BASICS
Atypical mole syndrome (AMS), also known as dysplastic nevi syndrome (DNS), B-K mole syndrome, or Clark nevi 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 in sporadic)
- Increased risk of melanoma (1,2)
- Up to 90% occurrence by age 80 years in certain high-risk individuals
- Earlier onset than sporadic melanoma cases
- Most arise de novo than from an existing nevus
- Higher risk for appearance at unusual sites (e.g., scalp)
- AMS terminology often used interchangeably with DNS, familial atypical multiple mole melanoma (FAMMM) syndrome, and B-K mole syndrome.
- 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 (3). Melanomas, in the setting of AMS, are most often superficial spreading or nodular type.
EPIDEMIOLOGY
Incidence
- Uncertain due to phenotype variability, limited data
- Up to 8% in Caucasian populations (4)
Prevalence
At least 32,000 cases in the United States per National Institutes of Health (NIH) (5)
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 mutation 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 (6,7), history of painful sunburns
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 is used with some high-risk individuals.
COMMONLY ASSOCIATED CONDITIONS
- Malignant melanoma, including ocular melanoma
- Ocular nevi
- Pancreatic cancer in CDKN2A mutation
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 on pathologic examination (8).
HISTORY
- Changing lesions: bleeding, scaling, size, texture, nonhealing, hyper- or hypopigmentation
- Large number of nevi
- Congenital nevi
- Sun exposure habits
- 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
- Goal to distinguish melanoma from AMS
- ABCDE mnemonic for skins lesions concerning for melanoma: Asymmetry, Border irregularity, Color variegation, Diameter >6 mm, and Evolving lesion
- Atypical mole (AM) is often defined as ≥5 mm + at least two other features.
- Melanoma typically with several characteristics of ABCDEs, with increased specificity for melanoma using >6 mm for diameter
- "Ugly duckling sign" (9)[B]
- Melanoma screening strategy of identifying malignant nevi straying from the predominant nevus pattern when numerous atypical nevi are present.
- Most common features of AM on dermoscopy magnification per the pattern analysis method include the following (10)[C]:
- 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 (11)[C]:
- 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 more detailed exam to distinguish between benign and malignant lesions, and for further classification to 1 of 11 subtypes.
- Genetic testing is available for CDKN2A mutations, but it is not recommended outside of research studies as results cannot be adequately used for management or surveillance (11)[C].
- 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 (12)[C].
Diagnostic Procedures/Other
- Biopsy is recommended for any lesion where melanoma cannot be excluded.
- 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 (12)[C].
- 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 may not change pathologic diagnosis, but for severely dysplastic nevi, consider reexcision, with surgical margins of 2 to 5 mm (13)[C].
Test Interpretation
"Dysplastic nevus" is a term more accurately reserved for histological findings. Features may 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 to treat AMS.
ISSUES FOR REFERRAL
- Consider referral to a dermatologist for routine skin exam in 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
- Cosmetic surgery consultation for cosmetically poor excision outcomes
ADDITIONAL THERAPIES
- Topical chemo- and immunotherapies have been unsuccessfully attempted to treat atypical moles.
- 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 because most melanomas in AMS 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 or other experienced physician:
- 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
- Dermoscopic evaluation for suspect lesions
- Ocular exam for those with familial AMS
- Excision of suspect lesions
- Total body photography at baseline
Patient Monitoring
- Monthly self-exams of skin
- Sun avoidance and sun protection
PATIENT EDUCATION
For young adults aged 10 to 24 years with fair skin, counsel to minimize exposure to ultraviolet radiation to reduce risk of skin cancer (USPSTF Grade B)[A]. No evidence for adults >24 years (USPSTF Grade I)[A]
- Fair skin: light eye, hair, or skin color, freckles
- Educate on sun avoidance, proper application of sunscreen, use of protective clothing (e.g., hats), avoidance of tanning booths and sunburns.
- Teach "ABCDE" mnemonic + "ugly duckling sign" to assess nevi and identify potential melanomas.
- Provide instruction on skin self-exam techniques.
- A sample listing of patient-centric review sources on this topic are as follows:
- American Academy of Dermatology (cancer.about.com/od/skincancermelanoma/p/abcdeskincancer.htm)
- Skin Cancer Foundation (http://www.skincancer.org/skin-cancer-information/dysplastic-nevi)
- Melanoma Research Foundation (http://www.melanoma.org/understand-melanoma/what-is-melanoma)
PROGNOSIS
- Most AM 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. A classification system developed by Rigel (14) 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 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.
COMPLICATIONS
- Malignant melanoma
- Poor cosmetic outcomes from biopsy
REFERENCES
11 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):989-996.22 Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: I. Common and atypical naevi. Eur J Cancer. 2005;41(1):28-44.33 Silva JH, S Ħ 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):493-499.44 Naeyaert JM, Brochez L. Clinical practice. Dysplastic nevi. N Engl J Med. 2003;349(23):2233-2240.55 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; 2009.66 Csoma Z, T ³th-Moln Ħr E, Balogh K, et al. Neonatal blue light phototherapy and melanocytic nevi: a twin study. Pediatrics. 2011;128(4):e856-e864.77 Matichard E, Le H İnanff A, Sanders A, et al. Effect of neonatal phototherapy on melanocytic nevus count in children. Arch Dermatol. 2006;142(12):1599-1604.88 Goldsmith LA, Askin FB, Chang AE, et al. NIH Consensus conference. Diagnosis and treatment of early melanoma. JAMA. 1992;268(10):1314-1319.99 Scope A, Dusza SW, Halpern AC, et al. The "ugly duckling" sign: agreement between observers. Arch Dermatol. 2008;144(1):58-64.1010 Salopek TG, Kopf AW, Stefanato CM, et al. Differentiation of atypical moles (dysplastic nevi) from early melanomas by dermoscopy. Dermatol Clin. 2001;19(2):337-345.1111 Kefford R, Bishop JN, Tucker M, et al. Genetic testing for melanoma. Lancet Oncol. 2002;3(11):653-654.1212 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.e16.1313 Strazzula L, Vedak P, Hoang MP, et al. The utility of re-excising mildly and moderately dysplastic nevi: a retrospective analysis. J Am Acad Dermatol. 2014;71(6):1071-1076.1414 Rigel DS, Rivers JK, Friedman RJ, et al. Risk gradient for malignant melanoma in individuals with dysplastic naevi. Lancet. 1988;1(8581):352-353.
ADDITIONAL READING
- Czajkowski R, Placek W, Drewa G, et al. FAMMM syndrome: pathogenesis and management. Dermatol Surg. 2004;30(2, Pt 2):291-296.
- Farber MJ, Heilman ER, Friedman RJ. Dysplastic nevi. Dermatol Clin. 2012;30(3):389-404.
- Friedman RJ, Farber MJ, Warycha MA, et al. The "dysplastic" nevus. Clin Dermatol. 2009;27(1):103-115.
- 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. JAMA Dermatol. 2014;150(8):819-827. doi:10.1001/jamadermatol.2014.514.
- 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.
- 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.
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
ICD9
- 216.9 Benign neoplasm of skin, site unspecified
- 216.4 Benign neoplasm of scalp and skin of neck
- 216.3 Benign neoplasm of skin of other and unspecified parts of face
- 216.5 Benign neoplasm of skin of trunk, except scrotum
- 216.6 Benign neoplasm of skin of upper limb, including shoulder
- 216.7 Benign neoplasm of skin of lower limb, including hip
SNOMED
- 254819008 atypical mole syndrome (disorder)
- 254818000 Dysplastic nevus of skin (disorder)
- 400010006 Melanocytic nevus of skin (disorder)
CLINICAL PEARLS
- 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).