Bilateral Primary Uveal Melanoma

Bilateral Primary Uveal Melanoma Bad Luck or Bad Genes? Arun D. Singh, MD, Carol L. Shields, MD, Jerry A. Shields, MD, Patrick De Potter, MD Background: The occurrence of bilateral primary uveal melanoma has been assumed to be a rare, random event. Bilaterality of a primary cancer is suggestive of an inherited cancer predisposition. The authors therefore evaluated patients with bilateral primary uveal melanoma for such cancer predisposition. Methods: The charts of 4500 patients with uveal melanoma were reviewed for the presence of bilaterality. The clinical profile of patients with bilateral primary uveal melanoma was studied. The presence of ocular melanocytosis, familial atypical mole and melanoma syndrome, neurofibromatosis type 1, cutaneous melanoma, familial uveal melanoma, Li-Fraumeni syndrome, and second primary cancers also was investigated. Results: Of 4500 patients with primary uveal melanoma, 8 (0.18%) were identified to have bilateral primary uveal melanoma. Using the annual incidence rate (Shammas and Watzke) and normal approximation to the binomial, the expected number of patients with primary bilateral uveal melanoma in the authors' series was calculated to be less than one person. Observation of eight patients with bilateral primary uveal melanoma represented greater than expected occurrence (p < 0.0001). The mean age at diagnosis in the first eye was 56 years. The interval between the diagnosis of uveal melanoma in the two eyes ranged from 2 to 32 years (median, 10.5 years). Two patients had bilateral ocular melanocytosis. Ocular melanocytosis was more common (2/8, 25%) in patients with bilateral uveal melanoma compared with those with unilateral uveal melanoma (60/4492, 1.3%). This difference was statistically significant (P = 0.001). No relation to familial atypical mole and melanoma syndrome, cutaneous melanoma, neurofibromatosis type 1, familial uveal melanoma, second primary cancers, or Li-Fraumeni syndrome was observed. Conclusions: Bilateral primary uveal melanoma occurs more frequently than expected by chance, and may be associated with ocular melanocytosis. In the authors' series, there was no clinical evidence of an inherited genetic predisposition for bilateral primary uveal melanoma. Unidentified germ-line mutations may be involved in pathogenesis of bilateral primary uveal melanoma. Ophthalmology 1996;103:256-262

Cancers with an inherited predisposition are characterized by a family history of similar cancers, young age at diOriginally received: June IS, 1994. Revision accepted: November 14, 1995. From the Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia. Supported by the The Macula Foundation, New York, New York, and the Eye Tumor Research Foundation, Philadelphia, Pennsylvania. Reprint requests to Jerry A. Shields, MD, Oncology Service, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107.

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agnosis, multiple or bilateral primary tumors, and phenotypic associations. 1 These features are well recognized in patients with retinoblastoma, the prototype of inherited cancers. 2 Bilateral primary carcinoma in paired organs such as breast and kidney are suggestive of a genetic predisposition such as hereditary breast carcinoma and von Hippel Lindau syndrome, respectively. 3-5 The genetic basis of uveal melanoma is not known. 6 Certain predisposing factors such as ocular melanocytosis, neurofibromatosis type 1, and familial atypical mole and melanoma syndrome (FAM-M syndrome, previously

Singh et al . Bilateral Primary Uveal Melanoma termed dysplastic nevus syndrome) have been implicated for uveal melanoma.? Association between familial uveal melanoma and Li-Fraumeni syndrome, an autosomal dominant syndrome with a predisposition to multiple cancers, also has been suggested. 8 Primary uveal melanoma is rarely bilateral. 9 Since the report of Shine lO in 1930, approximately 44 well-documented cases of bilateral primary uveal melanoma have been reported worldwide. 11-29 In the absence of any identifiable predisposing factors, the occurrence of bilateral primary uveal melanoma has been assumed to be a rare, random event. Bilaterality of a primary cancer in a paired organ is indicative of a genetic predisposition. 1 Therefore, we investigated the role of genetic predisposition in eight patients with bilateral primary uveal melanoma seen at the Oncology Service of Wills Eye Hospital.

Table 1. Clinical Profile of Eight Patients with Bilateral Primary Uveal Melanoma Group Study group Patients Eyes Race White Black Asian Sex M F First affected eye Right Left Location Choroid Ciliochoroid Iridociliary Iris Treatment First affected eye Enucleation Proton irradiation None Second affected eye Plaque Enucleation Status Alive Dead

Patients and Methods The computerized database was reviewed and all patients with bilateral primary uveal melanoma that was diagnosed between July 1976 and December 1993 were identified. All patients received a diagnosis of uveal melanoma based on the ophthalmoscopic, fluorescein angiographic, and ultrasonographic appearance and confirmed histopathologically in those eyes treated by enucleation. Detailed clinical information was obtained at the time of initial presentation. Each patient underwent a complete systemic evaluation by a general oncologist to exclude the presence of a nonocular site for primary melanoma and to exclude the presence of metastatic melanoma. Relevant information, including histopathology reports, were obtained from physicians involved in the management before referral. Presence of FAM-M melanoma syndrome, cutaneous melanoma, and other nonmelanocytic primary malignancies in the proband and family members was questioned. Based on the information available, family pedigrees were constructed. The age at diagnosis of unilateral and bilateral primary uveal melanoma was statistically compared using the Student's t test. The expected incidence of bilaterality in 4500 patients with uveal melanoma in our series was calculated for statistical evaluation.

Results Since 1976, more than 4500 patients with uveal melanoma have been managed at the Oncology Service of Wills Eye Hospital. During this period, eight patients with bilateral primary uveal melanoma were identified. The clinical profile of the patients is summarized in Table 1. All eight patients (4 men and 4 women) were white. The age (mean ± standard deviation) at onset of the first uveal melanoma was 56 ± 10.52 years (range, 42-69 years) and of the second eye involvement with uveal melanoma was 68 years (range, 46-88 years). The interval between the diagnosis of first and second primary uveal melanoma ranged from 2 to 32 years (median, 10.5 years; mean,

No.

8 16 8 0 0

4 4 4 4 12

3

1 0

6 1 1*

7 1

5

3t

* Patient refused treatment.

t

Death was due to metastatic uveal melanoma in two patients.

11.8 years). The age (mean ± standard deviation) at diagnosis of our patients with unilateral primary uveal melanoma was 59.1 ± 14.26 years (range, 14-87 years). Statistically significant difference was not observed between the mean age at diagnosis of patients with unilateral involvement and patients with bilateral primary uveal melanoma (P > 0.05) (Table 2). The right eye in four patients and the left eye in four patients were affected initially. The uveal melanoma was completely within the choroid in 12 eyes and affected the ciliary body and choroid in three eyes. In one patient, the melanoma was located in the iris and ciliary body. Six of the eight first affected eyes were treated by enucleation, whereas seven of the second affected eyes were treated with radioactive plaque application. Results of histopathologic examination were not available in patients conservatively managed with local radiotherapy. The median duration of follow-up for patients with bilateral uveal melanoma was 4 years (range, 6 months to 50 years). As of December 1993, five patients were alive and three had died. Two patients died of the metastatic spread of uveal melanoma. Bilateral ocular me-

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Table 2. Statistical Results of Age at Diagnosis and Prevalence of Ocular Melanocytosis in Patients with Primary Unilateral and Bilateral Uveal Melanomas

Mean age at diagnosis (yrs) Ocular melanocytosis

Unilateral (n = 4492)

Bilateral (n = 8)

P

59 60

56 2

>0.05 0.001

lanocytosis was noted in two of eight patients with bilateral uveal melanoma (Fig 1). Of the remaining 4492 patients with unilateral uveal melanoma, 60 (1.3%) had ocular or oculodermal melanocytosis associated with the ipsilateral uveal melanoma. This difference was statistically significant (P = 0.00 I) (Table 2). Two women had a history of unilateral breast cancer. None of the eight patients with bilateral primary uveal melanoma had FAM-M syndrome, cutaneous melanoma, or neurofibromatosis type I. Family history of uveal melanoma was also negative in all eight patients. Using the estimates of Shammas and Watzke, the expected incidence of bilaterality in the current sample is ([7.5 X 10-6][0.5][4500][8]), where 7.5 X 10-6 is the annual incidence rate of choroidal melanomas after 20 years of age, 0.5 corrects for the patient being uniocular and 4500 X 8 represents the 4500 patients in the sample X the 8-year estimated average follow-up time (i.e., person years).30 The estimate derived indicates that less than bilateral uveal melanoma should develop in one person in the current sample, which is in contrast to the eight observed patients with bilateral uveal melanoma. Using the normal approximation to the binomial, the difference between expected and observed occurrence of bilateral uveal melanoma was statistically significantly (P < O.OOOI)Y

Discussion In 1977, Sham mas and Watzke 30 estimated that only one case of bilateral uveal melanoma will occur every 18 years in the United States. It is now 18 years since this estimate was published. Over these years, six patients with bilateral primary uveal melanoma from the United States have been reported,18,19,27,29 and we add eight patients from our series. The discrepancy between the estimated and the observed incidence of bilateral primary uveal melanoma could be due to many possible factors, such as underestimation of the true incidence of bilaterality by Shammas and Watzke,30 ascertainment bias in our series, increased incidence of unilateral uveal melanoma, improved survival, misdiagnosis of uveal melanoma or presence of a subset population within unilateral uveal melanoma population in which bilateral primary uveal melanomas are predisposed to develop. The prediction of bilateral primary uveal melanoma to occur once every 18 years in the United States was

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based on the 1971 demographic data, which included a white population and the life expectancy of the people within that population. 30 Because the risk of bilaterality is low (2 X 10-8), even major changes in demographic data will not significantly alter the predicted occurrence of bilaterality. Ascertainment bias cannot explain the discrepancy of excess of observed patients, because the entry point for most of the patients in our series (6 of 8) was the first affected eye. The estimates of Shammas and Watzke 30 apply to the total population of the United States-the population from which all our patients were derived. A rise in incidence of unilateral uveal melanoma and improved survival of these patients also can increase the likelihood of bilaterality. But these rates have remained stableY Misdiagnosis of bilateral primary uveal melanoma could account for an excess of observed patients, although it is less likely, because the accuracy in the clinical diagnosis of uveal melanoma has improved over the last 30 years. 33 ,34 Currently, less than 0.75% to 1.9% of eyes with uveal melanoma that result in enucleation receive clinical misdiagnoses. 34,35 Most of the reported findings during the last century have lacked convincing documentation and were likely to have been diseases such as choroiditis, choroidal metastasis, or bilateral diffuse uveal melanocytic proliferation. 36-44 Eight eyes from our series that were treated by conservative methods have lacked histopathologic confirmation. However, in these patients the diagnosis was strongly suspected based on clinical, fluorescein angiographic, and ultrasonographic appearance. 9 Systemic oncologic evaluation excluded nonocular primary melanoma in all patients. Metastatic cutaneous melanoma can extend rarely to the uvea. 45 ,46 Although not absolute, certain features are helpful in differentiating primary uveal melanoma from metastatic melanoma to the uvea. The features suggestive of primary uveal melanoma include a dome or mushroom configuration, unifocality, presence of a basal choroidal pigmentation, suggestive of a pre-existing nevus, and absence of tumor emboli in choroidal vessels on histopathologic examination. In addition, melanocytic choroidal metastasis often are composed of epithelioid cells. 47 Metastasis from primary uveal melanoma of one eye to the contralateral uvea also can occur, but is extremely rare. 48 Perhaps, there is a subset of patients with primary uveal melanoma who are predisposed to bilateral tumors. Environmental, immunologic, and genetic factors can predispose to the development of multiple primary tumors. 49 Roles of environmental factors such as sunlight exposure, radiation, and occupational exposure to chemicals in causing uveal melanoma have been investigated. 50-53 Relation of sunlight exposure and uveal melanoma is not clearly established. Habits such as gardening and lack of eye protection while outdoors is statistically more common in patients with uveal melanoma than in control subjects. 50 However, in a Western Canadian study, cumulative sunlight exposure was not found to correlate with presence of uveal melanoma. 51 Lack of correlation between radiation exposure and uveal melanoma also has been reported. 52 Although an exploratory study of occupational exposure and risk of uveal melanoma suggested

Singh et al . Bilateral Primary Uveal Melanoma

Figure 1. Bilateral uveal melanoma in a patient with bilateral ocular melanocytosis. A 54-year-old white man with bilateral ocular melanocytosis (top) was seen in 1982 with a large juxtapapillary choroidal melanoma in the left eye (center left) for which the left eye w asenucleated (center right). Eight years later, a small choroidal melanocytic lesion with orange pigment was observed in the right eye (bottom left) which slowly evolved into a juxtapapillary choroidal melanoma (bottom right) over 3 years. This lesion was treated with a custom-designed episcleral plaque application.

some association between farming, fishing, forestry, and metal industry, no specific causative agent has been implicated.53 Precise role of environmental factor(s) is difficult to evaluate in our series due to a small number of patients. Role of immunosuppression in the development of uveal melanoma is not known. Inherited or congenital conditions associated with the development of uveal melanoma include ocular and

oculodermal melanocytosis, FAM-M syndrome, neurofibromatosis type I, and possibly Li-Fraumeni syndrome. 7 ,8,54- 57 Ocular and oculodermal melanocytosis is estimared to occur approximately 35 times more often in patients with uveal melanoma than in the general white population. 55- 58 The presence of ocular and oculodermal melanocytosis in 60 (1.3%) of the 4492 patients with uveal melanoma is comparable to previously

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published reports. 54 Ocular melanocytosis in two (25%) of eight patients with bilateral uveal melanoma was significantly more common than in patients with unilateral uveal melanoma (P = 0.001). Unilateral uveal melanoma in a patient with bilateral ocular melanocytosis has been reported. 59 To our knowledge, this is the first report to describe occurrence of bilateral uveal melanoma in association with bilateral ocular melanocytosis. Familial atypical mole and melanoma syndrome and cutaneous melanoma also have been associated with uveal melanoma. 57 None of the patients in our series had FAMM syndrome or cutaneous melanoma. Similarly, we did not observe the occurrence of bilateral primary uveal melanoma in a series of eight patients with primary uveal melanoma and FAM-M syndrome. 6o Only one patient with bilateral primary uveal melanoma with FAM-M syndrome has been reported. 61 In this patient, a history of multiple cutaneous melanomas and involvement of the left eye simultaneous to pulmonary metastasis is suggestive of metastatic melanoma to the uvea rather than a primary uveal melanoma. Li-Fraumeni syndrome, an autosomal dominant syndrome which is characterized by an inherited predisposition to cancer, manifests as a soft tissue sarcoma, brain tumors, leukemia, and others cancers in many members of a family.62-64 There was no clinical evidence of LiFraumeni syndrome in any of the eight patients, although, two of the female patients had unilateral breast cancers. Breast cancer as a component of Li-Fraumeni syndrome, tends to be bilateral, and patients also usually have a family history of multiple primary cancers. Neurofibromatosis type 1 rarely is associated with uveal melanoma. 55,56 None of the patients in our series had evidence of neurofibromatosis type 1. Only one previously reported patient with bilateral primary uveal melanoma had neurofibromatosis. 65 The multiple iris nodules described in this report are suggestive of Lisch nodules rather than iris melanoma. Cancer predisposition syndrome is suspected in patients with bilateral primary cancers. I Cancer tends to develop at an earlier age in patients who have a cancer predisposition syndrome. The mean age at diagnosis of the first affected eye in the patients with bilateral involvement was not significantly different from the mean age at diagnosis of unilateral patients (56 and 59 years, respectively; P > 0.05). This suggests lack of an inherited cancer predisposition. The other clinical features indicative of an inherited cancer predisposition such as positive family history also was lacking in our series. Similarly, we did not observe any instance of bilaterality in 56 patients (27 families) with familial uveal melanoma. 6 We are aware of only one reported patient of familial uveal melanoma with bilateral primary uveal melanomas. 29 The diagnosis in the other reported patient remains presumptive. 8 Recent molecular genetic studies have. demonstrated germline mutations of CDKN2 gene in kindreds with familial cutaneous melanoma and FAM-M syndrome. 66-68 The cyclin-dependent kinase-4 inhibitor gene (CDKN2 gene) also known as p16 INK4 or multiple tumor suppressor gene 1 (MTS 1) negatively regulates the cell cycle through inhibition of cyclin-dependent kinase-4 and maps to the

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chromosome 9p21 region. 69-71 Two patients in the current series, from whom blood samples could be obtained, were screened for germline mutations involving CDKN2 gene with negative results.72 Similar lack of CDKN2 gene germline mutations in 11 patients with familial uveal melanoma also have been observed eliminating CDKN2 gene as a uveal melanoma predisposition gene in majority of patients (unpublished data). In summary, bilateral primary uveal melanoma occurs much more frequently than expected by chance, and may be associated with ocular melanocytosis. In our series, there was no clinical evidence of an inherited genetic predisposition for bilateral primary uveal melanoma. We did not observe an association of primary bilateral uveal melanoma with FAM-M syndrome, familial uveal melanoma, neurofibromatosis type 1, or Li-Fraumeni syndrome. Occurrence of bilaterality in primary uveal melanoma is probably not a random event. Unidentified germline mutations may be involved in the pathogenesis of bilateral primary uveal melanoma. Perhaps, future molecular genetic studies will demonstrate underlying germline mutations in such patients.

References 1. Ponder BAJ. Inherited cancer syndromes. In: Carney D,

2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Sikora K, eds. Genes and Cancer. New York: John Wiley & Sons, 1990;99-106. Gallie BL, Dumm JM, Hamel PA, et al. How do retinoblastoma tumours form? Eye 1992;6:226-31. Anderson DE. Familial versus sporadic breast cancer. Cancer 1992;70: 1740-6. Maher ER, Yates JR. Familial renal cell carcinoma: clinical and molecular genetic aspects. Br J Cancer 1991;63:176-9. Neumann HPH, Berger DP, Sigmund G, et al. Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 1993;329:1531-8. Singh AD, Shields CL, De Potter P, et al. Familial Uveal Melanoma: Clinical Observations on 56 patients. Ophthalmology 1994; 10 1: 110. Singh AD, Donoso LA. Genetic aspects of uveal melanoma. Int Ophthalmol Clin 1993;33(3):47-52. Jay M, McArtney ACE. Familial malignant melanoma of the uvea and p53: Victorian detective story. Surv Ophthalmol 1993;37:457-62. Shields JA, Shields CL. Intraocular tumors: A Text and Atlas. Philadelphia: WB Saunders, 1992; 156. Shine FW. Report ofacase of bilateral sarcoma of the uveal tract. NY Eye Ear Infirm Clin Rep 1930;1:31-3. Cordes FC, Cook RD. Simultaneous bilateral primary ocular malignant melanoma. Report of a case. Tran Am Ophthalmol Soc 1949;47:80-92. Stallard HB. A case of malignant melanoma of the choroid successfully treated by radon seeds. Trans Ophthalmol Soc U. K. 1949;69:293-6. Wiesinger H, Phipps GW, Guerry D III. Bilateral melanoma of choroid associated with leukemia and meningioma. Arch Ophthalmol 1959;62:889-93. Tade AA. Bilateral primary melanoblastoma of the choroid [in Russian]. Vestn Oftalmol 1960; no. 4:30-5. Buschmann W, Goder G. Das doppelseitige maligne Melanoblastom der Aderhaut. Graefes Arch OphthalI964;167: 225-38.

Singh et al . Bilateral Primary Uveal Melanoma 16. Bietti G, Vozza R. Melanoblastoma bilterale della coroide. Clin Oculi 1968;12:52-61. 17. Giarelli L, Silvestri F, Brandt M. Ein bilaterales Melanoblastom der Aderhaut, das beiderseits mit einem benignen Melanom vergesellschaftet ist. Albrecht von Graefes Arch Klin Exp Ophthalmol 1972;185:227-34. 18. Osborn EE, Walker JP, Weiter JJ. Bilateral choroidal melanomas: case report. Ann Ophthalmol 1980;12:1154-5. 19. Lubin JR, Gragoudas ES, Albert DM, Weichselbaum RR. Bilateral malignant choroidal melanomas. Int Ophthalmol Clin 1980;20(2): 103-15. 20. Lau T. Das primar doppelseitige maligne Melanom der Chorioidea. Fallbericht mit einem Beitrag zur Histogenese des Tumors. Klin Monatsbl Augenheilkd 1981; 179:333-5. 21. Lommatzch PK, Hallermann D, von Domarus D. Treatment of bilateral choroidal malignant melanoma. In: Blankenship G, Daicker B, Gailloud C, et ai, eds. Current Concepts in Diagnosis and Treatment ofVitreoretinal Diseases. Basel: S. Krager, 1981; 105-13. (Dev Ophthalmol;2). 22. Ide CH, Ford T, Oxenhandler RW, et al. Gleichzeitiges bilaterales malignes Melanom der Chorioidea ohne ursprunglichen Nachweis von Matastasen. Ophthalmol 1983;80: 304-8. 23. Brovkina AF, Mezentseva GA. Bilateral uveal melanoma [in Russian]. Vestn OftalmoI 1984;101:31-3. 24. Migdal C, MacFarlane A. Bilateral primary choroidal melanoma. Br J Ophthalmol 1984;68:268-71. 25. Seregard S, Daunius C, Kock E, Popovic V. Two cases of primary bilateral malignant melanoma ofthe choroid. Br J Ophthalmol 1988;72:244-5. 26. Eide N. Simultaneous bilateral primary choroidal melanoma. Acta Ophthalmol 1989;67:216-20. 27. Waterhouse WJ, Fries PD, Char DH et al. Bilateral ciliary body melanomas. Can J Ophthalmol 1989;24:125-8. 28. Zygulska-Mach H, Slomska J, Heitzman J, Somska J. 6 cases of bilateral melanoma of the uvea [in Polish]. Klin Oczna 1992;94:157-8. 29. Crawford JB, Char DH. Histopathology of melanomas treated with charged particle radiation. Ophthalmology 1987;94:639-43. 30. Shammas HF, Watzke RC. Bilateral choroidal melanomas. Case report and incidence. Arch Ophthalmol 1977;95:61723. 31. Colton T. Statistics in Medicine. Boston: Little, Brown & Company, 1974;153-8. 32. Strickland D, Lee JAH. Melanomas of eye: stability of rates. Am J Epidemiol 1981;113:700-2. 33. Ferry AP. Lesions mistaken for malignant melanoma of posterior uvea. Arch Ophthalmol 1964;72:463-9. 34. Shields JA, McDonald PR. Improvements in the diagnosis of posterior uveal melanomas. Arch Ophthalmol 1974;91: 259-64. 35. Shields JA, Shields CL. Intraocular tumors: A Text and Atlas. Philadelphia: WB Saunders, 1992; 138. 36. Schiess-Gemuseus H. Kleinzelliges Melanosarcoma choroidis beider Augen. Virchows Arch Path Anat 1865;33: 495-503. 37. Landesburg M. Sarkom der Chorioidea, sehr langsamer eigentumlicher Verlauf. Archiv F Ophthal 1869;15:210-4. 38. Carter RB. Cases of sarcomata of irides. Trans Clin Soc Lond 1874;7:60-73. 39. Dixon LS. Cases of sarcoma of choroid and retinitis albuminurica. Trans Am Ophthalmol Soc 1873-9;2:432-4. 40. Hirschberg J. The malignant tumors of the eye. II. Sarcoma uveae. Arch Ophthalmol 1881; 10:68-72.

41. Ten Doeschate G. Over metastatisch Sarkoom in het ogg. Ned Tijdschr Geneeska 1919;2: 1432-6. 42. Mullaney J, Mooney D, O'Connor M, McDonald GSA. Bilateral ovarian carcinoma with bilateral uveal melanoma. Br J Ophthalmol 1984;68:261-7. 43. Tsukahara S, Wakui K, Ohzeki S. Simultaneous bilateral primary diffuse malignant uveal melanoma: case report with pathological examination. Br J Ophthalmol 1986;70:33-8. 44. Barr CC, Zimmerman LE, Curtin VT, Font RL. Bilateral diffuse melanocytic uveal tumors associated with systemic malignant neoplasms. A recently recognized syndrome. Arch Ophthalmol 1982;100:249-55. 45. Einhorn LH, Burgess MA, Gottlieb JA. Metastatic patterns of choroidal melanoma. Cancer 1974;34:1001-4. 46. de Bustros S, Augsburger JJ, Shields JA, et al. Intraocular metastases from cutaneous malignant melanomas. Arch Ophthalmol 1985;103:937-40. 47. Font RL, Naumann G, Zimmerman LE. Primary malignant melanoma of the skin metastatic to the eye and orbit. report often cases and review of the literature. Am J Ophthalmol 1967;63:738-54. 48. Shields JA, Shields CL, Shakin EP, Kobetz LE. Metastasis of choroidal melanoma to the contralateral choroid, orbit, and eyelid. Br J Ophthalmol 1988;72:456-60. 49. National Cancer Institute, Danish Cancer Registry, Boice JD Jr. Multiple Primary Cancers in Connecticut and Denmark. Bethesda, MD: U.S. Dept. Health and Human Services; Boice JD Jr, Storm HH, Curtis RE, et al. Introduction to study of multiple primary cancers. (National Cancer Institute Monograph;68)(NIH pub;85-2714). 50. Tucker MA, Shields JA, Hartge P, et al. Sunlight exposure as risk factor for intraocular malignant melanoma. N Engl J Med 1985;313:789-92. 51. Gallagher RP, Elwood JM, Rootman J, et al. Risk factors for ocular melanoma: Western Canada Melanoma Study. J Natl Cancer Inst. 1985;74:775-8. 52. Jensen ~A. Malignant melanomas of the uvea in Denmark 1943-52: Clinical, histopathological and prognostic study. Acta Ophthalmol (Suppl) 1963;75: 17-78. 53. Ajani UA, Seddon JM, Hseih C, Egan KM, Albert DM, Gragoudas ES. Occupation and risk of uveal melanoma: An exploratory study. Cancer 1992;70:2891-900. 54. Gonder JR, Shields JA, Albert DM, et al. Uveal malignant melanoma associated with ocular and oculodermal melanocytosis. Ophthalmology 1982;89:953-60. 55. Specht CS, Smith TW. Uveal malignant melanoma and von Recklinghausen's neurofibromatosis. Cancer 1988;62:8127.

56. Wiznia RA, Freedman JK, Mancini AD, Shields JA. Malignant melanoma of the choroid in neurofibromatosis. Am J Ophthalmol 1978;86:684-7. 57. Rodriguez-Sains RS. Ocular findings in patients with dysplastic nevus syndrome. Ophthalmology 1986;93:661-5. 58. Gonder JR, Ezell PC, Shields JA, Augsburger JJ. Ocular melanocytosis. A study to determine the prevalence rate of ocular melanocytosis. Ophthalmology 1982;89:950-2. 59. Gonder JR, Shields JA, Shakin JL, Albert DM. Bilateral ocular melanocytosis and malignant melanoma of the choroid. Br J Ophthalmol 1981;65:843-5. 60. Singh AD, Shields CL, Shields JA, Eagle RC, De Potter P. Uveal melanoma and familial atypical mole and melanoma (FAM-M) syndrome. Ophthalmic Genetics 1995;16:53-61. 61. Oosterhuis JA, Went LN, Lynch HT. Primary choroidal and cutaneous melanomas, bilateral choroidal melanomas and familial occurrence of melanomas. Br J Ophthalmol 1982;66:230-3.

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62. Li FP, Fraumeni JF. Soft tissue sarcomas, breast cancer and other neoplasms: a familial syndrome? Ann Intern Med 1969;71 :747-52. 63. Birch JM, Hartley AL, Blair V, et al. Cancer in the families of children with soft tissue sarcoma. Cancer 1990;60:2239-48. 64. Garber JE, Goldstein AM, Kantor AF, et al. Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res 1991 ;51:6094-7. 65. Goldstein I, Wexler D. Melanosis uveae and melanoma of the iris in neurofibromatosis (Recklinghausen). Arch Ophthalmol 1930;3:288-96. 66. Hussussian 0, StruewingJP, Goldstein AM, etal. Germline pl6 mutations in familial melanoma. Nature Genetics 1994;8:15-21. 67. Kamb A, Shattuck-Eidens D, Eeles R, et al. Analysis of the p16 (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet 1994;8:23-6.

68. Gruis NA, van der Velden PA, Sandkuijl LA, et al. Homozygotes for CDKN2 (pI6) germ line mutations in Dutch familial melanoma kindreds. Nature Genetics 1995;10:3513.

69. Kamb A, Gruis NA, Weaver-Feldhaus J, et al. A cell regulator potentially involved in genesis of many tumor types. Science 1994;264:436-40. 70. Nobori T, Miura K, Wu DJ, et al. Deletion of the cyelin dependent kinase-4 inhibitor gene in multiple human cancers. Nature 1994;368:753-6. 71. Serrano M, Hannon GJ, Beach DA. A new regulatory motif in cell-cyele control causing specific inhibition of cyelin D/ CDK 4. Nature 1993;366:704-7. 72. Singh AD, Nagai H, Croce CM, et al. Absence of germline mutations involving the cyelin dependent kinase-4 inhibitor (pI6) gene in uveal melanoma. Invest Ophthalmol Vis Sci I995;36(Suppl):770.

Centennial Advertisement Eye-fix tip tray, ca. 1900.*

• Centennial advertisement provided courtesy of the Museum of Ophthalmology, Foundation of the American Academy of Ophthalmology, San Francisco, California

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