Atypical Mole (Dysplastic Nevus) Syndrome

Descriptive text is not available for this image BASICS

Atypical mole syndrome (AMS), also known as dysplastic nevi syndrome (DNS), B-K mole syndrome, Clark nevi syndrome, or familial atypical multiple mole melanoma (FAMMM) syndrome, is a condition characterized by a large number of pigmented nevi with architectural disorder, which arise sporadically or by inheritance and are associated with an increased risk of melanoma.

DESCRIPTION

There is no consensus on criteria for AMS.

  • Elevated total body nevi count, including clinically atypical nevi, is usually >50 and often >100.
    • Larger number in hereditary AMS versus sporadic atypical nevi (as few as <10)
  • Increased risk of melanoma
    • Up to 90% occurrence by age 80 years in certain high-risk individuals
    • Earlier onset than in sporadic melanoma
    • More arise de novo than from an existing nevus (1)[A]
    • Higher risk for appearance at unusual sites (e.g., scalp, eyes, and sun-protected areas)
  • Median age of diagnosis for melanoma in AMS is 10 to 20 years earlier than the general population, with documented cases of melanoma as early as in the 2nd and 3rd decades of life.

EPIDEMIOLOGY

Incidence

Uncertain due to phenotype variability, limited data

Prevalence

Affects between 2% and 8% of fair-skinned adults as well as those with high exposure to ultraviolet radiation

ETIOLOGY AND PATHOPHYSIOLOGY

  • Cyclin-dependent kinase inhibitor 2A (CDKN2A) mutations have been observed in familial DNS and multiple melanomas. The CDKN2A gene on 9p21 encodes for the proteins p16 and p14. p16 binds to CDK4/6 and is a negative cell-cycle regulator via inhibition of the CDK-cyclin D interaction needed for cell cycle progression from G1 to S. p14 functions by stabilizing the tumor-suppressor protein p53 in the G1 phase of the cell cycle.
  • Familial cases of germline CDKN2A mutations are transmitted in an autosomal dominant fashion.
  • No clear somatic mutation patterns in sporadic cases

Genetics

CDKN2A gene mutation is observed in 25–40% of hereditary cases, with autosomal dominant inheritance but variable expressivity and incomplete penetrance.

RISK FACTORS

Family history of melanoma or multiple nevi, sun exposure, neonatal blue-light phototherapy, history of painful sunburns

GENERAL PREVENTION

  • Primary prevention with sun avoidance, sun protection (may be especially important in presence of already-dysplastic nevi (2)
  • Secondary prevention of melanoma with routine skin exams, biopsy of suspect lesions, and environmental risk mitigation as above

COMMONLY ASSOCIATED CONDITIONS

  • Malignant melanoma, including ocular melanoma
  • Ocular nevi
  • Pancreatic cancer in CDKN2A mutation

Descriptive text is not available for this image DIAGNOSIS

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

HISTORY

  • Changing lesions: bleeding, scaling, size, texture, nonhealing, hyper- or hypopigmentation
  • Large number of nevi
  • Congenital nevi
  • Sun exposure
  • Prior skin biopsies
  • Prior melanoma
  • Immunosuppression (e.g., AIDS, chemotherapy, pancreatic cancer)
  • First- or second-degree relatives with:
    • AMS
    • Melanoma
    • Pancreatic cancer

PHYSICAL EXAM

  • Full-body skin exams, with photography to track new and changing nevi
  • Goal to distinguish melanoma from atypical mole (AM)
  • ABCDE mnemonic for skin lesions concerning for melanoma: Asymmetry, Border irregularity, Color variegation, Diameter >6 mm, and Evolving lesion
    • AM is often defined as ≥5 mm and at least two other features.
    • Melanoma typically has several characteristics of ABCDEs, with increased specificity for melanoma if lesion diameter is >6 mm.
  • “Ugly duckling sign” (4)[B]:
    • Melanoma screening strategy for increasing accuracy of diagnosis of melanoma by identifying malignant nevi straying from the predominant nevus pattern when numerous atypical nevi are present
  • Most common features of AM on dermoscopy include (5):
    • Reticular pattern most common
    • Uniform pigmentation most common followed by multifocal hypo- or hyperpigmentation
    • Homogenous brown globules
    • Pigmentation with central heterogeneity and abrupt termination
  • Dermatoscopic features more suggestive of melanoma include (6):
    • Depigmented areas
    • Whitish veil
    • Homogenous areas distributed irregularly, in multiple areas, or >25% of total lesion
    • ≥4 colors

DIFFERENTIAL DIAGNOSIS

  • Common nevus: acquired or congenital
  • Melanoma
  • Seborrheic keratosis
  • Dermatofibroma
  • Lentigo
  • Pigmented actinic keratosis
  • Pigmented basal cell carcinoma
  • Blue rubber bleb nevus syndrome

DIAGNOSTIC TESTS & INTERPRETATION

Diagnosis is first suspected with history and physical exam and then confirmed by biopsy and histopathology.

Initial Tests (lab, imaging)

  • Dermoscopy can be used for a more detailed exam of nevus to aid in distinguishing between benign and malignant lesions as well as for further classification to any of the 11 subtypes; however, the degree of success is dependent on the skill of the examiner.
  • Reflectance confocal microscopy (RCM) may provide more specificity than dermoscopy in distinguishing AM from melanoma.
  • When the total nevus count is high and following each nevus is impractical, total body photography may aid in the evaluation of evolving nevi as well as in documenting new nevi.

Follow-Up Tests & Special Considerations

Genetic testing is available for CDKN2A mutations, but it is not recommended outside of research studies because results cannot be adequately used for management or surveillance.

Diagnostic Procedures/Other

  • Biopsy is recommended for any lesion where melanoma cannot be excluded or in the presence of clinically concerning features (e.g., recent growth) (7)[B].
  • Biopsy entails full-thickness biopsy of the entire lesion with a narrow 1- to 3-mm margin of normal skin down to fat for adequate depth assessment.
    • Excisional biopsy, elliptical or punch excision, provides the most accurate diagnosis and should be performed when possible.
    • Scoop shave biopsy can also be used, but care must be taken to not transect the lesion.
  • Reexcision of mild to moderately dysplastic nevi with positive margins likely does not change pathologic diagnosis or outcomes (2),(8)[A], but for severely dysplastic nevi which shares features with melanoma, consider reexcision, with surgical margins of 2 to 5 mm (9)[C].
  • Genetic testing can help diagnosis in ambiguous situations, but studies are limited.

Test Interpretation

“Dysplastic nevus” is a term more accurately reserved as a histologic diagnosis. Features may include melanocyte proliferation in the dermoepidermal junction extending through at least three rete ridges in a specific pattern, fusing of rete ridges, dermal fibrosis, neovascularization, and interstitial lymphocytic inflammation (9).

Descriptive text is not available for this image TREATMENT

MEDICATION

No medications have been shown to treat AMS (9)[C].

ISSUES FOR REFERRAL

  • Routine skin exams and total-body photography for those patients at high risk for melanoma
  • Ophthalmologic exams for ocular nevi/melanoma screening/papilledema
  • Oncology or specialized genetics study group involvement if strong family predisposition to pancreatic cancer

ADDITIONAL THERAPIES

  • Topical chemo- and immunotherapies have been unsuccessfully attempted to treat AMS (9)[C].
  • Laser treatment should be avoided because it is both unsafe and ineffective for melanocytic nevi (9)[C].

SURGERY/OTHER PROCEDURES

Surgical excision of all atypical nevi is not recommended because most melanomas in AMS appear de novo on healthy skin and therefore has low clinical value and is not cost-effective. Excision of all atypical nevi also leads to both poor cosmetic outcomes and a false sense of security. Lesions suspicious for melanoma should be biopsied or removed surgically.

Descriptive text is not available for this image ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Close follow-up with a dermatologist or other physician experienced with assessment of atypical nevi:

  • Total body skin exam (including nails, scalp, genital area, and oral mucosa) every 6 months initially, starting at puberty; may be reduced to annually once nevi are stable
  • Total body photography at baseline and intervals to track new and changing nevi
  • Dermoscopic evaluation of suspicious lesions
  • Excision of suspicious lesions
  • Ocular exam for those with familial AMS

Patient Monitoring

Monthly self-exams of skin

PATIENT EDUCATION

For young adults with fair skin, counsel to minimize exposure to ultraviolet radiation to reduce risk of skin cancer (USPSTF grade B).

PROGNOSIS

  • Most AMs either regress or do not change.
  • Multiple classification schemes have been developed over the years to delineate risk of melanoma in patients with AMS. Individuals with a family history of melanoma are at greatest risk. The Rigel classification system can be 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 first-degree relatives plus grandparents and uncles/aunts) and stratified as follows:
    • 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. In patients with melanoma, presence of the CDKN2A mutation may not worsen overall survival rates.

COMPLICATIONS

  • Malignant melanoma
  • Poor cosmetic outcomes from biopsy

Authors

Sahil Mullick, MD, FAAFP
Lakshmi Gopinath Jaisankar, MD

REFERENCES

  1. Dessinioti C, Befon A, Stratigos AJ. The association of nevus-associated melanoma with common or dysplastic melanocytic nevus: a systematic review and meta-analysis. Cancers (Basel). 2023;15(3):856.  [PMID:36765817]
  2. Spaccarelli N, Drozdowski R, Peters MS, et al. Dysplastic nevus part II: dysplastic nevi: molecular/genetic profiles and management. J Am Acad Dermatol. 2023 Jan;88(1):13–20.  [PMID:36252690]
  3. Goldsmith LA, Askin FB, Chang AE, et al. Diagnosis and treatment of early melanoma: NIH consensus development panel on early melanoma. JAMA. 1992;268(10):1314–1319.
  4. Gaudy-Marqueste C, Wazaefi Y, Bruneu Y, et al. Ugly duckling sign as a major factor of efficiency in melanoma detection. JAMA Dermatol. 2017;153(4):279–284.  [PMID:28196213]
  5. Hofmann-Wellenhof R, Blum A, Wolf IH, et al. Dermoscopic classification of atypical melanocytic nevi (Clark nevi). Arch Dermatol. 2001;137(12):1575–1580.  [PMID:11735707]
  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.  [PMID:11556242]
  7. Wiedemeyer K, Hartschuh W, Brenn T. Dysplastic nevi: morphology and molecular and the controversies in-between. Surg Pathol Clin. 2021;14(2):341–357.  [PMID:34023110]
  8. Vuong KT, Walker J, Powell HB, et al. Surgical re-excision vs. observation for histologically dysplastic naevi: a systematic review of associated clinical outcomes. Br J Dermatol. 2018;179(3):590–598.  [PMID:29570779]
  9. 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.e1–1.e18.  [PMID:22703915]

ADDITIONAL READING

Perkins A, Duffy RL. Atypical moles: diagnosis and management. Am Fam Physician. 2015;91(11):762–767.  [PMID:26034853]

Descriptive text is not available for this image CODES

ICD10

  • D22.9 Melanocytic nevi, unspecified
  • D22.4 Melanocytic nevi of scalp and neck
  • D22.30 Melanocytic nevi of unspecified part of face
  • D22.5 Melanocytic nevi of trunk
  • D22.70 Melanocytic nevi of unspecified lower limb, including hip
  • D22.60 Melanocytic nevi of unspecified upper limb, including shoulder

SNOMED

  • 254819008 atypical mole syndrome (disorder)
  • 254818000 Dysplastic nevus of skin (disorder)
  • 400010006 Melanocytic nevus of skin (disorder)

CLINICAL PEARLS

  • In describing nevi, “atypical” is a clinical term, whereas “dysplastic” is a histologic term.
  • AMS is a risk factor for melanoma, although most atypical moles/dysplastic nevi are not precursors of melanoma. Melanoma in AMS tends to arise from healthy skin despite a large number of atypical nevi.
  • ~20% of individuals with familial AMS will develop pancreatic cancer by age 75 years.
  • Patients with AMS tend to produce neoplasms in unusual sites such as the scalp, eyes, and sun-protected areas (e.g., gluteal folds).

Last Updated: 2026

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