Dysplastic nevus syndrome

Melanoma is an increasingly common cutaneous malignancy. In 1990, an estimated 27,600 persons will develop malignant melanoma, and 6,300 will die of the disease. (1) The incidence of melanoma has doubled every decade since 1930. At current rates, one in 100 white children in the United States will eventually develop melanoma. (2) Because there is no satisfactory treatment for metastatic disease, the only cure for melanoma is early diagnosis and prompt surgical excision. (3)

Growth Phase of Melanoma and Survival

Fortunately, melanomas are usually external, providing an opportunity for detection in situ during the minimally invasive radial growth phase in which malignant cells spread laterally and superficially. This radial growth phase may last several months to several years, which gives a clinical "window of opportunity" for early recognition and removal of localized tumor. Melanomas removed early, while less than 0.76 mm in depth, are associated with a ten-year survival rate of about 98 percent. (3)

The appearance of a papule or nodule within a lesion indicates the development of a clone of malignant cells capable of deeper invasion and metastasis; this is termed the vertical growth phase. The prognosis worsens with increased tumor thickness. For melanomas 3 mm or greater in depth, the ten-year survival rate is less than 50 percent. (3) Other factors, such as anatomic site, ulceration and the histologic mitotic index, further refine the prognosis and are summarized elsewhere. (4) Screening for Melanoma:

Targeting Those at Increased Risk

It is prudent to identify patients at increased risk for melanoma (Table 1), (5) Since they may benefit most from a skin screening examination and patient education to promote the detection of suspicious lesions.

Patients with a tendency to sunburn or freckle and those with numerous common moles are at increased risk for melanoma (5,6); this risk appears to be comparable to the independent risk of expressing the dysplastic nevus trait (7) (i.e., a 6 percent lifetime risk of melanoma, which is about seven times the normal risk). Even the presence of a few dysplastic nevi may be significant. With a family history of two or more melanomas, the lifetime risk among individuals with dysplastic nevi exceeds 50 percent. (8)

Patients at increased risk may benefit from a thorough skin examination and education about the ABCD warning signs of melanoma (A for lesion asymmetry, B for border irregularity, C for color variation, and D for diameter enlargement, particularly if the diameter is greater than 6 mm). (3) Skin cancer screening is clearly productive in the early detection of suspicious lesions. (5,9,10) Complete skin examinations reveal more than six times the pathology of examinations limited to exposed sites only. (11-14) A complete examination includes the intertriginous areas, palms, soles, scalp and mucosal surfaces.

DYSPLASTIC NEVUS SYNDROME

In 1978, Clark and associates (15) found many large, asymmetric, irregularly shaped and irregularly pigmented nevi in certain familial melanoma patients and in half of their close relatives. Among these melanoma-prone relatives, representing the most severe expression of the dysplastic nevus syndrome, the risk of melanoma was nearly 150 times greater when these distinctive nevi were present. The median age for the development of melanoma in these patients was 32 years, compared with a median age of 51.2 years for the development of nonfamilial melanoma. (16) Transmission of the dysplastic nevus trait was autosomal dominant. (8)

Subsequently, "sporadic" dysplastic nevi were recognized in one-third of non-familial melanoma cases. (7,17) Familial dysplastic nevi also may occur in the absence of melanoma or a family history of melanoma (11); nevertheless, these nevi identify individuals and blood relatives at increased risk. In a prospective study of patients in a general dermatology practice, (11) about 5 percent of adolescent and adult white patients were found to have incidental, histologically confirmed dysplastic nevi. A random selection of these patients showed a sevenfold increased risk of melanoma among the dysplastic nevus-bearing blood relatives of these dysplastic nevus patients. (12) summarizes the classification of patients with dysplastic nevus syndrome. (16) Recognizing Normal Nevi

In order to appreciate dysplastic nevi, it is important to recognize normal nevi. (18) Common melanocytic nevi normally are not present at birth (the congenital melanocytic nevus is a distinct entity) but are acquired during childhood, adolescence and young adulthood. The histologic features of normal skin, the freckle and the lentigo are depicted schematically in Figure 2 [omitted]. The histologic characteristics of junctional, compound, intradermal and dysplastic nevi are shown in Figure 3 [omitted].

The common acquired melanocytic nevus tends to pass through certain predictable developmental stages. It begins as a focal, flat proliferation of melanocytes, most often in sun-exposed skin. This is termed a junctional nevus, because all of the melanocytes are located in the epidermis above the dermoepidermal junction. A junctional nevus is flat. The nevus may persist in this morphology, or it may mature into a compound nevus.

In addition to the epidermal component, the compound nevus has nests of melanocytes in the dermis. This dermal component elevates the surface, which appears papular. Clinically, the compound nevus is generally symmetric, with a round or oval border that sharply demarcates the nevus from the surrounding skin. The color may range from an even tan or brown to a rich mahogany, and no significant color variation occurs within the lesion. The compound nevus is commonly less than 6 mm in diameter.

With time, the epidermal component of the compound nevus regresses, leaving an intradermal nevus. The aging nevus may lose its color, much as hair tends to gray with age. Ultimately, over the fifth, sixth and seventh decades, the nevus undergoes regression, leaving a skin tag or an unremarkable site. By the end of their lives, the very elderly generally have no apparent moles. (19)

The average young adult has about 25 common nevi. (20) The acquisition of new nevi continues into the late 20s in men and into the early 30s in women. New or changing nevi, particularly after age 30, should be examined carefully to rule out melanoma. Recognizing Dysplastic Nevi Unlike common acquired nevi, dysplastic nevi do not pass through predictable developmental stages. Their deviation from this orderly progression may manifest as asymmetry, irregular shape, hazy border, irregular pigmentation and, sometimes, large size. These features may be suggestive of melanoma.

Evidence of the dysplastic nevus syndrome usually first appears during puberty or adolescence. Dysplastic nevi are of ten prevalent on the scalp, buttocks and female breasts, sites infrequently populated by common acquired nevi. (8,21) Consequently, nevi found in these unusual locations merit particular attention. Although large size (diameter greater than 6 mm) raises suspicion of a dysplastic nevus, the nevus may be as small as 2 mm in diameter. (11,12) Histopathologic confirmation by a dermatopathologist is essential for correct diagnosis.

FAMILY HISTORY

In patients with histologically confirmed dysplastic nevi, the magnitude of the risk of melanoma depends on the family history. 16 Patients with dysplastic nevi who have two or more blood relatives with both dysplastic nevi and melanoma have a greater than 50 percent cumulative lifetime risk of melanoma. (8)

Patients with dysplastic nevi but no family history of melanoma have a 6 percent lifetime risk, which is high enough to warrant self-examinations, sun-exposure reduction and periodic, thorough, professional skin examinations. (10,22) Many allegedly sporadic cases of melanoma are found to be familial when more extensive family screening is undertaken. (23)

Technique for Examining Nevi

Physicians have an opportunity to study the spectrum of normal nevi each time they apply a stethoscope to the back, a common site of nevi. The more often one looks at normal nevi, the more quickly an unusual mole will catch one's attention.

Proper examination of the skin is enhanced by illumination with a bright, even, incandescent light. (24) A halogen light source is especially effective, because it emits a continuous-spectrum white light. The incandescent gooseneck lamps that are standard equipment in offices and emergency departments also provide a continuous spectrum of light; however, the red-orange spectral emission of these lights may mask the pink hues of dysplastic nevi, an important clue to identification. (Pink color is usually absent in normal common nevi.) Fluorescent light hinders diagnostic accuracy, because its discontinuous emission spectrum turns the pink hues of dysplastic nevi to a dull gray.

Any nevus that appears even slightly unusual merits closer evaluation. A magnifying lens may be helpful. To better reveal the color patterns, the nevus may be coated with a few drops of soap or oil, stretched between two fingers and then viewed under a proper color-balanced light source (25).This examination technique can greatly increase diagnostic accuracy.

Histologic confirmation by a certified dermatopathologist is essential. The clinician should be aware that the significance of "minimal dysplastic changes" is controversial (26) but that "moderate" or "severe" dysplastic changes should be regarded as significant.

Differential Diagnosis

The most common pigmented lesions include freckles, lentigines, junctional nevi, intradermal nevi and seborrheic keratoses. Freckles are tan and flat; they tend to darken with sun exposure and lighten during months of nonexposure. Lentigines may be tan, brown or brownish black; they also are flat, but their pigmentation remains constant. junctional nevi are flat and may be clinically indistinguishable from lentigines. Compound nevi differ in that they are palpable and hairs may project. Intradermal nevi also are raised, but they tend to be flesh-colored.

Seborrheic keratoses, particularly when pigmented or irritated, may resemble dysPlastic nevi or melanomas. The common seborrheic keratosis is a tan or brown plaque with a slightly verrucous or keratotic surface. The lesion often feels waxy and usually appears "stuck on," as though it could be scraped off the skin with a fingernail. Common seborrheic keratoses frequently have a verrucous surface, small pore-like, keratin-plugged follicular orifices and/or tiny, round, tan or cream-colored inclusion cysts, making differentiation easy. The surface fissures of hyperkeratotic seborrheic keratoses distinguish them from dysplastic nevi.

The dermatofibroma is composed of a central, firm, dermal scar, often with an ill-defined rim of hyperpigmentation. This lesion frequently occurs on the legs of women. Because the dermatofibroma may have an erythematous component, it is sometimes called a sclerosing hemangioma. The dermatofibroma with a hazy border and erythema may resemble a dysplastic nevus. The "dimple sign" helps distinguish the dermatofibroma: on lateral compression, the lesion will indent slightly.

When pigmented, actinic keratoses may show shades of brown and pink. These lesions are usually located on chronically sun-exposed areas (e.g., head, neck, hands, forearms). Their roughened quality is best appreciated on palpation.

Some blue nevi and compound nevi in the process of regression (immunologically mediated destruction) may appear atypical and may resemble dysplastic nevi.

Dysplastic nevi are most frequently confused with developing common acquired nevi at the stage when a flat junctional nevus is evolving into an elevated compound nevus. This transformation generally occurs during the second and third decades of life. With sunburn or hormonal stimulation, the nevus may develop a rich, reddish brown to mahogany pigmentation that may be eye-catching. The sun-stimulated nevus also may develop irregularly scalloped, macular, hazily bordered areas, clinically simulating a dysplastic nevus.

Biopsy

When dysplastic nevus syndrome is suspected, the diagnosis requires histopathologic confirmation. Selecting the most appropriate pigmented lesions for biopsy requires experience and skill to minimize the probability of a false-negative result. At times, more than one biopsy may be required.

An excisional biopsy of a suspected dysplastic nevus is most useful when it includes a 2-mm margin of surrounding skin. The epidermis immediately surrounding the lesion is called the "shoulder," and it may be the site of the most characteristic histologic changes. (27)

Other biopsy techniques may miss the pertinent pathology. A superficial shave biopsy may transect deeper portions of a lesion that may be melanoma, precluding accurate assessment of tumor depth. Partial biopsy with a punch may miss the area of greatest diagnostic value.

Follow-Up

For patients who have dysplastic nevi or are otherwise identified to be at increased risk for melanoma, a thorough skin examination is indicated to document the location and size of suspicious nevi and to rule out malignant melanoma. When many different pigmented lesions are present (e.g., common nevi, dysplastic nevi, seborrheic keratoses, dermatofibromas), photodocumentation is a practical and efficient method for comparing interval change. The clinician may set up a 35-mm camera with a macro lens for use in the office, or the patient may be referred to a professional photographer or to a dermatologist who has photographic equipment.

During follow-up examinations, the patient's skin is compared with baseline photographs or projected slides to detect new or changing nevi. (29) Patients with numerous pigmented lesions may be given a duplicate set of photographs for use in monthly self-examinations. (22,23,29)

Periodic, complete, professional skin examinations, which may be incorporated into routine physical examinations, can detect changing lesions. These lesions should be removed for histologic examination to exclude evolving melanomas (30,31). Examinations at more frequent intervals (e.g., every three to four months) are prudent for patients at greatest risk of melanoma, such as dysplastic nevus patients with a family history of melanoma and those with immunologic impairment from leukemia or immunosuppressive therapy. (32) For patients with familial dysplastic nevi but no family history of melanoma, yearly examinations may be reasonable. The magnitude of melanoma risk for patients with truly sporadic dysplastic nevi is not known. (12) Family screening may clarify a patient's category of melanoma risk and may also identify relatives at increased risk.

Patient Education: Self-Examination and Sun Avoidance

The educated patient is often the first to appreciate changing nevi. Ideally, the patient may be educated to conduct monthly self-examinations, avoid prolonged sun exposure and use a sunscreen product.

Studies in Australia, where the incidence of melanoma is the highest in the world, have shown that a history of intense sun exposure and sunburn before ten years of age greatly increases the risk of melanoma. (33) Considerable evidence suggests that sun exposure stimulates the expression and progression of the dysplastic nevus syndrome phenotype. (16) Therefore, counseling on the avoidance of ultraviolet light is prudent for patients at increased risk of melanoma. (33)

Long-wave ultraviolet A (UVA) radiation, as well as shorter-wave ultraviolet B (UVB) radiation, may place the patient at risk. The most intense and damaging ultraviolet rays occur between 10 a.m. and 3 p.m. These rays can penetrate fog and clouds. A thin, loosely woven garment offers little protection against ultraviolet light; only heavier, thickly woven clothing can block these rays.

Patients should be advised to routinely use a sunscreen with a sun protection factor (SPF) of at least 15. The sunscreen should be applied to all exposed skin. Midday sun exposure is best avoided whenever possible. Sunbathing is unwise. Patients need to be aware that many sunscreens protect against UVB radiation only. Even so-called "waterproof" sunscreens are washed off to some degree by swimming or perspiration and should be reapplied about every hour. (34)

The use of educational literature with color illustrations of normal and abnormal pigmented lesions is invaluable and time-saving in patient education. Some of the available publications are listed in Table 4.

Final Comment

Recognition of dysplastic nevi and early melanomas requires time and practice. Management of patients with dysplastic nevi includes the following: (1) a complete skin examination; (2) baseline photographs and, if warranted, serial photodocumentation; (3) excisional biopsy and histologic examination of suspicious lesions, to confirm the diagnosis of dysplastic nevus syndrome and to rule out melanoma, and (4) periodic, careful follow-up. Family screening is valuable, because it may clarify a patient's risk and identify other family members at increased risk.

Patient education should include regular self-examinations and sun-exposure reduction through sun avoidance and the use of a sunscreen. With heightened physician vigilance, better patient education and follow-up of patients at increased risk, many cases of melanoma may be treated early, and the serious morbidity of this malignancy may be prevented. (3)

ACKNOWLEDGMENTS: Photographic grant support was provided by the Norcal Mutual Professional Liability Company, San Francisco. The skill and dedication of Richard W Sagebiel, M. D., in the histopathologic evaluation of specimens are greatly appreciated.

REFERENCES

1 .Silverberg E, Boring CC, Squires TS. Cancer statistics, 1990. CA 1990;40:9-26.

2. Seidman H, Mushinski MH, Gelb SK, Silverberg E. Probabilities of eventually developing or dying of cancer-United States, 1985. CA 1985;35:36-56.

3 .Friedman RJ, Rigel DS, Kopf AW. Early detection of malignant melanoma: the role of physician examination and self-examination of the skin. CA 1985;35:130-51.

4. Cohen PJ, Lambert WC, Hill GJ, Schwartz RA. Melanoma. In: Scwartz RA, ed. Skin cancer: recognition and management. New York: Springer-Verlag, 1988:99-140.

5. Howell JB. Spotting sinister spots. J Am Acad Dermatol 1986;15(4 Pt 1):722-6.

6. Swerdlow AJ, English J, MacKie RM, et al. Benign melanocytic naevi as a risk factor for malignant melanoma. Br Med J [Clin Res] 1986;292:1555-9.

7. Roush GC, Nordlund JJ, Forget B, Gruber SB, Kirkwood JM. Independence of dysplastic nevi from total nevi in determining risk for nonfamilial melanoma. Prev Med 1988;17: 273-9.

8. Green MH, Clark WH Jr, Tucker NU, Kraemer KH, Elder DE, Fraser MC. High risk of malignant melanoma in melanoma-prone families with dysplastic nevi. Ann Intern Med 1985;102:458-65.

9. MacKie RM. Early recognition of malignant melanoma [Editorial]. J Am Acad Dermatol 1986; 15(4 Pt 1): 707-8.

10. Rigel DS, Rivers JK, Kopf AW, et al. Dysplastic nevi. Markers for increased risk for melanoma. Cancer 1989;63:386-9.

11. Crutcher WA, Sagebiel RW. Prevalence of dysplastic naevi in a community practice [Letterl. Lancet 1984;1(8379):729.

12. Tucker MA, Crutcher WA, Hartge P, Sagebiel RW. Dysplastic nevi patients frequently have family members with dysplastic nevi or cutaneous melanoma. Proc Am Assoc Cancer Res 1989;30:320.

13. Rigel DS, Friedman RJ, Kopf AW, et al. Importance of complete cutaneous examination for the detection of malignant melanoma. J Am Acad Dermatol 1986; 14(5 Pt 1): 857-60.

14. Lookingbill DP. Yield from a complete skin examination. Findings in 1157 new dermatology patients. J Am Acad Dermatol 1988;18 (1 Pt 1):31-7.

15. Clark WH Jr, Reimer RR, Greene M, Ainsworth AM, Mastrangelo MJ. Origin of familial malignant melanoma from heritable melanocytic lesions. The B-K mole syndrome.' Arch Dermatol 1978;114:732-8.

16. Kraemer KH, Greene MH. Dysplastic nevus syndrome. Familial and sporadic precursors of cutaneous melanoma. Dermatol Clin 1985; 3:225-37.

17. Elder DE, Goldman LI, Goldman SC, Greene MH, Clark HW jr. Dysplastic nevus syndrome: a phenotypic association of sporadic cutaneous melanoma. Cancer 1980;46:1787-94.

18. Crutcher WA, Cohen PJ. The dysplastic nevus syndrome. In: Schwartz RA, ed. Skin cancer: recognition and management. New York: Springer-Verlag, 1988:141-51.

19. Clark WH Jr, Elder DE, Guerry D 4th, Epstein MN, Greene MH, Van Horn M. A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Hum Pathol 1984; 15:1147-65.

20. Holly EA, Kelly JW, Shpall SN, Chiu SH. Number of melanocytic nevi as a major risk factor for malignant melanoma. J Am Acad Dermatol 1987;17:459-68.

21. Tucker NK, Greene MH, Clark YM Jr, Kraemer KH, Fraser MC, Elder DE. Dysplastic nevi on the scalp of prepubertal children from melanoma-prone families. J Pediatr 1983; 103: 65-9.

22. Greene MH, Clark WH Jr, Tucker MA, et al. Acquired precursors of cutaneous malignant melanoma. The familial dysplastic nevus syndrome. N Engl J Med 1985;312:91-7.

23. Crijns MB, Vink J, Bergman W. Does the sporadic dysplastic nevus syndrome really exist? [Abstract] J Invest Dermatol 1989;92:415.

24. Du Vivier A. Spotting the malignant melanoma. Br Med J [Clin Res] 1982;285:670-1.

25. Kelly JW, Crutcher WA, Sagebiel RW. Clinical diagnosis of dysplastic melanocytic nevi. A clinicopathologic correlation. J Am Acad Dermatol 1986;14:1044-52.

26. Klein LJ, BarT RJ. Histologic atypia in clinically benign nevi. A prospective study. J Am Acad Dermatol 1990;22(2 Pt 1):275-82.

27. Crutcher WA. Dysplastic nevi-markers and precursors of malignant melanoma [Letter]. West J Med 1987; 147:459.

28. MacKie RM, English JS, Ashworth J, Doherty V. Managing the dysplastic naevus [Letter]. Lancet 1983;2(8361):1249-50.

29. Slue W, Kopf AW, Rivers JK. Total-body photographs of dysplastic nevi. Arch Dermatol 1988;124:1239-43.

30. Clark WH Jr. The dysplastic nevus syndrome. Arch Dermatol 1988;124:1207-10 [Published erratum appears in Arch Dermatol 1989;125: 539].

31. Sagebiel RW. The dysplastic melanocytic nevus. J Am Acad Dermatol 1989;20:496-501.

32. Tucker MA. Individuals at high risk of melanoma. In: MacKie RM, ed. Pigment cell. Vol 9. Basel, Switzerland: Karger, 1988-.95-109.

33. Holman CD, Armstrong BK. Cutaneous malignant melanoma and indicators of total accumulated exposure to the sun: an analysis separating histogenetic types. J Natl Cancer Inst 1984; 73:75-82.

34. Pathak MA. Sunscreens and their use in the preventive treatment of sunlight induced skin damage. J Dermatol Surg Oncol 1987;13: 739-50.

35. Davis NC, Herron JJ. Queensland melanoma project: organization and a plea for comparable surveys. Med J Aust 1966;1:643-4.

TABLE 1

Risk Factors for Malignant Melanoma

Fair skin

Sunburns readily or tans poorly

History of excessive sun exposure during the first decade of life

Severe sunburns in childhood and adolescence

Principally indoor occupation, with intermittent, intense sun exposure due to outdoor recreational habits

Personal and/or family history of malignant melanomas

Increased number of common melanocytic nevi

Large congenital nevus

Dysplastic nevus

Adapted from Howell IB. Spotting sinister spots. J Am Acad Dermatol 1986;15(4 Pt 1):722-6.

TABLE 4

Some Recommended Patient Education Resources

Skin Cancer Foundation, Box 561, Department DN, New York, NY 10156

Dysplastic Nevi and Malignant Melanoma: A Patient's Guide

The ABCD's of Moles and Melanomas

Self-Examination of the Skin: The Patient's Role in Early Detection

The Many Faces of Malignant Melanoma

Atypical Mole and Melanoma Education Foundation, P. 0. Box 2099, Napa, CA 94558

Atypical Moles and Malignant Melanoma: A Patient Education Brochure

American Academy of Dermatology, Communications Department,

P.O. Box 3116, Evanston, IL 60204-3116

Melanoma/Skin Cancer: You Can Recognize the Signs Stop-Look for the Danger Signs in Pigmented Lesions of the Skin (bookmark)

Office of Cancer Communication, National Cancer Institute, Bethesda, MD20892

About Dysplastic Nevi

American Cancer Society, 90 Park Avenue, New York, NY 10016

Why You Should Know About Melanoma

Early Detection of Primary Cutaneous Melanoma

Early Detection of Malignant Melanoma: The Role of Physician

Examination and Self-Examination of the Skin

Norcal Mutual Professional Liability Company, 50 Fremont St., San Francisco, CA 94105-2235

Melanoma: A Costly Oversight (videotape)

WILLIAM A. CRUTCHER, M. D. is medical director of the Pigmented Lesion Clinic of the Melanoma Center at Children's Hospital of San Francisco.

PHILIP J. COHEN, M.D. is currently pursuing a research fellowship in immunology. He trained in dermatology at the New Jersey Medical School, Newark, and at the National Institutes of Health, Bethesda, Md.

COPYRIGHT 1990 American Academy of Family Physicians
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