- Email: [email protected]
Human models of melanoma
Human Models of Melanoma MARTIN
A. WEINSTOCK,
MD, PHD
A
human model for melanoma is a circumstance in which melanoma is particularly common. We can use models to gain an understanding of melanoma in two ways: (1) by studying the differences between the model and general susceptible population, we can link those differences to the etiology and pathogenesis of melanoma; (2) by studying differences in melanoma susceptibility among individuals in the model circumstances, we may be able to identify more readily etiologic factors and mechanisms. This article considers the potential of immunosuppression, xeroderma pigmentosum, albinism, psoralen photochemotherapy (PUVA), and artificial high-dose ultraviolet radiation exposures to serve as models for melanoma. Familial melanoma, another model, is discussed by Bergman and Fusaro elsewhere in this issue.
Immunosuppression The immune system has long been thought to play an important role in the etiology of melanoma because of the inflammation commonly observed in association with primary lesions, the foci of apparent regression that is a frequent clinical feature of these lesions, and the documented instances of complete spontaneous regression, even of metastatic disease.’ Several groups of immunosuppressed patients have been shown to have an increased incidence of melanoma. One of the most frequently studied models is Hodgkin’s disease. Most (but not all) of the reports of long-term From the Dermatoepidemiology Unit, VA Medical Center, Roger Williams Medical Center and Brown University School ofMedicine, Providence, Rhode Island. Address correspondence to Martin A. Weinstock, Dermafoepidemiology Unit-2121, VA Medical Center, 830 Chalkstone Avenue, Providence, RI 02908. Supported by National Cancer Institute Grant 49531 and Department of Veterans'Affairs medical research funds.
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1992 by Elsevier
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follow-up of Hodgkin’s disease patients have noted that their risk was at least double the risk expected in the general population. 2-6 Similar observations have been made for non-Hodgkin’s lymphoma2*’ and leukemia,2*8 but not for most other common sites of malignancy.2~9J0 Organ transplantation is another human model of immunosuppression. Both renal transplant recipients” and bone marrow transplant recipientG appear to have a severalfold increase in melanoma incidence, although there is some uncertainty regarding the magnitude of the risk because of the small numbers of cases. One study suggested a particularly close association between melanoma and nevi in the renal transplant population.13 The genetic immunodeficiency disorders may also predispose to melanoma. l4 There have been numerous case reports of melanoma among human immunodeficiency virus (HIV)-infected patients. 15-** One report suggests that melanoma is more common than expected among HIV-infected dermatology patients, 23 but the data currently available are insufficient to establish the melanoma incidence rate in this group or any link to degree of immunodeficiency. These models undoubtedly will be further elucidated as the recorded experience with them expands.
Xeroderma Pigmentosum Xeroderma pigmentosum (XP) is a group of genetic disorders with characteristic clinical features and defective DNA repair. **s*~The clinical features include acute photosensitivity in early infancy, which is classically the first sign although it may frequently be absent. This is followed by the more consistently present freckling in sunexposed areas which, by early childhood, develops into actinic poikiloderma (mottled hypo- and hyperpigmentation with telangiectasia, atrophy, and xerosis). The actinic poikiloderma is a dramatic finding, even in dark-skinned blacks afflicted with this disorder.
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Corresponding changes occur in exposed mucous membranes and the eyes. Actinic keratoses and other dysplastic neoplasms appear in the affected areas; cutaneous malignancies typically follow during childhood. Neurologic abnormalities are characteristic of a subgroup. The incidence of melanoma in Xl’ is extraordinarily high: before the age of 20 years, more than 2000 times higher than the general population.26 It is suspected that the most etiologically relevant difference between XI’ and normal individuals with respect to melanoma incidence is DNA repair in epidermal melanocytes of ultraviolet B radiation (UVB)-induced pyrimidine dimers, yet several pathogenic mechanisms must be considered.*’ The evidence of particular susceptibility to UVB is strong.28,29 Cell lines from XP patients are also particularly susceptible to certain chemical carcinogens.30 XI’ patients appear to have reduced defenses against peroxides and oxygen radicals3i Patients with XI’ also have reduced natural killer cell function, and may have other disorders of immune function.32 It is not known whether these other deficiencies are due to the DNA repair defect. Two other syndromes are associated with DNA repair defects: Cockayne’s syndrome and trichothiodystrophy. These disorders, however, have not been associated with increased melanoma risk. Hence, although defective DNA repair may well be the key component in the extraordinarily high melanoma incidence in XI’, the relative importance of the various abnormalities found in XI’ for melanoma risk remains to be ascertained. It is nevertheless clear from the XI’ model that genetic defects can have a remarkable effect on melanoma risk. Relatives of XI’ patients have not been shown to have an elevated melanoma risk. One study found no melanoma history among 10 16 blood relatives of XI’ patients, compared with 3 spouse controls who did have this history.33 Differences in melanoma risk within the XI’ population are not well documented. A report of cases from the United States suggested that the complementation group C subtype might be more susceptible to melanoma than other subtypes. 34 Similar claims have been made for complementation group D based on cases from Germany. 35 Reports of Japa nese cases do not clearly support either hypothesis. 36,37 These data must be evaluated cautiously; the numbers of cases evaluated are small, correction for age or other variables and even simple significance testing were not performed, and the cases studied were presumably not independent observations, as the number of families represented is presumably substantially less than the number of cases, and melanoma is known to aggregate in families. Anecdotal evidence supports the presumption that meticulous protection from ultraviolet radiation will prevent
the occurrence of melanoma in these patients.34,38 Clearly the anatomic distribution of melanoma in XI’ (65% on the head and neck) supports a direct and potent etiologic role of sun exposure in this genetically hypersusceptible grou~.*~ Other evidence regarding determinants of melanoma incidence among XI’ patients is lacking. Although this review focuses on the etiology of melanoma, it has also been observed that a relatively high (but still tiny) proportion of melanomas in XP patients spontaneously resolve.34
Albinism Oculocutaneous albinism is a group of genetic disorders characterized by white or light skin and hair color, nystagmus, and photophobia caused by a relative or absolute inability to synthesize melanin. The prevalence of albinism itself has been estimated to be 4 to 13 per 100,000 in Caucasian populations. 39,40 These estimates may vary with ethnicity and in particular may be higher in populations with dark natural skin color (which facilitates diagnosis) or significant inbreeding. Among albinos in one Canadian population-based series, one third were tyrosinase negative, that is, completely unable to produce melanin.40 Melanoma occurs in albinos, although its incidence in this group is unknown. Some have speculated that the incidence is high46; others, that it is 10w.~* Twenty-two reports are summarized in Table 1. If one were to assume that albinos had the same melanoma risk as Caucasians and that the previously cited prevalence estimates of albinism apply to the U.S. population, then the incidence of melanoma in albinos in the United States would have been approximately one to two cases per year during the past decade. It is therefore noteworthy that three albino patients with invasive melanoma and one each with in situ melanoma and lentigo maligna were reported in the United States in the 1980s (see Table 1). This is a small number of cases, yet it is reasonable to assume that the vast majority of cases are not published and, therefore, that the incidence of melanoma in albinos is at least roughly similar to the incidence in the general population, if not higher. It is notable nevertheless that more cases have not been reported, which strongly suggests that the incidence of melanoma in albinos is not increased by several orders of magnitude, as is observed with XI’. Photoprotection from the small amount of pigment made by tyrosinasepositive albinos cannot explain the limited number of melanoma case reports, as most of the sufficiently detailed reports (including all three invasive U.S. cases from the 1980s) are of tyrosinase-positive individuals. We may therefore infer that even in the absence of melanin, the
5811 59 59 60
56 57
47§ 48 49 50 51 52 53 54 55
41 42 43 44 45 46 46
England Tanzania The Netherlands United States United States England
India United States Italy South Africa United States South Africa South Africa Honduras United States Nigeria Germany United States United States United States United States Austria
Geographic Location Sex M F M F M M ? M M F M M F M M F M ? F F M F
Age 27 40 30 ? 38 ? ? 22 45 50s 42 19 54 42 14 40 58 ? 46 27 43 22 White White Hispanic White
? ?
Hindu White ? Bantu ? Bantu ? ? White Black White White Black ? ? White
Ethnic Group
? ? Yes No Yes Yes
Positive (HI’S) ? Positive Positive ? Positive
? ? ? AN None ?
None
None
? ? ? ? -
Mucosal ? ? ? Lentigo maligna ? Polyploid 1 nodular, 3 SSM ? ? SSM SSM In situ Ocular No Yes ? No Yes Yes Yes
Yes
-
Leg ? Lower leg Upper back Shoulder Choroid
Leg Knee Shoulder, leg, arm, arm
Lumbar region Calf Back ? Thigh Lower lip ? Occult primary Buccal gingiva Anal canal Back Knee Back
CN ? ? ? CN ? ? -
Anatomic Site
Precursor Lesion*
7 ? ? ? ? ? ? -
Qwt
Histologic
Yes ? ? ? Yes ? ? -
Positive ? D-(t),EM-(t) ? ? FM-(t) FM-(t) Positive ? FM-(t)Em+(t) Positive Positive Positive Negative
(neg),D-0)
D-W)
Tyrosinase Status*
Primary Lesion Amelanotic?
1.25 4.21 1.5, 1.9, 0.4, 0.7 ? ? 2.11 0.78 ?
? ? ? ? ? ? ? ? ? ? ? -
Thickness of Primary in (mm)
No ? No No No No
Yes Yes Yes ? Yes ? ? Yes Yes Yes Yes Yes No No No No
Known Metastatic Disease
2Y 2Y 0
Y ? 1 mo
2 yr 2 y, 0, 0
1Y 0 4mo 0 0
0 1 mo ? ? 3mo ? ? 3mo 0 ?
Duration of MetastasisFree Follow-up
l
D-_(t), tumor reported to be dopa negative; D-W, tvmorand normal skin reported to be dopa negative; EM-_(t), no evidence of melanin deposition observed in tumorsections with electron microscopy; EM+(t), electron microscopy of tumor cells revealed “lightly pigmented” melanosomes wtth granular material thought to represent “abortive melanogenesis’: (negJ, presumed tyrosinase negative because the clinical description mentioned completely white scalp and body hair (except for slight yellowing of the distal scalp hairs) and irides “without color’: FM--O, no evidence of melanin observed in tumor sections after staining with Fontana-Masson; HPS, Herman&-Pudtak syndrome. t SSM, superficial spreading melanoma. $ AN, acquired nevus; CN, congenital nevus. 6 The diagnosis was suspected but not proven by the histologic findings. 7 Additional features from personal communication, F. H. J. Rampen, 1991.
1985 1985 1985 1987 1987 1989
1952 1957 1958 1960 1963 1964 1964 1965 1967 1969 1974 1977 1981 1982 1982 1984
Year of Report and Reference
Table 1. Cases of Malignant Melanoma and Lentigo Maligna in Albinism
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1992;10:83-89 skin has important mechanisms for protection against melanoma. Other factors must also be considered. In tropical, developing countries, albinos frequently die of metastatic squamous cell carcinoma at an early age, perhaps before a potential melanoma has fully developed. In developed countries in temperate climates, albinos may be particularly assiduous in protecting themselves from the sun, unlike their nonalbino lightly pigmented sun-worshipping contemporaries. Indeed, the large case series of albinos with nonmelanoma skin cancer derive from tropical, not temperate climates. It is also of interest that only one case was clearly documented to be tyrosinase negative. This may be a result of the relative difficulty of documenting the absence of tyrosinase activity, which requires specialized laboratory techniques, and the relative ease of documenting its presence, as any clinical or microscopic manifestation of melanin production is sufficient. One can hope that additional data will elucidate the true risk of melanoma in albinos and therefore contribute to our understanding of the roles of melanin and sun-related behaviors in the etiology of melanoma.
Psoralens With Ultraviolet Light The use of psoralens with ultraviolet A light (PUVA) for psoriasis appears to cause a dramatic increase in the incidence of squamous cell carcinoma of the skin, and has also been associated with basal cell carcinoma and other cutaneous abnormalities usually attributed to solar ultraviolet radiation.61*62 The psoralen compound intercalates in DNA and causes crosslinks when photoactivated with UVA. PUVA is also known to have immunosuppressive effects. The effects of PUVA on melanocytes are pronounced, and indeed are used therapeutically in the treatment of vitiligo. Of particular relevance here are the mottled pigmentary disturbances and PUVA lentigines which are frequently observed.63*64 The latter have not been directly linked to melanoma, but are characterized by hypertrophic and sometimes atypical melanocytes.65 Numerous case reports of melanoma in PUVA-treated patients have been published; however, in the largest follow-up study to date of PUVA-treated patients (1380 patients followed for an average of 10 years) only 3 melanomas were found (versus 2.05 expected if PUVA did not affect risk). 66 Longer follow-up of patients in this and other large series will be required to determine whether PUVA increases melanoma risk.
Other Artificial Ultraviolet Light Exposures Many Caucasians expose themselves to artificial sources of ultraviolet radiation such as sunbeds, sunlamps, and
medical phototherapy devices (without ingestion of photosensitizing chemicals) for cosmetic or therapeutic purposes. These individuals have not been the subject of large-scale cohort investigation, so our knowledge of the relationship of these exposures to melanoma derives from case - control studies. Although the artificial ultraviolet radiation exposures from these sources can be characterized as intense, they are otherwise quite diverse and poorly differentiated from each other in case-control studies. Some presumably included large amounts of ultraviolet B radiation (280 to 320 nm); others may have involved primarily ultraviolet A (above 320 nm); and some may have contained significant quantities of ultraviolet C (below 280 nm), which is not part of the terrestrial solar radiation spectrum. This further complicates the interpretation of the epidemiologic evidence. Two studies have found a significant association of these exposures with melanoma, as well as a biologically plausible gradient of risk with exposure characteristic~~‘*~~;one found a significant effect and did not report a risk gradienP9; eight others found no association.70-77 The lack of detailed analysis on this point among many of the negative studies precludes detailed comparisons.
Conclusions A variety of special exposures or genetic defects serve as potential human models for melanoma and, therefore, provide additional perspective on the importance of several actual and possible causes. Further study of these situations may yield more definitive conclusions with important implications for understanding melanoma in the population
at large.
Acknowledgments Dr. Walter Quevado assisted in the interpretation of published melanosome electron micrographs. Thanks to Dr. Richard King for his comments regarding albinism, and Dr. Kenneth Kraemer and Dr. Anthony Gaspari for their comments regarding xeroderma pigmentosum. Dr. Victor Pricolo and Dr. A. Hermann Schmid were most helpful with translations.
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3. Boivin J-F, O’Brien K. Solid cancer risk after treatment of Hodgkin’s disease. Cancer 1988;61:2541-6. 4. Kaldor JM, Day NE, Band I’, et al. Second malignancies following testicular cancer, ovarian cancer and Hodgkin’s disease: An international collaborative study among cancer registries. Int J Cancer 1987;39:571-85. 5. Tucker MA, Misfeldt D, Coleman N, et al. Cutaneous malignant melanoma after Hodgkin’s disease. Ann Intern Med 1985;102:37-41. 6. Tucker MA, Coleman CN, Cox RS, et al: Risk of second cancers after treatment for Hodgkin’s disease. N Engl J Med 1988;318:76-81. 7. Travis LB, Curtis RE, Boice JD, et al. Second cancers following non-Hodgkin’s lymphoma. Cancer 1991;67:2002-9. 8. Greene MH, Hoover RN, Fraumeni JF. Subsequent cancer in patients with chronic lymphocytic leukemia: A possible immunologic mechanism. J Nat1 Cancer Inst 1978;61:33740. 9. Boice JD, Day NE, Andersen A, et al. Second cancers following radiation treatment for cervical cancer. An international collaboration among cancer registries. J Nat1 Cancer Inst 1985;74:955-75. 10. Enblad R, Adami H-O, Glimelius B, et al. The risk of subsequent primary malignant diseases after cancers of the colon and rectum: A nationwide cohort study. Cancer 1990;65:2091100. 11. Sheil AGR. Cancer after transplantation. 1986;10:389-96.
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12. Witherspoon RP, Fisher LD, Schoch G, et al. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med 1989;321:784-9. 13. Greene MH, Young TI, Clark WH. Malignant melanoma in renal-transplant recipients. Lancet 1981;1:1196-9. 14. Spector BD, Perry GS, Kersey JH. Genetically determined immunodeficiency diseases (GDID) and malignancy: Report from the immunodeficiency - cancer registry. Clin Immunol Immunopathol 1978;11:12-29. 15. Gupta S, Imam A. Malignant melanoma in a homosexual man with HTLV-III/LAV exposure. Am J Med 1987;102730. 16. Kaplan MH, Sadick N, McNutt NS, et al. Dermatologic findings and manifestations of acquired immunodeficiency syndrome (AIDS). J Am Acad Dermatol1987;16:485-506. 17. Krause W, Mittag H, Gieler U, et al. A case of malignant melanoma in AIDS-related complex. Arch Dermatol 1987;123:867-8.
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20. Spatz A, Prade M, Duvillard P, et al. Malignant melanoma and Kaposi’s sarcoma: A possible additional syndrome to AIDS-related complex. AIDS 1990;4:264. 21. Tindall B, Finlayson R, Mutimer K, et al. Malignant melanoma associated with human immunodeficiency virus infection in three homosexual men. J Am Acad Dermatol 1989;20:587-91. 22. van Ginkel CJW, Sang RTL, Blaauwgeers JLG, et al. Multiple primary malignant melanomas in an HIV-positive man. J Am Acad Dermatol 1991;24:284-5. 23. Rasokat H, Steigleder GK, Kendick C, et al. Malignes Melanom und HIV-Infektion. Z Hautkr 1989;64:581- 7. 24. Kraemer KH, Lee MM, Scotto J. Xeroderma pigmentosum: Cutaneous, ocular, and neurologic abnormalities in 830 published cases. Arch Dermatol 1987;123:241-50. 25. Kraemer KH, Slor H. Xeroderma pigmentosum. matol 1985;3:33-69.
Clin Der-
26. Kraemer KH, Lee MM, Scotto J. DNA repair protects against cutaneous and internal neoplasia: Evidence from xeroderma pigmentosum. Carcinogenesis 1984;5:51 l-4. 27. Longstreth JD, editor. Ultraviolet radiation and melanoma with a special focus on assessing the risks of stratospheric ozone depletion. Washington, DC: US Environmental Protection Agency, 1987. 28. Keyse SM, Moss SH, Davies DJG. Action spectra for inactivation of normal and xeroderma pigmentosum human skin fibroblasts by ultraviolet radiations. Photochem Photobiol 1983;37:30712. 29. Ramsay CA, Giannelli F. The erythemal action spectrum and deoxyribonucleic acid repair synthesis in xeroderma pigmentosum. Br J Dermatol 1975;92:49-56. 30. Wolff S, Rodin B, Cleaver JE. Sister chromatid exchanges induced by mutagenic carcinogen in normal and xeroderma pigmentosum cells. Nature 1977;265:347-9. 31. Schallreuter KU, Wood JM, Pittelkow MR. Xeroderma pigmentosum patients have defects in anti-oxidant defense against oxygen radicals and peroxides. J Invest Dermatol 1991;96:599. Abstract. 32. Norris PG, Limb GA, Hamblin AS, et al. Immune function, mutant frequency, and cancer risk in the DNA repair defective genodermatoses xeroderma pigmentosum, Cockayne’s syndrome, and trichothiodystrophy. J Invest Dennatol 1990;94:94-100. 33. Swift M, Chase C. Cancer in families with xeroderma pigmentosum. J Nat1 Cancer Inst 1979;62:1415-21. 34. Lynch HT, Fusaro RM, Johnson JA. Xeroderma pigmentosum: Complementation group C and malignant melanoma. Arch Dermatol 1984;120:175-9.
18. Merkle T, Braun-Falco 0, Friischl M, et al. Malignant melanoma in human immunodeficiency virus type 2 infection. Arch Dermatol 1991;127:266-7.
35. Jung EG, Bohnert E, Fischer E. Heterogeneity of xeroderma pigmentosum (XP): Variability and stability within and between the complementation groups C, D, E, I and variants. Photodermatology 1986;3:125-32.
19. Moore GE, Cook DD. AIDS in association with malignant melanoma and Hodgkin’s disease. J Clin Oncol 1985; 3:1437.
36. Fukuro S, Yamaguchi J, Mamada A, et al. Xeroderma pigmentosum group D patient bearing lentigo maligna without neurological symptoms. Dermatologica 1990;181:129 -33.
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37. Takebe H, Nishigori C, Satoh Y. Genetics and skin cancer of xeroderma pigmentosum in Japan. Jpn J Cancer Res 1987;78:1135-43.
57. Luande J, Henschke CI, Mohammed N. The Tanzanian human albino skin: Natural history. Cancer 1985;55:18238.
38. Lynch HT, Frichot BC, Lynch JF. Cancer control in xeroderma pigmentosum. Arch Dermatol 1977;113:193-5.
58. van der Esch El’, Rampen FHJ. Punch biopsy of melanoma. J Am Acad Dermatol 1985;13:899-902.
39. Froggatt P. Albinism in Northern Ireland. Ann Hum Genet (London) 1960;24:213-38.
59. Schulze KE, Rapini RI’, Duvic M. Malignant melanoma in oculocutaneous albinism. Arch Dermatol 1989;125:15836.
40. McLeod R, Lowry RB. Incidence of albinism in British Columbia (B.C.). Separation by hairbulb test. Clin Genet 1976;9:77-80. 41. Bhende YM. Malignant amelanotic melanoma of the skin in an albino. Indian J Med Sci 1952;6:755-9. 42. Young TE. Malignant melanoma in an albino. Arch Path01 1957;64:186-91. 43. Leonardi R, Grass0 S. Melanoblastoma matol 1958;33:24-26.
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44. Higginson J, Oettle AG. Cancer incidence in the Bantu and “Cape Colored” races of South Africa: Report of a cancer survey in the Transvaal (1953-55). J Nat1 Cancer Inst 1960;24:589-671.
60. Casswell AG, McCartney ACE, Hungerford JL. Choroidal malignant melanoma in an albino. Br J Ophthalmol 1989;73:840-5. 61. Hiinigsmann H, Wolff K, Fitzpatrick TB, et al. Oral photochemotherapy with psoralens and UVA (PUVA): Principles and practice. In: Fitzpatrick TB, Eisen AZ, Wolff K, et al, editors. Dermatology in general medicine. New York: McGraw-Hill Book Co, 1987:1533-58. 62. Stern RS, Lange R, et al. Non-melanoma skin cancer occurring in patients treated with PUVA five to ten years after first treatment. J Invest Dermatol 1988;91:120-4.
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63. Gschnait F, Wolff K, Honigsmann H, et al. Long-term photochemotherapy: Histopathological and immunofluorescence observations in 243 patients. Br J Dermatol 1980;103:11-22.
47. Duron RA. Melanoma malign0 de1 albino. Rev Med Honduras 1965;33:149-56.
64. Rhodes AR, Stem RS, Melski JW. The PUVA lentigo: An analysis of predisposing factors. J Invest Dermatol 1983;81:459-63.
45. Kennedy BJ, Zelickson AS. Melanoma in an albino. JAMA 1963;186:839-41. 46. Oettle AG. Skin 1963;10:197-214.
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48. Garrington GE, Scofield HH, Cornyn J, Lacy GR. Intraoral malignant melanoma in a human albino. Oral Surg Oral Med Oral Path01 1967;24:224-30. 49. Oluwasanmi JO, Williams AO, Alli AF. Superficial cancer in Nigeria. Br J Cancer 1969;23:714-28. 50. Halama J, Sziegoleit M. Zur Kasuistik des Melanomalignoms bei Albinos. Strahlentherapie 1974;148:1368. 5 1. Alpert LI, Damjanov I. Malignant melanoma in an albino: Diagnosis supported by ultrastructure. Mt Sinai J Med 1977;45:447-50. 52. Stoll DB, Ruschak P, Kauh Y, et al. Lentigo maligna in a woman with oculocutaneous albinism. Arch Dermatol 1981;117:360-1. 53. Scott MJ, Giacobetti R, Zugerman C. Malignant melanoma with oculocutaneous albinism. J Am Acad Dermatol 1982;7:684-5. 54. Wood C, Graham D, Willsen J, Strefling A. Albinism and amelanotic melanoma: Occurrence in a child with positive test results for tyrosinase. Arch Dermatol1982;118:283-4. 55. Pehamberger H, Hijnigsmann H, Wolff K. Dysplastic nevus syndrome with multiple primary amelanotic melanomas in oculocutaneous albinism. J Am Acad Dermatol 1984; 11:731-5. 56. Kinnear PE, Tuddenham EGD. Albinism with haemorrhagic diathesis: Hermansky-Pudlak syndrome. Br J Ophthalmol 1985;69:904-8.
65. Rhodes AR, Harrist TJ, Momtaz K. The PUVA-induced macule: A lentiginous proliferation of large, sometimes cytologically atypical, melanocytes. J Am Acad Dermatol 1983;9:47-58. 66. Gupta nomas A case Study.
AK, Stern RS, Swanson NA, et al. Cutaneous melain patients treated with psoralens plus ultraviolet A: report and the experience of the PUVA Follow-up J Am Acad Dermatol 1988;19:67-76.
67. Swerdlow AJ, English JSC, Ma&e RM, et al. Fluorescent lights, ultraviolet lamps, and risk of cutaneous melanoma. Br Med J 1988;297:647-50. 68. Walter SD, Marrett LD, From L, et al. The association of cutaneous malignant melanoma with the use of sunbeds and sunlamps. Am J Epidemiol 1990;131:232-43. 69. Adam SA, Sheaves JK, Wright NH, et al. A case-control study of the possible association between oral contraceptives and malignant melanomas. Br J Cancer 1981;44:4550. 70. Beitner H, Norell SE, Ringborg U, et al. Malignant melanoma: Aetiological importance of individual pigmentation and sun exposure. Br J Dermatol 1990;122:43-51. 71. Elwood JM, Williamson C, Stapleton PJ. Malignant melanoma in relation to moles, pigmentation, and exposure to fluorescent and other lighting sources. Br J Cancer 1986;53:65-74.
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72. English DR, Rouse IL, Xu Z, et al. Cutaneous malignant melanoma and fluorescent lighting. J Nat1 Cancer Inst 1985;74:1191-7. 73. Garbe C, Kruger S, Stadler R, et al. Markers and relative risk in a German population for developing malignant melanoma. Int J Dermatol 1989;28:517-23. 74. Holly EA, Kelly JW, Shpall SN, Chiu S-H. Number of melanocytic nevi as a major risk factor for malignant melanoma. J Am Acad Dermatol 1987;17:459-68.
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75. Klepp 0, Magnus K. Some environmental and bodily characteristics of melanoma patients. A case-control study. Int J Cancer 1979;23:482-6. 76. Ma&e RM, Freudenberger T, Aitchison TC. Personal riskfactor chart for cutaneous melanoma. Lancet 1989;2:48790. 77. Osterlind A, Tucker MA, Stone BJ, Jensen OM. The Danish case-control study of cutaneous malignant melanoma. II. Importance of UV-light exposure. Int J Cancer 1988; 42:319-24.
A. WEINSTOCK,
MD, PHD
A
human model for melanoma is a circumstance in which melanoma is particularly common. We can use models to gain an understanding of melanoma in two ways: (1) by studying the differences between the model and general susceptible population, we can link those differences to the etiology and pathogenesis of melanoma; (2) by studying differences in melanoma susceptibility among individuals in the model circumstances, we may be able to identify more readily etiologic factors and mechanisms. This article considers the potential of immunosuppression, xeroderma pigmentosum, albinism, psoralen photochemotherapy (PUVA), and artificial high-dose ultraviolet radiation exposures to serve as models for melanoma. Familial melanoma, another model, is discussed by Bergman and Fusaro elsewhere in this issue.
Immunosuppression The immune system has long been thought to play an important role in the etiology of melanoma because of the inflammation commonly observed in association with primary lesions, the foci of apparent regression that is a frequent clinical feature of these lesions, and the documented instances of complete spontaneous regression, even of metastatic disease.’ Several groups of immunosuppressed patients have been shown to have an increased incidence of melanoma. One of the most frequently studied models is Hodgkin’s disease. Most (but not all) of the reports of long-term From the Dermatoepidemiology Unit, VA Medical Center, Roger Williams Medical Center and Brown University School ofMedicine, Providence, Rhode Island. Address correspondence to Martin A. Weinstock, Dermafoepidemiology Unit-2121, VA Medical Center, 830 Chalkstone Avenue, Providence, RI 02908. Supported by National Cancer Institute Grant 49531 and Department of Veterans'Affairs medical research funds.
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1992 by Elsevier
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Co., Inc.
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follow-up of Hodgkin’s disease patients have noted that their risk was at least double the risk expected in the general population. 2-6 Similar observations have been made for non-Hodgkin’s lymphoma2*’ and leukemia,2*8 but not for most other common sites of malignancy.2~9J0 Organ transplantation is another human model of immunosuppression. Both renal transplant recipients” and bone marrow transplant recipientG appear to have a severalfold increase in melanoma incidence, although there is some uncertainty regarding the magnitude of the risk because of the small numbers of cases. One study suggested a particularly close association between melanoma and nevi in the renal transplant population.13 The genetic immunodeficiency disorders may also predispose to melanoma. l4 There have been numerous case reports of melanoma among human immunodeficiency virus (HIV)-infected patients. 15-** One report suggests that melanoma is more common than expected among HIV-infected dermatology patients, 23 but the data currently available are insufficient to establish the melanoma incidence rate in this group or any link to degree of immunodeficiency. These models undoubtedly will be further elucidated as the recorded experience with them expands.
Xeroderma Pigmentosum Xeroderma pigmentosum (XP) is a group of genetic disorders with characteristic clinical features and defective DNA repair. **s*~The clinical features include acute photosensitivity in early infancy, which is classically the first sign although it may frequently be absent. This is followed by the more consistently present freckling in sunexposed areas which, by early childhood, develops into actinic poikiloderma (mottled hypo- and hyperpigmentation with telangiectasia, atrophy, and xerosis). The actinic poikiloderma is a dramatic finding, even in dark-skinned blacks afflicted with this disorder.
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Corresponding changes occur in exposed mucous membranes and the eyes. Actinic keratoses and other dysplastic neoplasms appear in the affected areas; cutaneous malignancies typically follow during childhood. Neurologic abnormalities are characteristic of a subgroup. The incidence of melanoma in Xl’ is extraordinarily high: before the age of 20 years, more than 2000 times higher than the general population.26 It is suspected that the most etiologically relevant difference between XI’ and normal individuals with respect to melanoma incidence is DNA repair in epidermal melanocytes of ultraviolet B radiation (UVB)-induced pyrimidine dimers, yet several pathogenic mechanisms must be considered.*’ The evidence of particular susceptibility to UVB is strong.28,29 Cell lines from XP patients are also particularly susceptible to certain chemical carcinogens.30 XI’ patients appear to have reduced defenses against peroxides and oxygen radicals3i Patients with XI’ also have reduced natural killer cell function, and may have other disorders of immune function.32 It is not known whether these other deficiencies are due to the DNA repair defect. Two other syndromes are associated with DNA repair defects: Cockayne’s syndrome and trichothiodystrophy. These disorders, however, have not been associated with increased melanoma risk. Hence, although defective DNA repair may well be the key component in the extraordinarily high melanoma incidence in XI’, the relative importance of the various abnormalities found in XI’ for melanoma risk remains to be ascertained. It is nevertheless clear from the XI’ model that genetic defects can have a remarkable effect on melanoma risk. Relatives of XI’ patients have not been shown to have an elevated melanoma risk. One study found no melanoma history among 10 16 blood relatives of XI’ patients, compared with 3 spouse controls who did have this history.33 Differences in melanoma risk within the XI’ population are not well documented. A report of cases from the United States suggested that the complementation group C subtype might be more susceptible to melanoma than other subtypes. 34 Similar claims have been made for complementation group D based on cases from Germany. 35 Reports of Japa nese cases do not clearly support either hypothesis. 36,37 These data must be evaluated cautiously; the numbers of cases evaluated are small, correction for age or other variables and even simple significance testing were not performed, and the cases studied were presumably not independent observations, as the number of families represented is presumably substantially less than the number of cases, and melanoma is known to aggregate in families. Anecdotal evidence supports the presumption that meticulous protection from ultraviolet radiation will prevent
the occurrence of melanoma in these patients.34,38 Clearly the anatomic distribution of melanoma in XI’ (65% on the head and neck) supports a direct and potent etiologic role of sun exposure in this genetically hypersusceptible grou~.*~ Other evidence regarding determinants of melanoma incidence among XI’ patients is lacking. Although this review focuses on the etiology of melanoma, it has also been observed that a relatively high (but still tiny) proportion of melanomas in XP patients spontaneously resolve.34
Albinism Oculocutaneous albinism is a group of genetic disorders characterized by white or light skin and hair color, nystagmus, and photophobia caused by a relative or absolute inability to synthesize melanin. The prevalence of albinism itself has been estimated to be 4 to 13 per 100,000 in Caucasian populations. 39,40 These estimates may vary with ethnicity and in particular may be higher in populations with dark natural skin color (which facilitates diagnosis) or significant inbreeding. Among albinos in one Canadian population-based series, one third were tyrosinase negative, that is, completely unable to produce melanin.40 Melanoma occurs in albinos, although its incidence in this group is unknown. Some have speculated that the incidence is high46; others, that it is 10w.~* Twenty-two reports are summarized in Table 1. If one were to assume that albinos had the same melanoma risk as Caucasians and that the previously cited prevalence estimates of albinism apply to the U.S. population, then the incidence of melanoma in albinos in the United States would have been approximately one to two cases per year during the past decade. It is therefore noteworthy that three albino patients with invasive melanoma and one each with in situ melanoma and lentigo maligna were reported in the United States in the 1980s (see Table 1). This is a small number of cases, yet it is reasonable to assume that the vast majority of cases are not published and, therefore, that the incidence of melanoma in albinos is at least roughly similar to the incidence in the general population, if not higher. It is notable nevertheless that more cases have not been reported, which strongly suggests that the incidence of melanoma in albinos is not increased by several orders of magnitude, as is observed with XI’. Photoprotection from the small amount of pigment made by tyrosinasepositive albinos cannot explain the limited number of melanoma case reports, as most of the sufficiently detailed reports (including all three invasive U.S. cases from the 1980s) are of tyrosinase-positive individuals. We may therefore infer that even in the absence of melanin, the
5811 59 59 60
56 57
47§ 48 49 50 51 52 53 54 55
41 42 43 44 45 46 46
England Tanzania The Netherlands United States United States England
India United States Italy South Africa United States South Africa South Africa Honduras United States Nigeria Germany United States United States United States United States Austria
Geographic Location Sex M F M F M M ? M M F M M F M M F M ? F F M F
Age 27 40 30 ? 38 ? ? 22 45 50s 42 19 54 42 14 40 58 ? 46 27 43 22 White White Hispanic White
? ?
Hindu White ? Bantu ? Bantu ? ? White Black White White Black ? ? White
Ethnic Group
? ? Yes No Yes Yes
Positive (HI’S) ? Positive Positive ? Positive
? ? ? AN None ?
None
None
? ? ? ? -
Mucosal ? ? ? Lentigo maligna ? Polyploid 1 nodular, 3 SSM ? ? SSM SSM In situ Ocular No Yes ? No Yes Yes Yes
Yes
-
Leg ? Lower leg Upper back Shoulder Choroid
Leg Knee Shoulder, leg, arm, arm
Lumbar region Calf Back ? Thigh Lower lip ? Occult primary Buccal gingiva Anal canal Back Knee Back
CN ? ? ? CN ? ? -
Anatomic Site
Precursor Lesion*
7 ? ? ? ? ? ? -
Qwt
Histologic
Yes ? ? ? Yes ? ? -
Positive ? D-(t),EM-(t) ? ? FM-(t) FM-(t) Positive ? FM-(t)Em+(t) Positive Positive Positive Negative
(neg),D-0)
D-W)
Tyrosinase Status*
Primary Lesion Amelanotic?
1.25 4.21 1.5, 1.9, 0.4, 0.7 ? ? 2.11 0.78 ?
? ? ? ? ? ? ? ? ? ? ? -
Thickness of Primary in (mm)
No ? No No No No
Yes Yes Yes ? Yes ? ? Yes Yes Yes Yes Yes No No No No
Known Metastatic Disease
2Y 2Y 0
Y ? 1 mo
2 yr 2 y, 0, 0
1Y 0 4mo 0 0
0 1 mo ? ? 3mo ? ? 3mo 0 ?
Duration of MetastasisFree Follow-up
l
D-_(t), tumor reported to be dopa negative; D-W, tvmorand normal skin reported to be dopa negative; EM-_(t), no evidence of melanin deposition observed in tumorsections with electron microscopy; EM+(t), electron microscopy of tumor cells revealed “lightly pigmented” melanosomes wtth granular material thought to represent “abortive melanogenesis’: (negJ, presumed tyrosinase negative because the clinical description mentioned completely white scalp and body hair (except for slight yellowing of the distal scalp hairs) and irides “without color’: FM--O, no evidence of melanin observed in tumor sections after staining with Fontana-Masson; HPS, Herman&-Pudtak syndrome. t SSM, superficial spreading melanoma. $ AN, acquired nevus; CN, congenital nevus. 6 The diagnosis was suspected but not proven by the histologic findings. 7 Additional features from personal communication, F. H. J. Rampen, 1991.
1985 1985 1985 1987 1987 1989
1952 1957 1958 1960 1963 1964 1964 1965 1967 1969 1974 1977 1981 1982 1982 1984
Year of Report and Reference
Table 1. Cases of Malignant Melanoma and Lentigo Maligna in Albinism
86
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1992;10:83-89 skin has important mechanisms for protection against melanoma. Other factors must also be considered. In tropical, developing countries, albinos frequently die of metastatic squamous cell carcinoma at an early age, perhaps before a potential melanoma has fully developed. In developed countries in temperate climates, albinos may be particularly assiduous in protecting themselves from the sun, unlike their nonalbino lightly pigmented sun-worshipping contemporaries. Indeed, the large case series of albinos with nonmelanoma skin cancer derive from tropical, not temperate climates. It is also of interest that only one case was clearly documented to be tyrosinase negative. This may be a result of the relative difficulty of documenting the absence of tyrosinase activity, which requires specialized laboratory techniques, and the relative ease of documenting its presence, as any clinical or microscopic manifestation of melanin production is sufficient. One can hope that additional data will elucidate the true risk of melanoma in albinos and therefore contribute to our understanding of the roles of melanin and sun-related behaviors in the etiology of melanoma.
Psoralens With Ultraviolet Light The use of psoralens with ultraviolet A light (PUVA) for psoriasis appears to cause a dramatic increase in the incidence of squamous cell carcinoma of the skin, and has also been associated with basal cell carcinoma and other cutaneous abnormalities usually attributed to solar ultraviolet radiation.61*62 The psoralen compound intercalates in DNA and causes crosslinks when photoactivated with UVA. PUVA is also known to have immunosuppressive effects. The effects of PUVA on melanocytes are pronounced, and indeed are used therapeutically in the treatment of vitiligo. Of particular relevance here are the mottled pigmentary disturbances and PUVA lentigines which are frequently observed.63*64 The latter have not been directly linked to melanoma, but are characterized by hypertrophic and sometimes atypical melanocytes.65 Numerous case reports of melanoma in PUVA-treated patients have been published; however, in the largest follow-up study to date of PUVA-treated patients (1380 patients followed for an average of 10 years) only 3 melanomas were found (versus 2.05 expected if PUVA did not affect risk). 66 Longer follow-up of patients in this and other large series will be required to determine whether PUVA increases melanoma risk.
Other Artificial Ultraviolet Light Exposures Many Caucasians expose themselves to artificial sources of ultraviolet radiation such as sunbeds, sunlamps, and
medical phototherapy devices (without ingestion of photosensitizing chemicals) for cosmetic or therapeutic purposes. These individuals have not been the subject of large-scale cohort investigation, so our knowledge of the relationship of these exposures to melanoma derives from case - control studies. Although the artificial ultraviolet radiation exposures from these sources can be characterized as intense, they are otherwise quite diverse and poorly differentiated from each other in case-control studies. Some presumably included large amounts of ultraviolet B radiation (280 to 320 nm); others may have involved primarily ultraviolet A (above 320 nm); and some may have contained significant quantities of ultraviolet C (below 280 nm), which is not part of the terrestrial solar radiation spectrum. This further complicates the interpretation of the epidemiologic evidence. Two studies have found a significant association of these exposures with melanoma, as well as a biologically plausible gradient of risk with exposure characteristic~~‘*~~;one found a significant effect and did not report a risk gradienP9; eight others found no association.70-77 The lack of detailed analysis on this point among many of the negative studies precludes detailed comparisons.
Conclusions A variety of special exposures or genetic defects serve as potential human models for melanoma and, therefore, provide additional perspective on the importance of several actual and possible causes. Further study of these situations may yield more definitive conclusions with important implications for understanding melanoma in the population
at large.
Acknowledgments Dr. Walter Quevado assisted in the interpretation of published melanosome electron micrographs. Thanks to Dr. Richard King for his comments regarding albinism, and Dr. Kenneth Kraemer and Dr. Anthony Gaspari for their comments regarding xeroderma pigmentosum. Dr. Victor Pricolo and Dr. A. Hermann Schmid were most helpful with translations.
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