A Natural History of Melanomas and Dysplastic Nevi: An Atlas of Lesions in Melanoma-Prone Families

Margaret A. Tucker, Mary C. Fraser, Alisa M. Goldstein, Jeffery P. Struewing, Mary A. King, John T. Crawford, Ellen A. Chiazze, Deborah P. Zametkin, Laura S. Fontaine, Wallace H. Clark, Jr.

Disclosures

Dermatology Nursing. 2003;15(3) 

In This Article

Results

Prior to the families' enrollment into the current study, 194 melanomas occurred among 140 individuals. Of the 151 primary lesions for which we were able to measure thickness on review, 100 were classified as T1a lesions and 7 were classified as T1b lesions (see Table 1 ). The majority of the T1 lesions were superficial spreading melanomas; there were three nodular melanomas, two lentigo maligna melanomas, two unclassified lesions, and one acral lentiginous melanoma. Sixty-four lesions had an identified precursor lesion; 43 of these were histologically dysplastic nevi.

At the time of the initial examination, 22 melanomas were identified on 14 people, 6 of whom had previous melanomas (see Figures 1-4). Eighteen had radial growth phase only; four had radial and vertical phase growth. There was one thick melanoma (measuring 2.85 mm, Clark Level 4). The average thickness of all other lesions was 0.45 mm among those with CDKN2A mutations, 0.32 mm among those with CDK4 mutations, and 0.47 mm among those with unknown mutations (see Table 1 ). All but two (one of which was lentigo maligna melanoma) had an identified precursor lesion; 17 of the precursor lesions were dysplastic nevi. These four lesions are representative of prevalent lesions suspicious for melanoma. Three of these lesions were the first melanoma for each individual and, typical of these familial melanomas, occurred at an early age (35 years, 30 years, and 35 years, respectively); the fourth lesion was a severely dysplastic nevus.

Figure 1.

Radial growth phase melanoma arising from a dermal nevus (CDKN2A mutation). This lesion, which measured < 4 mm, was present at the time of initial examination on the center back of a 35-year-old patient. Based on history, there had been a nevus present at this site for an extended period. Neither the patient nor the spouse was concerned about the lesion. After specific questioning regarding changes in the lesion, the spouse believed that it had darkened. There were small islands of pigment at the periphery of the lesion. This clearly was the darkest lesion on the skin at the time of examination and was highly suspicious for melanoma. The patient had approximately 50 nevi measuring > 2 mm, many of which were atypical but did not meet all the clinical criteria of dysplastic nevi. The lesion was excised because of its intense pigmentation and loss of normal skin markings.

Figure 2.

De novo severe epithelioid melanocytic dysplasia (CDKN2A mutation). The lesion was present on the posterior thigh several centimeters below the gluteal fold. This lesion was present at the time of the initial evaluation of a 41-year-old patient with a history of three previous in situ melanomas. At the time of examination, > 175 nevi measuring > 2 mm were noted, many of which were clinically dysplastic. The patient had undergone multiple nevus biopsies in the past, some of which were dysplastic. The pigmented lesion measured 6 mm in dimension and was characterized by asymmetry, very indistinct irregular borders, a deeply pigmented papule with apparent infiltration of the epidermis, and some loss of skin markings in the area of the papule. There was slight hypopigmentation surrounding the lesion. In the area of hypopigmentation there were normal skin markings. The lesion had been itching slightly for a few months. The lesion was excised because of its atypical appearance, dark pigmentation in the area of the papule, focal loss of the normal skin markings, and history of change over several months.

Figure 3.

Superficial spreading melanoma arising from dysplastic nevus (CDK4 mutation). This lesion was on the shoulder of a 30-year-old patient at the time of initial evaluation. The lesion had been enlarging and darkening for > 1 year and measured 7 mm in maximum dimension at the time of examination. There was some erythema at the base and mild scaling over the entirety of the black portion of the lesion, with loss of normal skin markings. There was diffusion of the pigment into the surrounding normal skin at the superior border of the lesion. There was an apparent remnant of a precursor nevus at the left border area from approximately the 7 o'clock to 9 o'clock position. The rest of the lesion was a homogeneously black infiltrative lesion with mildly irregular borders. The patient had approximately 100 nevi measuring > 2 mm, many of which were clinically dysplastic. The lesion was excised because of the clinical suspicion of melanoma.

Figure 4.

Superficial spreading melanoma without precursor lesion (unknown mutation). A 5-mm lesion was present on the upper arm of a 35-year-old patient. This lesion had increased somewhat in diameter over several months. At the time of the initial evaluation it was the most atypical lesion on the patient. It measured 5 mm in dimension and had dusky pigmentation, indistinct borders, and prominent erythema throughout. This lesion demonstrated the difficulty in clinicopathologic correlation because of its rather innocuous appearance and lack of dark pigmentation. The patient had multiple clinical dysplastic nevi on examination. The lesion was biopsied because of the history of some change over the previous months and its appearance with prominent erythema and dusky pigmentation.

A major part of the care for these melanoma-prone families is education regarding sun and ultraviolet protection. When queried, many of the family members reported that their sun exposure patterns changed after enrollment in the study (Tucker et al., 1993). Family members are urged repeatedly to minimize midday exposure, use protective clothing and sunscreens, and avoid burning. Clinical recommendations for these family members include regular self-examinations and routine health care provider examinations. Family members are provided with copies of their clinical photographs for their use in self-examinations, and for the use of the clinicians who examine them. The majority of family members receive their care from local physicians, and frequency of followup and rates of biopsies vary among providers. The clinical recommendations for these family members include biopsy of lesions changing in a manner worrisome for melanoma or new lesions suspicious for melanoma. Some health care providers are more aggressive in removing lesions. Greater than 2,000 lesions have been removed from over 300 family members and subsequently reviewed by Dr. Wallace Clark.

In a prospective followup of all the family members, 86 new melanomas were found to have occurred in 37 individuals, 16 of whom did not previously have melanoma. Seventy-two melanomas were classified as T1a (Balch et al., 2001) lesions (≤1.0 mm and ≤Clark Level 3, no ulceration) with an average thickness of 0.31 mm; 6 melanomas were classified as T1b (≤1.0 mm and > Clark Level 3, no ulceration) with an average thickness of 0.62 mm; 5 melanomas were classified as T2a with an average thickness of 1.39 mm; 1 melanoma was classified as T3a, 2.10 mm thick; and 2 melanomas were of unknown thickness (see Table 1 ). The lesions that were at least T2a occurred in individuals who were not compliant with the care guidelines. Among the 16 individuals without previous melanoma, no one who followed the guidelines has developed metastatic disease to date. The average thickness among families with CDKN2A mutations was 0.44 mm, among families with CDK4 mutations was 0.27 mm, and the average thickness among those with no known mutations was 0.38 mm. Sixty-three melanomas had a radial growth phase only, 18 had a radial and a vertical growth phase, and 5 had a vertical growth phase only. Fifty-one had identified precursor lesions on histologic review, 32 of which clearly were dysplastic nevi. The distribution of precursor lesions did not vary by mutation status. In addition, new lesions that were highly suspicious for melanoma occurred in areas without previous known nevi which had no identifiable precursor on histologic review.

The two lesions shown in Figures 5 and 6 were new lesions that were highly suspicious for melanoma and occurred in areas previously examined without identified nevi.

De novo superficial spreading melanoma (CDKN2A mutation). Figure A shows the right popliteal fossa of a 37-year-old patient on which there were two small nevi to the left, close to the medial aspect. It is interesting to note that the right center part of the popliteal fossa had no pigmented lesions. Two years later, when the patient was quite tan, repeat overviews (B) demonstrated the persistent medial nevi and no lesions in the central area. Two years later, on routine followup (C), there was a new lesion detected to the right of the previously noted nevi. Figure D shows a close-up of the lesion. The superior border was quite dark with obvious elevation of the epidermis fading into a flat, less pigmented area on the inferior border of the lesion. There was fairly prominent erythema. The patient had > 650 nevi, a high proportion of which were clinically dysplastic, and had undergone many biopsies. The lesion was biopsied because of a high suspicion for melanoma.

Figure 6.

Superficial spreading melanoma without precursor lesion (unknown mutation). This 6-mm lesion was present on the posterior helix of the ear when the 43-year-old patient returned for a followup visit after 10 years. At the time of the initial examination, the patient did not have nevi on the ears. The patient had received routine care from multiple physicians for several medical problems requiring frequent examinations. None of the physicians had noted the lesion, and it was unknown to the patient. It had very indistinct borders and was asymmetric, varying from tan brown, minimally elevated areas to a very dark brown to black papule in the center of the lesion. There was some scale and loss of skin markings in the central papule. The patient had approximately 150 nevi, many of which were clinically dysplastic nevi. The lesion was excised as highly suspicious for melanoma.

The lesions presented herein are typical of nevi changing in a manner worrisome for melanoma; the lesions were biopsied soon after the photographs were taken (see Figures 7-10).

Figure 7.

Superficial spreading melanoma arising from a dysplastic nevus (CDKN2A mutation). Figure A shows an area on the right lower back of a 52-year-old patient. The lesion of interest is indicated by an arrow directly above the circled lesion #28. There was a uniformly pigmented irregular nevus, which was not different from the other nevi in the local area. It was not particularly dark, and did not prompt a close-up photograph or removal at the time of this examination. The patient had > 100 nevi, many of which were clinically dysplastic, and had undergone many previous biopsies. Figure B shows an overview of the same area 3 years later. The previously mentioned lesion now is circled as #35. In comparison with the earlier photograph, the lesion was quite different. On the right side of the lesion, there was a new extension that was much darker than the other lesions in that area. Figure C shows a close up of the lesion. It measured 14 mm in diameter on the long axis. On the left side of the lesion were two areas of minimal elevation separated by a depressed depigmented central area. The depressed region extended to the dark area noted on the overview. The borders of the lesion were indistinct. The lesion was quite asymmetric and variably pigmented, with a black central papule. Because the lesion was clinically very suspicious for melanoma, an excisional biopsy was performed.

Figure 8.

De novo severe epithelioid dysplasia (CDK4 mutation). Figure A was taken as a followup photograph when a lesion detected in a 23-year-old patient approximately doubled in size in comparison with photographs taken 8 years earlier. The lesion also had become more irregular with a slightly darker area in the lower pole of the lesion. Despite the slight variability in pigmentation, the lesion still was not extremely dark and was not worrisome. Three years later (B), the lesion had become more irregular with a new dark focus on the right lower pole of the lesion. The lower half of the nevus was approximately 1.5 times as wide as the upper half of the nevus. Figure C shows the close-up photograph corresponding to Figure B with the new dark focus in the right lower pole. The lesion measured < 5 mm x 5 mm and was irregular in outline with indistinct borders. Figure D, taken 1 year later, shows an overview of the lesion in which the area between the upper and lower pole had filled in somewhat. The lower half of the lesion had become uniformly darkly pigmented except for the farthest left part of the lesion. Figure E corresponds to Figure D and demonstrates the indistinct borders, the asymmetric and irregular outline of the lesion, and the slightly pebbly appearance of the dark portion of the inferior half of the lesion. The patient had > 300 nevi, many of which were clinically dysplastic. The lesion was excised because of the increase in size to nearly 6 mm x 6 mm and the increase in the dark area in the lower pole.

Figure 9.

Figure A shows a lesion on the upper left anterior axillary line that was typical of the > 500 nevi detected on a 22-year-old patient. The lesion was irregular, predominantly flat with an indistinct outline, variable pigmentation, and asymmetric configuration. The lesion did not appear to differ significantly from multiple other dysplastic nevi at the time of the examination. Figure B was taken 6 years later. In the interval time period, the nevus had enlarged, changed in configuration, and developed a central papule. Because of the increasing area of the more deeply pigmented flat component and the change in size and outline, the lesion was biopsied.

Figure 10.

Dermal nevus with overlying dysplasia (unknown mutation). Figure A shows a typical lesion on the back of a 44-year-old patient at the time of the initial evaluation. The patient had > 500 nevi, many of which were clinically dysplastic. The lesion measured 6 mm in greatest diameter and was irregular in outline with indistinct borders, variable pigmentation, and a predominantly flat configuration. It was not worrisome for melanoma. Figure B shows the lesion 1.5 years later. In the interim, the area to the left of the lesion had become more uniformly pigmented and had changed in outline. The central area, which was the darkest area of the nevus in the previous figure, is essentially unchanged, but the area to the right was minimally darker. The whole nevus still was predominantly flat, but there were two areas in which there was beginning papule formation. Figure C shows the lesion 2 years later, when the two areas at the lower pole that were dark before were nearly coalescent. The area to the left of the lesion was somewhat darker with a pebbly surface. There was beginning small papule formation both on the left and the right sides of the lesion. In addition, the superior right area was becoming more deeply pigmented with some suggestion of papule formation as well. Figure D was taken 1.5 years later when the superior area on the right was uniformly elevated in a plaque-like fashion and light tan. The dark areas at the inferior and left had become coalescent. There were two papules in the dark area in what had become the center of the lesion, and there was a new area of pigmentation inferior to those two papules which was not prominent previously. The area to the far left of the lesion had become a more discreet dark area than in previous photographs. The skin markings were relatively intact throughout the entire lesion, but because of the gradual change over time and the increasing pigmentation, the nevus was removed.

When they first appear, nevi that eventually become dysplastic often are indistinguishable from nevi that will become ordinary compound or dermal nevi (see Figures 11-13). When they reach a dimension of approximately 3 mm, the first abnormality in the morphology frequently is an irregular outline or indistinct borders. These lesions were first photographed when they appeared as new nevi in comparison with previous overview photographs. Over time, they developed the clinical characteristics of dysplastic nevi. Evaluating patterns of new nevus development over time was difficult in these families because they altered their sun-exposure patterns. In general, although family members may develop new clinical dysplastic nevi at any age, it certainly is more common in the 2nd, 3rd, and 4th decades of life.

Figure 11.

Development of clinically dysplastic nevus (CDKN2A mutation). Figure A shows an overview of the left posterior shoulder of a 50-year-old patient with > 100 nevi, many of which were clinically dysplastic. The skin was freckled with actinic damage, some acneiform lesions, and several nevi. Figure B shows a newly prominent nevus arising from previously unremarkable skin 5 years later, which is circled and labeled as #13. Figure C is the first close-up photo of #13. The lesion measured 6 mm and was predominantly circular and flat with indistinct borders, an irregular outline, and minimally variable pigmentation. Figure D depicts the lesion 2 years later, when it was somewhat darker, especially centrally. The pigment had extended at the lower pole in which there also was minimal papule formation. Figure E shows a similar overview to Figure B an additional 5 years later. The emerging papule is observed more clearly in Figure F. At that time, the lesion measured 8 mm x 7 mm and was predominantly flat, with an irregular outline, indistinct borders, and minimally variable pigmentation.

Figure 12.

Development of a clinically dysplastic nevus (CDK4 mutation). Figure A is a close-up of a new nevus that appeared in the interval since the 26-year-old patient's previous examination. The patient had > 200 nevi, many of which were clinically dysplastic. At the time this lesion appeared, the patient was developing several new lesions. The new lesion was a 2-mm flat lesion with minimal pigment variation. It was minimally asymmetric, with a small irregular extension at the 1 o'clock position, and minimally indistinct borders. Figure B is the same lesion 6 months later. At that time it measured 5 mm in greatest diameter and was more asymmetric, with increasingly indistinct borders. Figure C was taken 1 year later, when the nevus had increased by 1 mm but remained relatively uniformly dark, with little asymmetry. Six months later (D), a new lightly pigmented extrusion, was visible at the 8 o'clock position, which became more prominent 6 months later (E). The lesion remained stable in configuration and size for 6 months (F), but there were the beginnings of central papule formation in the darkly pigmented areas. Skin markings remained normal. One year later (G), the lesion was stable but was decreasing in pigmentation. Six months later (H), the papule formation was more prominent and the extrusion at the 8 o'clock position had regressed. Six months later (I), this area was less prominent and the papule formation was more obvious.

Figure 13.

Development of a clinically dysplastic nevus (unknown mutation). Figure A shows a new 3-mm lesion on the upper back of a 34-year-old patient with > 600 nevi, many of which were clinically dysplastic. The borders were indistinct, the pigment varied from erythematous tan at the 10 o'clock position to dark brown to less pigmented at the 4-5 o'clock position, and the lesion was flat. Figure B is the same lesion 1 year later. The lesion at that time measured 5 mm and demonstrated all the clinical criteria of a dysplastic nevus. It was a flat, asymmetric lesion with quite variable pigmentation and irregular, indistinct borders. Figure C is the same lesion 5 years later. At that time the lesion was < 1 mm larger in greatest diameter and had become much less pigmented. It still was predominantly flat, but had developed some papular areas. Figure D shows the same lesion 3 years later. It measured 2 mm larger. The area at the 10 o'clock position, which previously was dark tan, had lightened. The central dark area had increased in size and substantially darkened. There were new dark areas at the 3 o'clock and 4 o'clock positions. Using epiluminescence microscopy, the pigment pattern was found to be normal. This lesion was typical of the other clinical dysplastic nevi noted on this patient.

Removal of all nevi or all clinically dysplastic nevi in these family members was not recommended because many individuals were found to have several hundred nevi (some exceeding 500). The vast majority of clinically dysplastic or other nevi, similar to other precursor states, either remain relatively stable over time or regress. The clinically dysplastic nevi shown in Figures 14 to 16 changed minimally over many years, despite their clearly abnormal morphology.

Figure 14.

Minimal change in a clinically dysplastic nevus (CDKN2A mutation). Figure A shows a 7 mm x 4 mm flat, irregularly shaped, indistinctly bordered lesion with variable pigmentation in non sun-exposed skin. The 34-year-old patient had > 200 nevi, many of which were clinically dysplastic. Fourteen years later (B), the lesion measured 8 mm x 5 mm and had changed only minimally. In the upper-mid lesion, the pigment extended upward in a peninsula. In general, the lesion was lighter and the borders were less distinct.

Minimal change in a clinically dysplastic nevus. The lesion on a 28-year-old patient was photographed from a low sun exposure site because of its 6-mm diameter, predominantly flat morphology, area of increased pigmentation from the 10 o'clock to 11 o'clock positions, and irregular outline with indistinct borders from the 2-4 o'clock position. Over a 4-year period, minimal change occurred. The lesion increased in diameter by 1 mm (toward the 5 o'clock position). The previously hyperpigmented area on the upper left side decreased in size, and the pigmentation became less varied. However, overall, the lesion remained predominantly stable over time. The patient had approximately 500 nevi measuring > 2 mm, many of which were clinically dysplastic.

Figure 16.

Minimal change in a clinically dysplastic nevus (unknown mutation). Figure A shows an irregular flat nevus occurring in a 17-year-old patient with an eccentric brown, diamond-shaped area on the left and an indistinct pink, flat extension to the lower right. Figure B is the same lesion 2 years later. The superior portion of the brown diamond had become more distinct with a pink peninsula. The left point of the diamond had enlarged and become lighter and more diffuse. The right lower pink area had receded back toward the diamond. Figure C was taken 4 years later. The smudge at the lower right had become even less distinct with three small tan macules. The left portion of the lesion also had regressed somewhat. Three years later (D), the lesion essentially was unchanged. Five years later (E), the right side smudged border had receded back to the brown diamond. Over a 14-year period, there was minimal variation in a mostly stable lesion. The patient had > 450 nevi measuring > 2 mm, many of which were clinically dysplastic.

The nevi shown in Figures 17-19 regressed. Often, when a clinically dysplastic nevus begins to differentiate, a central papule appears, and the flat surrounding area becomes less pigmented and less prominent over time. In contrast to lesions suspicious for melanoma, the skin markings remain normal, and there is no visual evidence of stretched or thinned epidermis or telangiectasia in the papule. The papule is soft, similar to a compound or dermal nevus. When the lesion becomes less pigmented, it becomes the color of the baseline skin, similar to a dermal nevus. It does not lose pigment like a regressing melanoma or halo nevus. When the papule flattens, it usually does so proportionally and gradually. An asymmetric involution or change should prompt biopsy. The majority of dysplastic nevi differentiate to dermal nevi or regress and completely disappear over time. Although regression of lesions can occur at any age, it is more common in individuals age > 50 years. In these families, regression also appears to be related to sun protection over time. In contrast to a regressed melanoma (see Figure 7) or halo nevus, the site of a regressed dysplastic nevus, like a regressed dermal nevus, appears similar to the surrounding skin.

Figure 17.

Evolving and regressing clinical dysplastic nevus (CDKN2A mutation). This lesion, which measured > 3 mm (A), was photographed at the time of the initial evaluation because of its deep, variable pigmentation in a non sun-exposed area, irregular shape, and indistinct borders. At that time, the 27-year-old patient was noted to have floridly expressed clinical dysplastic nevi. Nineteen months later (B), the lesion had lightened substantially, enlarged slightly, and developed more distinct borders. Three years later (C), after an intervening pregnancy, the lesion was flat, barely measured 5 mm, and had minimally variable pigmentation and indistinct borders. One year later (D), after a second pregnancy, the lesion was predominantly papular and more erythematous with minimally indistinct borders and a flat component at the 3 o'clock position. Three months later (E), the lesion had faded substantially, flattened, decreased in size, and developed more indistinct borders. Nineteen months later (F), there was a remnant flesh-colored, flat papule measuring < 1 mm.

Figure 17.

Evolving and regressing clinical dysplastic nevus (CDKN2A mutation). This lesion, which measured > 3 mm (A), was photographed at the time of the initial evaluation because of its deep, variable pigmentation in a non sun-exposed area, irregular shape, and indistinct borders. At that time, the 27-year-old patient was noted to have floridly expressed clinical dysplastic nevi. Nineteen months later (B), the lesion had lightened substantially, enlarged slightly, and developed more distinct borders. Three years later (C), after an intervening pregnancy, the lesion was flat, barely measured 5 mm, and had minimally variable pigmentation and indistinct borders. One year later (D), after a second pregnancy, the lesion was predominantly papular and more erythematous with minimally indistinct borders and a flat component at the 3 o'clock position. Three months later (E), the lesion had faded substantially, flattened, decreased in size, and developed more indistinct borders. Nineteen months later (F), there was a remnant flesh-colored, flat papule measuring < 1 mm.

Figure 19.

Evolving and regressing clinical dysplastic nevus (unknown mutation). A close-up photograph was taken of this 5-mm lesion because of the central darker area, indistinct borders, and erythematous base (A). The 15-year-old patient had > 200 nevi, many of which were clinical dysplastic nevi. This lesion was less atypical than many others found at the time of this examination. Figure B was taken 15 months later, when the lesion was 2 mm larger. The lesion had grown more in the area from the 9 o'clock to the 1 o'clock position with a more irregular, indistinct border. The pigment appeared less uniform, with the base pigmentation somewhat lighter, making the contrast between the darker and lighter areas more pronounced. The same linear dark plaque can be noted at the upper pole of the lesion. Two years later, the lesion had faded somewhat (C) at a time when other lesions were lightening. The linear dark plaque at the upper pole was much lighter, and the lower pole had changed from convex to concave. The erythematous base was less prominent, except at the upper pole. Four years later (D), the central dark area measured approximately 1 mm in greatest dimension and the entire lesion had faded dramatically. At the upper pole, there were some vestiges of pigment, which appeared to be outside the lesion. Three years later, the nevus has continued to fade, with some suggestion of beginning papule formation in the center (E). Five years later (F), the lesion was difficult to see, with only minimal darkened areas. Thus, over a 16-year period, the lesion progressed from a small to a larger dysplastic nevus, then regressed to a barely visible lesion.

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