A Theory of Site Distribution of Melanomas: Queensland, Australia

A Theory of Site Distribution of Melanomas: Queensland, AustraliaAuthor(s): Adèle GreenSource: Cancer Causes & Control, Vol. 3, No. 6 (Nov., 1992), pp. 513-516Published by: SpringerStable URL: http://www.jstor.org/stable/3552859 .

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Cancer Causes and Control, 3, 513 - 516

A theory of site distribution of

melanomas: Queensland, Australia

Addle Green

(Received 2 June 1992; accepted in revised form 24 July 1992)

Although sun exposure is believed to be associated causally with cutaneous melanoma, the high incidence on less sun-exposed areas such as the back, as well as on chronically exposed sites such as the face, suggests that the association with sunlight is less straightforward than for other skin cancers. To explain this enigmatic site distribution, a theory of site-dependent susceptibility of melanocytes to malignant transformation is pro- posed. As possible evidence, all melanomas diagnosed in the state of Queensland, Australia, over a one-year period were surveyed for histologic evidence of benign melanocytic nevus cells adjacent to the melanoma, and analyzed according to anatomic distribution. Results showed a regional variation in the proportion of melanomas with adjacent nevi not explicable by regional variation in nevus density, which suggests that there is a varying susceptibility of nevi to malignant change. Given that nevus cells are equivalent to melanocytes, this finding would support the hypothesis that melanocytes at-large have a differential response to the mitogenic stimulus of sunlight according to anatomic site.

Key words: Australia, melanoma, nevi, site distribution.

Introduction The determinants of the site distribution of cutaneous melanoma are not understood. Although there is general agreement that sun exposure is causal,' the anatomic distribution of cutaneous melanoma suggests that its relation to sunlight is less straightforward than for other skin cancers. Squamous cell carcinoma, for example, occurs mostly on the face, the backs of hands and forearms,2 and thus clearly is associated with excessive sun exposure. On the other hand, when relative surface area is allowed for, cutaneous melanoma occurs frequently not only on chronically exposed sites such as the face, but also on the back in White populations, e.g. in the United States and Australia."- Even when regional variation in the epidermal distribution of melanocytes' is taken into account, the surface distribution of melanoma cannot be interpreted simply.?

One prevailing explanation of this apparent incon-

sistency is the 'intermittent exposure' theory. This proposes that the development of melanoma is associated with periodic intense exposure of untanned skin to sunlight as indicated by sunburn or by recreational (as opposed to occupational) activity and not with cumulative sun exposure.' It is postulated that chronic sun exposure protects melanocytes by promoting a constant degree of suntan and epithelial thickening, thereby decreasing the risk of melanoma;' whereas, intermittent intense sun exposure stimulates melanocytes-hence the higher rates of melanoma on the trunk and limbs observed in indoor compared with outdoor workers in England and Wales,"' and Canada.' However, the intermittent exposure theory does not explain the excess of melanomas of the head and neck that was noted specifically in outdoor workers compared with indoor workers in England and Wales,'o nor the objective evidence that chronic solar damage to the

The author is with the Queensland Institute of Medical Research, Brisbane, Queensland, Australia. Address correspondence to Dr Green, Epidemiology Department, Queensland Institute of Medical Research, 300 Herston Rd., Brisbane, Queensland 4029, Australia.

? 1992 Rapid Communications of Oxford Ltd Cancer Causes and Control. Vol 3. 1992 513



A. Green

Table 1. Cutaneous melanoma histologically associated with nevus cells according to anatomic site, Queensland, Austra- lia, 1979-80

Site Nevus-associated Total melanoma melanoma

No. Relative No. Relative tumor tumor

densityl? density

Chronically exposed Face 2 1.5 149 7.7 Ear 0 - 14 3.2 Forearm 0 - 27 0.5 Dorsum of

hand 0 - 5 0.2

Variably exposed Scalp 0 - 9 0.3 Neck 6 4.2 50 2.4 Trunk (front) 8 1.0 72 0.6 Trunk (back) 27 3.5 246 2.2 Upper arm 3 0.6 94 1.4 Thigh 4 0.4 48 0.3 Leg 9 1.1 149 1.2 Dorsum

of foot 0 - 3 0.1

Other Buttocks 0 - 2 0.0

Palms, soles 0 - 4 0.1 Unknown 3 33

Total 62 905

* Relative tumor density equal to one corresponds to density of tumors on whole of body.

skin, denoting total accumulated exposure to the sun, is associated significantly with melanoma."

Among the strongest of all known risk factors for melanoma are nevi or common moles' which are benign tumors of melanocytes. Compared with sunlight alone, the role of nevi or melanocytes interacting with sunlight in the development of melanoma at a particular site has received scant attention. Because the minority of melanomas are associated with nevus cells on histologic examination," and because the site distribution of nevi does not closely parallel that of melanoma,2 benign nevi are not considered generally to be precursor lesions." Rather, nevi are considered sys- temic markers of risk for melanoma," perhaps because they manifest an increased propensity of melanocytes to proliferate.12

There is some evidence that the stability of neval melanocytes differs not only between individuals, but also at a site-specific level within individuals. In their study of tumor progression in the melanocytic system, Clark et al"' observed that nevi of the face and scalp evolve and stabilize far more rapidly than nevi of the

trunk or the extremities. Thus, nevi on the head and neck are the least likely to have an early-stage junc- tional component" or to become malignant.16 This

study was undertaken to gather further evidence of site-specific mutability of nevi, as possible evidence of the site-specific susceptibility of melanocytes in general, to malignant change.

Materials and methods The pathology reports of all cutaneous melanomas

diagnosed in the state of Queensland in a 12-month period beginning July, 1979, were examined. These

reports had been gathered in the course of a previous population-based study." These data were used to cal- culate, for each anatomic site, the relative tumor densi- ties' of all melanomas and, separately, of those melanomas in which adjacent benign nevus cells had been reported routinely by the pathologist. To calcu- late the relative tumor density for a particular site, the

proportion of tumors which occurred at that site is div- ided by the proportion of skin surface area which the

particular site represents.' A relative tumor density equal to one corresponds to the density of tumors on the whole body.

Results As indicated in Table 1, the greatest excess of melanomas in general was observed on two of the most

chronically exposed sites, namely, the face and the ear. (Twelve of the 14 melanomas on the ear occurred in men. Of those on the face, 77 percent were classified as

lentigo meligna melanoma, as were 43 percent of those on the ear.) In contrast, the greatest excess among the subset of melanomas with a neval component tended to occur on sites which are not exposed constantly to sun-

light in most people, namely the neck and the back

(including the shoulder). Melanomas overall occurred over seven times more densely on the face but only about twice as densely on the back, as on the body as a whole. Nevus-associated melanomas on the other hand, occurred only one and a half times more densely on the face as they did on the body as a whole, but 3.5 times more densely on the back. This pattern was observed in each age group studied, namely, under 30 years, 30-59 years, and 60 years and over. In persons under 30 years, despite the high overall proportion of nevus-associated melanomas and a limited number of cases, none of the three facial melanomas diagnosed had a neval component. Melanomas on the back occurred twice as densely as on the body overall in this age group, while nevus-associated melanomas

514 Cancer Causes and Control. Vol 3. 1992



Site distribution of melanomas

occurred 2.3 times as densely on the back as on the body as a whole. In persons aged 60 and over, melanomas overall occurred 1.5 times more densely on the back but 13.9 times as densely on the face as on the body as a whole. In contrast, nevus-associated melanomas occurred 3.4 times more densely on the back but only 2.8 times more densely on the face as on the body overall. The pattern in the 30-59 year age group closely resembled the overall pattern. There were no material differences according to sex of patients.

Discussion Queensland pathologists may not always have noted nevus cells when adjacent to a melanoma in their rou- tine reports, resulting in the slightly lower proportion (seven percent) of nevus-associated lesions in this study compared with an overall frequency of about 20 percent in special studies of nevi-and melanomas." However, those melanomas that were reported as con- tiguous with a nevus were unlikely to have been selec- ted by anatomic site. Moreover, the site-dependence of nevus-associated melanomas observed in the present study is consistent with other findings. 6.8 The reported distribution is not simply a function of the distribution of benign nevi-which occur twice as densely on the back, but six times as densely on the face as on the body overall, based on the largest study of the regional distribution of nevi to date.'9 Given an unbiased sample, these findings suggest that the small proportion of melanomas that were associated with a nevus arose after lower total doses of ultraviolet radiation than received prior to the development of those melanomas not associated with a nevus.

The enigma of the site distribution of cutaneous melanoma' ,,8 arises with the assumption that all melanocytes have an equal probability of malignant change. Based on the apparent regional variation in the susceptibility of neval melanocytes to malignant transformation observed here and elsewhere16 and given that nevus cells are melanocytes morphologically and bio- chemically,20 a corresponding regional variation in susceptibility of all melanocytes to malignant transformation may exist. Such variation would explain why all sites where melanomas occur are not necess- arily chronically exposed to sunlight. That is, at sites of less stable melanocyte populations such as the trunk," mutagenesis and tumor promotion could occur after infrequent sun exposure or relatively small total doses of ultraviolet radiation. Conversely, highly melanized and differentiated melanocytes would not be as suscep- tible to the mitogenic stimulus of sunlight'32 and melanoma at the sites of these stable pigment cells would be associated with high total doses of UV radiation. On

the face, constant exposure to sunlight results in an increase in the number of functioning melanocytes and enhanced melanin transfer to surrounding keratino- cytes through differentiation of melanocytes and increasing arborization of their dendrites.2,2 As observed in diverse populations,'•" when facial melanoma does occur, it is associated with cumulative exposure, histologic subtype notwithstanding.

This hypothesis of host-environment interaction thus provides a mechanism for a site-specific etiology of melanoma.24 Moreover there is the potential to chal- lenge it in the laboratory by testing the mutability of established cultures of melanocytes derived from different anatomic sites, at various levels of melanization.22

References

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2. Green A, Beardmore G, Hart V, Leslie D, Marks R, Staines D. Skin cancer in a Queensland population. JAm Acad Dermatol 1988; 19: 1045-53.

3. Pearl DK, Scott EL. The anatomic distribution of skin cancers. Int J Epidemiol 1986; 15: 502-6.

4. Newell GR, Sider JG, Bergfelt L, Kripke ML. Incidence of cutaneous melanoma in the United States by histology with special reference to the face. Cancer Res 1988; 48: 5036-41.

5. Green A, MacLennan R, Youll P, Martin N. Site distribution of cutaneous melanoma in Queensland. Int J Cancer 1992 (in press).

6. Szabo G. The regional anatomy of the human integu- ment with special reference to the distribution of hair fol- licles, sweat glands and melanocytes. Philos Trans Royal Soc London 1967; 252: 447-85.

7. Crombie IK. Distribution of malignant melanoma on the body surface. BrJ Cancer 1981; 43: 842-9.

8. Armstrong BK. Epidemiology of melanoma: intermittent or total accumulated exposure to the sun? J Derm Surg Oncol 1988; 14: 835-49.

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10. Beral V, Robinson N. The relationship of malignant melanoma, basal and squamous cell skin cancers to indoor and outdoor work. BrJ Cancer 1981; 44: 886-91.

11. Ross PM. Apparent absence of a benign percursor lesion: implications for the pathogenesis of malignant melanoma. J Am Acad Dermatol 1989; 21: 529-38.

12. Green A, Swerdlow AJ. Epidemiology of melanocytic nevi. Epidemiol Reviews 1989; 11: 204-21.

13. Elder D. Human melanocytic neoplasms and their eti- ologic relationship with sunlight. i Invest Dermatol 1989; 92: 297S-303S.

14. Clark WH, Elder DE, Guerry D, et aL A study of tumor progression: the precursor lesions of superficial spreading and nodular melanoma. Hum Pathol 1984; 15: 1147-65.

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young adults. J Invest Dermatol 1960; 34: 125-8. 16. Heenan PJ, Armstrong BK, English DR, Holman CDJ.

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18. Black WC. Residual dysplastic and other nevi in superficial spreading melanoma: clinical correlations and association with sun damage. Cancer 1988; 62: 163-73.

19. Pack GT, Lenson N, Gerber DM. Regional distribution of moles and melanomas. Arch Surg 1952; 65: 862-70.

20. Magana-Garcia M, Ackerman AB. What are nevus cells? AmJ Dermatopathol 1990; 12: 93-102.

21. Jimbow K, Uesugi T. New melanogenesis and photobi-

ological processes in activation and proliferation of precursor melanocytes after UV-exposure: ultrastructural differentiation of precursor melanocytes from Langer- hans cells. J Invest Dermatol 1982; 78: 108-15.

22. Gordon PR, Mansur CP, Gilchrest BA. Regulation of human melanocyte growth, dendricity, and melanization by keratinocyte derived factors. J Invest Dermatol 1989; 92: 565-72.

23. Cristofolini M, Franceschi S, Tasin L, et aL Risk factors for cutaneous melanorna in a northern Italian population. IntJ Cancer 1987; 39: 150-4.

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A Theory of Site Distribution of Melanomas: Queensland, Australia