38 MALIGNANT MELANOMA OF SKIN AND SUNSPOT ACTIVITY SIR,-Dr Houghton and colleagues (April 8, p. 759) reported that the incidence of maligant melanoma in Connecticut during the period 1935-75 varied cyclically, the peaks correlating closely with periods of peak sunspot activity. Incidence data from the Alberta and Saskatchewan cancer registries for the periods 1953-75 and 1950-75, respectively, showed similar cyclic variation of rates for malignant melanoma of skin (see figure). Years of peak sunspot activity were 1947-49, 1957-59, and 1967-72 (data cited by Houghton et al.) Incidence rates for Saskatchewan reached peaks in 1957-59 and 1965-67 and increased again from 1970 to 1973; peaks in Alberta occurred about 2 years later and rates varied more dramatically among females than males. This sex differential may be explained by the fact that malignant melanoma of skin tends to occur on exposed regions and in Canada women’s clothes expose more skin than men’s, at least during the warm T’t months. Houghton et al. provided a plausible rationale for the association between sunspot activity and incidence of malignant melanoma: the increased flux of cosmic rays results in destruction of stratospheric ozone so that more ultraviolet radiation reaches the earth’s surface. These workers also noted cyclic variation of malignant melanoma incidence-rates in New York State and Finland but not Norway. The estimated average latent period between the peak of sunspot activity and the peak of malignant melanoma incidence rates was 2 years in Connecticut, 1-2 years in New York State, and 0-1 years in Finland. The cyclic variation of malignant melanoma incidence-rates in the Canadian provinces could also be explained by an average latent period of 0-2 years. However, one could postulate an average latent period of about 10 years (e.g., the 1957-59 malignant melanoma incidence peak could be related to the 19479 sunspot peak). The average latent period between first exposure to a car-
cinogen and the diagnosis of cancer in man is generally thought to be twenty years or more. Little is known concerning the effect of single or intermittent high exposures to a carcinogen to which relatively low exposure has occurred since birth (e.g., ultraviolet light). There may be a precedent for shorter latency in the increased risk of endometrial carcinoma among women exposed to exogenous ccstrogens for treatment of menopausal and postmenopausal symptoms.1,2 The estimated period between first exposure to exogenous oestrogens and diagnosis of endometrial carcinoma is 5-10 years.3 The endome’trium is exposed to endogenous oestrogens throughout life, just as exposed skin is subjected to ultraviolet light throughout life. Conceivably, exposure to exogenous oestrogens or excessive amounts of ultraviolet light results in the acceleration of
of pre-existing malignancies localised, respectively, within the endometrium and skin. Such reasoning may explain the short latent periods discussed above.
Malignant melanoma incidence data for Alberta and Saskatchewan, respectively, were provided by Dr M. Grace and the Saskatchewan Cancer Commission.
Bureau of Epidemiology, Laboratory Centre for Disease Control, Health and Welfare Canada,
Ottawa Canada K1A 0L2
DONALD T. WIGLE
HEPATOCELLULAR CARCINOMA IN YOUNG WOMEN ON ORAL CONTRACEPTIVES
SIR,-The report by Baum et al." of a possible association between benign liver tumours and oral contraceptives was rapidly followed by a series of such cases. The first report of the association of liver tumour and oestrogen treatment came from France in 1953.5 The case was reported as primary livercell carcinoma. Although most of the liver tumours reported in young women on oral contraceptives have been benign, several primary malignant tumours have been reported.6 The registry started in 1973 at the University of Louisville now has more than 200 examples of liver tumours in women of the reproductive age. 20 are hepatocellular carcinomas in women aged 17-46 (mean age 25). All 20 tumours were in non-cirrhotic livers. Pain was the presenting symptom in 13, and 3 of these had rupture of the liver; 3 had an abdominal mass; 3 were first suspected and diagnosed at laparotomy; and 1 patient presented with vomiting as the only symptom. 1 patient was terminal at admission, and was the only patient with clinical jaundice before diagnosis. 17 patients had taken oral contraceptives for 6-120 months (average 57 months)-mestranol in 6, ethinylaestradiol in 5, both types of oestrogen in 4, and type unknown in 20. Most tumours were well differentiated and none contained carcinoma of bileduct origin. Granular or globular deposits were present in the cytoplasm. These deposits, which were periodic-acid/Schiff positive and resistant to diastase digestion, proved to be ocj-antitrypsin by immunoperoxidase testing. 8 of 9 tumours so tested were positive. The deposits represent a protein marker for both benign and malignant steroid-associated liver tumours. 15 patients are dead of disease; and 11 of these are known to have had metastatic spread to lymph-nodes, peritoneum, 1. Smith D. C., Prentice, R., Thompson, D. J., Herrmann, W. L. New Engl. J. Med 1975, 293, 1164. 2. Ziel, H. K., Finkle, W. D. ibid 1975, 293, 1167. 3. Marrett, L. D., Elwood, J. M., Meigs, J. W., Flannery, J T. Gynecol. Oncol.
incidence-rate (5-year moving average) ot malIgmelanoma of skin (I.C.D.A. 172) in Alberta and Saskatchewan.
1978, 6, 183. Baum, J. K , Brookstein, J. J., Holtz, F., Klein, E. W. Lancet, 1973, ii, 926. Caroli, J., Paraf, A., Carbonnier, A., Vallin, J. Revue int. Hepat. 1953, 3,
LC.D.A.= International Classification of Diseases adapted for use in the United States.
t eighth revision;
W. M., Mays, 1, 31. Palmer, P. E., Christopherson, 68, 736.
E. T., Barrows, G. W
M., Wolfe, H. J. Am. J. clin.
39 mesentery, omentum, adrenal glands, spleen, gallbladder, ovary, pleura, lung, or bone. The average survival-time for the patients who died was 7 months. In the United States hepatoma is usually associated with cirrhosis.8 A large survey at the Mayo Clinic between 1948 and 1963 revealed 69 cases of hepatoma. Only 15 were in females of which 4 were non-cirrhotic cases between the ages of 20 and 49.9 None of the 20 patients in our series had cirrhosis or fibrosis. 2 of the 3 patients not thought to be taking steroids were at term pregnancy or early post partum where high endogenous levels of oestrogen would be expected. We have examined 2 additional hepatomas in women age 51 and 57who had been on large doses of conjugated equine oestrogen for 28 and 10 years, respectively. Both tumours occurred in non-cirrhotic livers, and both were solitary lesions. Hepatocellular carcinomas have been reported in males in association with androgenic anabolic steroids,’"’" but, unlike the tumours presented here, the androgen-associated tumours tended not to metastasise. With the benign liver tumours associated with oral contraceptives the oestrogen rather than the progestin component has been the major suspect. However, these progestins are structurally related to the anabolic steroids, and liver tumours have been reported in 4 patients taking medroxyprogesterone acetate or norethindront acetate, without oestrogen.l2 Both the benign and malignant liver tumours occur in nonusers and in males as well as in women on oral contraceptives. Probably most of these tumours have a multifactoral setiology and sex steroids play a limited, albeit important role in the pathogenesis. Most patients with hepatoma have cirrhosis. Patients with cirrhosis may have menstrual problems, infertility, and breast changes (in women) and gynscomastia, testicular atrophy, decreased libido, impotence, and infertility (in men). Perhaps cestrogens play a role in the development of hepatomas in patients with cirrhosis. There is no statistical evidence that oral contraceptives are causative. Department of Pathology, University of Louisville School of Medicine, Louisville, Kentucky 40201, U.S.A.; and Department of Surgery University of Kentucky School of Medicine, Lexington, Kentucky
W. M. CHRISTOPHERSON E. TRUMAN MAYS GEORGE BARROWS
PIGMENTED SKIN LESIONS IN BABIES BORN TO UNDERWEIGHT FORMER ORAL-CONTRACEPTIVE USERS
SIR,-Oestrogens and cestrogen-progestagen combinations increases in both melanocyte-count and intracellular and extracellular melanin content.’ Chloasma (hyperpigmentation, especially of the face) is a common side-effect of oral contraception.2 Oestrogen receptors are found in some malignant melanomas,3 and a two-fold increase in melanoma incidence has been observed in women taking oral contraceptives or cause
oestrogens .4 We have studied pigmented lesions and other congenital malformations in 2994 babies born to women who had used oral contraceptives since any previous pregnancy and in 13 832 controls. The retrospective cohort study covered over 98% of births in three Jerusalem hospitals in 1974-76. Women were questioned about oral-contraceptive use on the day after
Prevalence at birth of pigmented skin lesions in newborns of former oral-contraceptive users and controls, by relative
delivery, and by interviewers made by the neonatalogists.
who did not know the diagnoses The doctors who examined. the babies did not know about maternal contraceptive use. The results of the study have been reported in detail elsewhere.5 Pigmented lesions were reported in 14 (4.68/1000) babies of former oral-contraceptive users and in 34 (2-46/1000) controls, giving a relative risk of 1.9. Although this excess was not statistically significant it was observed in all subgroups of maternal age, birth order, social class, height, hospital of birth, and smoking, and in three of four ethnic groups studied. Half of the cases in the oral-contraceptive group were born to thin mothers, and the relative risk was 6-4 in pill users who weighed under the 30th percentile for their height at the time of conception, compared to controls of similar weight (see figure). This association with underweight was not confined to any particular age or ethnic group, so far as could be ascertained from the small numbers available. Pigmented lesions increased in prevalence with increasing maternal age, both in former pill users and controls, as did hxmangiomas. The latter were also more common in the offspring of women who had been underweight at the time of conception, both in oral-contraceptive users and controls. Changes in pigmentation and pituitary, adrenal, thyroid, and sex hormone disturbances are well-known to occur in malnutrition.6,7 Oral contraceptives cause widespread metabolic changes, interfering with vitamin, protein, carbohydrate, and lipid biochemistry. Our findings, although they require confirmation in studies applying standard diagnostic criteria to the different skin lesions observed, suggest that possible interactions of the pill with nutrition should be sought in benign and malignant skin conditions in adult users.
Supported by contract lation Research, N.I.H.,
Department of Medical Ecology, Hebrew University ofJerusalem, Jerusalem, Israel * Present address:
8. Edmonson, H. A., Steiner, P. E. Cancer, 1954, 7, 462. 9 Parker, J. D., Dahlin, D. C., Stauffer, M. H. Mayo Clin. Proc. 1970, 45, 25. 10. Bernstein, M. S., Hunter, R. L., Yachnin, S. New Engl. J. Med. 1971, 284, 1135. 11. Johnson, F. L., Feagler, J. R., Lerner, K. G., Majerus, P. W., Siegel, M., Hartmann, J. R., Thomas, E. D. Lancet, 1972, ii, 12. 12. Nissen, E. D., Kent, D. R., Nissen, S. E. Contemp. Ob/Gyn, 1976, 8, 103. 1. Snell, R. S , Bischitz, P. G. J. invest. Derm. 1960, 35, 73. 2 Jelinek, J. E Archs Derm. 1970, 101, 181. 3. Fisher, R. I , Neifeld, J. P., Lippman, M. E. Lancet, 1976, ii, 337. 4 Beral, V., Ramcharan, S., Faris, R. Br. J. Cancer, 1977, 36, 804.
N01-HD-4-2853 from the Center for
Contraceptive Drug Study,
SUSAN HARLAP Kaiser-Permanente Medcal
Center, Walnut Creek, California 94596, U.S.A. 5. Harlap, S., Davies, A. M. The Pill and Births: the Jerusalem study. Center for Population Research, N.I.C.H.D., National Institutes of Health, Beth-
esda, Maryland, U.S.A., 1978. 6. Olson, R. E. Am. J. clin. Nutr. 1975, 28, 626. 7. Milner, R. D. Nutr. Rev. 1972, 30, 103. 8. Doar, J. W. H. Clin. Endocr. Metab. 1973, 2, 503. 9. Kalkhoff, R. K.J. Steroid Biochem. 1975, 6, 949. 10. Anderson, K. E., Bodansky, O., Kappas, A. Adv. clin. Chem. 1976, 18, 247. 11. Wallace, R. B., Hoover, J., Sandler, D., Rifkind, B. M., Tyroler, H. A. Lancet, 1977, ii, 11.