D thors have presented data on

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1 DEVELOPMENT AND ELIMINATION OF PIGMENTED MOLES, AND THE ANATOMICAL DISTRIBUTION OF PRIMARY MALIGNANT MELANOMA E. M. NICHOLLS, MD+ In Sydney, Australia, the number of pigmented moles per person increases to age in males and 2&29 in females, the most exposed parts of the body reaching peak values soonest. A decline then begins so that moles are almost absent in persons 8 years old. On each part of the body, depigmented spots and nevi with definite or faint halos are more common soon after the peak values have been reached. The delayed development of moles on sunlightprotected parts of the body may be related to the fact that in European pop ulations the frequency of malignant melanoma increases as the Equator is approached but many of the additional melanomas are found in anatomical sites minimally exposed to sunlight. ESPITE THE FACT THAT A NUMBER OF AU- D thors have presented data on the incidence, development, and elimination of pigmented moles, little positive evidence has been brought forward on the relationship between their formation and the amount of sunlight falling on particular parts of the skin. However, for many years now, the relationship between sunlight and malignant melanoma has been under consideration.~7~9-11~22 Europeans living in Australia have three times as much melanoma as those in Canada. Within Australia, Queensland (latitude: 1 S - 29"s) has three times the incidence of Victoria (latitude: 34"s - 39OS). This would clearly implicate sunlight but for the paradox that in the populations closer to the Equator many of the additional melanomas are found on parts only minimally exposed.288j1.22 In several publications,l3- the simplest be- * Senior Lecturer, School of Human Genetics, University of New South Wales, Sydney, Australia. t Photographic technique: Kodak 35 mm Plus X film. Filter 2" x 2" Tiffen 18A. Developed Ilford Contrast FF 1:2, 5 min. at 68F. Agitation every minute. Lighting-3 Bowens flash heads at 4 joules each, 3Q" distance from subject at 45" angle. Address for reprints: E. M. Nicholls, MD, School of Human Genetics, University of New South Wales, Sydney, Australia. The author is grateful to Dr. B. K. Walder who obliged with case material. Special acknowledgment is due to the Department of Medical Illustration, University of New South Wales, for development of the photographic method. Received for publication February nign neoplasms derived from melanocytes have been considered. Further analysis of counts of moles is presented here, and observations made on depigmented conditions of the skin are recorded. The latter studies were made because of reports that the halo nevus represents a mode of dissolution of moles.4,1%2.23 A case of malignant melanoma is presented, and the clinical findings in this case are used to further the thesis that pigmented moles, depigmented spots of the skin, and melanoma may all be direct or indirect results of excessive sunlight exposure. MATERIALS AND METHODS The number of moles on 1,518 individuals (57 females and 948 males) were counted. A mole was as previously defined,14 a pigmented lesion 2 or more mm in diameter, and either palpable or seen to be deforming the surface architecture of the skin when viewed tangentially in a strong light. This definition would, if applied rigidly, exclude freckles but include pigmented seborrheic keratoses; when recognized, these lesions were not included in the data. The number of moles was recorded by region of body, by age of subject, and by sex. The skin of many subjects was photographed in the ultraviolet component of the light from a powerful flashlight surce.t Reflection of long wave-length ultraviolet light

2 I ( TABLE 1. Number of Pigmented Moles at Various Ages (Peak Values in Italics) Upper Lower Right Left Right Left Aee No. Total Head Neck Chest Abdomen back back arm arm lee lee Males Females o so o oo Of g.73 L, ft.26 P U ( 4 w < 2.8 e.29 g

3 No. 1 from relatively depigmented skin was responsible for the high contrasts obtained. RESULTS Table 1 indicates the result of counting moles on 1,518 subjects. It is seen that males in Sydney, Australia, get their peak number of moles at age, whereas females get their peak number at age At the peak value, the number of moles in males is greater than in females. The most exposed parts of the body reach peaks of frequency sooner than the less exposed parts. In accord with this observation, it is to be noted that the female upper torso lags further behind exposed parts of the body than does the male upper torso. It may also be noted that the male upper back and the female leg -sites having a high frequency of melanoma-develop many moles. Patient 1 (Fig. 1) was first seen in 1964, when he had 129 pigmented moles and 3 halo nevi. Seen again in 1972, he had pigmented moles. Halo nevi were still present, PIGMENTED MOLES - Nicholls 193 and also depigmented spots were present in the same area. There were no depigmented spots on his face. Patient 2 (Figs. 24), age 21, presented with malignant melanoma. There are freckles, moles, and depigmented spots shown in Fig. 2; there is one halo nevus visible at the lower left hand side of the figure. He has no depigmented spots on the face. There are many depigmented spots on his back and also one halo nevus (Fig. 3). The malignant melanoma developed prior to his 21st birthday and was on his right lower leg (Fig. 4). It is seen to be spreading from a central area which has undergone a partial regression. There are depigmented hairs in the central area and a faint halo surrounding the melanoma. Table 2 shows the distribution of moles on this subject when examined in DISCUSSION It is a commonplace observation that freckles are most numerous on sunlight-exposed FIG. 1 (left). Freckles, moles, depigmented spots, and halo nevi on the face and chest of a 22- year-old man (photographic method described in text). FIG. 2 (right). Freckles, moles, and depigmented spots on chest and arms of a 21-year-old man with melanoma.

4 194 CANCER July 1973 Vol. 32 FIG. 3 (left). Back of patient in Fig. 2. FIG. 4 (right). Malignant melanoma on Rt. calf of patient in Fig. 2. skin. It has not been so apparent that most pigmented moles may be due to sunlight exposure, although the view that malignant melanoma is due in some way to sunlight is now widely accepted. The conclusion from the data presented in this paper is that sunlight is an important cause of pigmented moles. Moles begin to form at an early age on exposed parts of the body (Table 1). An elimination mechanism also begins to play a part at an early age. A number of authors have suggested that there is a reaction of the immune system against the neoplastic cells, and if this is so then it seems likely that the mechanism is one of cell-mediated immunity. Round cell infiltration is seen in halo nevi, the most obvious situation in which active elimination of TABLE 2. Distribution of Moles on Patient 2, 21 Yearsof Age, with Primary Melanoma of the Right Lower Leg Face 2 Chest 8 Neck 2 Abdomen 4 IIpper back 7 Lower back 5 R Upper arm 5 R lipper leg R Lower arm 3 R Lower leg 13 L Upper arm 1 L Upper leg L Lower arm L Lower leg 12 moles may be seen. The halo nevus, as generally pictured, is an extreme case which attracts attention; however, most people with moles have one or more with a detectable pale halo. In the case of the more obvious halo nevi, when the mole at the center of the halo has been completely eliminated, the white spot may remain for years before repigmentation occurs. A moderately effective elimination mechanism would leave many small white spots as in Figs. 1-3 or, if fully effective, would eliminate abnormal cells without leaving a visible spot. Mitchell12 described the microscopic features of the skin of excessively sun-exposed Europeans; normal melanocytes, bizarre melanocytes, and small areas devoid of melanocytes were observed. Since one third or more of malignant melanomas arise in preexisting benign moles, the changing proportion of moles on the various regions of the body may account for the anomalous distribution of malignant melanoma in relation to sunlight exposure. Patient 2 had 92 moles in all, 55 of them on the legs (Table 2). With this bias in the distribution of the benign melanomas, it may not be surprising that his malignant melanoma was on a leg. If white spotting is indicative of actual or incipient mole formation at an earlier time,

5 No. 1 then this patient has clearly been subject to a great deal of this activity on more exposed parts, while less exposed parts are now demonstrating the greatest number of developed moles. The frequency of melanoma is proportional to age" so that the aging subject with many moles on a relatively covered area may become more prone as time goes on to develop a melanoma in one of these moles. It has been suggested that multiple somatic mutations may be the cause of moles.14 According to this theory, the early appearance of moles on sunlight-exposed parts of the skin is attributable to the mutagenic effect of ultravi- PIGMENTED MOLES Nicholls 195 olet light. That further moles appear on areas relatively protected from sunlight as time goes on is attributable to the more gradual accumulation of mutational defects in clones of cells in these areas. That the moles should disappear after a time, and that no more should appear, is not predictable from this theory. It seems likely that the disappearance of developed moles and the non-appearance of potential new moles may be different expressions of the same phenomenon. A better understanding of the causes of this phenomenon would be of considerable help in the understanding of host-tumor relationship. REFERENCES 1. Becker, S. W., Jr.: Pigmentary lesions common to the skin and oral cavity. Oral Surg. 28: , Davis, N. C., Herron, J. J.. and McLeod, G. R.: Malignant melanoma in Queensland. Lancet ii:4741, Doll, R.: The age distribution of cancer: Implications for models of carcinogensis. J. R. Stat. Soc. A. 134:133-6, Frank, S. B., and Cohen, H. J.: The halo nevus. Arch. Dermatol. 89: , Herron, J. J.: The geographical distribution of Malignant melanoma in Queensland. Lancet ii:47-41, Lancaster, H..: Some geographical aspects of mortality from melanoma in Europeans. Med. J. Aust. 1 : , Lancaster, H. O., and Nelson, J.: Sunlight as a cause of melanoma; a clinical survey. Med. J. Awt. 1: , Lee, J. A. H., and Yongchaiyudha. S.: Incidence of and mortality from malignant melanoma by anatomical site. J. Natl. Cancer Znst. 47: , McGovern, V. J., and Goulston, E.: Malignant moles in childhood. Med. J. Aust. 1: , McGovern, V. J., and Mackie, B. S.: The relationship of solar radiation to melanoblastoma. Aust. NZ J. Surg. 28~ , Milton, G. W.: Malignant melanoma and a study of some aspects of cancer. J. R. Coll. Surg. Edinb. 14:193-22, Mitchell, R. E.: The effect of prolonged solar radiation on melanocytes of the human epidermis. J. Invest. Dermatol. 41: , Nicholls. E. M.: Somatic variability and pigmentation. M. D. Thesis, University of Adelaide, *. Genetic susceptibility and somatic mutation in the production of freckles, birthmarks and moles. Lancet i:71-73, *. The genetics of red hair. Hum. Hered. 19:3642, Pack, G. T., Lenson, N., and Gerber, D. M.: Regional distribution of moles and melanomas. Arch. Sttrg. 65:862-87, Stegmaier,. C.: Natural regression of the melanocytic nevus. J. Invest. Dermatol. 32:413421, Stegmaier,. C., and Becker, S. W., Jr.: Incidance of melanocytic nevi in young adults. J. Invest. Dermotol. 34: , Stegmaier,. C.. Becker, S. W.. Jr., and Medenica, M.: Multiple halo nevi. Arch. Dermatol. 99:lEO- 189, Swanson. T. L.. Wavte. D. M.. and Helwie. E. B.: IJltrastructure- %f halo ' nevi. 1.. Invest. D&natol , Walton, R. G.: Pigmented nevi. Pediatr. Clin. North Am. 18: , Ward, W. H.: Melanoma. Carcinoma of the skin and sunlight. Aust. J. Dermatol. 9:7& Wayte, D. M., and Helwig, E. B.: Halo nevi. Cancer 22: