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Uveal Malignant Melanoma Associated with Ocular and Oculodermal Melanocytosis
Uveal Malignant Melanoma Associated with Ocular and Oculodermal Melanocytosis JOHN R. GONDER, MD, JERRY A. SHIELDS, MD,* DANIEL M. ALBERT, MD,t JAMES J. AUGSBURGER, MD,* PHILIP T. LAVIN, PhD:\:
Abstract: Seventeen patients with ocular or oculodermal melanocytosis were identified among 1,250 Caucasian patients with uveal malignant melanoma. The uveal melanomas in these seventeen patients were similar in size, cell type, and tendency to metastasize to those occurring in reported populations without ocular or oculoderma! melanocytosis. Clinical and histopathologic study of these 17 cases indicated that all of the affected eyes had episcleral and choroidal melanocytosis and that other ocular and periocular tissues (sclera, iris, conjunctiva, angle structures, and optic disc) were involved less commonly. The uveal malignant melanoma that was present in each of these cases involved the eye with melanocytosis. Furthermore, the melanoma arose from the zone of uveal melanocytosis in every eye with sectoral involvement. Statistical analysis of these data supports the contention that uveal malignant melanoma has a higher incidence in white persons with ocular or oculodermal melanocytosis than in those without these conditions.[Key words: ocular melanocytosis, oculodermal melanocytosis, uveal malignant melanoma.] Ophthalmology 89:953-960, 1982
From the Wills Eye Hospital and Research Institute, Thomas Jefferson University, Philadelphia'; the Harvard Medical School, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Bostont; and the Harvard School of Public Health, Division of Biostatistics and Epidemiology, Sidney Farber Cancer Institute, Boston, Massachusetts.+ Dr. Gonder was a fellow in Ophthalmic Pathology at Harvard Medical School and in vitreoretinal diseases on the Retina Service at Wills Eye Hospital. Supported in part by the R. Samuel McLaughlin Foundation, National Eye Institute Grant EY01917, the Retinal Research and Development Foundation, Philadelphia, The Pennsylvania Lions Sight Conservation and Eye Research Foundation, the Ocular Oncology Fund and Research Department, Wills Eye Hospital, and the National Cancer Institute Grant Ca06516. Presented at the Eighty-sixth Annual Meeting of the American Academy of Ophthalmology, Atlanta, Georgia, November 1-6, 1981. Reprint requests to Jerry A. Shields, MD, Oncology Service, Wills Eye Hospital, 9th & Walnut Streets, Philadelphia, PA 19107.
0161-6420/82/0800/0953/$01.20
© American Academy of Ophthalmology
Ocular melanocytosis is described as a melanocytic hyperpigmentation involving the uveal tract and episclera. 1 The association of dermal melanocytosis, hyperpigmentation involving the skin of the eyelids and periorbital areas, and ocular melanocytosis is referred to as oculodermal melanocytosis. 2-4 Both ocular and oculodermal melanocytosis have been associated with uveal malignant melanoma. 5- 20 Although this association is well recognized, several questions regarding ocular and oculodermal melanocytosis and their relationship with uveal malignant melanoma still remain. How prevalent are ocular and oculodermal melanocytosis in the white population? What ocular tissues are involved by the melanocytes in ocular melanocytosis? How prevalent is uveal malignant melanoma in the affected eyes of persons with ocular and oculodermal melanocytosis? Is there any difference between the cell type and biologic behavior of the uveal malignant
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OPHTHALMOLOGY • AUGUST 1982 • VOLUME 89 • NUMBER 8
melanomas that occur in patients with ocular melanocytosis and those that occur in patients without ocular melanocytosis? The authors reviewed 17 cases of patients with ocular or oculodermal melanocytosis and uveal malignant melanoma in order to answer some of these questions.
PATIENTS AND METHODS The study group consisted of two subgroups of patients with uveal malignant melanomas. The first subgroup consisted of 550 consecutive cases of uveal malignant melanoma on file in the Pathology Department at the Massachusetts Eye and Ear Infirmary between 1957 and 1980. The second subgroup consisted of 700 consecutive patients diagnosed on clinical grounds as having uveal malignant melanoma in the Oncology Service of Wills Eye Hospital between 1974 and 1980. The records of these 1,250 Caucasian patients were reviewed for clinical evidence of ocular or oculodermal melanocytosis and ocular pathologic specimens from the patients with these conditions were studied to identify the tissue sites involved by melanocytosis. The pathologic characteristics of the uveal melanomas in these eyes and the clinical follow-up on these patients were reviewed also. The nonenucleated eye was examined for the presence of melanoma and melanocytosis in the clinical subgroup but not the pathology subgroup.
RESULTS Six ofthe 550 cases from the Massachusetts Eye and Ear Infirmary pathology subgroup (1.09%) were found to have ocular melanocytosis, but none were found to have oculodermal melanocytosis. Eight of the 700 patients from the Wills Eye Hospital clinical subgroup (1.14%) had ocular melanocytosis, and three (0.42%) had oculodermal melanocytosis. The prevalence of the association of uveal malignant melanoma and ocular or oculodermal melanocytosis in the combined subgroups was 1.36% (17/1250). Ocular melanocytosis (14 cases) was over four times as common as oculodermal melanocytosis (three cases) in the combined group. The pertinent clinical and histopathologic data on the 17 cases of ocular and oculodermal melanocytosis associated with uveal malignant melanomas are presented in Tables 1 and 2. One of the 14 patients with ocular melanocytosis was affected bilaterally, 21 but none of the three patients with oculodermal melanocytosis exhibited bilateral involvement. In all 17 patients, the uveal malignant melanoma was ipsilateral to the ocular or oculodermal melanocytosis. The mean age of the 17 patients with ocular or oculodermal melanocytosis and uveal malignant mela954
noma was 58.4 years, and the median age was 61 years. The youngest patient was 36 years of age, and the oldest was 74 years of age at the time ofthe'clinical diagnosis of the melanoma. Ten of the 17 patients (58.8%) were men and seven (41.2%) were women. The most common clinical presentation, decreased vision in the involved eye, was reported in 12 ofthe 17 patients. The mean duration of symptoms in the 12 patients was approximately four months. Five patients had the diagnosis of uveal malignant melanoma made on routine examination. The tissues involved by melanocytosis on clinical examination in the 11 eyes of ten patients in the Wills Eye Hospital clinical subgroup are indicated in Table 3. The episclera contained discrete patches of melanotic hyperpigmentation of various sizes and locations in all 11 eyes (Fig 1). The choroid had diffuse or sectorial hyperpigmentation in all 11 eyes, while the iris was involved in nine eyes (82%). The angle structures were examined in four patients, and all showed hyperpigmentation. The conjunctiva was involved by melanocytosis in four of 11 cases (36.4%) (Fig 2). The optic disc, lens, and cornea were not involved clinically in any of these patients. The tissues involved by melanocytosis on histopathologic examination in the enucleated eyes are indicated in Table 2. The episclera in all 14 eyes contained isolated patches of hyperpigmented dendritic melanocytes (Fig 3). The ciliary body and choroid were involved in all 14 eyes, diffusely in 11, and sectorially in 3 (Figs 4, 5). Other ocular tissues involved by melanocytosis in this histopathologic study were the sclera (14/14) (Fig 6), iris (12/14) (Fig 7), the anterior chamber angle structure (10/14) (Fig 7), optic disc (51 14) (Fig 8), and the conjunctiva (2/14) (Fig 9). In the three eyes (cases 11, 14, 15) with sectorial involvement of the ciliary body and choroid, melanocytosis of the episclera, iris, anterior chamber angle structures, and sclera was present in the same section. Although not specifically assessed in this study, some orbital tissues adherent to the enucleated globes, including the dural sheaths of the optic nerve (Fig 10), the posterior ciliary arteries (Fig 6), and the extraocular muscles were noted to be involved in the melanocytic process in both ocular and oculodermal melanocytosis. The uveal malignant melanomas occurring in these 17 persons were ipsilateral to the eye with melanocytosis in all cases. Furthermore, the melanoma arose within an area of melanocytosis and not from an uninvolved sector of the uvea in all eyes with sectorial melanocytosis (Fig 5). All of the uveal malignant melanomas in these 17 patients were located in the choroid and/or ciliary body, and none of them involved the iris. Fourteen of the 17 patients with melanocytosis and uveal melanoma were managed by enucleation of the eye containing the uveal malignant melanoma. Three patients in the clinical subgroup were managed by irradiation (cobalt plaque) brachytherapy. Histopathologic study of the 14 enucleated eyes revealed three
et al • MELANOMA AND MELANOCYTOSIS
GONDER,
Table 1. General Data on Melanocytosis Patients Who Have Uveal Membranes Basal Tumor Dimensions (mm) Height (mm)
Tumor Volume
Case
Age
Sex
Eye
1 2 3 4 5 6 7 8 9 10 11 12 13
56 48 67 57 64 59 39 59 36 61 66 74 51
F
L R R L R R R L L R R R L
5x 5 N/A N/A 6x 7 N/A 11 x 8 10 x 9 11 x 10 8x9 10 x 10 9 x 10 12 x 13 15 x 15
3 N/A N/A 7 N/A 5 5.6 5.0 8 7 10 9 8.2
75.0 90.75 250.0 294.0 400.00 440.00 504.00 550.00 576.00 700.00 900.00 1404.0 1845.0
Mixed Mixed Spindle B Mixed Spindle B
14 15 16 17
71 60 63 61
R L R R
18 14 15 25
x x x x
8.0 13.0 12.0 11.0
2160.0 2548.0 2700.0 4125.0
Epitheloid Mixed Mixed Mixed
M M M M M
F
M M
F F
M M
F F F
M
15 14 15 15
Cell Type
Melanocytosis
Mixed Mixed Mixed Spindle B Mixed
Ocular Ocular Ocular Ocular Ocular Ocular Ocular Ocular Ocular Oculodermal Oculodermal Ocular Oculodermal + melanocytoma Ocular Ocular Ocular Ocular
NlA-no accurate measurements available. * No histology available; patient treated with cobalt plaque. Table 2. Histopathology of Ocular and Oculodermal Melanocytosis Tissues Involved by the Melanocytic Process Number of Eyes 11 eyes from patients with ocular melanocytosis 3 eyes from patients with oculodermal melanocytosis 14 total eyes *
Conjunctiva
Episclera
Sclera
Chamber Angle
Iris
Ciliary Body
Choroid
Optic Nerve
Extraocular Tissue
2
11
11
7
10
11
11
3
3
0 2
3 14
3 14
3 10
2 12
3 14
3 14
2 5
1 4
Extraocular tissues included dura, posterior ciliary arteries, and extraocular muscles. Table 3. Clinical Review of Ocular and Oculodermal Melanocytosis Tissues Involved by the Melanocytic Process Number of Eyes
8 eyes (patients with ocular melanocytosis) 3 eyes (patients with oculodermal melanocytosis) Total 11 eyes
Conjunctiva
Episclera
Chamber Angle
Iris
Lens
Ciliary Body
3
8
3
7
0
3
1 4
3 11
1 4
2 9
0 0
1 4
-
tumors of spindle B cell type, ten of mixed cell type, and one of epithelioid cell type. The approximate sizes of the uveal melanomas in all 17 patients were recorded as tumor volumes calculated as the product of basal dimensions of the tumor in
Optic Nerve
Skin
8
0
0
3 11
0 0
3 3
Choroid
millimeters times the tumor thickness in millimeters (Table 1). The 14 uveal malignant melanomas ranged in volume from 75 mm 3 to 4,125 mm 3 • The mean volume was 1150 mm3 , with a median tumor volume of 576 mm3 • Eleven of the 17 melanomas were less than 1000 mm 3 • 955
OPHTHALMOLOGY. AUGUST 1982 • VOLUME 89 • NUMBER 8
Fig 1. Top left, a patient with bilateral ocular melanocytosis and a malignant melanoma of the choroid of the right eye. Note the episcleral pigmentation. Both irides demonstrate involvement by the pigmentary process. Fig 2. Top right, a photograph of the left lower conjunctival fornix of the patient in Figure I demonstrating the epibulbar and conjunctival pigmentation (see Fig 9). Fig 3. Left, a photomicrograph demonstrates the episcleral pigmentation (small arrow) in a person with ocular melanocytosis. Also, note the pigmentation of the sclera, scleral nerve loop, Schlemm's canal, trabecular meshwork, ciliary body and choroid (periodic acid-Schiff, original magnification x 16).
Figs 4A-B. A, left, involvement ofthe iris in ocular melanocytosis is well demonstrated in this photograph. Note the marked pigmentation of the anterior iris and stroma. This is the involved portion of the iris of the patient in Figure 5A. There is artifactual disruption of the ciliary body and retina (hematoxylin-eosin, original magnification x 16). B, right, in comparison to Figure 5A the inferior portion of the iris of the patient in Figure 9A was not involved by the ocular melanocytosis. Note the lack of pigmentation of the ciliary body and iris. There is artifactual separation of the iris pigment epithelium (hematoxylin-eosin, original magnification x 16).
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Figs SA-C. A. top left. this patient demonstrates sectorial ocular melanocytosis. The iris is hyperpigmented in the superior nasal sector (arrows). In this same sector, the choroid was also involved. B, top right. in the hyperpigmented superior nasal sector, a malignant melanoma of the choroid was found. C,left. on histopathology, the malignant melanoma of the choroid was of the mixed cell type (hematoxylin-eosin, original magnification x 140).
Fig 6. Top left. dendritic melanocytes can be found in the orbital soft tissues. This photomicrograph shows meianocytes along a short posterior ciliary artery. The choroid and sclera also show marked pigmentation (hematoxylin-eosin, original magnification x 16).Fig 7. Top right. the trabecular meshwork and Schlemm's canal are noted to be involved in ocular melanocytosis. The iris and ciliary body are also heavily pigmented in this photograph (hematoxylin-eosin, original magnification x40). Fig 8. Bottom left, melanocytes can be noted to involve the lamina cribrosa of the optic nerve in an eye with ocular melanocytosis (hematoxylin-eosin, original magnification x 100). Fig 9. Bottom center, dendritic melanocytes (arrow) can be noted in the substantia propria of the conjunctiva in this patient with ocular melanocytosis (hematoxylin-eosin, original magnification x 100). (Same patient as Figs 1 and 2.) Fig 10. Bottom right. a photomicrograph of the optic nerve demonstrating the hyperpigmentation of the choroid, sclera, and dural sheaths (periodic acid-Schiff, original magnification x 16).
OPHTHALMOLOGY. AUGUST 1982 • VOLUME 89 • NUMBER 8
Three of the 15 patients (20%) with ocular or oculodermal melanocytosis and a uveal malignant melanoma (cases 5, 7, and 9) died of metastatic uveal malignant melanoma during a mean post-treatment follow-up of2.7 years. Two of the patients who died of disseminated malignant melanoma had a uveal tumor characterized histologically as a mixed cell type, and the other had a tumor consisting almost exclusively of spindle B melanoma cells. One ofthe patients with mixed-cell type uveal melanoma had extrascleral extension at the time of enucleation. Two patients died during follow-up of causes other than metastatic uveal melanoma. None of the surviving patients has any evidence of metastatic malignant melanoma.
DISCUSSION In 1939 Ota described, and later classified with Tanino, the pigmentary process that now bears his name (nevus of Ota, Nevus Fuscoceruleus Ophthalmomaxillaris Ota).2 The nevus of Ota, a pigmentary process of the facial skin, frequently involves the globe. Pigmentation of the globe alone, referred to as ocular melanosis, was described in 1912 by CoatsY In 1956 Fitzpatrick proposed the terms oculodermal melanocytosis, ocular melanocytosis, and dermal melanocytosis to replace the terms nevus of Ota and melanosis oculi. 3 Ocular and oculodermal melanocytosis are typically unilateral congenital melanocytic hyperpigmentations. 22 - 3o Infrequently, persons can develop the pigmentation during later life, most notably at puberty or during pregnancy.4 Furthermore, the hyperpigmentation can increase with advancing age. 31 The ocular and extraocular tissues that are involved in persons with ocular and oculodermal melanocytosis have been well documented in previous reports. 1,2,4,22,30 However, the frequency of involvement of each of these tissues has not been established. Our data suggest that, from a clinical standpoint, the episclera and the choroid are involved in every case and that the melanocytosis involves the iris in 82% and the conjunctiva in 36%. The anterior chamber angle structures were examined in four patients in the clinical subgroup and were involved by the melanocytic process in all cases (100%). Data from the histologic studies confirmed the presence of episcleral and choroidal melanocytosis in all affected eyes. In addition, the sclera and ciliary body were involved by the hyperpigmented melanocytes in all affected eyes. Furthermore, melanocytosis involved the iris in 85.7%, the anterior chamber angle structures in 71.4%, the optic disc in 35.1%, and the conjunctiva in 14.3% of affected eyes. Contrasted with clinical findings, these histologic findings indicate that melanocytosis of the sclera and the optic disc is often present but not readily detected clinically. Melanocytosis of the anterior chamber angle structures, as noted in four of the persons in the clinical 958
subgroup, was confirmed in the histologic study of enucleated globes. Melanocytosis ofthe conjunctiva is more evident clinically than on histopathologic study. This is probably due to the fact that minimal conjunctiva is excised at enucleation. The extent of melanocytic hyperpigmentation of the ocular tissues in ocular and oculodermal melanocytosis ranged from diffuse involvement of the episclera and uveal tract, including the iris, ciliary body, and choroid (14 cases), to sectorial involvement of these ocular tissues (three cases) in this group of patients. Sectorial melanocytic hyperpigmentation has not been well recognized in the literature, but it did account for 17.6% of our cases. Hulke 5 (1861) wrote one of the first reports of a patient with oculodermal melanocytosis and uveal malignant melanoma. Coats (1912), II Reese (1925),16 and Doherty (1927)24 were among the earlier clinicians to review the literature on ocular melanocytosis and to propose that ocular melanocytosis may predispose to the development of uveal malignant melanoma. Since these first reports, the literature has documented the association of ocular and oculodermal melanocytosis with uveal malignant melanoma,5-20 as well as with melanomas of the orbit,32,33 central nervous system,34.35 and skin.36 Our series of 17 cases of ocular (14 cases) and oculodermal (three cases) melanocytosis associated with uveal malignant melanoma further documents this association. In our series, more people had ocular melanocytosis with associated uveal malignant melanoma than oculodermal melanocytosis with a uveal malignant melanoma. Since this study did not determine nor has the literature stated the relative prevalences of the two forms of melanocytosis in the white popUlation, these data and other literature reviews can neither support nor refute the assertion that ocular and/or oculodermal melanocytosis predisposes to the development of a uveal malignant melanoma. The cell type of the 14 malignant uveal melanomas managed by enucleation was spindle B in 20%, mixed in 66.7%, and epithelioid in 6.7%. This distribution of malignant melanoma cell types parallels the frequency of melanoma cell types found in larger popUlations with uveal malignant melanoma. 37 Tumor volume did not correlate well with prognosis for death from metastatic uveal malignant melanoma in this small series. This observation is in agreement with the findings reported by McLean and associates,3S who found tumor volume to be of limited prognostic significance for small melanomas. Recently Blodi 10 has challenged the contention of Reese 16 and Yanoff and Zimmerman 6 that the incidence of uveal malignant melanoma is increased in eyes with ocular and oculodermal melanocytosis. Statistic analysis of the data from this study provides some insight into this controversy. Seventeen of 1,250 patients with uveal malignant melanoma had ocular or oculodermal melanocytosis for a prevalence rate in a uveal melanoma population
GONDER, et al • MELANOMA AND MELANOCYTOSIS
of 1.36%. Fourteen of the 17 patients had ocular melanocytosis for a prevalence rate in a uveal melanoma population of 1.23%. Three of the 17 patients had oculodermal melanocytosis for a prevalence rate in a uveal melanoma population of 0.24%. As all 17 patients with uveal melanoma and ocular or oculodermal melanocytosis were referred for diagnosis and management of the uveal melanoma alone and not for the ocular melanocytosis, this series of uveal melanoma patients is probably representative of a true cross section of the uveal melanoma population. This would imply that the actual prevalence rate of ocular melanocytosis in an uveal melanoma population, if it were known, would approximate the prevalence rate (1.36%) determined in this study. However, the authors recognize that Wills Eye Hospital and the Massachusetts Eye and Ear Infirmary are large referral centers, and this may increase the observed prevalence rates. The prevalence rate for ocular melanocytosis in the white population studied by Gonder and associates during their screening of 13,150 consecutive patients at Wills Eye Hospital was 0.04% (2/5241 white persons).39 The prevalence rate for ocular melanocytosis in the uveal melanoma population and in the white population studied can be assessed using tests of hypothesis relating to differences in prevalence rates for two populations under the assumption that a binomial distribution governs the prevalence of ocular melanocytosis in these two populations. In contrast to the prevalence rate of ocular melanocytosis in the white population (0.04%), the prevalence of ocular melanocytosis was 1.09% (MEEI Series) and 1.57% (Wills Series) in the uveal melanoma populations, corresponding to a 35-fold relative risk when pooled for comparison to the white population. When each study result is contrasted with the white population, the true prevalence rates for ocular melanocytosis for these two study populations were significantly different (P = 0.0001) from the white population using a twosided test of hypothesis of equal prevalence rates against unrestricted alternatives. In fact, prevalence rates one-third as large as those observed for each of the study subgroups would also have been significantly different from the white population. The calculation of the power (the power is the probability of detecting the observed prevalence rates, assuming that these were the true prevalence rates) demonstrated for both the MEEI and WEH series that differences in these observed prevalence rates could be detected with a 99% probability. In other words, this difference in prevalence rates is unlikely to be due to chance alone, implying that ocular melanocytosis predisposes to the development of a uveal malignant melanoma. The patient populations chosen for this study and the fact that this study is not a controlled matched prospective study does not allow an accurate calculation of the risk of a person with ocular melanocytosis developing a uveal malignant melanoma. However, generalizations can be drawn from this study knowing
that the prevalence of ocular melanocytosis was 35 times greater in the uveal melanoma population than in the white study population. The patient populations chosen for this study (referral center populations) may partially account for the discrepancy in the prevalence rates. However, these populations would tend to increase the detected prevalence rates, and, therefore, the 35-fold increase in the prevalence of ocular melanocytosis in the uveal melanoma population could be considered a maximum. If the presence of ocular melanocytosis was the sole governing factor producing this difference in prevalence rates, then the prevalence of uveal melanomas in a population of persons with ocular melanocytosis would be increased by a factor of 35 or 0.021%.40 However, as discussed, multiple factors are influencing the detected prevalence rates and, therefore, this figure should only be regarded as estimated maximum.
REFERENCES 1. Zimmerman LE Melanocytes, melanocytic nevi and melanocytomas. Invest Ophthalmol 1965; 4: 11-41. 2. Ota M, Tanino H. Nevus fusco-caeruleus ophthalmomaxillaris. Tokyo Med J 1939; 63:1243-5. 3. Fitzpatrick TB, Zeller R, Kukita A, Kitamura H. Ocular and dermal melanocytosis. Arch Ophthalmol 1956; 56:830-2. 4. Gupta GP, Gangwar DN. Naevus of Ota. Br J Ophthalmol 1965;
49:364-8. 5. Hulke Jw. A series of cases of carcinoma of the eyeball. Royal London Ophthalmic Hosp Rep 1861; 3:279-86. 6. Yanoff M, Zimmerman LE. Histogenesis of malignant melanomas of the uvea. III. The relationship of congenital ocular melanocytosis and neurofibromatosis to uveal melanomas. Arch Ophthalmol 1967; 77:331-6. 7. Font RL, Reynolds AM Jr, Zimmerman LE. Diffuse malignant melanoma of the iris in the nevus of Ota. Arch Ophthalmol
1967; 77:513-8. 8. Yamamoto T. Malignant melanoma of the choroid in the nevus of Ota. Ophthalmologica 1969; 159:1-10. 9. Albert DM, Scheie HG. Nevus of Ota with malignant melanoma of the choroid. Report of a case. Arch Ophthalmol 1963; 69:
774-7. 10. Blodi FC. Ocular melanocytosis and melanoma. Am J Ophthalmol 1975; 80:389-95. 11. Coats G. Unilateral diffuse melanosis of the uvea, with small elevations on the surface of the iris. Trans Ophthalmol Soc UK
1912; 32:165-71. 12 Frezzotti R, Guerra R. Dragoni GP, Bonanni P. Malignant melanoma of the choroid in a case of naevus of Ota. Br J Ophthalmol 1968; 52:922-4 13. Halasa A. Malignant melanoma in a case of bilateral nevus of Ota. Arch Ophthalmol 1970; 84:176-8. 14. Makley TA Jr, King CM. Malignant melanoma in melanosis oculi. Trans Am Acad Ophthalmol Otolaryngol 1967; 71 :638-41. 15. Mohandessan M, Fetkenhour C, O'Grady R. Malignant melanoma of choroid in a case of nevus of Ota. Ann Ophthalmol
1979; 11: 189-92. 16. Reese AB. Melanosis oculi. A case with microscopic findings. Am J Ophthalmol 1925: 8:865- 70. 17. Roy PE, Schaeffer EM. Nevus of Ota and choroidal melanoma. Sury Ophthalmol 1967; 12:130-40.
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18. Sabates FN, Yamashita T. Congenital melanosis oculi complicated by two independent malignant melanomas of the choroid. Arch Ophthalmol 1967; 77:801-3. 19. Seelenfreund MH, Freilich DB. Ocular melanocytosis and malignant melanoma. NY State J. Med 1979; 79:916-17. 20. Gonder JR, Shields JA, Albert DM. Malignant melanoma of the choroid associated with oculodermal melanocytosis. Ophthalmology 1981; 88:372-6. 21. Gonder JR, Shields JA, Shakin JL, Albert DM. Bilateral ocular melanocytosis with malignant melanoma of the choroid. Br J Ophthalmol 1981: 65:843-5. 22. Cowan TH, Balistocky M. The nevus of Ota or oculodermal melanocytosis; the ocular changes. Arch Ophthalmol 1961; 65:483-92. 23. Hidaho A, Kajima H, Ikido S, et al. Natural history of nevus of Ota. Arch Dermatol 1967; 95:187-95. 24. Doherty WB. Cases of melanosis oculi with microscopic findings Am J Ophthalmol 1927; 10:1-8. 25. Estima A, Carneiro R. Ota naevus: presentation of a case. Br J. Plast Surg 1972; 25:49-52. 26. Helmick ED, Pringle RW. Oculocutaneous melanosis or nevus of Ota. Arch Ophthalmol 1956; 56:833-8. 27. Kopf AW, Weidman AI. Nevus of Ota. Arch Dermatol 1962; 85: 195- 208. 28. Lever WF, Schaumberg-Lever G. Melanocytic nevi and malignant melanoma. In: Lever WF, Schaumberg-Lever G, eds. Histopathology of the Skin, 5th ed. Philadelphia: JB Lippincott, 1975; 660-1. 29. Mishima Y, Mevorah B. Nevus Ota and nevus Ito in American Negroes. J Invest Dermatol 1961; 36:133-54.
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30. Stafford WR. Congenital melanosis oculi. Report of a case. Arch Ophthalmol 1962; 68:738-41. 31. Jensen CDF, Haffly GN. An unusual case of p'rogressive melanosis oculi. Am J. Ophthalmol 1948; 31 :1476-9. 32. Hagler WS, Brown CC. Malignant melanoma of the orbit arising in a nevus of Ota. Trans Am Acad Ophthalmol Otolaryngol 1966; 70:817-22. 33. Jay B. Malignant melanoma of the orbit in a case of oculodermal melanosis (Naevus of Ota). Br J Ophthalmol 1965; 49: 359-63. 34. Enriquez R, Egbert B, Bullock J. Primary malignant melanoma of central nervous system: pineal involvement in a patient with nevus of Ota and multiple pigmented skin nevi. Arch Pathol 1973; 95:392-5. 35. Sang DN, Albert DM, Sober AJ, McMeekin TO. Nevus of Ota with contralateral cerebral melanoma. Arch Ophthalmol 1977; 95:1820-4. 36. Dorsey CS, Montgomery H. Blue nevus and its distinction from Mongolian spot and the nevus of Ota. J Invest Dermatol 1954; 22:225-36. 37. Yanoff M, Fine BS, eds Ocular Pathology: A Text and Atlas. Hagerstown, MD: Harper & Row, 1975; 747. 38. McLean IW, Foster WD, Zimmerman LE. Prognostic factors in small malignant melanomas of choroid and ciliary body. Arch Ophthalmol 1977; 95:48-58. 39. 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. 40. Graham BJ, Duane TD. Ocular Melanoma Task Force Report. Am J Ophthalmol 1980; 90:728-33.
Abstract: Seventeen patients with ocular or oculodermal melanocytosis were identified among 1,250 Caucasian patients with uveal malignant melanoma. The uveal melanomas in these seventeen patients were similar in size, cell type, and tendency to metastasize to those occurring in reported populations without ocular or oculoderma! melanocytosis. Clinical and histopathologic study of these 17 cases indicated that all of the affected eyes had episcleral and choroidal melanocytosis and that other ocular and periocular tissues (sclera, iris, conjunctiva, angle structures, and optic disc) were involved less commonly. The uveal malignant melanoma that was present in each of these cases involved the eye with melanocytosis. Furthermore, the melanoma arose from the zone of uveal melanocytosis in every eye with sectoral involvement. Statistical analysis of these data supports the contention that uveal malignant melanoma has a higher incidence in white persons with ocular or oculodermal melanocytosis than in those without these conditions.[Key words: ocular melanocytosis, oculodermal melanocytosis, uveal malignant melanoma.] Ophthalmology 89:953-960, 1982
From the Wills Eye Hospital and Research Institute, Thomas Jefferson University, Philadelphia'; the Harvard Medical School, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Bostont; and the Harvard School of Public Health, Division of Biostatistics and Epidemiology, Sidney Farber Cancer Institute, Boston, Massachusetts.+ Dr. Gonder was a fellow in Ophthalmic Pathology at Harvard Medical School and in vitreoretinal diseases on the Retina Service at Wills Eye Hospital. Supported in part by the R. Samuel McLaughlin Foundation, National Eye Institute Grant EY01917, the Retinal Research and Development Foundation, Philadelphia, The Pennsylvania Lions Sight Conservation and Eye Research Foundation, the Ocular Oncology Fund and Research Department, Wills Eye Hospital, and the National Cancer Institute Grant Ca06516. Presented at the Eighty-sixth Annual Meeting of the American Academy of Ophthalmology, Atlanta, Georgia, November 1-6, 1981. Reprint requests to Jerry A. Shields, MD, Oncology Service, Wills Eye Hospital, 9th & Walnut Streets, Philadelphia, PA 19107.
0161-6420/82/0800/0953/$01.20
© American Academy of Ophthalmology
Ocular melanocytosis is described as a melanocytic hyperpigmentation involving the uveal tract and episclera. 1 The association of dermal melanocytosis, hyperpigmentation involving the skin of the eyelids and periorbital areas, and ocular melanocytosis is referred to as oculodermal melanocytosis. 2-4 Both ocular and oculodermal melanocytosis have been associated with uveal malignant melanoma. 5- 20 Although this association is well recognized, several questions regarding ocular and oculodermal melanocytosis and their relationship with uveal malignant melanoma still remain. How prevalent are ocular and oculodermal melanocytosis in the white population? What ocular tissues are involved by the melanocytes in ocular melanocytosis? How prevalent is uveal malignant melanoma in the affected eyes of persons with ocular and oculodermal melanocytosis? Is there any difference between the cell type and biologic behavior of the uveal malignant
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OPHTHALMOLOGY • AUGUST 1982 • VOLUME 89 • NUMBER 8
melanomas that occur in patients with ocular melanocytosis and those that occur in patients without ocular melanocytosis? The authors reviewed 17 cases of patients with ocular or oculodermal melanocytosis and uveal malignant melanoma in order to answer some of these questions.
PATIENTS AND METHODS The study group consisted of two subgroups of patients with uveal malignant melanomas. The first subgroup consisted of 550 consecutive cases of uveal malignant melanoma on file in the Pathology Department at the Massachusetts Eye and Ear Infirmary between 1957 and 1980. The second subgroup consisted of 700 consecutive patients diagnosed on clinical grounds as having uveal malignant melanoma in the Oncology Service of Wills Eye Hospital between 1974 and 1980. The records of these 1,250 Caucasian patients were reviewed for clinical evidence of ocular or oculodermal melanocytosis and ocular pathologic specimens from the patients with these conditions were studied to identify the tissue sites involved by melanocytosis. The pathologic characteristics of the uveal melanomas in these eyes and the clinical follow-up on these patients were reviewed also. The nonenucleated eye was examined for the presence of melanoma and melanocytosis in the clinical subgroup but not the pathology subgroup.
RESULTS Six ofthe 550 cases from the Massachusetts Eye and Ear Infirmary pathology subgroup (1.09%) were found to have ocular melanocytosis, but none were found to have oculodermal melanocytosis. Eight of the 700 patients from the Wills Eye Hospital clinical subgroup (1.14%) had ocular melanocytosis, and three (0.42%) had oculodermal melanocytosis. The prevalence of the association of uveal malignant melanoma and ocular or oculodermal melanocytosis in the combined subgroups was 1.36% (17/1250). Ocular melanocytosis (14 cases) was over four times as common as oculodermal melanocytosis (three cases) in the combined group. The pertinent clinical and histopathologic data on the 17 cases of ocular and oculodermal melanocytosis associated with uveal malignant melanomas are presented in Tables 1 and 2. One of the 14 patients with ocular melanocytosis was affected bilaterally, 21 but none of the three patients with oculodermal melanocytosis exhibited bilateral involvement. In all 17 patients, the uveal malignant melanoma was ipsilateral to the ocular or oculodermal melanocytosis. The mean age of the 17 patients with ocular or oculodermal melanocytosis and uveal malignant mela954
noma was 58.4 years, and the median age was 61 years. The youngest patient was 36 years of age, and the oldest was 74 years of age at the time ofthe'clinical diagnosis of the melanoma. Ten of the 17 patients (58.8%) were men and seven (41.2%) were women. The most common clinical presentation, decreased vision in the involved eye, was reported in 12 ofthe 17 patients. The mean duration of symptoms in the 12 patients was approximately four months. Five patients had the diagnosis of uveal malignant melanoma made on routine examination. The tissues involved by melanocytosis on clinical examination in the 11 eyes of ten patients in the Wills Eye Hospital clinical subgroup are indicated in Table 3. The episclera contained discrete patches of melanotic hyperpigmentation of various sizes and locations in all 11 eyes (Fig 1). The choroid had diffuse or sectorial hyperpigmentation in all 11 eyes, while the iris was involved in nine eyes (82%). The angle structures were examined in four patients, and all showed hyperpigmentation. The conjunctiva was involved by melanocytosis in four of 11 cases (36.4%) (Fig 2). The optic disc, lens, and cornea were not involved clinically in any of these patients. The tissues involved by melanocytosis on histopathologic examination in the enucleated eyes are indicated in Table 2. The episclera in all 14 eyes contained isolated patches of hyperpigmented dendritic melanocytes (Fig 3). The ciliary body and choroid were involved in all 14 eyes, diffusely in 11, and sectorially in 3 (Figs 4, 5). Other ocular tissues involved by melanocytosis in this histopathologic study were the sclera (14/14) (Fig 6), iris (12/14) (Fig 7), the anterior chamber angle structure (10/14) (Fig 7), optic disc (51 14) (Fig 8), and the conjunctiva (2/14) (Fig 9). In the three eyes (cases 11, 14, 15) with sectorial involvement of the ciliary body and choroid, melanocytosis of the episclera, iris, anterior chamber angle structures, and sclera was present in the same section. Although not specifically assessed in this study, some orbital tissues adherent to the enucleated globes, including the dural sheaths of the optic nerve (Fig 10), the posterior ciliary arteries (Fig 6), and the extraocular muscles were noted to be involved in the melanocytic process in both ocular and oculodermal melanocytosis. The uveal malignant melanomas occurring in these 17 persons were ipsilateral to the eye with melanocytosis in all cases. Furthermore, the melanoma arose within an area of melanocytosis and not from an uninvolved sector of the uvea in all eyes with sectorial melanocytosis (Fig 5). All of the uveal malignant melanomas in these 17 patients were located in the choroid and/or ciliary body, and none of them involved the iris. Fourteen of the 17 patients with melanocytosis and uveal melanoma were managed by enucleation of the eye containing the uveal malignant melanoma. Three patients in the clinical subgroup were managed by irradiation (cobalt plaque) brachytherapy. Histopathologic study of the 14 enucleated eyes revealed three
et al • MELANOMA AND MELANOCYTOSIS
GONDER,
Table 1. General Data on Melanocytosis Patients Who Have Uveal Membranes Basal Tumor Dimensions (mm) Height (mm)
Tumor Volume
Case
Age
Sex
Eye
1 2 3 4 5 6 7 8 9 10 11 12 13
56 48 67 57 64 59 39 59 36 61 66 74 51
F
L R R L R R R L L R R R L
5x 5 N/A N/A 6x 7 N/A 11 x 8 10 x 9 11 x 10 8x9 10 x 10 9 x 10 12 x 13 15 x 15
3 N/A N/A 7 N/A 5 5.6 5.0 8 7 10 9 8.2
75.0 90.75 250.0 294.0 400.00 440.00 504.00 550.00 576.00 700.00 900.00 1404.0 1845.0
Mixed Mixed Spindle B Mixed Spindle B
14 15 16 17
71 60 63 61
R L R R
18 14 15 25
x x x x
8.0 13.0 12.0 11.0
2160.0 2548.0 2700.0 4125.0
Epitheloid Mixed Mixed Mixed
M M M M M
F
M M
F F
M M
F F F
M
15 14 15 15
Cell Type
Melanocytosis
Mixed Mixed Mixed Spindle B Mixed
Ocular Ocular Ocular Ocular Ocular Ocular Ocular Ocular Ocular Oculodermal Oculodermal Ocular Oculodermal + melanocytoma Ocular Ocular Ocular Ocular
NlA-no accurate measurements available. * No histology available; patient treated with cobalt plaque. Table 2. Histopathology of Ocular and Oculodermal Melanocytosis Tissues Involved by the Melanocytic Process Number of Eyes 11 eyes from patients with ocular melanocytosis 3 eyes from patients with oculodermal melanocytosis 14 total eyes *
Conjunctiva
Episclera
Sclera
Chamber Angle
Iris
Ciliary Body
Choroid
Optic Nerve
Extraocular Tissue
2
11
11
7
10
11
11
3
3
0 2
3 14
3 14
3 10
2 12
3 14
3 14
2 5
1 4
Extraocular tissues included dura, posterior ciliary arteries, and extraocular muscles. Table 3. Clinical Review of Ocular and Oculodermal Melanocytosis Tissues Involved by the Melanocytic Process Number of Eyes
8 eyes (patients with ocular melanocytosis) 3 eyes (patients with oculodermal melanocytosis) Total 11 eyes
Conjunctiva
Episclera
Chamber Angle
Iris
Lens
Ciliary Body
3
8
3
7
0
3
1 4
3 11
1 4
2 9
0 0
1 4
-
tumors of spindle B cell type, ten of mixed cell type, and one of epithelioid cell type. The approximate sizes of the uveal melanomas in all 17 patients were recorded as tumor volumes calculated as the product of basal dimensions of the tumor in
Optic Nerve
Skin
8
0
0
3 11
0 0
3 3
Choroid
millimeters times the tumor thickness in millimeters (Table 1). The 14 uveal malignant melanomas ranged in volume from 75 mm 3 to 4,125 mm 3 • The mean volume was 1150 mm3 , with a median tumor volume of 576 mm3 • Eleven of the 17 melanomas were less than 1000 mm 3 • 955
OPHTHALMOLOGY. AUGUST 1982 • VOLUME 89 • NUMBER 8
Fig 1. Top left, a patient with bilateral ocular melanocytosis and a malignant melanoma of the choroid of the right eye. Note the episcleral pigmentation. Both irides demonstrate involvement by the pigmentary process. Fig 2. Top right, a photograph of the left lower conjunctival fornix of the patient in Figure I demonstrating the epibulbar and conjunctival pigmentation (see Fig 9). Fig 3. Left, a photomicrograph demonstrates the episcleral pigmentation (small arrow) in a person with ocular melanocytosis. Also, note the pigmentation of the sclera, scleral nerve loop, Schlemm's canal, trabecular meshwork, ciliary body and choroid (periodic acid-Schiff, original magnification x 16).
Figs 4A-B. A, left, involvement ofthe iris in ocular melanocytosis is well demonstrated in this photograph. Note the marked pigmentation of the anterior iris and stroma. This is the involved portion of the iris of the patient in Figure 5A. There is artifactual disruption of the ciliary body and retina (hematoxylin-eosin, original magnification x 16). B, right, in comparison to Figure 5A the inferior portion of the iris of the patient in Figure 9A was not involved by the ocular melanocytosis. Note the lack of pigmentation of the ciliary body and iris. There is artifactual separation of the iris pigment epithelium (hematoxylin-eosin, original magnification x 16).
956
Figs SA-C. A. top left. this patient demonstrates sectorial ocular melanocytosis. The iris is hyperpigmented in the superior nasal sector (arrows). In this same sector, the choroid was also involved. B, top right. in the hyperpigmented superior nasal sector, a malignant melanoma of the choroid was found. C,left. on histopathology, the malignant melanoma of the choroid was of the mixed cell type (hematoxylin-eosin, original magnification x 140).
Fig 6. Top left. dendritic melanocytes can be found in the orbital soft tissues. This photomicrograph shows meianocytes along a short posterior ciliary artery. The choroid and sclera also show marked pigmentation (hematoxylin-eosin, original magnification x 16).Fig 7. Top right. the trabecular meshwork and Schlemm's canal are noted to be involved in ocular melanocytosis. The iris and ciliary body are also heavily pigmented in this photograph (hematoxylin-eosin, original magnification x40). Fig 8. Bottom left, melanocytes can be noted to involve the lamina cribrosa of the optic nerve in an eye with ocular melanocytosis (hematoxylin-eosin, original magnification x 100). Fig 9. Bottom center, dendritic melanocytes (arrow) can be noted in the substantia propria of the conjunctiva in this patient with ocular melanocytosis (hematoxylin-eosin, original magnification x 100). (Same patient as Figs 1 and 2.) Fig 10. Bottom right. a photomicrograph of the optic nerve demonstrating the hyperpigmentation of the choroid, sclera, and dural sheaths (periodic acid-Schiff, original magnification x 16).
OPHTHALMOLOGY. AUGUST 1982 • VOLUME 89 • NUMBER 8
Three of the 15 patients (20%) with ocular or oculodermal melanocytosis and a uveal malignant melanoma (cases 5, 7, and 9) died of metastatic uveal malignant melanoma during a mean post-treatment follow-up of2.7 years. Two of the patients who died of disseminated malignant melanoma had a uveal tumor characterized histologically as a mixed cell type, and the other had a tumor consisting almost exclusively of spindle B melanoma cells. One ofthe patients with mixed-cell type uveal melanoma had extrascleral extension at the time of enucleation. Two patients died during follow-up of causes other than metastatic uveal melanoma. None of the surviving patients has any evidence of metastatic malignant melanoma.
DISCUSSION In 1939 Ota described, and later classified with Tanino, the pigmentary process that now bears his name (nevus of Ota, Nevus Fuscoceruleus Ophthalmomaxillaris Ota).2 The nevus of Ota, a pigmentary process of the facial skin, frequently involves the globe. Pigmentation of the globe alone, referred to as ocular melanosis, was described in 1912 by CoatsY In 1956 Fitzpatrick proposed the terms oculodermal melanocytosis, ocular melanocytosis, and dermal melanocytosis to replace the terms nevus of Ota and melanosis oculi. 3 Ocular and oculodermal melanocytosis are typically unilateral congenital melanocytic hyperpigmentations. 22 - 3o Infrequently, persons can develop the pigmentation during later life, most notably at puberty or during pregnancy.4 Furthermore, the hyperpigmentation can increase with advancing age. 31 The ocular and extraocular tissues that are involved in persons with ocular and oculodermal melanocytosis have been well documented in previous reports. 1,2,4,22,30 However, the frequency of involvement of each of these tissues has not been established. Our data suggest that, from a clinical standpoint, the episclera and the choroid are involved in every case and that the melanocytosis involves the iris in 82% and the conjunctiva in 36%. The anterior chamber angle structures were examined in four patients in the clinical subgroup and were involved by the melanocytic process in all cases (100%). Data from the histologic studies confirmed the presence of episcleral and choroidal melanocytosis in all affected eyes. In addition, the sclera and ciliary body were involved by the hyperpigmented melanocytes in all affected eyes. Furthermore, melanocytosis involved the iris in 85.7%, the anterior chamber angle structures in 71.4%, the optic disc in 35.1%, and the conjunctiva in 14.3% of affected eyes. Contrasted with clinical findings, these histologic findings indicate that melanocytosis of the sclera and the optic disc is often present but not readily detected clinically. Melanocytosis of the anterior chamber angle structures, as noted in four of the persons in the clinical 958
subgroup, was confirmed in the histologic study of enucleated globes. Melanocytosis ofthe conjunctiva is more evident clinically than on histopathologic study. This is probably due to the fact that minimal conjunctiva is excised at enucleation. The extent of melanocytic hyperpigmentation of the ocular tissues in ocular and oculodermal melanocytosis ranged from diffuse involvement of the episclera and uveal tract, including the iris, ciliary body, and choroid (14 cases), to sectorial involvement of these ocular tissues (three cases) in this group of patients. Sectorial melanocytic hyperpigmentation has not been well recognized in the literature, but it did account for 17.6% of our cases. Hulke 5 (1861) wrote one of the first reports of a patient with oculodermal melanocytosis and uveal malignant melanoma. Coats (1912), II Reese (1925),16 and Doherty (1927)24 were among the earlier clinicians to review the literature on ocular melanocytosis and to propose that ocular melanocytosis may predispose to the development of uveal malignant melanoma. Since these first reports, the literature has documented the association of ocular and oculodermal melanocytosis with uveal malignant melanoma,5-20 as well as with melanomas of the orbit,32,33 central nervous system,34.35 and skin.36 Our series of 17 cases of ocular (14 cases) and oculodermal (three cases) melanocytosis associated with uveal malignant melanoma further documents this association. In our series, more people had ocular melanocytosis with associated uveal malignant melanoma than oculodermal melanocytosis with a uveal malignant melanoma. Since this study did not determine nor has the literature stated the relative prevalences of the two forms of melanocytosis in the white popUlation, these data and other literature reviews can neither support nor refute the assertion that ocular and/or oculodermal melanocytosis predisposes to the development of a uveal malignant melanoma. The cell type of the 14 malignant uveal melanomas managed by enucleation was spindle B in 20%, mixed in 66.7%, and epithelioid in 6.7%. This distribution of malignant melanoma cell types parallels the frequency of melanoma cell types found in larger popUlations with uveal malignant melanoma. 37 Tumor volume did not correlate well with prognosis for death from metastatic uveal malignant melanoma in this small series. This observation is in agreement with the findings reported by McLean and associates,3S who found tumor volume to be of limited prognostic significance for small melanomas. Recently Blodi 10 has challenged the contention of Reese 16 and Yanoff and Zimmerman 6 that the incidence of uveal malignant melanoma is increased in eyes with ocular and oculodermal melanocytosis. Statistic analysis of the data from this study provides some insight into this controversy. Seventeen of 1,250 patients with uveal malignant melanoma had ocular or oculodermal melanocytosis for a prevalence rate in a uveal melanoma population
GONDER, et al • MELANOMA AND MELANOCYTOSIS
of 1.36%. Fourteen of the 17 patients had ocular melanocytosis for a prevalence rate in a uveal melanoma population of 1.23%. Three of the 17 patients had oculodermal melanocytosis for a prevalence rate in a uveal melanoma population of 0.24%. As all 17 patients with uveal melanoma and ocular or oculodermal melanocytosis were referred for diagnosis and management of the uveal melanoma alone and not for the ocular melanocytosis, this series of uveal melanoma patients is probably representative of a true cross section of the uveal melanoma population. This would imply that the actual prevalence rate of ocular melanocytosis in an uveal melanoma population, if it were known, would approximate the prevalence rate (1.36%) determined in this study. However, the authors recognize that Wills Eye Hospital and the Massachusetts Eye and Ear Infirmary are large referral centers, and this may increase the observed prevalence rates. The prevalence rate for ocular melanocytosis in the white population studied by Gonder and associates during their screening of 13,150 consecutive patients at Wills Eye Hospital was 0.04% (2/5241 white persons).39 The prevalence rate for ocular melanocytosis in the uveal melanoma population and in the white population studied can be assessed using tests of hypothesis relating to differences in prevalence rates for two populations under the assumption that a binomial distribution governs the prevalence of ocular melanocytosis in these two populations. In contrast to the prevalence rate of ocular melanocytosis in the white population (0.04%), the prevalence of ocular melanocytosis was 1.09% (MEEI Series) and 1.57% (Wills Series) in the uveal melanoma populations, corresponding to a 35-fold relative risk when pooled for comparison to the white population. When each study result is contrasted with the white population, the true prevalence rates for ocular melanocytosis for these two study populations were significantly different (P = 0.0001) from the white population using a twosided test of hypothesis of equal prevalence rates against unrestricted alternatives. In fact, prevalence rates one-third as large as those observed for each of the study subgroups would also have been significantly different from the white population. The calculation of the power (the power is the probability of detecting the observed prevalence rates, assuming that these were the true prevalence rates) demonstrated for both the MEEI and WEH series that differences in these observed prevalence rates could be detected with a 99% probability. In other words, this difference in prevalence rates is unlikely to be due to chance alone, implying that ocular melanocytosis predisposes to the development of a uveal malignant melanoma. The patient populations chosen for this study and the fact that this study is not a controlled matched prospective study does not allow an accurate calculation of the risk of a person with ocular melanocytosis developing a uveal malignant melanoma. However, generalizations can be drawn from this study knowing
that the prevalence of ocular melanocytosis was 35 times greater in the uveal melanoma population than in the white study population. The patient populations chosen for this study (referral center populations) may partially account for the discrepancy in the prevalence rates. However, these populations would tend to increase the detected prevalence rates, and, therefore, the 35-fold increase in the prevalence of ocular melanocytosis in the uveal melanoma population could be considered a maximum. If the presence of ocular melanocytosis was the sole governing factor producing this difference in prevalence rates, then the prevalence of uveal melanomas in a population of persons with ocular melanocytosis would be increased by a factor of 35 or 0.021%.40 However, as discussed, multiple factors are influencing the detected prevalence rates and, therefore, this figure should only be regarded as estimated maximum.
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