Naevocytic naevi as an atavism; Their relationship to melanoma risk

Medical Hyporhese? (IYXXI 27. 71-75 Q Longman Group UK Lfd 198X

Naevocytic Naevi as an Atavism; To Melanoma Risk

Their Relationship

FRANS H. J. RAMPEN Department Netherlands

of Dermatology,

University

of Nijmegen,

Javasfraat

104,6524

MJ Nijmegen,

The

Abstract - Common “acquired” naevocytic naevi (moles) are often regarded as caused by ultraviolet radiation although no proof of this assumption exists. An alternative view is presented herein, describing moles as atavistic relics. When the remote ancestors of Homo sapiens lost their fur, coat colour patterns also disappeared, leaving behind small rudimentary defects of the pigmentary system. These remnants are known to us as naevocytic naevi.

Introduction Recently the number and distribution of naevocytic naevi in healthy Caucasians have attracted renewed interest amongst clinicians (l-4). This revival is mainly due to the fact that mole counts have been related to melanoma risk. The relative and independent contribution of benign naevi to the occurrence of cutaneous melanoma has been clearly identified (5-7). Mole proneness appears to be a much greater risk factor than sun behaviour characteristics. Whether cutaneous melanoma is induced by solar radiation remains a debatable issue (8). There are marked differences in site and age distribution, occupational characteristics and secular trends. between basal and squamous cell carcinomas of the skin and malignant melanoma. These differences seem incompatible with the sun exposure aetiology of melanoma. The lack of solar elastosis at the site of a melanoma supports the idea that chronic 71

insolation is not the cause of this tumour (9). There are now cogent arguments against cumulative ultraviolet exposure as the main cause of melanoma; indeed it may even be protective (10). Also, the current concept of intense intermittent (notably recreational) ultraviolet exposure, however attractive, merits critical appraisal (I 1, 12). We have suggested that melanoma risk according to body region is proportional to the number of moles in that region (3). Females have a preponderance of melanomas on the legs, whereas in males the preferred site is the back. Mole counts on the legs are higher in females than in males; on the trunk counts are higher in males than in females (1, 3, 13). In this respect it is also pertinent to note that many melanoma patients state that their tumour arose from a preexisting mole, and that pre-existing moles are often found in histologic association with melanoma.

72 Moles and complexion

There exists a large body of evidence that the occurrence of naevi is closely related to the subject’s skin complexion. Complexion trait is characterized by the genetically determined natural (constitutive) skin colour and the reaction pattern to ultraviolet exposure (ability to tan and propensity to burn). Further biologic features of skin complexion are hair and eye colour and freckling tendency. Melanoma is especially common in fair-skinned persons who burn easily rather than tan (5, 14). Like melanomas, also moles are more frequent in subjects with a light skin complexion (3, 15). The theory that skin phenotype is genetically determined and that this very phenotype is related to mole proneness is crucial in our understanding of melanoma aetiology. Melanoma of the skin is very rare in negroids, apart from acral lentiginous melanoma (16). In blacks naevocytic naevi are also uncommon. Pack and coworkers found that the average number of naevi in blacks was 2.3 against an average of 14.6 in white subjects (17, 18). It has been reported that within a black population subjects with a relatively light complexion have greater total counts than those with a very dark brown skin (19, 20). Caucasians with light complexion constituents have higher average mole counts that those with a dark complexion, irrespective of site, sex and age (3, 15). However, English et al. have shown diametrically opposed results (4). This greater risk of naevi in the dark complexion categories may be due to the fact that only pigmented lesions were considered; subjects with a light complexion often show numerous naevi that are not pigmented et all. The latter data are quite unexpected in the light of the already mentioned unanimous evidence that melanoma risk is increased in light-skinned individuals (5, 14) and that melanoma is strongly associated with the presence of naevocytic naevi (5, 7). Moles and sunlight

There is little or no consistent evidence as to how naevocytic naevi develop. It may be hypothesized that somatic mutant changes in melanocytes are induced postnatally by exposure to ultraviolet light, leading to the appearance of moles (21). Moles then comprise clones derived from mutant melanocytes and may be regarded as truly “acquired”. This postulation, however, seems to be more appropriate for freckles than

MEDICAL HYPOTHESES

for naevi. Freckles can be experimentally induced by intense, “sunburn” exposure to ultraviolet-B (22). Freckles are not present in early infancy, they characteristically appear in childhood and then continue to develop during puberty, adolescence and adult life. They are confined to sun-exposed areas and are most numerous and prominent where exposure to the sun has been greatest. Naevocytic naevi on the other hand have never been unequivocally shown to appear as a result of ultraviolet exposure. They can be found on all parts of the body, including areas that are relatively protected like the hairy scalp, buttocks and anogenital region. Moreover, they seem to be most numerous on the trunk, especially the back. with a rather equal distribution. They show no clear preference for the shoulders and scapular regions. They are not especially conspicuous in the face or on the forearms and dorsa of the hands where sun exposure is greatest. Unlike freckles, naevocytic naevi do not exhibit seasonality. They persist for decades showing a gradual evolution from macular (junctional) naevi to elevated (compound) naevi. With advancing age dissolution occurs (23). Peak numbers of moles are observed at age 15-30; they are uncommon in aging subjects (2, 13). The natural history of moles with their gradual disappearance as time goes on and the nonappearance of potential new ones during adult life is difficult to understand from the ultraviolet exposure theory. Sunworship is not exclusively a phenomenon of the teenage period but it is also a favorite leisure habit of many adults. Exposure to ultraviolet radiation showed an inverse correlation with naevus counts in a study by Kopf et al. (24). These authors demonstrated a relative paucity of naevi in subjects with the greatest sun exposure. Dark-skinned people show a better tolerance to the sun than fairer people. Thus, they expose themselves to the sun more frequently and more intensively than their light-skinned counterparts. People with a dark complexion have also lower mole counts (3). The association between low mole counts and intensive sun exposure is thus not so unexpected as the adherents to the solar aetiology of naevi would believe. Recent findings by our group are in accordance with those of Kopf et al. (unpublished). The time usually spent in the sun, the number of holidays in sunny climates and the use of artificial ultraviolet devices showed no correlation with mole counts, irrespective of skin

NAEVOCYTIC NAEVI AS AN ATAVISM

type. Dysplastic naevi were even more numerous in people with relatively limited sun exposure. The fact that the occurrence of naevi, especially dysplastic naevi, is not directly related to sun exposure contrasts with two recent publications, indicating that the prevalence of naevi in patients with the dysplastic naevus syndrome is higher on relatively sun-exposed surfaces than on more sun-protected areas (25, 26). These studies suggest the possibility that sunlight plays an important role in the induction of naevi. Here, we would like to advance an alternative theory regarding the aetiology of common naevi. This theory may explain the various inconsistencies in epidemiologic trends regarding the prevalence of naevi in relation to body site and the alleged influence of ultraviolet radiation. Moles as an atavism It is generally acknowledged that Homo- sapiens exhibits racial differences in constitutive skin colour, which character is inherited as a polygenie trait (27). Based on these differences a skin typing system has been proposed according to burning and tanning histories (28). Other evolutionary or genetically determined complexion variables have grossly escaped the attention of researchers in the. field of dermatology so far. For instance, moles are regarded by many as acquired, sunlight-induced hyperplasias of melanocytes (24, 29). Others believe they are somatic mutations of melanocytes postnatally (21). However, moles may well be atavistic remnants of colour patterns once prevalent in our remote ancestors. Most animal species have a characteristic coloration pattern, generally regarded as a protective device which renders them camouflaged in their natural habitat. At the dawn of man colour adaptation gradually lost its function. What is left behind are tiny pigmentary spots, called moles, which are more and more becoming a nuisance to mankind because of their renowned malignant potential. Some aspects of mole patterns in humans need be explained. Moles are more predominant on the back as compared to the chest and abdomen (3, 13). This is in agreement with animal colour patterns. The ladybird, the lizard and the lion all have their dots and stripes predominantly on the back. Even the sloth, hanging all day with his stomach towards the universe, exhibits most of his pigmentary pattern on the back. The observation by Kopf et al. of fewer naevocytic naevi

73 on the lateral thoracic wall in dysplastic naevus syndrome patients fits well in this evolutionary model (25). Special creation of pigmentary spots as an adaptation mechanism in the armpit seems rather dysfunctional and nature has thus not made provision for them. What about the paucity of naevi on the buttocks (26)? Without drawing too close a parallel, it is obvious that in some animal species the hindquarters have distinctive fur colour schemes, for example the bright colours of the baboon’s perianal region. A second explanation for the relative lack of naevi on the buttocks in mankind would be the disproportional development of the pelvic girdle during late embryonic life (Figure). Melanoblasts migrate from the neural crest to the skin early during embryogenesis. Melanocyte precursors can be identified in human skin during the eighth week of gestation. At that time the skeleton and muscles of the pelvic girdle are still in an early stage of development. This is consistent with the fact that the embryo differentiates in a cephalo-caudal direction. Moreover, the limb buds have been shown to develop most actively at their distal (apical) ends (30). Hence, the proximal part of the lower limb segment and the pelvic girdle are about the last mesenchymal structures to reach full phenotypic expression. This is probably related to the erect gait of human beings, a characteristic adopted relatively late during evolutionary development. It may be objected that the density of melanocytes on the buttocks is not appreciably different from that on other body sites (31, 32). However, melanocytes are dendritic and potentially mobile cells forming specific units with their surrounding keratinocytes, the epidermal melanin unit (33). Contact inhibiton precludes rapprochement between neighbouring melanocytes resulting in a more or less even distribution over the entire integument. Naevocytes on the other hand do not show contact inhibition. They are grouped together and their location in the skin is probably fixed after lodging there in early embryonic life. Thus, melanocytes and naevocytes are phylogenetically different cell systems. Melanocytes represent the melanin forming components of the epidermal melanin units (33). Physiologically, they constitute an adaptation mechanism of the skin to ultraviolet challenges. Naevocytes, on the other hand, may represent a non-physiological heirloom from the fur colouring of our

74

MEDICAL HYPOTHESES

displays only few melanocytes, whilst many are present in hair bulbs (36). A further implication of this dualistic model is the classification of cutaneous melanoma into two different histogenie types according to their supposed cell of origin (melanocytic vs. naevocytic melanoma) (37, 38). It is suggested that common naevi are remains of fur colour patterns of our primeval ancestors. Man has become prone to naevi by the factors both of domestication and phylogenesis (34). Pigment cells present in animal hairs have changed in man into naevocytic naevi when our predecessors lost their fur. The study of fur colour schemes in animal species may provide important clues for better understanding of their possible atavistic relics in humans. Figure At the time melanoblasts finish their migration from the neural crest to the skin the pelvic girdle is still in an early phase of development (left). The relative paucity of naevi on the buttocks may be explained by the disproportional proliferation of the pelvic girdle during late embryonic and postnatal life as illustrated by the prehistoric Venus of Lespugne. France, connected with fertility magic (right).

animal predecessors. Coat colour patterns once present in. our ancestors have gradually disappeared, leaving behind small rudimentary markings. The pattern of naevi in man exhibits a striking concordance with the location of different kinds of piebald patterns in mammals (34). Pigment spots identical to the naevocytic naevi in humans have been described in the skin of dogs, horses, and especially in the skin of hairless animals. Furthermore, facial naevi in man have been considered as remnants of tactile hairs in animals (34). Laidlaw and Murray regarded pigmented moles as caricatures of the meissnerian tactile corpuscles of reptiles and amphibia by virtue of their similar innervation (35). Conclusion The precise nature of naevocytes is a matter of speculation. It is hypothesized that melanocytes and naevocytes form different pigment cell systems in vertebrate skin. Human constitutive skin pigmentation is determined by melanocytes whereas common moles are comprised of naevocytes. Both cell systems have a different ontogeny *and exhibit a different biological behaviour. Constitutive skin colour is not necessarily genetically controlled in a fashion similar to naevi. For instance, in mice furbearing skin

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