Cutaneous melanoma and bilateral retinoblastoma

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Cutaneous melanoma and bilateral retinoblastoma Lee S. Albert, MD, Arthur J. Sober, MD, and Arthur R. Rhodes, M D

Boston, Massachusetts We report the case of an otherwise healthy 37-year-old man who had had bilateral enucleation during early childhood for bilateral retinoblastomas, in addition to two cutaneous melanomas (the first appearing at age 27 years). He also had dysplastic melanocytic nevi and a history of cutaneous melanoma in his mother. Retinoblastoma may aggregate in families and is associated with DNA abnormalities of chromosome 13. Recent reports have emphasized the appearance of second malignancies in retinoblastoma survivors. The second malignancies include osteosarcoma, soft tissue sarcoma, and cutaneous melanoma. Cutaneous melanoma also may aggregate in families, usually in the setting ofdysplastic melanocytic nevi. The features of this case and of similar reported cases suggest that there may be a greater than expected association between retinoblastoma and cutaneous melanoma. (J AM ACAD DERMATOL 1990;23:1001-4.) Retinoblastoma may aggregate in families as an autosomal dominant trait that results from a mutation or deletion of chromosome 13.1 Cutaneous melanoma also may aggregate in families and may be strongly associated with dysplastic melanocytic nevi ( D M N ) . D M N are believed to be potential precursors of melanoma as well as markers of increased risk of melanoma. 2 Autosomal dominant and polygenetic modes of inheritance have been proposed for familial D M N and cutaneous melanoma. 2-5 Linkage analysis has been used to localize a putative familial melanoma gene to chromosome 1.6, 7 W e report the case of a man who was treated for bilateral retinoblastomas during early childhood and in whom two cutaneous melanomas subsequently developed during adulthood. He also had histologically documented D M N and a family history of cutaneous melanoma. Although retinoblastoma and cutaneous melanoma previously have been reported in the same patient, g"19the association between a hereditary form of retinoblastoma (i.e., bilateral retinoblastoma) and a hereditary form of melanoma (i.e., familial cutaneous melanoma occurring in the setting of D M N ) is particularly strikFrom the Dermatology Service, Massachusetts General Hospital, and the Department of Dermatology, Harvard Medical School. Supported in part by National Institutes of Health grant No. 5T32AR07098-15 (L. S. A.) and by the Marion Gardner Jackson Trust (Bank of Boston, Trustee) (A. J. S.). Reprint requests: Arthur R. Rhodes, MD, Dermatology, University of Pittsburgh School of Medicine, 3601 Fifth Ave., Pittsburgh, PA 152t3. 16/4/15993

ing. Retinoblastoma and cutaneous melanoma may represent manifestations of a single cancer susceptibility trait, closely linked cancer traits, or a chance occurrence of two relatively uncommon cancers in the same person. CASE REPORT

A 27-year-old blind white man of Italian extraction was examined at the Pigmented Lesion Clinic of Massachuetts General Hospital on June 29, 1979, because of a lesion on the upper part of the back that had changed during the previous 4 to 6 months. A preexisting lesion had been present at the site since early infancy or birth. At age 18 months he was treated for bilateral retinoblastomas by enucleation of the left eye, orbital radiation (9600 tad), and chemotherapy with 18.5 mg parenteral triethylenemelamine. The right eye was enucleated when the patient was 35 months of age. As an adult he had excisions of a compound nevus, a lipoma, and an epidermal nevus. He had no prior personal history of cutaneous melanoma. The patient had blue eyes before surgical enucleation. He reported that during his younger years he burned easily and tanned only with great difficulty (type II skin). His mother had had a melanoma excised from her leg at age 51 years. The patient's father was stated to have died of a heart attack at age 60 years. The patient's mother and one of three brothers, examined by the same dermatologist, were said to be free of atypical-appearing nevi. We were not able to examine family members who lived out of state. A family history of retinoblastoma was denied. Communication with the family's ophthalmologist revealed that both parents had been carefully examined and were believed to be free of ocular tumors. At the time of the patient's birth, the patient's father was 35 years old and his mother 33 years old. 1001

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Examination of the patient in 1979 revealed a wellappearing man who had red hair, bilateral eye prostheses, marked freckling on sun-exposed sites, and a slightly elevated plaque, 15 • 12 ram, with markedly irregular borders and brown, black, blue, and red variegations, located on the left upper part of the back. Total excision and histopathologic examination revealed superficial spreading melanoma invasive to anatomic level II, 0.4 mm microscopic tumor thickness, in contiguity with a benign dermal nevus (but no detectable DMN). Neither clinical evidence of metastatic disease nor other lesions considered suspicious for melanoma were observed. He had five other nevi with a diameter of 5 mm or larger. Baseline photographs of the nevi were obtained, and he was examined annually. On July 2, 1985, a mole suspected of malignancy was excisedfrom the left side of the groin and was interpreted as a DMN with focal moderate cellular atypia of the intraepidermal component. On Feb. 27, 1987, a brown-tan nevus (8 mm in greatest diameter) on the left upper part of the shoulder was noted to have changed from a preexisting nevus seen in prior photographs. Excision and histopathologic examination revealed superficial spreading melanoma, invasive to anatomic level II, 0.55 mm microscopictumor thickness, arising in contiguity with a DMN. At his most recent examination on April 28,1989, the patient had no evidence of metastatic disease or other nevi suspected of malignancy. DISCUSSION

The occurrence of D M N and multiple primary cutaneous melanomas in a person who has a family history of melanoma is believed to represent a hereditary trait. 3 The presence of bilateral retinoblastoma (or of unilateral retinoblastoma in a person who has a positive family history of retinoblastoma) is also believed to represent a hereditary trait. 1 The occurrence of retinoblastoma and familial melanoma in the same person suggests either hereditary linkage between these two diseases or, alternatively, the chance occurrence of two rare diseases. Recent reports have emphasized the occurrence of second malignancies in survivors of retinoblastoma, including osteosarcoma, soft tissue sarcoma, and cutaneous melanoma. 8-2~The cumulative incidence of second malignancies in retinoblastoma survivors 20 years after diagnosis has been reported to be as low as 3.4%20 and as high as 50%. 8 The reasons for such variability in incidence of second malignancies are numerous and may include bias in case selection (patients who have unusual diseases m a y be more likely to be referred to reporting institutions), bias in ascertainment (patients who have had one malignancy are subsequently followed up

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more closely), and bias in reporting (two rare events that occur in the same person are more likely to be reported). Occurrence of second malignancies raises the possibilities of hereditary linkage, versus chance. Such is the ease of cutaneous melanoma in retinoblastoma survivors. Numerous reports of cutaneous melanoma and retinoblastoma in the same patient have been published.8~ 9 Traboulsi et al. 13 estimated that cutaneous melanomas represented 7% of second malignancies in retinoblastoma survivors. A n association between retinoblastoma and D M N also has been reported. Tucker et al. 18 examined 45 patients who had retinoblastoma and a second malignancy, three of whom had cutaneous melanoma, and five of whom (including the three who had melanoma) also had DMN. The prevalence rate of D M N has been observed to be 2% to 5 % in white adults in the United States2~, 22 and as high as 7% in Australia. 23 Traboulsi et al. 13 reported six survivors of retinoblastoma in whom cutaneous melanoma developed; two of the six survivors had D M N and multiple primary cutaneous melanomas. Several explanations have been offered for second malignancies in survivors of retinoblastoma. Radiation therapy may be causally related, except that second primary malignancies occur even in patients who are not treated with radiation. 8, 11 Moreover, in retinoblastoma patients who are treated with radiation, second primary malignancies often develop outside the field of radiation.8 Cutaneous melanoma within the field of radiation appears to be a rare event. In two of six retinoblastoma survivors reported by Traboulsi et al. 13 and in one of two retinoblastoma survivors reported by Draper et al., 9 cutaneous melanoma developed in a radiation field. In contrast, in two retinoblastoma patients reported by Der Kinderen et al., 19five by Meadows et al., 1~four by Abramson et al., 8 one by Tefft et al., 16 and three by Tucker et al., 18 cutaneous melanoma developed at sites outside the field of radiation. The controversy surrounding the role of radiation exposure in the causation of cutaneous melanoma is not settled. 24, 25 Of 1130 patients who had cutaneous melanoma in the Melanoma Clinical Cooperative Group, 26 radiation therapy was not believed to be a factor in any case (A. J. S., personal observation). The patient described herein received parenteral chemotherapy with triethylenemelamine, a known mutagen. 27 Chemical mutagens theoretically might increase the risk of a second cancer. However, none of the previously reported cases of cutaneous mela-

Volume23 Number 5, Part 2 November 1990 noma in retinoblastoma survivors was stated to be associated with chemotherapy,s-19 In retinoblastoma survivors, eyclophosphamide has been implicated in second primary cancers, particularly osteosarcoma, but not in cutaneous melanoma.9 According to one study, no evidence of an increased risk of developing nonocular cancer was found in retinoblastoma survivors who had been treated with cyclophosphamide and triethylenemelamine, alone or in combination. 19 Blood relatives of persons who have had hereditary retinoblastoma have an increased risk for nonocular cancer. 2s-30 Der Kinderen et a1.15,19studied the families of 141 patients who had hereditary retinoblastoma and found pancreatic cancer in three fathers. Bergman et al.3t reported an excess of pancreatic cancer in two familial cutaneous melanoma kindreds. On the basis of this association, Der Kinderen et al. 15 hypothesized a link between retinoblastoma, cutaneous melanoma, and pancreatic cancer. One recent study found no increased risk of nonocular cancer in parents of children with retinoblastoma. 2~ Bilateral retinoblastoma is believed to represent an autosomal dominant trait, but neither of our patient's parents had evidence of retinoblastoma. The cause of our patient's bilateral retinoblastoma may be a germinal mutation, and the occurrence of cutaneous melanoma in the patient and his mother could be unrelated to the retinoblastoma. Alternatively, the two cancers may be linked and nonpenetrance could account for the absence of the retinoblastoma trait in the mother)' 32 Mosaicism for the retinoblastoma trait also is a possible explanation for the absence of retinoblastoma in our patient's mother. 1.32 Chromosome 13 is believed to be the site of the retinoblastoma locus. According to the "two hit" hypothesis of carcinogenesis,33 a germinal abnormality and a subsequent somatic mutation are believed to lead to familial retinoblastoma, whereas two somatic mutations are believed to be required to produce nonfamilial retinoblastoma. Retinoblastoma tumor cells in some cases have homozygous deletions of a segment on chromosome 13.34 In familial cutaneous melanoma kindreds, autosomal dominant inheritance for D M N has been implicated on the basis of segregation analyses of pedigrees. 2-4 According to linkage analysis in melanoma-prone families, a putative gene for D M N and cutaneous melanoma has been mapped to chromosome 1.6.7 A

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true link between familial cutaneous melanoma and retinoblastoma might suggest the possibility of chromosome 13 involvement as well. Using Southern blot analysis to study retinoblastoma and cutaneous melanoma cells in vitro, Friend et aI.34 detected homozygous chromosome 13 deletions in 7 of 49 retinoblastoma cell lines but in none of 17 cutaneous melanoma cell lines obtained from patients with neither a personal nor family history of retinoblastoma. Although the role of chromosome 13 abnormalities in at least some cases of cutaneous melanomas cannot be excluded, such a role has not been demonstrated. Familial cutaneous melanoma, DMN, and retinoblastoma appear to aggregate in the same person more frequently than can be expected on the basis of chance alone. According to Connecticut Tumor Registry data, the prevalence rate of cutaneous melanoma in 1982 was 80.6 per 100,000 for men (or 1/1241) and 77.0 per 100,000 for women (1/ 1298). 35 Therefore the expected prevalence rate of cutaneous melanoma in retinoblastoma survivors should be no greater than 1 per 1200 persons. (It should be recalled that the lifetime cutaneous melanoma risk in white persons is 1 in 123.21) The cumulative incidence of retinoblastoma during childhood, which can be used as an upper estimate of prevalence of retinoblastoma in adults (assuming survival), is between 1 in 15,000 and 1 in 28,000.1 The true prevalence of retinoblastoma among adults is likely to be lower because of the mortality risk associated with the tumor. For purposes of this discussion, using the higher figure of 1 per 15,000 as an estimate of the prevalence of retinoblastoma in adults, we propose that if the association between melanoma and retinoblastoma were purely by chance, then the likelihood of both diseases occurring in the same person is estimated to be less than 1 in 18 million (the product of 80.6/100,000 and 1/ 15,000). The numerous cases of associated retinoblastoma and cutaneous melanoma suggest that the two events are not likely to occur in the same person on the basis of chance alone. A lifetime study of retinoblastoma survivors would be hdpful in detecting a link with cutaneous melanoma. Our report supports a putative association between retinoblastoma and familial cutaneous melanoma. Genetic linkage may exist between retinoblastoma and familial cutaneous melanoma, although a chance association is also possible. Although a personal history of retinoblastoma ap-

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p e a r s to b e a risk f a c t o r f o r c u t a n e o u s m e l a n o m a , t h e r e w e r e no cases o f r e t i n o b l a s t o m a a m o n g 1130 cases o f c u t a n e o u s m e l a n o m a r e c o r d e d b y t h e Mela n o m a C l i n i c a l C o o p e r a t i v e G r o u p before 197826 (A. J. S., p e r s o n a l o b s e r v a t i o n ) . F u r t h e r s t u d y is req u i r e d to d e t e r m i n e t h e s t r e n g t h of association between retinoblastoma and cutaneous melanoma. Until m o r e i n f o r m a t i o n is available, e x a m i n a t i o n of r e t i n o b l a s t o m a survivors for a t y p i c a l moles and early m e l a n o m a m a y b e p r u d e n t . REFERENCES

1. Vogel F. Genetics ofretinoblastoma. HumGenet 1979;52:154. 2. Greene MH, Clark W H Jr, Tucker MA, et al. High risk of malignant melanoma in melanoma-prone families with dysplastie nevi. Ann Intern Med 1985;102:458-65. 3. Greene MH, Clark W H Jr, Tucker MA, et al. Acquired precursors of cutaneous malignant melanoma: the familial dysplastic nevus syndrome. N Engl J Meal 1985;312: 91-7. 4. Lynch HT, Fusaro RM, Kimberling W J, et al. Familial atypical multiple mole-melanoma (FAMM M) syndrome: segregation analysis. J Med Genet 1983;20:342-4. 5. Happle R, Traupe H, Vakilzadeh F, et al. Arguments in favor of a polygenic inheritance of precursor nevi [Editorial]. J AM ACAD DERMATOL 1982;6:540-3. 6. Bale S J, Dracopoli NC, Tucker MA, et al. Mapping the gene for hereditary cutaneous malignant melanoma-dysplastic nevus to chromosome lp. N Engl J Med 1989; 320:1367-72. 7. Greene MH, Goldin LR, Clark WH, et al. Familial cutaneous malignant melanoma: autosomal dominant trait possibly linked to the Rh locus. Proc Natl Acad Sci USA 1983;80:6071-5. 8. Abramson DH, EIIsworth RM, Kitchin FD, et al. Second nonocular tumors in retinoblastoma survivors: are they radiation induced? Ophthalmology 1984;91:1351-5. 9. Draper G J, Sanders BM, Kingston JE. Second primary neoplasms in patients with retinoblastoma. Br J Cancer 1986;53:661-71. 10. Meadows AT, Baum E, Fossati-Bellani F, et al. Second malignant neoplasms in children: an update from the Late Effects Study Group. J Clin Oncol 1985;3:532-8. 1 I. Abramson DH, Ronner H J, Ellsworth RM. Second tumors in nonirradiated bilateral retinoblastoma. Am J Ophthalmol 1979;87:624-7. t2. Lueder GT, Judisch F, O'Gorman TW. Second nonocular tumors in survivors of heritable retinoblastoma. Arch Ophthalmol 1986;104:372-3. 13. Traboulsi El, Zimmerman LE, Manz HJ. Cutaneous malignant melanoma in survivors of heritable retinoblastoma. Arch Ophthalmol 1988;106:1059-61. 14. Ngo RS, Ronan SG, Manaligod JR. Cutaneous malignant melanoma and bilateral retionoblastomas: a ease report and review of' the literature. Pediatr Pathol 1986;6:227-32. 15, Der Kinderen D J, Koten JW, Den Otter W, et al. Retinoblastoma, melanoma, and pancreatic cancer. Lancet 1986;2:1335-6.

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16. Tefft M, Vawter GF, Mitus A. Second primary neoplasms in children. Am J Roentgcnol 1968;103:800-22. 17. Casson AG, Maroun FB, Arnold AM, et al. Retinoblastoma, eosinophilic granuloma, and malignant melanoma: a case report. Med Pediatr Oncol 1984;12:347-8. 18. Tucker MA, Strong LC, Li FP, et al. Retinoblastoma (RB) and the dysplastic nevus syndrome (DNS): association with second primary cancers (SC), including cutaneous malignant melanoma (CMM) [Abstract]. Am Soc Clin Oncol Abs 1981;22:405. 19. Der Kinderen D J, Koten JW, Nagelkerke NJD, et al. Non-ocular cancer in patients with hereditary retinoblastoma and their relatives, lnt J Cancer 1988;41:499-504. 20. Winther J, Olsen JH, de Nully Brown P. Risk of nonocular cancer among retinoblastoma patients and their parents: a populatlon-based study in Denmark 1943-1984. Cancer ! 988;62:1458-62. 21. Rhodes AR, Weinstook MA, Fitzpatrick TB, et al. Risk factors for cutaneous melanoma: method of recognizing predisposed individuals. JAMA 1987;258:3146-54. 22. Crutcher WA, Sagebiel RW. Prcvalcnce of dysplastic nevi in a community practice [Letter]. Lancet 1984;1:729. 23. Nordlund J J, Kirkwood J, Forget BM, et al. Demographic study of clinically atypical (dysplastic) nevi in patients with melanoma and comparison subjects. Cancer Res 1985; 45:1855-61. 24. Johnson CJ. Cancer incidence in an area of radioactive fallout downwind from the Nevada test site. JAMA 1984;251:230-6. 25. Caldwell GG, Kelley D, Zack M, et al. Mortality and cancer frequency among military nuclear test (Smoky) participants, 1957 through 1979. JAMA 1983;250:620-4. 26. Sober A J, Blois MS, Clark WH Jr, et al. Primary malignant melanoma of the skin--1130 cases from the Melanoma Clinical Cooperative Group. In: Proceedings of the Fifteenth International Congress of Dermatology, Mexico City Oct 16-22, 1977. Amsterdam: Excerpta Medica, 1979. 27. Luippold HE, Gooch PC, Brewen JG. The production of chromosomal aberrations in various mammalian cells by triethylenemelamine. Genetics 1978;88:317-26. 28. Fedrick J, Baldwin JA. Incidence of cancer in relatives of children with retinoblastoma. Br Med J 1978;1:83-4. 29. Bonaiti-Pellie C, Briard-Guillemot ML. Excess of cancer deaths in grandparents of patients with retinoblatoma. J Meal Genet 1980;17:95-101. 30. Strong LC, Herson J, Haas C, et al. Cancer mortality in relatives of retinoblastoma patients. JNCI 1984;73:303-l I. 31. Bergman W, Palan A, Went LN. Clinical and genetic studies in six Dutch kindreds with the dysplastic nevus syndrome. Ann Hum Genet 1986;50:249-58. 32. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Aead Sci USA 1971;68:820-3. 33. Friend SH, Dryja TP, Weinberg RA. Oncogenes and tumor-suppressing genes. N Engl J Med 1988;318:616-22. 34. Friend SH, Horowitz JM, Gerber MR, et al. Deletions of a DNA sequence in retinoblastomas and mesenchymal tumors: organization of the sequence and its encoded protein. Proc Natl Acad Sci USA 1987;84:9059-63. 35. Feldman AR, Kessler L, Myers MH, et al. The prevalence of cancer: estimates based on the Connecticut Tumor Registry. N Engl J Med 1986;315:1394-7.