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Dysplastic Nevus Syndrome

Andrew Kim, MD and Dori Goldberg, MD
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Subject: Dysplastic Nevus Syndrome

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Basics

Dysplastic nevus syndrome (DNS), also known as atypical mole syndrome (AMS), is a sporadic or hereditary disorder resulting in numerous clinically atypical nevi and an increased risk for developing malignant melanoma. 

Description

  • Condition resulting in elevated total body nevi count, including clinically atypical nevi

    • Usually >50, although often >100

    • Larger number in hereditary DNS versus sporadic dysplastic nevi (DN) (as few as <10 in sporadic, although high numbers also possible)

  • Increased risk of melanoma (1)

    • Up to 90% occurrence by age 80 years in certain high-risk individuals

    • Earlier onset than sporadic melanoma cases

    • Most arise out of healthy skin as opposed to a preexisting atypical nevus

    • Higher risk for appearance at unusual sites (e.g., scalp)

  • DNS terminology often used interchangeably with AMS, familial atypical multiple mole melanoma (FAMMM) syndrome, and B-K mole syndrome

  • Median age of diagnosis for melanoma is 10–20 years earlier than the general population, with documented cases of melanoma as early as in the early teens and 20s (2).

  • Melanomas in the setting of DNS are most often superficial spreading or nodular type.

Epidemiology

Incidence

Uncertain due to phenotype variability and limited data but ~10% of melanoma cases are diagnosed as familial. 

Prevalence

At least 32,000 cases in the United States per National Institutes of Health (NIH) calculations (3

Etiology and Pathophysiology

CDKN2A (cyclin-dependent kinase inhibitor 2A) mutations have been observed in kindreds with familial DNS and multiple melanomas. The CDKN2A gene on 9p21 encodes for the proteins p16 and p14. The p16 binds to CDK4 and 6 and is a negative cell-cycle regulator via inhibition of the CDK-cyclin D interaction needed for cell-cycle progression from G1 to S. Similarly, p14 functions by stabilizing the tumor-suppressor protein p53 in the G1 phase of the cell cycle. 
  • Unclear for sporadic cases, although somatic p16 inactivation noted in 40% of familial melanoma

  • Familial cases of germline CDKN2A mutations considered to be transmitted genetically in an autosomal dominant fashion.

Genetics

  • Autosomal dominant inheritance in hereditary cases but variable expressivity and incomplete penetrance

  • CDKN2A mutation observed in 25–40% of hereditary cases

Risk Factors

Family history DN, DNS, and/or melanoma 

General Prevention

  • No currently available prevention strategies

  • Treatment is directed toward secondary prevention of melanoma complications with routine skin exams, biopsy of suspect lesions, and environmental risk mitigation (e.g., sun protection and sun avoidance).

  • Experimental early detection protocols for pancreatic cancer in use with some high-risk individuals

Commonly Associated Conditions

  • Malignant melanoma, including ocular melanoma

  • Ocular nevi

  • Pancreatic cancer in CDKN2A mutation

Diagnosis

DNS is a clinical diagnosis with various classifications schemes proposed in the past. Although not widely accepted, diagnostic criteria as defined by the NIH require the 3 features of (i) malignant melanoma in ≥1 1st- or 2nd-degree relatives; (ii) numerous melanocytic nevi (frequently >50), some of which are clinically atypical; and (iii) nevi that have certain histologic features on pathologic examination (4). 

History

  • Changing lesions: bleeding, scaling, size, texture, nonhealing, hyper- or hypopigmentation

  • Prior skin biopsies

  • Prior melanoma

  • Pancreatic cancer

  • In 1st- or 2nd-degree relatives

    • DNS

    • Melanoma

    • Pancreatic cancer

Physical Exam

  • ABCDE mnemonic for pigmented lesions: Asymmetry, Border irregularity, Color variegation, Diameter >6 mm, and Evolving lesion

    • Melanoma typically with several characteristics of ABCDEs on gross exam (DN often defined as ≥5 mm + at least 2 other features)

    • Difficult differentiating DN from melanoma using these criteria

  • “Ugly duckling sign” (5)

    • Melanoma screening strategy of identifying atypical nevi straying from the predominant nevus pattern when numerous atypical nevi present.

  • Most common features of DN on dermatoscopy magnification per the pattern analysis method include the following (6):

    • Atypical pigment network

    • Irregular/peripheral depigmentation areas

    • Irregular distribution of brown globules

    • Pigmentation with central heterogeneity and abrupt termination

  • Some dermatoscopic features more suggestive of melanoma include the following (6):

    • Depigmented areas

    • Whitish veil

    • Homogenous areas distributed irregularly, in multiple areas, or >25% of total lesion

    • ≥4 colors

Differential Diagnosis

  • Acquired melanocytic nevi

  • Sporadic atypical nevi

  • Melanoma

  • Seborrheic keratosis

  • Dermatofibroma

  • Lentigo

  • Pigmented actinic keratosis

Diagnostic Tests & Interpretation

Initial Tests (lab, imaging)

Genetic testing is available for CDKN2A mutations, but it is not recommended outside of research studies as the results cannot be adequately used for management or surveillance (7)[C]. 
  • When the total nevus count is high and individually following each nevus impractical, total-body photography may aid in the evaluation of evolving nevi as well as in documenting new nevi (8)[C].

  • Further exam of nevi with a dermatoscope may help in distinguishing between benign and malignant pigmented lesions.

Diagnostic Procedures/Other

  • Biopsy is recommended of any new lesion where melanoma cannot be excluded or for any existing evolving lesion concerning for melanoma.

  • Preferred method entails full-thickness biopsy of the entire lesion with a narrow 2-mm margin of normal skin by excisional, incisional, or punch biopsy (8)[C].

    • Excisional biopsy provides the most accurate diagnosis and should be performed when possible.

    • Take care to provide a sufficiently deep sample down to the fat to allow assessment of the depth of any melanomas.

    • Scoop shave biopsy including a sufficient lateral and deep margin can also be used, but care must be taken to not transect the deep margin.

Test Interpretation

DN: Possible features include melanocyte proliferation in the dermoepidermal junction, bridging of rete ridges by melanocytic nests, dermal fibrosis, and interstitial lymphocytic inflammation. 

Treatment

Medication

No medications are available at this time to treat atypical nevi. 

Issues for Referral

  • Referral to a dermatologist for routine skin exam

  • Consider referral to a specialty pigmented lesion clinic.

  • Ophthalmologic exams for ocular nevi/melanoma screening

  • Oncology or specialized genetics study group involvement if strong family predisposition to pancreatic cancer

  • Possible cosmetic surgery consultation for cosmetically poor excision outcomes

Additional Therapies

  • Topical chemo- and immunotherapies therapies have been unsuccessfully attempted to treat atypical nevi.

  • Laser treatment should be avoided because it is both unsafe and ineffective for melanocytic nevi.

Surgery/Other Procedures

Surgical excision of all atypical nevi is not recommended as most melanomas in DNS appear de novo on healthy skin and the procedure leads to both poor cosmetic outcomes and a false sense of security. Lesions suspicious for melanoma should be biopsied or removed surgically. 

Ongoing Care

Follow-up Recommendations

Close follow-up with a dermatologist and sun avoidance/protection is highly advised. 

Patient Monitoring

  • Total body skin exam (including nails, scalp, genital area, and oral mucosa) every 3–6 months initially, starting at puberty; may be reduced to annually once nevi are stable.

  • Dermatoscopic evaluation for suspect lesions

  • Ocular exam for those with familial DNS

  • Excision of suspect lesions

  • Total body photography at baseline

  • Monthly self-exams of skin

  • Sun avoidance and sun protection

Patient Education

Prognosis

  • Multiple classification schemes have been developed over the years to delineate risk of melanoma in patients with DNS. Individuals with a family history of melanoma are at greatest risk. A classification system developed by Rigel is simply and readily applied in the clinical setting. Points are assigned based on incidence of melanoma, with 1 point given for a personal history with melanoma, and 2 points for each family member with melanoma (modified nuclear family consisting of 1st-degree relatives + grandparents and uncles/aunts) and stratified as follows (9):

    • Score = 0, Rigel group 0, 6% 25-year accumulated risk for melanoma

    • Score = 1, Rigel group 1, 10% risk

    • Score = 2, Rigel group 2, 15% risk

    • Score ≥3, Rigel group 3, 50% risk

  • The CDKN2A mutation has also been associated with a 60–90% risk of melanoma by age 80 years and a 17% risk for pancreatic cancer by age 75 years.

Complications

  • Malignant melanoma

  • Poor cosmetic outcomes from biopsy

References

1.
Newton  JA, Bataille  V, Griffiths  K, et al. How common is the atypical mole syndrome phenotype in apparently sporadic melanoma? J Am Acad Dermatol.  1993;29(6):989–996. [View Abstract]
2.
Silva  JH, Sá  BC, Avila  AL, et al. Atypical mole syndrome and dysplastic nevi: identification of populations at risk for developing melanoma—review article. Clinics (Sao Paulo).  2011;66(3):493–499. [View Abstract]
3.
Mize  DE, Bishop  M, Reese  E, et al. Familial atypical multiple mole melanoma syndrome. In: Riegert-Johnson  DL, Boardman  LA, Hefferon  T, et al, eds. Cancer Syndromes. Bethesda, MD: National Center for Biotechnology Information; 2009.
4.
NIH Consensus conference. Diagnosis and treatment of early melanoma. JAMA.  1992;268(10):1314–1319. [View Abstract]
5.
Grob  JJ, Bonerandi  JJ. The ’ugly duckling’ sign: identification of the common characteristics of nevi in an individual as a basis for melanoma screening. Arch Dermatol.  1998;134(1):103–104. [View Abstract]
6.
Salopek  TG, Kopf  AW, Stefanato  CM, et al. Differentiation of atypical moles (dysplastic nevi) from early melanomas by dermoscopy. Dermatol Clin.  2001;19(2):337–345. [View Abstract]
7.
Kefford  R, Bishop  JN, Tucker  M, et al. Genetic testing for melanoma. Lancet Oncol.  2002;3(11):653–654. [View Abstract]
8.
Duffy  K, Grossman  D. The dysplastic nevus: from historical perspective to management in the modern era: part I. Historical, histologic, and clinical aspects. J Am Acad Dermatol.  2012;67(1):1.e1–e16; quiz 17–18. [View Abstract]
9.
Rigel  DS, Rivers  JK, Friedman  RJ, et al. Risk gradient for malignant melanoma in individuals with dysplastic naevi. Lancet.  1988;1(8581):352–353. [View Abstract]

Additional Reading

  • Czajkowski  R, Placek  W, Drewa  G, et al. FAMMM syndrome: pathogenesis and management. Dermatol Surg.  2004;30(2, Pt 2):291–296. [View Abstract]

  • Farber  MJ, Heilman  ER, Friedman  RJ. Dysplastic nevi. Dermatol Clin.  2012;30(3):389–404. [View Abstract]

  • Friedman  RJ, Farber  MJ, Warycha  MA, et al. The “dysplastic” nevus. Clin Dermatol.  2009;27(1):103–115. [View Abstract]

  • Moloney  FJ, Guitera  P, Coates  E, et al. Detection of primary melanoma in individuals at extreme high risk: a prospective 5-year follow-up study [published online ahead of print June 25, 2014]. JAMA Dermatol. doi:10.1001/jamadermatol.2014.514.

  • Naeyaert  JM, Brochez  L. Clinical practice. Dysplastic nevi. N Engl J Med.  2003;349(23):2233–2240. [View Abstract]

  • Robson  ME, Storm  CD, Weitzel  J, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol.  2010;28(5):893–901. [View Abstract]

  • Slade  J, Marghoob  AA, Salopek  TG, et al. Atypical mole syndrome: risk factor for cutaneous malignant melanoma and implications for management. J Am Acad Dermatol.  1995;32(3):479–494. [View Abstract]

Codes

ICD10

  • D23.9 Other benign neoplasm of skin, unspecified

  • D23.4 Other benign neoplasm of skin of scalp and neck

ICD09

  • 216.9 Benign neoplasm of skin, site unspecified

  • 216.4 Benign neoplasm of scalp and skin of neck

SNOMED

  • 254818000 Dysplastic nevus of skin (disorder)

  • 254819008 atypical mole syndrome (disorder)

Clinical Pearls

  • Melanoma in DNS tends to arise from healthy skin despite a large number of atypical nevi.

  • ~20% of individuals with familial DNS will develop pancreatic cancer by age 75 years.

  • Patients with DNS tend to produce neoplasms in unusual sites such as the scalp, eyes, and double sun-protected areas (e.g., gluteal folds).

  • ~10% of melanomas are featureless on dermatoscopy.

 
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