribution patterns of these nevi, but it is not absolutely necessary because atypical moles also appear on sun-protected skin. Patients with FAMMM syndrome are at an increased risk for the development of melanoma, although the individual risk is variable.

Imaging Studies

Dermoscopy (epiluminescence microscopy) can be used to evaluate atypically pigmented lesions. In trained individuals, dermoscopy can improve accuracy in identifying melanoma from atypical nevi.[46] See Dermoscopy for more information.

In retrospective studies, 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.[34]

In 2012, in vivo confocal microscopy was used to identify a dysplastic nevus; pilot studies have shown significant reflectance confocal microscopy correlates. Some of the features identified were the presence of a ringed pattern, a meshwork pattern, atypical junctional cells in the center of the lesion, and irregular junctional nests with short interconnections.[47]

Multiphoton microscopy is a laser-scanning microscope that is able to provide assessment of Clark nevi. Although it is in its early stages of development, it promises to be a useful instrument to provide in vivo evaluation of these lesions.[48]

Procedures

All patients who have or had an atypical mole 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 atypical moles are normal histologically):

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.[11] 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.

Human leukocyte antigen (HLA) expression may be useful as an objective biomarker of atypical nevi. In one study, HLA class I heavy chain, β2m, and HLA class II β chain were expressed in 8.6% of common nevi, compared with approximately 72% of atypical melanocytic lesions. The level of HLA expression was correlated with the degree of cytological atypia and architectural disorder in dysplastic lesions.[50]

Medical Care

All patients diagnosed with one or more atypical mole 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.[34]

Patients with atypical moles should avoid all UV-emitting tanning devices and excessive sun exposure and should 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 atypical mole developing malignant transformation is low, the prophylactic removal of all atypical moles 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.[51] To decrease the risk of an inaccurate diagnosis, obtaining more than one biopsy specimen should be considered. A wider saucerization or excision may be indicated if there is significant atypia and a margin involved, but data suggest that reexcision of low-grade lesions is not necessary.[52, 53, 54, 55, 56]

Consultations

Atypical moles are clinically challenging, and clinical experience with pigmented lesions is often necessary for proper diagnosis. Persons with unusual nevi, familial atypical multiple-mole melanoma (FAMMM) syndrome, or many nevi, usually benefit from consultation with a dermatologist.

Prevention

Currently, no therapy is available to prevent the development of atypical moles. 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.[57, 58]

Because sun exposure and UV light may modify the number, appearance, and progression of some cases of atypical mole, 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.

Long-Term Monitoring

Patients with atypical moles 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.[59] Patients are also encouraged to perform monthly self-skin examinations, with a family member or significant other examining areas of the body that are difficult to self-visualize. Atypical moles may change over time; however, melanocytic lesions that develop one or more of the following conditions may require immediate excision and histologic examination:

Author

Manuel Valdebran, MD, Junior Specialist Physician, Visiting Scholar in Dermatology/Dermatopathology, Department of Dermatology, University of California, Irvine, School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Logan William Thomas, University of California, Irvine, School of Medicine

Disclosure: Nothing to disclose.

Vinod B Shidham, MD, FRCPath, Professor, Vice-Chair-AP, and Director of Cytopathology, Department of Pathology, Wayne State University School of Medicine, Karmanos Cancer Center and Detroit Medical Center; Co-Editor-in-Chief and Executive Editor, CytoJournal

Disclosure: Nothing to disclose.

Specialty Editors

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Rosalie Elenitsas, MD, Herman Beerman Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System

Disclosure: Received royalty from Lippincott Williams Wilkins for textbook editor.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Robin Travers, MD, Assistant Professor of Medicine (Dermatology), Dartmouth University School of Medicine; Staff Dermatologist, New England Baptist Hospital; Private Practice, SkinCare Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Scott M Acker, MD Associate Professor, Director of Dermatopathology, Departments of Dermatology and Pathology, University of Alabama at Birmingham

Scott M Acker, MD is a member of the following medical societies: Alpha Omega Alpha, American Medical Association, American Society for Clinical Pathology, and Southern Medical Association

Disclosure: Nothing to disclose.

Steven Brett Sloan, MD Assistant Professor, Department of Dermatology, University of Connecticut School of Medicine; Residency Site Director, Connecticut Veterans Affairs Healthcare System; Volunteer Clinical Instructor, Yale University School of Medicine

Steven Brett Sloan, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and Connecticut State Medical Society

Disclosure: Nothing to disclose.

Kimberly A Wenner, MD Assistant Chief of Dermatology, Madigan Army Medical Center

Kimberly A Wenner, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

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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 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” 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.

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.

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.

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 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 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” 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.