Precursor Lesions to Melanoma WILMA BERGMAN, MD, PHD RAMON M. FUSARO, MD, PHD
he field of precursor lesions to melanoma is subject to ongoing debate and evolving insights. Regarding congenital melanocytic nevi there is controversy about the management of these lesions. It has become apparent that patients with giant (“bathing trunk-type”) congenital nevi have an increased incidence of malignant melanoma developing in their lesions. Prophylactic excision is generally accepted treatment and these lesions should be removed in early childhood; however, the subject of debate has been enlarged to include all congenital nevi, including those of the “small” type. It is unclear to what extent melanoma develops in smaller congenital nevi and dermatologists disagree on the therapy of smaller lesions. The intensity of the controversy appears to be inversely proportional to the size of the nevus. Regarding dysplastic nevi there is controversy about diagnostic definitions both clinically and histologically. Some even deny the existence of dysplastic nevi! The Familial Atypical Multiple-Mole Melanoma (FAMMM) syndrome also has its contentions with regard to the genetic mechanism: Is a dominant gene localized on chromosome lp involved in all FAMMM families? Furthermore, the complete spectrum of the FAMMM syndrome including the occurrence of systemic cancer(s) and ocular melanoma is still debated. This review focuses on the aforementioned controversies in the field of precursor lesions to melanoma. Early detection of malignant melanoma reduces its morbidity and mortality. The most important method to achieve this is by professional and public education about the signs and symptoms of early melanoma and preven-
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From the Department of Dermatology, University of Leiden, Leiden, The Netherlands, and the Department of Preventive Medicine and Public Health, Creighfon University School of Medicine, Omaha, Nebraska. Address correspondence to Wilma Bergman, Department of Dermatology, University Hospital, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
0 1992 by Elsevier Science Publishing Co., Inc.
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tive health care in individuals with high-risk factors. This article deals with two of these benign high-risk melanocytic precursors: the dysplastic nevus (DN) and the congenital nevus (CN). A third precursor, lentigo maligna or Hutchinson’s melanotic freckle (Dubreuihl’s melanosis), which specifically gives rise to the relatively rare type of melanoma called lentigo maligna melanoma, is to be considered as a precancerous lesion and is not dealt with in this article. Although the familial occurrence of melanoma has been known for many decades,* the remarkable phenotype accompanying the hereditary variant of melanoma was only recognized in 1978 and was then named the B-K mole syndrome by Clark et al2 and the FAMMM syndrome by Lynch et a1.3 The phenotype of atypical pigmented lesions of the FAMMM syndrome is called “dysplastic” nevus (DN). The syndrome is also known as the “familial” type of the dysplastic nevus syndrome.’ In 1980, when dysplastic nevi were recognized to occur in the general population, individuals showing dysplastic nevi and lacking a family history of melanoma were diagnosed as having the “sporadic“ type of dysplastic nevus syndrome. The term dysplastic has been criticized because pathologists and clinicians have various concepts and definitions of the word. Furthermore, the specificity of the histologic criteria that have been recommended to identify DNs is being questioned by some authors and the clinicopathologic correlation is far from 100%.5-7 With regard to this ongoing debate it seems preferable to refer to these easily recognized unusual nevi as atypical nevi (ANs) or atypical moZes.8These terms are useful in epidemiologic studies as they do not suggest more than is known factually. For familial melanoma and ANs the term FAMMM syndrome satisfies the designation of the genetic context of the disorder. Congenital nevi (CNs) can be recognized clinically and histologically without much difficulty. There is not much
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Table 2. Clinical Characteristics Size Color
Shape Border Surface
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Nevi
Vary; larger-than-normal; often > 5 mm, some > 10 mm; melanoma usually > 10 mm Variegate; multiple shades of tan, brown, black, and pink; often red hue or red border; erythema; largely contrasting shades may indicate (early) melanoma Irregular; asymmetric; chaotic; notchy shape indicates superficial spreading melanoma Hazy; fades imperceptibly into surrounding skin; partially indistinct Usually macular or just palpable; little raised; sometimes centrally pebbly; “mammillated”; “cobblestoned”; asymmetric papule/nodule indicates melanoma
debate about definitions. Nevi that look like CNs and are said to have been absent at birth, but appeared a few months later are called congenifal nexus-like nevi (CNLNs) and are considered to have a melanoma risk indistinguishable from that of true CNS.~ With respect to CN management strategies, however, there is still ongoing debate concerning which congenital nevi should be removed prophylactically. Thus the field of congenital precursor lesions is subject to ongoing controversy.
Dysplastic Nevi Clinical Features Dysplastic nevi were first recognized in the setting of familial melanoma. The original description by Clark’s group is as follows: “A single prototypic B-K mole is about 10 mm in diameter, is irregular in outline, and is a haphazard mixture of tan, brown, black and pink. While seemingly flat on inspection, the B-K mole has a small palpable dermal component. There is striking variability from one mole to the next.” * The original description by Lynch’s group is as follows: “Multiple large moles of variable size and color (reddish-brown to bright red), irregular in shape with pigmentary leakage.” 3 A special article in the New England Journal of Medicine describes dysplastic nevi as having “irregular borders, a haphazard mixture of tan, brown, dark brown and pink colors and a margin that tends to be indistinct, fading into the adjacent normal skin; the topography may be quite complex and varied ranging from an almost completely macular surface through an irregular, ‘pebbly’ surface to a ‘fried egg’ appearance.” lo Table 1 summarizes all the clinical features of ANs ever mentioned. It should be noted that a single AN rarely ever shows all of these features, In considering the diagnosis of AN, a sum of the clinical features in several ANs is considered appropriate. Furthermore, none of these features is specific or diagnostic of an AN, and neither is one of these features obligatory. No consensus exists
about the exact number of features required for the clinical diagnosis of an AN. We have always used three or more criteria for the clinical diagnosis of an AN; however, in the setting of FAMMM families, ANs can sometimes be diagnosed histologically (at least according to our standards) by the presence of two clinical criteria.
Histopathology The histologic criteria of DNs originally described in 1978 concerned lesions that had been recognized as a phenotypic marker for familial melanoma. Clark’s group described these lesions as compound melanocytic nevi, in addition to the following distinctive features: atypical melanocytic hyperplasia, mesenchymal changes in the papillary dermis, and a lymphocytic infiltrate.* Atypical melanocytic hyperplasia is synonymous with melanocyfic dysplasia, that is, individual melanocytes or small clusters of melanocytes that have “some” of the structural features of malignant melanocytes. Furthermore, the situation is analogous to cervical dysplasia and senile (actinic) keratoses.* In their histologic evolution these criteria have been categorized in three major groups: (1) architectural atypia, (2) melanocytic/cytologic atypia, and (3) mesenchymal host response. Some authors, however, do not consider cytologic atypia as a mandatory criterion for diagnosis. 11-13Table 2 summarizes the histologic features that can be found in DNs, categorized as just described. Analogous to the clinical diagnosis of AN, the histologic diagnosis of DN requires several of the criteria listed in Table 2, preferably at least one feature from each category. It should be noted that none of the features from Table 2 is specific or diagnostic of DNs in itself.
Table 2. Histologic Features Diagnostic of Dwvlustic Nevi Features of architectural atypia Junctional activity Melanocytic preference for the tips of the rete ridges Irregular configuration of rete ridges Irregularity of junctional nests Bridging Impairment of maturation of dermal component Features of cellular atypia Large prominent melanocytes Nuclear pleomorphism Large nuclei Prominent nucleoli Dusty melanin pigment Prominent retraction artifact Stromal reactions Lymphocytic infiltrate Fibroplasia Angioneogenesis Melanophages
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No consensus exists about the exact number of features required for diagnosing DNs. Steijlen et al have studied the efficacy of these histopathologic criteria in a series of DNs from FAMMM family members and in a control series of nevi from autopsy cases.14 Individual diagnostic features had either a low sensitivity, a low specificity, or low predictive value. Discriminant analysis showed that (1) the presence of dustlike melanin in the cytoplasm of melanocytes, (2) irregular nevoid nests, (3) markedly increased junctional activity, and (4) melanocytic nuclei larger than or equal in size to adjacent keratinocytes were the most discriminating features.” Diagnostic criteria as published by Steijlen et al have been evaluated and substructured by immunohistochemical (expression of class I HLA antigens on melanocytes) and cytophotometric analysis (abnormalities in nuclear DNA content). Both markers were present in the large majority of those lesions categorized as markedly atypical DNs, in about half of the moderately atypical DNs, and in less than one third of mildly atypical DNs.15 Thus, these findings suggest reasonable arguments to be present for these diagnostic criteria and ranking of degree of atypia. Abandoning the criterion of cytologic atypia seems to increase the chance of histologically overdiagnosing DN. Nevoid lesions showing ascension of atypical melanocytes up to the granular layer of the epidermis should be diagnosed as melanoma in situ. Piepkorn and co-workers have suggested a scheme for rating melanocytic lesions that incorporates the histologic characteristics of DNs into the “normal biological development of melanocytic nevi.” W’ They regard histologic findings as seen in DNs as a normal proliferative phase of nevi; thus, in their opinion, “dysplastic nevi” correlate poorly with clinical phenotype. In their view, the overall clinical phenotype represents an individual’s melanoma risk just as it has been recognized originally by Clark et al2 and Lynch et a1.3 This theory suggests that patients with clinically atypical moles are at increased risk for melanoma, histologic appearance notwithstanding. The indication for excisional biopsy of ANs is primarily to rule out melanoma. Future studies are needed to develop uniform criteria for melanocytic dysplasia that correlate with clinical phenotype and biologic behavior, that is, melanoma risk.
Familial Atypical Multiple Mole Melanoma Syndrome The FAMMM syndrome is characterized by the familial occurrence of malignant melanoma of the skin in combination with multiple atypical precursor nevi, or dysplastic nevi. The FAMMM trait appears to be transmitted as a dominant gene in families, with variable expressivity, of the cutaneous phenoincluding nonpenetrance,
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typePzl and marked heterogeneity. The latter is important in understanding the expression of all cutaneous and systemic phenotypes. A recent monograph on hereditary melanoma reviews the subject.22 It has been estimated that about 6 to 10% of all cutaneous melanomas occur in persons with a positive family history of melanoma.23,24 The incidence of multiple primary melanomas is much higher in the hereditary form (12%) than in sporadic melanoma (3%). In our Dutch families we observed 10 multiple melanoma patients out of 38 patients (26%); 8 patients had two melanomas and 2 patients had three melanomas.25 It seems probable that genetically predisposed persons in younger generations, whose melanomas are being recognized while thin and prognostically favorable, survive and thus have time to develop a second or even third primary melanoma. Although the typical sporadic melanoma is a neoplasm of the fifth and sixth decades, familial melanoma usually occurs in much younger patients, in about the third decade; however, familial melanomas can occur at even younger ages. In our families prepubertal melanoma developed in one 9year-old and two 12-year-olds. All three cases developed melanoma from a dysplastic nevus, not from a congenital nevus. Atypical nevi may be recognized in children, but they increase in size and number considerably during puberty, with new lesions continuing to develop throughout adult life. It is remarkable that ANs in children can be recognized first on the scalp, in the skin area above and behind the ears. On the trunk, nevi in children of FAMMM families are at first very prominent, being larger and more numerous than nevi in other children from the same age group; it is only after puberty that the dysplastic features become recognizable. Also, nevi on the feet can be present in childhood. The FAMMM syndrome is classically characterized by many large atypical nevi, with the phenotype being described as “funny“; however, there is a marked variability in the phenotypic expression within and between families. For example, some members of a FAMMM kindred may have total mole counts into the hundreds, whereas others may show very few nevi or even no nevi at a11.26-2sAlmost all FAMMM gene carriers showing few or many ANs also show “normal” nevi; only a (variable) proportion of the total number of nevi can be recognized as being dysplastic. Atypical nevi may be found in normal individuals. Thus the presence of a few ANs is not an absolute criterion for establishing the diagnosis in a member of a FAMMM family. It is not known how many ANs are required for diagnosing a gene carrier, but because of the very variable phenotype it might be as few as one or two. It is also important to recognize that the absence of clinically atypical nevi does not rule out the presence of a FAMMM gene carrier. This
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problem clearly indicates the need for a biomarker; however, to date no such biomarker has been identified. There have been several investigative reports concerning the occurrence of systemic cancer in patients and their relatives with the FAMMM syndrome. The first of these was a study by Lynch et al of four FAMMM families that showed a significant fivefold increase in systemic cancers of variable anatomic sites such as the breast, respiratory tract, gastrointestinal tract, and lymphatic system.29 The Leiden group investigated cancer of all anatomic sites in nine FAMMM families which were ascertained in a clinic for pigmented lesions. 3o A significant excess of systemic cancer was observed in three of these nine families. The remaining families showed the normally expected rates of cancer. Interestingly, in these families there was an excessive number of cancers of the gastrointestinal tract. Nine of eighteen cancers involved the pancreas, whereas none had the common colorectal cancer. In The Netherlands, colorectal cancer is five times as frequent as pancreatic cancer. That three of these nine families showed a marked excess of systemic cancer, while the remaining families showed normal rates of cancer, indicates heterogeneity among these families. Greene et al performed a prospective study of 14 kindreds at the National Institutes of Health with hereditary cutaneous melanoma and the dysplastic nevus syndrome.31 They concluded that “no significant excess of non-melanoma cancers was documented.” Nonetheless, if the expression of systemic cancer is calculated with the use of only defined gene carriers (those with dysplastic nevi and/or malignant melanoma), their data show a significant increase in the occurrence of gastrointestinal cancer (P < .05). It would be important to determine whether these cancers were limited to only a few kindreds or all 14 kindreds, thereby verifying the concept of heterogeneity. Intraocular melanoma was first described in a FAMMM pedigree from Leiden, The Netherlands, in which one of the members not only had bilateral primary intraocular melanomas, one year apart, but multiple ANs and several cutaneous melanomas.29,32 Recently, five small families have been reported with the FAMMM syndrome, with one member of each family having ocular melanoma.33 Two cases were remarkably young: a 16year-old girl with a conjunctival melanoma and a 28year-old man with a choroidal melanoma. In addition four other families have been reported in the literature.34,35 These observations indicate that a small percentage of uveal and conjunctival melanomas may be explained by the presence of the FAMMM syndrome in the family. Furthermore, they emphasize the heterogeneity of the FAMMM syndrome and suggest that FAMMM
Clinics in Dermatology 1992;10:21-29 gene carriers are at risk not only for cutaneous melanoma, but also occasionally for ocular melanoma.
Genetics of fhe FAMMM Syndrome The precise genetic mechanism of the FAMMM syndrome remains unknown. The gene is claimed to be located on chromosome lp by one group36 and to be excluded from chromosome lp by two other group~.~~,~* In a recent genetic analysis workshop (GAW-7) of the American Society of Human Genetics, the FAMMM syndrome was discussed by expert biostatisticians, molecular biologists, and clinical geneticists. It is notable that the one finding consistent across all analyses was that dominant inheritance was strongly rejected.39 This conclusion was of particular interest because dominant inheritance is precisely the model postulated from clinical-genetic studies of FAMMM pedigrees and is the generally accepted mode of inheritance. It should be noted that from the beginning Happle et al in Germany warned against easy acceptance of a monogenic inheritance, that is, one dominant gene causing the FAMMM syndrome; in their view the FAMMM syndrome is due to polygenic inheritance.40-42 Cytogenetic studies of hereditary malignant melanoma have been sparse. 43-46 Past cellular studies of the FAMMM syndrome indicated a slightly increased sensitivity to ultraviolet (UV) light in lymphoblasts47 and fibroblasts*s from melanoma patients belonging to high-risk families, though this has not been found to be a general characteristic of the syndrome45,49; however, evidence has been presented for an increased mutability of cells from FAMMM patients after exposure to a UV-mimetic chemical substance.49 Increased sensitivity to x-rays of fibroblasts from FAMMM subjects has been reported.50 Cytogenetic studies by Lynch et al showed increased frequencies of cells with random chromosomal rearrangements, observed in cell cultures from dysplastic nevi (melanocytes) and normal skin (fibroblasts).51 In the fibroblast cultures, considerable clonal selection of cytogenetically abnormal cells occurred. A positive cytogenetic status was awarded to individuals whose changes were clonal in nature. Fifteen histologically verified DNs were studied from 12 individuals and all had cells with chromosomal abnormalities. The possibility that this finding was a cultural artifact was essentially eliminated by the numbers of such observations and by the finding of clonal evolution. Ten biopsies of clinically normal skin from FAMMM patients were studied. Seven contained fibroblasts with chromosome rearrangements. The phytohemagglutininstimulated lymphocytes were generally normal with respect to chromosomes.
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These cytogenetic findings seem to place the FAMMM syndrome among the chromosome instability syndromes and it seems to be the first one that is inherited as autosoma1 dominant. Other cancer-associated chromosome instability syndromes such as ataxia telangiectasia, Bloom’s syndrome, and Fanconi’s anemia are recessively inherited. The mechanism of the chromosome instability in FAMMM syndrome may be unique. One possible mechanism is that the FAMMM gene may be impairing chromosome stability which is followed by chromosomal rearrangements. Some of the rearrangements may involve genes that confer a proliferative advantage, especially to melanocytes. With further chromosome instability, the nevi make the transition to neoplasia and transform into malignant melanoma. This same instability may lead to cancer in other organ systems.
Management of FAMMM Families The Dutch Melanoma Consensus Meeting stated that “Persons with the familial dysplastic nevus syndrome have a greatly increased risk of melanoma. Checkups once to twice a year are required for a long period of time.” As the consensus text is being distributed widely, it is hoped that this statement will lead to earlier diagnosis of melanoma in FAMMM gene carriers throughout the country. Essential to the success of this program is the taking of a family history with regard to melanoma from all patients presenting with melanoma. Furthermore, all melanoma patients should be screened for the presence of ANs. The American Consensus Conference on Precursors to Malignant Melanoma in 1984 discussed the management of FAMMM families: Patients with AN and a family history of melanoma should be followed up frequently, with documentation of lesions and excision of changing nevi. The first degree relatives of patients with melanoma should be examined for AN and melanoma in view of the familial aggregation of both lesions. In patients with AN and any family history of melanoma, the indication for excising AN is the suspicion of early melanoma. Follow-up should be conducted every three to six months. Photography may be helpful to document the appearance of lesions. Furthermore patients with AN should be taught self-examination to detect changes in existing nevi and the emergence of new nevi. Finally, they would be prudent to avoid excessive sun exposure and use sunscreens.*2 The U.S. Consensus Conference on Melanoma, which was convened in the beginning of 1992, considered the aspects of systemic cancers occurring in conjunction with the FAMMM syndrome and also the risk of ocular mela-
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noma. Furthermore, there is a need to define “familial melanoma” more strictly, and consequently define exactly, which family members should be examined. Examination of first-degree relatives is insufficient to identify the complete spectrum of the FAMMM syndrome within a kindred.52 In the meantime several papers have reported results of screening of FAMMM family members. Greene et al evaluated the risk of melanoma in 401 members of 14 families.53 They found 39 new melanomas in 22 study participants over a period of 8 years. The probability of melanoma developing in family members with DNs was 56% from ages 20 to 59. Extrapolated to the age of 76, the curve reached 100%. To assess the effect of screening on the prognosis of melanoma patients in FAMMM families, we have studied three different categories of melanomas.25 The fist category comprised all melanomas diagnosed in nine Dutch families before the start of the screening procedures (in 1982); the second category comprised those melanomas detected at initial examination of the families, and the third category included all melanomas found during the course of follow-up. Screening was found to lead to detection of more melanomas in situ and less invasive melanomas with significantly thinner Breslow thicknesses. Furthermore, these thin melanomas were detected at an earlier age. These data were confirmed by others. We consider these results to be an indication of the effectiveness of our screening program.
Sporadic Dysplastic Nevus Syndrome In 1980, Elder et al recognized the prevalence of ANs in nonfamilial melanoma patients. These ANs were indistinguishable from those seen in FAMMM syndrome/B-K mole syndrome. 55 At that time the term dysplastic news syndrome was proposed to describe both the familial and nonfamilial (sporadic) variants of these melanoma-associated ANs. Recently our group published the results of a family study of 31 probands diagnosed as having the “sporadic” variant of dysplastic nevus syndrome; that is, they lacked a family history of melanoma.56 Thirty-one complete families (125 family members) were investigated. We found no cases of melanoma in these families. In 21 families, however, several family members showed clinically ANs, and in 10 families, the proband was the only person showing ANs. It is unclear how these “dysplastic nevus families without melanoma” should be regarded or how their melanoma risk should be ranked. Nordlund et al examined nearly 300 melanoma patients and 145 controls for the presence of ANs.~’ They found one or more ANs in 34% of the patients with melanoma and in 7% of the controls. Another survey found
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clinical or histologic evidence of DN in 57% of nonfamilial melanoma patients. 58With these data a crude approximation of melanoma risk in individuals with sporadic dysplastic nevus syndrome yielded a lifetime risk of 18%, 26 times the risk of the general population.59 An Australian study of ANs in patients with nonfamilial melanoma yielded a prevalence of 55%; 26% had at least five ANs.~O In the same study 17% of controls had at least one clinically determined AN, and 6% had at least five ANs. A Swedish study diagnosed ANs clinically in 18% of the general population. 61 In this study, subjects with ANs had a significantly larger number of common nevi and a more sun-sensitive skin type than subjects without ANs. This increased number of nevi is also associated with melanoma risk. The authors conclude: “As more than half of the Swedish population has over 50 nevi and close to one out of five has clinical DN, it is obvious that largescale screening programs will be too time consuming and expensive. It is therefore necessary to define more detailed subgroups, likely to develop melanoma”. Holly et al demonstrated an increased risk for development of malignant melanoma in patients with ANs compared with controls, They established that individuals with one to five ANs have a relative risk of 3.8 of developing melanoma and that individuals with over five ANs have a relative risk of 6.3 during an average of 27 months of follow-up.62 In the meantime two prospective follow-up studies for malignant melanoma in large groups of patients with DNs have been reported by the same gro~p.~~*~~In the first study combined data from familial and nonfamilial cases were reported, but in the second study a nonfamilial group could be discriminated from familial groups; however, the latter investigation included only cases with the so-called “classic” dysplastic nevus syndrome with over 100 nevi. Both studies indicated a clearly increased risk of developing melanoma when compared with general population data. Furthermore, the presence of a DN in a patient with a personal history of melanoma (no family history of melanoma) indicated an increased risk of a second primary melanoma. From the preceding it is concluded that the prevalence of ANs in the general population in countries with a high incidence of melanoma seems to be between 7 and 18%. Furthermore, there seems to be an increased risk of develand multiple primary melanomas oping melanoma among individuals showing DNs. It is not clear exactly how high this risk is and which other determinants (number of nevi, number of dysplastic nevi, skin phototype) play a role in creating this risk. Until new data are available it seems justified to evaluate persons with sporadic DNs once a year; however, most DNs probably remain stable over time.
Congenital Nevi Giant Congenital Nevi Giant CNs are large, pigmented, often verrucose, and characteristically hairy cutaneous maldevelopmental lesions of the neural crest. These nevi may occur alone or rarely may be associated with leptomeningeal melanocytosis. They usually cover a substantial part of the body, most classically the “bathing trunk” area. The literature before 1980 has been reviewed by Hendrickson and Ross.~~ The prevalence of giant CNs is not extensively documented; from a large South American study it appears to be about 1 per 20,000.66 The incidence of malignant transformation in giant CNs is unknown, although it is indisputable that giant CNs can provide the setting for development of melanoma as evidenced by avid case reporting. Most convincing is the reported 4.6% incidence of cancer in the Danish series that Lorentzen et al derived from follow-up studies of 151 patients with giant CNs registered in the Danish Health System from 1915 to 1975.67 Rhodes et al discussed this study and stressed several factors that may have resulted in underestimation of the risk of malignancy. 6* Lanier et al found a comparable incidence of 6.9%.69 The higher rates that have been frequently quoted in the literature may be distorted by patient selection, particularly those in pathology reviews. Uncertainty also exists as to whether malignant change in a giant CN is more common in children or adults. Several papers suggest it is more common in children.70 In some papers 60% of patients were less than 10 years of age. Cancer registries of deaths from melanoma in prepubertal children show that melanoma in childhood is very rare. In an Australian survey, 3 of 20 children’s melanomas had arisen in a giant CN.7* Furthermore, in the major children’s hospital in the state of Victoria, four children with melanoma were recorded in 56 years, with one of these arising in a giant CN. If the incidence of giant CNs is considered to be 1 per 20,000 births, then 160 children must have been born with a giant CN in the state of Victoria in that period. Many authors have regarded giant CNs as a significantly premalignant lesion in infants and children and have advocated removal as soon as possible.70 Removal for cosmetic reasons is another matter and depends largely on both the parents’ feelings about the appearance of the nevus and the emotional effect it has on the child. Several plastic surgeons have reported good cosmetic results from deep dermabrasion72 or curettage7j in the first few weeks of life. With these procedures most of the nevus cells are removed, thus theoretically reducing the chance of malignant transformation; however, some advise total excision because of subepidermal development of melanoma in a substantial percentage of transformed CNS.~~ In conclusion, on the basis of suffi-
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ciently established melanoma risk in childhood and on the basis of cosmetic considerations, removal of giant CNs as soon as possible is generally advocated.
7. Cassileth BR, Clark WH, Lusk EJ, et al. How well do physicians recognize melanoma and other problem lesions? J Am Acad Dermatol 1986;14:555-60.
Small and Medium-Size Congenital Nevi
8. Kopf AW, Friedman RJ, Rigel DS. Atypical mole syndrome. J Am Acad Dermatol 1990;16:117-8.
For purposes of discussion, congenital nevi have arbitrarily been divided according to size into small, less than 1.5 cm; medium, 1.5 up to 20 cm; and large, 20 cm or greater. l2 This categorization of CNs on size alone has been criticized.75 The relationship between small and medium-size CNs and malignant melanoma is a controversial subject and information is scanty. It is unclear to what extent melanoma develops in smaller CNs; the incidence has been reported to be increased, but the magnitude of that increase is not well established.‘* Rhodes et al investigated the relationship between small CNs and melanoma by seeking remnants of CNs in the pathology slides of 234 melanoma specimens.76 They found histologic features of CN in 8.1% of melanoma specimens. Furthermore, the presence of a CN could be ascertained by history in 15% of 134 melanoma patients,” and it became clear that malignant transformation usually occurs after puberty.78 As can be imagined from the controversy on melanoma risk from smaller CNs, there is also disagreement on their management. In a survey in the United States, the ratio of dermatologists observing small CNs to those removing these lesions was 4: 6.79 With respect to the management of smaller CN, the American Consensus Panel stated that “there are insufficient data at present to recommend prophylactic excision. A conservative management is recommended. Patients with CN should be examined periodically. If an alteration in the nevus is detected, a biopsy should be done.” I2
References 1. Cawley EP. Genetic aspects of malignant melanoma. Arch
Dermatol Syphil 1952;65:440-50. 2. Clark WH, Reimer RR, Greene MH, et al. Origin of familial malignant melanomas from heritable melanocytic lesions. Arch Dermatol 1978;114:732-8. 3. Lynch HT, Frichot BC III, Lynch JF. Familial atypical multiple mole-melanoma syndrome. J Med Genet 1978;15: 352-6. 4. Kraemer K. Dysplastic nevi as precursors to hereditary melanoma. J Dermatol Surg Oncol 1983;9:619-22. 5. Roush GC, Barnhill RL, Duray PH, et al. Diagnosis of the dysplastic nevus in different populations. J Am Acad Dermatol 1986;14:419-25. 6. Kelly JW, Crutcher WA, Sagebiel RW. Clinical diagnosis of dysplastic melanocytic nevi. J Am Acad Dermatol 1986;14:1044-51.
9. Kopf AW, Levine LJ, Rigel DS, et al. Prevalence of congenital nevus-like nevi, nevi spili, and cafe au lait spots. Arch Dermatol 1985;121:766-9. 10. Greene MH, Clark WH, Tucker MA, et al. Acquired precursors of cutaneous malignant melanoma. The familial dysplastic nevus syndrome. N Engl J Med 1985;312:91-7. 11. Ackerman AB, Mihara J. Dysplasia, dysplastic melanocytes, dysplastic nevi, the dysplastic nevus syndrome and the relation between dysplastic nevi and malignant melanoma. Hum Path01 1985;16:87-91. 12. Consensus development conference, October 24- 26,1983, National Institutes of Health, Bethesda MD: Precursors to malignant melanoma. JAMA 1984;251:1864-6. 13. Sagebiel RW. Diagnosis and management of premalignant melanocytic proliferations. Pathology 1985;17:285-90. 14. Steijlen PM, Bergman W, Hermans J, et al. The efficacy of histopathological criteria required for diagnosing dysplastic nevi. Histopathology 1988;12:289-300. 15. Bergman W, Ruiter DJ, Scheffer E, Van Vloten WA. Melanocytic atypia in dysplastic nevi. Immunochemical and cytophotometrical analysis. Cancer 1988;61:1660-6. 16. Piepkorn M. A hypothesis incorporating the histologic characteristics of dysplastic nevi into the normal biological development of melanocytic nevi. Arch Dermatol 1990;126:514-8. 17. Piepkorn M, Meyer LJ, Goldgar D, et al. The dysplastic melanocytic nevus: A prevalent lesion that correlates poorly with clinical phenotype. J Am Acad Dermatol 1989;20:407-15. 18. Reimer RR, Clark WH, Greene MH, et al. Precursor lesions in familial melanoma. A new genetic preneoplastic syndrome. JAMA 1978;239:744 - 6. 19. Greene MH, Goldin LR, Clark WH, et al. Familial cutaneous malignant melanoma: Autosomal dominant trait possibly linked to the Rh locus. Proc Nat1 Acad Sci USA 1983;80:6071-5. 20. Bale SJ, Chakravarti A, Greene MH. Cutaneous malignant melanoma and familial dysplastic nevi: Evidence for autosomal dominance and pleiotropy. Am J Hum Genet 1986;38:188-96. 21. Bergman W, Palan A, Went LN. Clinical and genetic studies in six Dutch kindreds with the dysplastic nevus syndrome. Ann Hum Genet 1986;50:249-58. 22. Lynch HT, Fusaro RM, editors. Hereditary malignant melanoma. Boca Raton (FL): CRC Press, 1991. 23. Greene MH, Fraumeni JF. The hereditary variant of malignant melanoma. In: Clark WH, Goldman L, Mastrangelo MJ, editors. Human malignant melanoma. New York: Grune & Stratton, 1979:139-66.
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24. Kopf AW, Hellman LJ, Rogers GS, et al. Familial malignant melanoma. JAMA 1986;256:1915-9. 25. Vasen HFA, Bergman W, Van Haeringen A, et al. The familial dysplastic nevus syndrome. Natural history and the impact of screening on prognosis. Eur J Cancer Clin Oncol 1989;25:337-41. 26. Lynch HT, Fusaro RM, Albano WA, et al. Phenotypic variation in the familial atypical multiple mole-melanoma syndrome (FAMMM). J Med Genet 1983;20:25-9. 27. Lynch HT, Fusaro RM, Pester J, Lynch JF. Familial atypical multiple mole melanoma (FAMMM) syndrome: Genetic heterogeneity and malignant melanoma. Br J Cancer 1980;42:58-70. 28. Lynch HT, Fusaro RM, Kimberling WJ, et al. Familial atypical multiple mole-melanoma (FAMMM) syndrome: Segregation analysis. J Med Genet 1983;20:342-4. 29. Lynch HT, Fusaro RM, Pester J, et al. Tumour spectrum in the FAMMM syndrome. Br J Cancer 1981;44:553-60. 30. Bergman W, Watson P, De Jong J, et al. Systemic cancer and the FAMMM syndrome. Br J Cancer 1990;61:932-6. 31. Greene MH, Tucker MA, Clark WH, et al. Hereditary melanoma and the dysplastic nevus syndrome: The risk of cancers other than melanoma. J Am Acad Dermatol 1987;16:792-7. 32. Oosterhuis JA, Went LN, Lynch HT. Primary choroidal and cutaneous melanomas, bilateral chordida melanomas and familial occurrence of melanomas. Br J Ophthalmol 1982;66:230-3. 33. Vink J, Crijns MB, Mooy CM, et al. Ocular melanoma in families with dysplastic nevus syndrome. J Am Acad Dermatol 1990;23:858-62. 34. Albert DM, Chang MA, Lampin K, et al. The dysplastic nevus syndrome, a pedigree with primary malignant melanomas of choroid and skin. Ophthalmology 1985;92: 1728-34. 35. Greene MH, Sander RJ, Chu FD, et al. The familial occurrence of cutaneous melanoma, intraocular melanoma and the dysplastic nevus syndrome. Am J Ophthalmology 1983;96:238-45. 36. Bale SJ, Dracopoli NC, Tucker MA, et al. Mapping the gene for hereditary cutaneous malignant melanoma-dysplastic nevus to chromosome lp. N Engl J Med 1989;320:136772. 37. Cannon-Albright LA, Goldgar DE, Wright EC, et al. Evidence against the reported linkage of the cutaneous melanoma-dysplastic nevus syndrome locus to chromosome 1~36. Am J Hum Genet 1990;46:912-8.
40. Traupe H, Macher E, Hamm H, Happle R. Mutation rate estimates are not compatible with autosomal dominant inheritance of the dysplastic nevus “syndrome.” Am J Med Genet 1989;32:155-7. 41. Happle R. Gregor Mendel und die dysplastischen Hautarzt 1989;40:70-6.
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42. Happle R. Arguments in favor of a polygenic inheritance of precursor nevi. J Am Acad Dermatol 1982;6:540-3. 43. Balaban G, Herlyn M, Guerry DP IV, Bartolo R. Cytogenetics of human malignant melanoma and premalignant lesions. Cancer Genet Cytogenet 1984;11:429-39. 44. Caporaso N, Greene MH, Tsai S, et al. Cytogenetics in familial malignant melanoma and dysplastic nevus syndrome Is dysplastic nevus syndrome a chromosome instability disorder? Cancer Genet Cytogenet 1987;24:299-305. 45. Jaspers NGJ, Roza-de Jongh EJM, Danselaar IG. Random chromosomal rearrangements in fibroblasts and lymphocytes from melanoma-prone individuals belonging to a family with the dysplastic nevus syndrome. Cancer Genet Cytogenet 1987;24:33-43. 46. Illeni MT, Rovini D, Grassi C, et al. Sister chromatid exchange analysis in familial groups of malignant-melanoma patients. Cancer Genet Cytogenet 1991;53:237-46. 47. Ramsay RG, Chen I’, Imray FP, et al. Familial melanoma associated with dominant ultraviolet radiation sensitivity. Cancer Res 1982;42:2909 - 12. 48. Smith PJ, Greene MH, Devlin DA, et al. Abnormal sensitivity to UV-radiation in cultured skin fibroblasts from patients with hereditary cutaneous malignant melanoma and dysplastic nevus syndrome. Int J Cancer 1982;30:39-45. 49. Howell JN, Greene MH, Comer RC, et al. Fibroblasts from patients with hereditary cutaneous malignant melanoma are abnormally sensitive to the mutagenic effect of simulated sunlight and 4-nitroquinoline l-oxide. Proc Nat1 Acad Sci USA 1984;81:1179-83. 50. Sanford KK, Parshad R, Greene MH, et al. Hypersensitivity to G2 chromatid radiation damage in familial dysplastic nevus syndrome. Lancet 1987;2:1111-5. 51. Lynch HT, Fusaro RM, Sandberg AA, et al. Chromosome instability and the FAMMM syndrome. Submitted for publication. 52. Lynch HT, Fusaro RM, Lynch JF. The NIH consensus report on “Precursors to malignant melanoma.” Am J Dermatopath01 1984;6(suppl 1):177-9. 53. Greene MH, Clark WH, Tucker MA, et al. High risk of malignant melanoma in melanoma-prone families with dysplastic nevi. Ann Intern Med 1985;102:458-65.
38. Van Haeringen A, Bergman W, Nelen MR, et al. Exclusion of the dysplastic nevus syndrome (DNS) locus from the short arm of chromosome 1 by linkage studies in Dutch families. Genomics 1989;5:61-4.
54. Masri GD, Clark WH, Guerry DP IV, et al. Screening and surveillance of patients at high risk for malignant melanoma result in detection of earlier disease. J Am Acad Dermatol 1990;22:1042-8.
39. Risch N, Sherman S. Genetic analysis workshop 7: Summary of the melanoma workshop. Cytogenetics and Cell Genetics 5g, 1992 (No 2 + 3):148-158.
55. Elder DE, Goldman LI, Goldman SC. Dysplastic nevus syndrome, a phenotypic association of sporadic cutaneous melanoma. Cancer 1980;46:1787-94.
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56. Crijns MB, Vink J, Van Hees CLM, et al. The occurrence of dysplastic nevi in first and second degree relatives of patients with “sporadic” dysplastic nevus syndrome. Arch Dermatol 1991;127:1346-51. 57. Nordlund JJ, Kirkwood J, Forget BM, et al. Demographic study of clinically atypical (dysplastic) nevi in patients with subjects. Cancer Res and comparison melanoma 1985;45:1855-61. 58. Elder DE, Greene MH, Guerry D. The dysplastic nevus syndrome. Our definition. Am J Dermatopathol 1982;4:45560. 59. Kraemer KH, Greene MH, Tarone R, et al. Dysplastic naevi and cutaneous melanoma risk. Lancet 1983;2:10767. Letter to the Editor. 60. Kelly JW, Holly EA, Shpall SN, Ahn DK. The distribution of melanocytic naevi in melanoma patients and control subjects. Au&alas J Dermatol 1989;30:1-8. 61. Augustsson A, Stiemer U, Suurkiila M, Rosdahl I. Prevalence of common and dysplastic naevi in a Swedish population. Br J Dermatol 1991;124:152-6. 62. Holly EA, Kelly JW, Shpall SN. Number of melanocytic nevi as a major risk factor for malignant melanoma. J Am Acad Dermatol 1987;17:459-68. 63
Rigel DS, Rivers JK, Kopf AW, et al. Dysplastic nevi: Markers for increased risk for melanoma. Cancer 1989;63:386-9.
64. Tiersten AD, Grin CM, Kopf AW, et al. Prospective followup for malignant melanoma in patients with atypical-mole (dysplastic-nevus) syndrome. J Dermatol Surg Oncol 1991;17:44-8. 65. Hendrickson MR, Ross JC. Neoplasms arising in congenital giant nevi. Am J Surg Path01 1981;5:109-35. 66. Castilla EE, Da Graca Dutra M, Orioli-Parreiras IM. Epidemiology of congenital pigmented naevi. I. Incidence rates and relative frequencies. Br J Dermatol 1981;104:307-15. 67. Lorentzen M, Pers M, Bretteville-Jensen G. The incidence of malignant transformation in giant pigmented nevi. Stand J Plast Reconstr Surg 1977;11:163-7.
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68. Rhodes AR, Wood WC, Sober AJ. Non-epidermal origin of malignant melanoma associated with a giant congenital nevocellular nevus. Plast Reconstr Surg 1981;67:782. 69. Lanier VC, Pickrell KL, Georgiade NG. Congenital giant nevi: Clinical and pathological considerations. Plast Reconstr Surg 1976;58:48-52. 70. Arons MS, Hurwits S. Congenital nevocellular nevi: A review of the treatment controversy and a report of 46 cases. Plast Reconstr Surg 1983;72:355-62. 71. Keipert JA. Giant pigmented naevus: The frequency of malignant change and indications for treatment in prepubertal children. Au&alas J Dermatol 1985;26:81-5. 72. Johnson HA. Permanent removal of pigmentation from giant hairy nevi by dermabrasion in early life. Br J Plast Surg 1977;30:321-8. 73. Moss ALH. Congenital “giant” naevus: A preliminary report of a new surgical approach. Br J Plast Surg 1987;40:410-9. 74. Rhodes AR, Wood WC, Sober AJ, Mihm MC. Non-epiderma1 origin of malignant melanoma associated with a giant congenital nevus. Plast Reconstr Surg 1981;67:782-90. 75. Rhodes AR. The risk of malignant melanoma arising in congenital melanocytic nevi. An argument against the assignment of risk based on size alone. Am J Dermatopathol 1984;6:184-8. 76. Rhodes AR, Sober AJ, Day CL, et al. The malignant potential of small congenital nevocellular nevi. J Am Acad Dermatol 1982;6:230-41. 77. Rhodes AR, Melski JW. Small congenital nevocellular nevi and the risk of cutaneous melanoma. J Pediatr 1982;100:219-24. 78. Illig L, Werdner F, Hunderker M, et al. Congenital nevi I 10 cm as precursors to melanoma. Arch Dermatol 1985;121:1274-81. 79. Sweren RJ. Management of congenital nevocytic nevi: A survey of current practices. J Am Acad Dermatol 1984;11:629-33.
he field of precursor lesions to melanoma is subject to ongoing debate and evolving insights. Regarding congenital melanocytic nevi there is controversy about the management of these lesions. It has become apparent that patients with giant (“bathing trunk-type”) congenital nevi have an increased incidence of malignant melanoma developing in their lesions. Prophylactic excision is generally accepted treatment and these lesions should be removed in early childhood; however, the subject of debate has been enlarged to include all congenital nevi, including those of the “small” type. It is unclear to what extent melanoma develops in smaller congenital nevi and dermatologists disagree on the therapy of smaller lesions. The intensity of the controversy appears to be inversely proportional to the size of the nevus. Regarding dysplastic nevi there is controversy about diagnostic definitions both clinically and histologically. Some even deny the existence of dysplastic nevi! The Familial Atypical Multiple-Mole Melanoma (FAMMM) syndrome also has its contentions with regard to the genetic mechanism: Is a dominant gene localized on chromosome lp involved in all FAMMM families? Furthermore, the complete spectrum of the FAMMM syndrome including the occurrence of systemic cancer(s) and ocular melanoma is still debated. This review focuses on the aforementioned controversies in the field of precursor lesions to melanoma. Early detection of malignant melanoma reduces its morbidity and mortality. The most important method to achieve this is by professional and public education about the signs and symptoms of early melanoma and preven-
T
From the Department of Dermatology, University of Leiden, Leiden, The Netherlands, and the Department of Preventive Medicine and Public Health, Creighfon University School of Medicine, Omaha, Nebraska. Address correspondence to Wilma Bergman, Department of Dermatology, University Hospital, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
0 1992 by Elsevier Science Publishing Co., Inc.
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0738-081x/92/$5.00
tive health care in individuals with high-risk factors. This article deals with two of these benign high-risk melanocytic precursors: the dysplastic nevus (DN) and the congenital nevus (CN). A third precursor, lentigo maligna or Hutchinson’s melanotic freckle (Dubreuihl’s melanosis), which specifically gives rise to the relatively rare type of melanoma called lentigo maligna melanoma, is to be considered as a precancerous lesion and is not dealt with in this article. Although the familial occurrence of melanoma has been known for many decades,* the remarkable phenotype accompanying the hereditary variant of melanoma was only recognized in 1978 and was then named the B-K mole syndrome by Clark et al2 and the FAMMM syndrome by Lynch et a1.3 The phenotype of atypical pigmented lesions of the FAMMM syndrome is called “dysplastic” nevus (DN). The syndrome is also known as the “familial” type of the dysplastic nevus syndrome.’ In 1980, when dysplastic nevi were recognized to occur in the general population, individuals showing dysplastic nevi and lacking a family history of melanoma were diagnosed as having the “sporadic“ type of dysplastic nevus syndrome. The term dysplastic has been criticized because pathologists and clinicians have various concepts and definitions of the word. Furthermore, the specificity of the histologic criteria that have been recommended to identify DNs is being questioned by some authors and the clinicopathologic correlation is far from 100%.5-7 With regard to this ongoing debate it seems preferable to refer to these easily recognized unusual nevi as atypical nevi (ANs) or atypical moZes.8These terms are useful in epidemiologic studies as they do not suggest more than is known factually. For familial melanoma and ANs the term FAMMM syndrome satisfies the designation of the genetic context of the disorder. Congenital nevi (CNs) can be recognized clinically and histologically without much difficulty. There is not much
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Table 2. Clinical Characteristics Size Color
Shape Border Surface
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Nevi
Vary; larger-than-normal; often > 5 mm, some > 10 mm; melanoma usually > 10 mm Variegate; multiple shades of tan, brown, black, and pink; often red hue or red border; erythema; largely contrasting shades may indicate (early) melanoma Irregular; asymmetric; chaotic; notchy shape indicates superficial spreading melanoma Hazy; fades imperceptibly into surrounding skin; partially indistinct Usually macular or just palpable; little raised; sometimes centrally pebbly; “mammillated”; “cobblestoned”; asymmetric papule/nodule indicates melanoma
debate about definitions. Nevi that look like CNs and are said to have been absent at birth, but appeared a few months later are called congenifal nexus-like nevi (CNLNs) and are considered to have a melanoma risk indistinguishable from that of true CNS.~ With respect to CN management strategies, however, there is still ongoing debate concerning which congenital nevi should be removed prophylactically. Thus the field of congenital precursor lesions is subject to ongoing controversy.
Dysplastic Nevi Clinical Features Dysplastic nevi were first recognized in the setting of familial melanoma. The original description by Clark’s group is as follows: “A single prototypic B-K mole is about 10 mm in diameter, is irregular in outline, and is a haphazard mixture of tan, brown, black and pink. While seemingly flat on inspection, the B-K mole has a small palpable dermal component. There is striking variability from one mole to the next.” * The original description by Lynch’s group is as follows: “Multiple large moles of variable size and color (reddish-brown to bright red), irregular in shape with pigmentary leakage.” 3 A special article in the New England Journal of Medicine describes dysplastic nevi as having “irregular borders, a haphazard mixture of tan, brown, dark brown and pink colors and a margin that tends to be indistinct, fading into the adjacent normal skin; the topography may be quite complex and varied ranging from an almost completely macular surface through an irregular, ‘pebbly’ surface to a ‘fried egg’ appearance.” lo Table 1 summarizes all the clinical features of ANs ever mentioned. It should be noted that a single AN rarely ever shows all of these features, In considering the diagnosis of AN, a sum of the clinical features in several ANs is considered appropriate. Furthermore, none of these features is specific or diagnostic of an AN, and neither is one of these features obligatory. No consensus exists
about the exact number of features required for the clinical diagnosis of an AN. We have always used three or more criteria for the clinical diagnosis of an AN; however, in the setting of FAMMM families, ANs can sometimes be diagnosed histologically (at least according to our standards) by the presence of two clinical criteria.
Histopathology The histologic criteria of DNs originally described in 1978 concerned lesions that had been recognized as a phenotypic marker for familial melanoma. Clark’s group described these lesions as compound melanocytic nevi, in addition to the following distinctive features: atypical melanocytic hyperplasia, mesenchymal changes in the papillary dermis, and a lymphocytic infiltrate.* Atypical melanocytic hyperplasia is synonymous with melanocyfic dysplasia, that is, individual melanocytes or small clusters of melanocytes that have “some” of the structural features of malignant melanocytes. Furthermore, the situation is analogous to cervical dysplasia and senile (actinic) keratoses.* In their histologic evolution these criteria have been categorized in three major groups: (1) architectural atypia, (2) melanocytic/cytologic atypia, and (3) mesenchymal host response. Some authors, however, do not consider cytologic atypia as a mandatory criterion for diagnosis. 11-13Table 2 summarizes the histologic features that can be found in DNs, categorized as just described. Analogous to the clinical diagnosis of AN, the histologic diagnosis of DN requires several of the criteria listed in Table 2, preferably at least one feature from each category. It should be noted that none of the features from Table 2 is specific or diagnostic of DNs in itself.
Table 2. Histologic Features Diagnostic of Dwvlustic Nevi Features of architectural atypia Junctional activity Melanocytic preference for the tips of the rete ridges Irregular configuration of rete ridges Irregularity of junctional nests Bridging Impairment of maturation of dermal component Features of cellular atypia Large prominent melanocytes Nuclear pleomorphism Large nuclei Prominent nucleoli Dusty melanin pigment Prominent retraction artifact Stromal reactions Lymphocytic infiltrate Fibroplasia Angioneogenesis Melanophages
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No consensus exists about the exact number of features required for diagnosing DNs. Steijlen et al have studied the efficacy of these histopathologic criteria in a series of DNs from FAMMM family members and in a control series of nevi from autopsy cases.14 Individual diagnostic features had either a low sensitivity, a low specificity, or low predictive value. Discriminant analysis showed that (1) the presence of dustlike melanin in the cytoplasm of melanocytes, (2) irregular nevoid nests, (3) markedly increased junctional activity, and (4) melanocytic nuclei larger than or equal in size to adjacent keratinocytes were the most discriminating features.” Diagnostic criteria as published by Steijlen et al have been evaluated and substructured by immunohistochemical (expression of class I HLA antigens on melanocytes) and cytophotometric analysis (abnormalities in nuclear DNA content). Both markers were present in the large majority of those lesions categorized as markedly atypical DNs, in about half of the moderately atypical DNs, and in less than one third of mildly atypical DNs.15 Thus, these findings suggest reasonable arguments to be present for these diagnostic criteria and ranking of degree of atypia. Abandoning the criterion of cytologic atypia seems to increase the chance of histologically overdiagnosing DN. Nevoid lesions showing ascension of atypical melanocytes up to the granular layer of the epidermis should be diagnosed as melanoma in situ. Piepkorn and co-workers have suggested a scheme for rating melanocytic lesions that incorporates the histologic characteristics of DNs into the “normal biological development of melanocytic nevi.” W’ They regard histologic findings as seen in DNs as a normal proliferative phase of nevi; thus, in their opinion, “dysplastic nevi” correlate poorly with clinical phenotype. In their view, the overall clinical phenotype represents an individual’s melanoma risk just as it has been recognized originally by Clark et al2 and Lynch et a1.3 This theory suggests that patients with clinically atypical moles are at increased risk for melanoma, histologic appearance notwithstanding. The indication for excisional biopsy of ANs is primarily to rule out melanoma. Future studies are needed to develop uniform criteria for melanocytic dysplasia that correlate with clinical phenotype and biologic behavior, that is, melanoma risk.
Familial Atypical Multiple Mole Melanoma Syndrome The FAMMM syndrome is characterized by the familial occurrence of malignant melanoma of the skin in combination with multiple atypical precursor nevi, or dysplastic nevi. The FAMMM trait appears to be transmitted as a dominant gene in families, with variable expressivity, of the cutaneous phenoincluding nonpenetrance,
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typePzl and marked heterogeneity. The latter is important in understanding the expression of all cutaneous and systemic phenotypes. A recent monograph on hereditary melanoma reviews the subject.22 It has been estimated that about 6 to 10% of all cutaneous melanomas occur in persons with a positive family history of melanoma.23,24 The incidence of multiple primary melanomas is much higher in the hereditary form (12%) than in sporadic melanoma (3%). In our Dutch families we observed 10 multiple melanoma patients out of 38 patients (26%); 8 patients had two melanomas and 2 patients had three melanomas.25 It seems probable that genetically predisposed persons in younger generations, whose melanomas are being recognized while thin and prognostically favorable, survive and thus have time to develop a second or even third primary melanoma. Although the typical sporadic melanoma is a neoplasm of the fifth and sixth decades, familial melanoma usually occurs in much younger patients, in about the third decade; however, familial melanomas can occur at even younger ages. In our families prepubertal melanoma developed in one 9year-old and two 12-year-olds. All three cases developed melanoma from a dysplastic nevus, not from a congenital nevus. Atypical nevi may be recognized in children, but they increase in size and number considerably during puberty, with new lesions continuing to develop throughout adult life. It is remarkable that ANs in children can be recognized first on the scalp, in the skin area above and behind the ears. On the trunk, nevi in children of FAMMM families are at first very prominent, being larger and more numerous than nevi in other children from the same age group; it is only after puberty that the dysplastic features become recognizable. Also, nevi on the feet can be present in childhood. The FAMMM syndrome is classically characterized by many large atypical nevi, with the phenotype being described as “funny“; however, there is a marked variability in the phenotypic expression within and between families. For example, some members of a FAMMM kindred may have total mole counts into the hundreds, whereas others may show very few nevi or even no nevi at a11.26-2sAlmost all FAMMM gene carriers showing few or many ANs also show “normal” nevi; only a (variable) proportion of the total number of nevi can be recognized as being dysplastic. Atypical nevi may be found in normal individuals. Thus the presence of a few ANs is not an absolute criterion for establishing the diagnosis in a member of a FAMMM family. It is not known how many ANs are required for diagnosing a gene carrier, but because of the very variable phenotype it might be as few as one or two. It is also important to recognize that the absence of clinically atypical nevi does not rule out the presence of a FAMMM gene carrier. This
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problem clearly indicates the need for a biomarker; however, to date no such biomarker has been identified. There have been several investigative reports concerning the occurrence of systemic cancer in patients and their relatives with the FAMMM syndrome. The first of these was a study by Lynch et al of four FAMMM families that showed a significant fivefold increase in systemic cancers of variable anatomic sites such as the breast, respiratory tract, gastrointestinal tract, and lymphatic system.29 The Leiden group investigated cancer of all anatomic sites in nine FAMMM families which were ascertained in a clinic for pigmented lesions. 3o A significant excess of systemic cancer was observed in three of these nine families. The remaining families showed the normally expected rates of cancer. Interestingly, in these families there was an excessive number of cancers of the gastrointestinal tract. Nine of eighteen cancers involved the pancreas, whereas none had the common colorectal cancer. In The Netherlands, colorectal cancer is five times as frequent as pancreatic cancer. That three of these nine families showed a marked excess of systemic cancer, while the remaining families showed normal rates of cancer, indicates heterogeneity among these families. Greene et al performed a prospective study of 14 kindreds at the National Institutes of Health with hereditary cutaneous melanoma and the dysplastic nevus syndrome.31 They concluded that “no significant excess of non-melanoma cancers was documented.” Nonetheless, if the expression of systemic cancer is calculated with the use of only defined gene carriers (those with dysplastic nevi and/or malignant melanoma), their data show a significant increase in the occurrence of gastrointestinal cancer (P < .05). It would be important to determine whether these cancers were limited to only a few kindreds or all 14 kindreds, thereby verifying the concept of heterogeneity. Intraocular melanoma was first described in a FAMMM pedigree from Leiden, The Netherlands, in which one of the members not only had bilateral primary intraocular melanomas, one year apart, but multiple ANs and several cutaneous melanomas.29,32 Recently, five small families have been reported with the FAMMM syndrome, with one member of each family having ocular melanoma.33 Two cases were remarkably young: a 16year-old girl with a conjunctival melanoma and a 28year-old man with a choroidal melanoma. In addition four other families have been reported in the literature.34,35 These observations indicate that a small percentage of uveal and conjunctival melanomas may be explained by the presence of the FAMMM syndrome in the family. Furthermore, they emphasize the heterogeneity of the FAMMM syndrome and suggest that FAMMM
Clinics in Dermatology 1992;10:21-29 gene carriers are at risk not only for cutaneous melanoma, but also occasionally for ocular melanoma.
Genetics of fhe FAMMM Syndrome The precise genetic mechanism of the FAMMM syndrome remains unknown. The gene is claimed to be located on chromosome lp by one group36 and to be excluded from chromosome lp by two other group~.~~,~* In a recent genetic analysis workshop (GAW-7) of the American Society of Human Genetics, the FAMMM syndrome was discussed by expert biostatisticians, molecular biologists, and clinical geneticists. It is notable that the one finding consistent across all analyses was that dominant inheritance was strongly rejected.39 This conclusion was of particular interest because dominant inheritance is precisely the model postulated from clinical-genetic studies of FAMMM pedigrees and is the generally accepted mode of inheritance. It should be noted that from the beginning Happle et al in Germany warned against easy acceptance of a monogenic inheritance, that is, one dominant gene causing the FAMMM syndrome; in their view the FAMMM syndrome is due to polygenic inheritance.40-42 Cytogenetic studies of hereditary malignant melanoma have been sparse. 43-46 Past cellular studies of the FAMMM syndrome indicated a slightly increased sensitivity to ultraviolet (UV) light in lymphoblasts47 and fibroblasts*s from melanoma patients belonging to high-risk families, though this has not been found to be a general characteristic of the syndrome45,49; however, evidence has been presented for an increased mutability of cells from FAMMM patients after exposure to a UV-mimetic chemical substance.49 Increased sensitivity to x-rays of fibroblasts from FAMMM subjects has been reported.50 Cytogenetic studies by Lynch et al showed increased frequencies of cells with random chromosomal rearrangements, observed in cell cultures from dysplastic nevi (melanocytes) and normal skin (fibroblasts).51 In the fibroblast cultures, considerable clonal selection of cytogenetically abnormal cells occurred. A positive cytogenetic status was awarded to individuals whose changes were clonal in nature. Fifteen histologically verified DNs were studied from 12 individuals and all had cells with chromosomal abnormalities. The possibility that this finding was a cultural artifact was essentially eliminated by the numbers of such observations and by the finding of clonal evolution. Ten biopsies of clinically normal skin from FAMMM patients were studied. Seven contained fibroblasts with chromosome rearrangements. The phytohemagglutininstimulated lymphocytes were generally normal with respect to chromosomes.
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These cytogenetic findings seem to place the FAMMM syndrome among the chromosome instability syndromes and it seems to be the first one that is inherited as autosoma1 dominant. Other cancer-associated chromosome instability syndromes such as ataxia telangiectasia, Bloom’s syndrome, and Fanconi’s anemia are recessively inherited. The mechanism of the chromosome instability in FAMMM syndrome may be unique. One possible mechanism is that the FAMMM gene may be impairing chromosome stability which is followed by chromosomal rearrangements. Some of the rearrangements may involve genes that confer a proliferative advantage, especially to melanocytes. With further chromosome instability, the nevi make the transition to neoplasia and transform into malignant melanoma. This same instability may lead to cancer in other organ systems.
Management of FAMMM Families The Dutch Melanoma Consensus Meeting stated that “Persons with the familial dysplastic nevus syndrome have a greatly increased risk of melanoma. Checkups once to twice a year are required for a long period of time.” As the consensus text is being distributed widely, it is hoped that this statement will lead to earlier diagnosis of melanoma in FAMMM gene carriers throughout the country. Essential to the success of this program is the taking of a family history with regard to melanoma from all patients presenting with melanoma. Furthermore, all melanoma patients should be screened for the presence of ANs. The American Consensus Conference on Precursors to Malignant Melanoma in 1984 discussed the management of FAMMM families: Patients with AN and a family history of melanoma should be followed up frequently, with documentation of lesions and excision of changing nevi. The first degree relatives of patients with melanoma should be examined for AN and melanoma in view of the familial aggregation of both lesions. In patients with AN and any family history of melanoma, the indication for excising AN is the suspicion of early melanoma. Follow-up should be conducted every three to six months. Photography may be helpful to document the appearance of lesions. Furthermore patients with AN should be taught self-examination to detect changes in existing nevi and the emergence of new nevi. Finally, they would be prudent to avoid excessive sun exposure and use sunscreens.*2 The U.S. Consensus Conference on Melanoma, which was convened in the beginning of 1992, considered the aspects of systemic cancers occurring in conjunction with the FAMMM syndrome and also the risk of ocular mela-
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noma. Furthermore, there is a need to define “familial melanoma” more strictly, and consequently define exactly, which family members should be examined. Examination of first-degree relatives is insufficient to identify the complete spectrum of the FAMMM syndrome within a kindred.52 In the meantime several papers have reported results of screening of FAMMM family members. Greene et al evaluated the risk of melanoma in 401 members of 14 families.53 They found 39 new melanomas in 22 study participants over a period of 8 years. The probability of melanoma developing in family members with DNs was 56% from ages 20 to 59. Extrapolated to the age of 76, the curve reached 100%. To assess the effect of screening on the prognosis of melanoma patients in FAMMM families, we have studied three different categories of melanomas.25 The fist category comprised all melanomas diagnosed in nine Dutch families before the start of the screening procedures (in 1982); the second category comprised those melanomas detected at initial examination of the families, and the third category included all melanomas found during the course of follow-up. Screening was found to lead to detection of more melanomas in situ and less invasive melanomas with significantly thinner Breslow thicknesses. Furthermore, these thin melanomas were detected at an earlier age. These data were confirmed by others. We consider these results to be an indication of the effectiveness of our screening program.
Sporadic Dysplastic Nevus Syndrome In 1980, Elder et al recognized the prevalence of ANs in nonfamilial melanoma patients. These ANs were indistinguishable from those seen in FAMMM syndrome/B-K mole syndrome. 55 At that time the term dysplastic news syndrome was proposed to describe both the familial and nonfamilial (sporadic) variants of these melanoma-associated ANs. Recently our group published the results of a family study of 31 probands diagnosed as having the “sporadic” variant of dysplastic nevus syndrome; that is, they lacked a family history of melanoma.56 Thirty-one complete families (125 family members) were investigated. We found no cases of melanoma in these families. In 21 families, however, several family members showed clinically ANs, and in 10 families, the proband was the only person showing ANs. It is unclear how these “dysplastic nevus families without melanoma” should be regarded or how their melanoma risk should be ranked. Nordlund et al examined nearly 300 melanoma patients and 145 controls for the presence of ANs.~’ They found one or more ANs in 34% of the patients with melanoma and in 7% of the controls. Another survey found
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clinical or histologic evidence of DN in 57% of nonfamilial melanoma patients. 58With these data a crude approximation of melanoma risk in individuals with sporadic dysplastic nevus syndrome yielded a lifetime risk of 18%, 26 times the risk of the general population.59 An Australian study of ANs in patients with nonfamilial melanoma yielded a prevalence of 55%; 26% had at least five ANs.~O In the same study 17% of controls had at least one clinically determined AN, and 6% had at least five ANs. A Swedish study diagnosed ANs clinically in 18% of the general population. 61 In this study, subjects with ANs had a significantly larger number of common nevi and a more sun-sensitive skin type than subjects without ANs. This increased number of nevi is also associated with melanoma risk. The authors conclude: “As more than half of the Swedish population has over 50 nevi and close to one out of five has clinical DN, it is obvious that largescale screening programs will be too time consuming and expensive. It is therefore necessary to define more detailed subgroups, likely to develop melanoma”. Holly et al demonstrated an increased risk for development of malignant melanoma in patients with ANs compared with controls, They established that individuals with one to five ANs have a relative risk of 3.8 of developing melanoma and that individuals with over five ANs have a relative risk of 6.3 during an average of 27 months of follow-up.62 In the meantime two prospective follow-up studies for malignant melanoma in large groups of patients with DNs have been reported by the same gro~p.~~*~~In the first study combined data from familial and nonfamilial cases were reported, but in the second study a nonfamilial group could be discriminated from familial groups; however, the latter investigation included only cases with the so-called “classic” dysplastic nevus syndrome with over 100 nevi. Both studies indicated a clearly increased risk of developing melanoma when compared with general population data. Furthermore, the presence of a DN in a patient with a personal history of melanoma (no family history of melanoma) indicated an increased risk of a second primary melanoma. From the preceding it is concluded that the prevalence of ANs in the general population in countries with a high incidence of melanoma seems to be between 7 and 18%. Furthermore, there seems to be an increased risk of develand multiple primary melanomas oping melanoma among individuals showing DNs. It is not clear exactly how high this risk is and which other determinants (number of nevi, number of dysplastic nevi, skin phototype) play a role in creating this risk. Until new data are available it seems justified to evaluate persons with sporadic DNs once a year; however, most DNs probably remain stable over time.
Congenital Nevi Giant Congenital Nevi Giant CNs are large, pigmented, often verrucose, and characteristically hairy cutaneous maldevelopmental lesions of the neural crest. These nevi may occur alone or rarely may be associated with leptomeningeal melanocytosis. They usually cover a substantial part of the body, most classically the “bathing trunk” area. The literature before 1980 has been reviewed by Hendrickson and Ross.~~ The prevalence of giant CNs is not extensively documented; from a large South American study it appears to be about 1 per 20,000.66 The incidence of malignant transformation in giant CNs is unknown, although it is indisputable that giant CNs can provide the setting for development of melanoma as evidenced by avid case reporting. Most convincing is the reported 4.6% incidence of cancer in the Danish series that Lorentzen et al derived from follow-up studies of 151 patients with giant CNs registered in the Danish Health System from 1915 to 1975.67 Rhodes et al discussed this study and stressed several factors that may have resulted in underestimation of the risk of malignancy. 6* Lanier et al found a comparable incidence of 6.9%.69 The higher rates that have been frequently quoted in the literature may be distorted by patient selection, particularly those in pathology reviews. Uncertainty also exists as to whether malignant change in a giant CN is more common in children or adults. Several papers suggest it is more common in children.70 In some papers 60% of patients were less than 10 years of age. Cancer registries of deaths from melanoma in prepubertal children show that melanoma in childhood is very rare. In an Australian survey, 3 of 20 children’s melanomas had arisen in a giant CN.7* Furthermore, in the major children’s hospital in the state of Victoria, four children with melanoma were recorded in 56 years, with one of these arising in a giant CN. If the incidence of giant CNs is considered to be 1 per 20,000 births, then 160 children must have been born with a giant CN in the state of Victoria in that period. Many authors have regarded giant CNs as a significantly premalignant lesion in infants and children and have advocated removal as soon as possible.70 Removal for cosmetic reasons is another matter and depends largely on both the parents’ feelings about the appearance of the nevus and the emotional effect it has on the child. Several plastic surgeons have reported good cosmetic results from deep dermabrasion72 or curettage7j in the first few weeks of life. With these procedures most of the nevus cells are removed, thus theoretically reducing the chance of malignant transformation; however, some advise total excision because of subepidermal development of melanoma in a substantial percentage of transformed CNS.~~ In conclusion, on the basis of suffi-
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ciently established melanoma risk in childhood and on the basis of cosmetic considerations, removal of giant CNs as soon as possible is generally advocated.
7. Cassileth BR, Clark WH, Lusk EJ, et al. How well do physicians recognize melanoma and other problem lesions? J Am Acad Dermatol 1986;14:555-60.
Small and Medium-Size Congenital Nevi
8. Kopf AW, Friedman RJ, Rigel DS. Atypical mole syndrome. J Am Acad Dermatol 1990;16:117-8.
For purposes of discussion, congenital nevi have arbitrarily been divided according to size into small, less than 1.5 cm; medium, 1.5 up to 20 cm; and large, 20 cm or greater. l2 This categorization of CNs on size alone has been criticized.75 The relationship between small and medium-size CNs and malignant melanoma is a controversial subject and information is scanty. It is unclear to what extent melanoma develops in smaller CNs; the incidence has been reported to be increased, but the magnitude of that increase is not well established.‘* Rhodes et al investigated the relationship between small CNs and melanoma by seeking remnants of CNs in the pathology slides of 234 melanoma specimens.76 They found histologic features of CN in 8.1% of melanoma specimens. Furthermore, the presence of a CN could be ascertained by history in 15% of 134 melanoma patients,” and it became clear that malignant transformation usually occurs after puberty.78 As can be imagined from the controversy on melanoma risk from smaller CNs, there is also disagreement on their management. In a survey in the United States, the ratio of dermatologists observing small CNs to those removing these lesions was 4: 6.79 With respect to the management of smaller CN, the American Consensus Panel stated that “there are insufficient data at present to recommend prophylactic excision. A conservative management is recommended. Patients with CN should be examined periodically. If an alteration in the nevus is detected, a biopsy should be done.” I2
References 1. Cawley EP. Genetic aspects of malignant melanoma. Arch
Dermatol Syphil 1952;65:440-50. 2. Clark WH, Reimer RR, Greene MH, et al. Origin of familial malignant melanomas from heritable melanocytic lesions. Arch Dermatol 1978;114:732-8. 3. Lynch HT, Frichot BC III, Lynch JF. Familial atypical multiple mole-melanoma syndrome. J Med Genet 1978;15: 352-6. 4. Kraemer K. Dysplastic nevi as precursors to hereditary melanoma. J Dermatol Surg Oncol 1983;9:619-22. 5. Roush GC, Barnhill RL, Duray PH, et al. Diagnosis of the dysplastic nevus in different populations. J Am Acad Dermatol 1986;14:419-25. 6. Kelly JW, Crutcher WA, Sagebiel RW. Clinical diagnosis of dysplastic melanocytic nevi. J Am Acad Dermatol 1986;14:1044-51.
9. Kopf AW, Levine LJ, Rigel DS, et al. Prevalence of congenital nevus-like nevi, nevi spili, and cafe au lait spots. Arch Dermatol 1985;121:766-9. 10. Greene MH, Clark WH, Tucker MA, et al. Acquired precursors of cutaneous malignant melanoma. The familial dysplastic nevus syndrome. N Engl J Med 1985;312:91-7. 11. Ackerman AB, Mihara J. Dysplasia, dysplastic melanocytes, dysplastic nevi, the dysplastic nevus syndrome and the relation between dysplastic nevi and malignant melanoma. Hum Path01 1985;16:87-91. 12. Consensus development conference, October 24- 26,1983, National Institutes of Health, Bethesda MD: Precursors to malignant melanoma. JAMA 1984;251:1864-6. 13. Sagebiel RW. Diagnosis and management of premalignant melanocytic proliferations. Pathology 1985;17:285-90. 14. Steijlen PM, Bergman W, Hermans J, et al. The efficacy of histopathological criteria required for diagnosing dysplastic nevi. Histopathology 1988;12:289-300. 15. Bergman W, Ruiter DJ, Scheffer E, Van Vloten WA. Melanocytic atypia in dysplastic nevi. Immunochemical and cytophotometrical analysis. Cancer 1988;61:1660-6. 16. Piepkorn M. A hypothesis incorporating the histologic characteristics of dysplastic nevi into the normal biological development of melanocytic nevi. Arch Dermatol 1990;126:514-8. 17. Piepkorn M, Meyer LJ, Goldgar D, et al. The dysplastic melanocytic nevus: A prevalent lesion that correlates poorly with clinical phenotype. J Am Acad Dermatol 1989;20:407-15. 18. Reimer RR, Clark WH, Greene MH, et al. Precursor lesions in familial melanoma. A new genetic preneoplastic syndrome. JAMA 1978;239:744 - 6. 19. Greene MH, Goldin LR, Clark WH, et al. Familial cutaneous malignant melanoma: Autosomal dominant trait possibly linked to the Rh locus. Proc Nat1 Acad Sci USA 1983;80:6071-5. 20. Bale SJ, Chakravarti A, Greene MH. Cutaneous malignant melanoma and familial dysplastic nevi: Evidence for autosomal dominance and pleiotropy. Am J Hum Genet 1986;38:188-96. 21. Bergman W, Palan A, Went LN. Clinical and genetic studies in six Dutch kindreds with the dysplastic nevus syndrome. Ann Hum Genet 1986;50:249-58. 22. Lynch HT, Fusaro RM, editors. Hereditary malignant melanoma. Boca Raton (FL): CRC Press, 1991. 23. Greene MH, Fraumeni JF. The hereditary variant of malignant melanoma. In: Clark WH, Goldman L, Mastrangelo MJ, editors. Human malignant melanoma. New York: Grune & Stratton, 1979:139-66.
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68. Rhodes AR, Wood WC, Sober AJ. Non-epidermal origin of malignant melanoma associated with a giant congenital nevocellular nevus. Plast Reconstr Surg 1981;67:782. 69. Lanier VC, Pickrell KL, Georgiade NG. Congenital giant nevi: Clinical and pathological considerations. Plast Reconstr Surg 1976;58:48-52. 70. Arons MS, Hurwits S. Congenital nevocellular nevi: A review of the treatment controversy and a report of 46 cases. Plast Reconstr Surg 1983;72:355-62. 71. Keipert JA. Giant pigmented naevus: The frequency of malignant change and indications for treatment in prepubertal children. Au&alas J Dermatol 1985;26:81-5. 72. Johnson HA. Permanent removal of pigmentation from giant hairy nevi by dermabrasion in early life. Br J Plast Surg 1977;30:321-8. 73. Moss ALH. Congenital “giant” naevus: A preliminary report of a new surgical approach. Br J Plast Surg 1987;40:410-9. 74. Rhodes AR, Wood WC, Sober AJ, Mihm MC. Non-epiderma1 origin of malignant melanoma associated with a giant congenital nevus. Plast Reconstr Surg 1981;67:782-90. 75. Rhodes AR. The risk of malignant melanoma arising in congenital melanocytic nevi. An argument against the assignment of risk based on size alone. Am J Dermatopathol 1984;6:184-8. 76. Rhodes AR, Sober AJ, Day CL, et al. The malignant potential of small congenital nevocellular nevi. J Am Acad Dermatol 1982;6:230-41. 77. Rhodes AR, Melski JW. Small congenital nevocellular nevi and the risk of cutaneous melanoma. J Pediatr 1982;100:219-24. 78. Illig L, Werdner F, Hunderker M, et al. Congenital nevi I 10 cm as precursors to melanoma. Arch Dermatol 1985;121:1274-81. 79. Sweren RJ. Management of congenital nevocytic nevi: A survey of current practices. J Am Acad Dermatol 1984;11:629-33.
