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Malignant Melanoma of the Choroid Associated with Oculodermal Melanocytosis
Ocular Pathology for Clinicians Edited by Frederick A. Jakobiec, MD
Malignant Melanoma of the Choroid Associated with Oculodermal MeIano cytosis JOHN R. GONDER, MD, JERRY A. SHIELDS, MD,* DANIEL M. ALBERT, MDt
Abstract: A 66-year-old white woman with oculodermal melanocytosis developed a malignant melanoma of the choroid in the right eye. The association of uveal melanoma with ocular and oculodermal melanocytosis is discussed. A differential diagnosis of ocular and oculodermal melanocytosis with emphasis on primary acquired melanosis is presented. Accurate diagnosis of ocular and oculodermal melanocytosis is important as these conditions have been reported to develop malignant melanoma of the skin, uveal tract, orbit, meninges, and brain. [Key words: malignant melanoma, ocular melanocytosis, oculodermal melanocytosis.] Ophthalmology 88:372-376, 1981
Ocular and oculodermal melanocytosis are usually congenital pigmentations. Pigmentation of the uvea, episclera and periorbital skin is called oculodermal melanocytosis (nevus of Ota1 ), whereas pigmentation of the uvea and episclera without skin involvement is termed ocular melanocytosis (melanosis oculi). Pigmentation of the skin without globe involvement is termed dermal melanocytosis. Hulke,2 in 1861, recorded a malignant melanoma arising in the eye of a patient with oculodermal melanocytosis. Subsequently, other reports have further documented the relationship between uveal melanoma and ocular and oculodermal melanocytosis 3 -1 4 and have led to specuFrom the Wills Eye Hospital and Research Institute, Thomas Jefferson University: Philadelphia, and the Harvard Medical School, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary: Boston. Dr. Gonder was a Fellow in Ophthalmic Pathology at Harvard Medical School and is now a Fellow in vitreoretinal diseases on the Retina Service at Wills Eye Hospital. Supported in part by the R. Samuel McLaughlin Foundation and National Eye Institute grant EY01917, The Retina Research and Development Foundation, Philadelphia, the Pennsylvania Lions Sight Conservation and Eye Research Foundation and the Ocular Oncology Fund, Wills Eye Hospital. Reprint requests to Jerry A. Shields, MD, Ocular Oncology Service, Wills Eye Hospital, Ninth and Walnut Streets, Philadelphia, PA 19107.
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lation regarding the malignant potential of ocular and oculodermal melanocytosis. In this article, we report and illustrate a typical case of oculodermal melanocytosis to help the clinician be more aware of this condition and differentiate it from other ocular pigmentations. The occurrence of a malignant melanoma of the choroid in our patient emphasizes the need for an accurate clinical diagnosis and follow-up of persons with ocular and oculodermal melanocytosis.
CASE REPORT A 66-year-old white woman was referred to the Oncology Service of Wills Eye Hospital for evaluation of a tumor of the choroid in the right eye. One week prior to presentation, the patient noted decreased vision in the right eye. She had been aware of photopsia and floaters for four weeks. Her past ocular history revealed that the pigmentation of the periocular skin and episclera on the right side had been present from birth, but more noticeable since age 12. The patient's family history and past medical history were unremarkable. External ocular examination revealed cutaneous pigmentation of the periocular region of the right eye (Fig 1). Visual acuity with correction was hand movements and 6/9-1 in the right and left eyes, respectively. The intraocular pressure by applanation was 16 mm Hg bilaterally. Slit-lamp examination confirmed episcleral pigmentation (Fig. 2). Funduscopic 0161-6420/8110400/0372/$00.95
© American Academy of Ophthalmology
GONDER, et al • OCULAR PATHOLOGY FOR CLINICIANS
Fig 1. Left, facial view of the patient demonstrating the pigmentation of the right periorbital ski n in oculodermal melanoc ytosis. Fig 2. Right, a closeup picture of the right globe of the patient demonstrating the patches of episcleral pigmentation.
Fig 3. Left, a low-power photomicrograph of the enucleated right eye demonstrating a moderately pigmented choroidal melanoma adjacent to the optic nerve (hematoxy lin and eosin , original magnification x 10). Fig 4. Right , a highpower photomicrograph of the choroidal melanoma demonstrating both small epithelioid and plump spindle-B melanoma cells. Note the pigment in some melanoma cells (hematoxylin and eosin . original magnification x 100).
examination of the right eye showed a pigmented choroidal tumor partially obscured by a vitreous hemorrhage. Fluorescein angiography and ultrasonography were compatible with the diagnosis of malign ant melanoma of the choroid and it was elected to perform an incisional P-32 test and to enucleate the eye if the test res ults were positive. At the time of surgery transillumination showed a shadow adjacent to the optic disc. The P-32 uptake result was 364% increase over the control. 15 The patient underwent enucleation of the right eye . Pathology. The enucleated eye meas ured 24 x 24 x 24 mm. The episclera showed fairly well defined patches of tlat pigmentation, extending from the limbal region to the posterior pole. The globe was opened obliquely, revealing a large. mushroom-shaped choroidal tumor meas uring 9 x \0 x 9
mm . The anterior segment, lens , iris and ciliary body were unremarkable. Low-power microscopic examination revealed a large, moderately pigmented tumor (Fig. 3). It was diagno sed as a mixed-cell type malignant melanoma (Fig. 4). The limbal conjunctiva and episclera showed pigmented dendritic melanoc ytes. Hyperpigmented melanocytes were present in the iri s, ciliary body , and choroid . Similar melanocytes were also observed in the sc lera, in emissary canals. and along the posterior ciliary arteries (Fig 5). The retina adjacent to the tumor was detached by an accumulation of blood. The retina overlying the tumor apex was invaded by the tumor. Vitreou s hemorrhage was present. Pathologic diagnoses were (I) malignant melanoma of the choroid of the mixed-cell type with no extrascl eral exten-
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DISCUSSION Ocular and oculodermal melanocytosis develop as congenital pigmentations in the majority of persons. However, others can acquire or show increased pigmentation· at puberty (as with this patient) or during
pregnancy.16,17 Oculodermal melanocytosis is common in the Oriental race, with a reported prevalence of 0.5%.18 In ocular and oculodermal melanocytosis, the pigmentation can involve the conjunctiva, episclera, uveal tract and optic disc. 19 - 22 Oculodermal melanocytosis, in addition, may have pigmentation of the skin, of the eyelid, temple, forehead, cheek,
Fig S. Left. a low-power photomicrograph of the anterior chamber angle demonstrating heavily pigmented melanocytes in the iris, ciliary body, trabecular meshwork, Schlemn's canal and episclera (hematoxylin and eosin, original magnification x 40). Right. a ol w-power photomicrograph demonstrating the heavily pigmented choroid superiorly . The underlying sclera contains melanocytes. A short posterior ciliary artery can be seen to exit posteriorly from the sclera. Note the pigmented melanocytes associated with this vessel (hematoxylin and eosin, original magnification x 16). Fig 6. Top , an external eye photograph of idiopathic primary acquired melanosis showing diffuse pigmentation of the conjunctiva and hyperpigmented nodules at the limbus (Courtesy of Dr. J . Ballantyne). Bottom, an external eye photograph of the right globe of a patient with ocular melanocytosis demonstrating the episcleral pigmentation . Contrast with Fig 6 (top) .
Fig 7. Left, a photomicrograph of primary acquired melanosis demonstrating melanocytes along the basal layer of the epithelium . Note the nesting of these melanocytes. The pigmented cells below the basal layer are melanophages (periodic-Acid-Schiff, original magnification x \(0). Right. a photomicrograph of ocular melanocytosis involving the conjunctiva. The basal layer of the epithelium is uninvolved. An increased number of pigmented melanocytes can be seen in the substantia propria (hematoxylin and eosin, original magnification x 1(0).
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the orbit, the meninges, and the oral and nasal mucosa. 16 ,17,23-25 Histopathologic study, as illustrated in our case, shows an increased number of hyperpigmented melanocytes in the involved tissues. A similar histologic picture is seen in the blue nevus and mongolian spot26 and the melanocytoma. 3,27 Abnormalities of migration of the neural crest cells (which are the embryologic precursors of the melanocyte) may account for the development of ocular melanocytosis, oculodermal melanocytosis, and other similar conditions. 28 Both ocular and oculodermal melanocytosis have been described in association with the development of malignant melanoma. The statement that ocular melanocytosis is a premalignant condition predisposing to uveal melanomas, while oculodermal melanocytosis rarely gives rise to uveal melanoma has been challenged. 3 Ocular and oculodermal melanocytosis most likely represent different degrees of the same pigmentary abnormality, and both should have equal predisposition to the development of melanoma. A review of the literature shows uveal melanomas to arise in both conditions. 2- 14 In fact, uveal melanomas have occurred in cases of bilateral, ocular,9 and oculodermal melanocytosis. 8 Melanomas have also been reported to occur in the orbit,29,30 the central nervous system,14,31.32 and skin 26 in oculodermal melanocytosis. Coats,5 Reese,lO and Yanoff and Zimmerman3 have stated that there is an increased incidence of malignant melanoma in ocular and oculodermal melanocytosis. Blodp3 has challenged this belief, citing a case of malignant melanoma of the choroid in the uninvolved eye of a patient with ocular melanocytosis. The definitive answer to this question could possibly be obtained by a prospective study of patients with ocular or oculodermal melanocytosis. The pigmentation of ocular and oculodermal melanocytosis is to be differentiated from other real or apparent pigmentary disturbances of the globe, conjunctiva, and skin. The blue to black appearance of the globe associated with thin sclera occurring in osteogenesis imperfecta and staphylomas may be confused with the episcleral pigmentation of ocular melanocytosis. Ochronosis produces a brown discoloration of the sclera that usually occurs in the palpebral fissure and results from the oxidation of homogentistic acid. An Axenfeld's intrascleral nerve loop and other emissary canals may demonstrate pigmentation of the adjacent episclera and if the pigmentation is extensive, it may be difficult to differentiate from ocular melanocytosis. Simple heterochromia of the iris lacks the conjunctival, episcleral, or choroidal hyperpigmentation of ocular melanocytosis. Other pigmentary disturbances of the conjunctiva may be difficult to differentiate from the conjunctival pigmentation of ocular melanocytosis. Racial conjunctival pigmentation is most commonly found at the limbus and is more frequent in the non-Caucasian races. The pigmentation does not involve the episclera
as in ocular melanocytosis. On histopathologic study, the basal layer of the epithelium is hyperpigmented and does not demonstrate the increased hyperpigmented melanocytes of the substantia propria seen in ocular melanocytosis. Secondary benign acquired conjunctival melanosis shows a similar hyperpigmentation of the basal layer of the epithelium. 34 This type of melanosis can be secondary to irradiation, pregnancy, or Addison's disease. Clinically, secondary benign acquired conjunctival melanosis is a flat conjunctival hyperpigmentation. It may be confused with and must be differentiated from both ocular melanocytosis and the primary idiopathic acquired melanosis. 35 Primary idiopathic acquired melanosis is a disease of persons ages 40 to 50 years. It is usually unilateral and characteristically a flat, diffuse brown lesion of the conjunctiva (Fig 6). It spreads in a waxing and waning fashion. The lesion has a definite malignant potential for the development of a conjunctival melanoma but not for the development of choroidal melanomas as in ocular melanocytosis. Primary acquired melanosis may represent the conjunctival counterpart of lentigo maligna and superficial spreading melanoma in situ of the skin. 35 .36 When primary acquired melanosis of the conjunctiva occurs simultaneously with lentigo malign a of the skin of the lid, it must be differentiated from the oculodermal melanocytosis. On histopathologic study, primary acquired melanosis shows activity of the melanocytes near the basal layer of the epithelium. In distinction, oculodermal melanocytosis that involves the conjunctiva has hyperpigmented dendritic melanocytes deep in the substantia propria (Fig 7). However, the pigmentation in ocular and oculodermal melanocytosis is more often episcleral than conjunctival, and this can be clinically confirmed by the fact that the bulbar conjunctiva can be moved freely over the pigmentation. Management of ocular and oculodermal melanocytosis depends, of course, on an accurate clinical diagnosis. The dermal pigmentation can be subtle, remote from the lids, and may be overlooked. It has been pointed out that this may result in an underdiagnosis of oculodermal melanocytosis. 3 As persons with melanocytosis have been documented to develop malignant melanomas of the globe, skin, orbit and central nervous system, they should be carefully examined and have regular follow-up examinations for evidence of such tumors. In particular, all examinations should include a fundus examination by indirect ophthalmoscopy. The management of a malignant melanoma developing in such a person is no different than the management of melanoma in patients without melanocytosis. 36
REFERENCES 1. Ota M. Navus fusco-caeruleus ophthalmomaxillaris. Tokyo Med J 1939; 63:1243-5. 2. Hulke JW. A series of cases of carcinoma of the eyeball. Royal London Ophthalmic Hosp Rep 1861; 3:279-86.
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3. Yanoff M, Zimmerman LE. Histogenesis of malignant melanomas of the uveal. III. The relationship of congenital ocular melanocytosis and neurofibromatosis to uveal melanomas. Arch Ophthalmol 1967; 77:331-6. 4. Albert DM, Scheie HG. Nevus of Ota with malignant melanoma of the choroid: report of a case. Arch Ophthalmol 1963; 69:774-7. 5. 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. 6. Font RL, Reynolds AM Jr, Zimmerman LE. Diffuse malignant melanoma of the iris in the nevus of Ota. Arch Ophthalmol 1967; 77:513-8. 7. 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. 8. Halasa A. Malignant melanoma in a case of bilateral nevus of Ota. Arch Ophthalmol 1970; 84:176-8. 9. Makley TA Jr, King CM. Malignant melanoma in melanosis oculi. Trans Am Acad Ophthalmol Otolaryngol 1967; 71:638-41. 10. Reese AB. Melanosis oculi. A case with microscopic findings. Am J Ophthalmol 1925; 8:865- 70. 11. Roy PE, Schaeffer EM. Nevus of Ota and choroidal melanoma. Surv Ophthalmol 1967; 12: 130-4. 12. Sabates FN, Yamashita T. Congenital melanosis oculi complicated by two independent malignant melanomas of the choroid. Arch Ophthalmol 1967; 77:801-3. 13. Seelenfreund MH, Freilich DB. Ocular melanocytosis and malignant melanoma. NY State J Med 1979; 79:916- 7. 14. Yamamoto T. Malignant melanoma of the choroid in the nevus of Ota. Ophthalmologica 1969; 159:1-10. 15. Shields JA. Accuracy and limitations of the 3 2 p test in the diagnosis of ocular tumors: an analysis of 500 cases. Ophthalmology 1978; 85:950-66. 16. Gupta GP, Gangwar DN. Naevus of Ota. Br J Ophthalmol 1965; 49:364-8. 17. Mishima Y, Mevorah B. Nevus Ota and nevus Ito in American Negroes. J Invest Dermatol 1961; 36:133-54. 18. Fitzpatrick TB, Zeller R, Kukita A, Kitamoura H. Ocular and dermal melanocytosis. Arch Ophthalmol 1956; 56:830-2. 19. Cowan TH, Balistocky M. The nevus of Ota or oculodermal melanocytosis: the ocular changes. Arch Ophthalmol 1961; 65:483-92. 20. Doherty WB. Cases of melanosis oculi, with microscopic findings. Am J Ophthalmol 1927; 10:1-8.
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21. Helmick ED, Pringle RW. Oculocutaneous melanosis or nevus of Ota. Arch Ophthalmol 1956; 56:833-8. 22. Stafford WR. Congenital melanosis oculi: report of a case. Arch Ophthalmol 1962; 68:738-41. 23. Da Costa Estima A, Dos Santos Carneiro R. Ota naevus: presentation of a case. Br J Plast Surg 1972; 25:49-52. 24. Kopf AW, Weidman AI. Nevus of Ota. Arch Dermatol 1962; 85:195-208. 25. Lever WF, SChamburgh-Lever G. Melanocytic nevi and malignant melanoma. In: Lever WF, Schaumburgh-Lever G, eds. Histopathology of the skin. 5th ed. Philadelphia; JB Lippincott, 1975; 32:646- 76. 26. Dorsey CS, Montgomery H. Blue nevus and its distinction from mongolian spot and nevus of Ota. J Invest Dermatol 1954; 22:225-6. 27. Zimmerman LE. Melanocytes, melanocytic nevi, and melanocytomas. Invest Ophthalmol 1965; 4:11-41. 28. Bolande RP. The neurocristopathies: a unifying concept of disease arising in neural crest maldevelopment. Hum Pathol 1974; 5:409-29. 29. Hagler WS, Brown CC. Malignant melanoma of the orbit arising in a nevus of Ota. Trans Am Acad Ophthalmol Otolaryngol 1966; 70:817 -22. 30. Jay B. Malignant melanoma of the orbit in a case of oculodermal melanosis (naevus of Ota) Br J Ophthalmol 1965; 49:359-63. 31. 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; 95392-5. 32. Sang DN, Albert DM, Sober AJ, McMeekin TO. Nevus of Ota with contralateral cerebral melanoma. Arch Ophthalmol 1977; 95:1820-4. 33. Blodi FC. Ocular melanocytosis and melanoma. Am J Ophthalmol 1975; 80:389-95. 34. Henkind P. Conjunctival melanocytic lesions: natural history. In: Jakobiec FA, ed. Ocular and Adnexal tumors. Birmingham, AL: Aesculapius Publishing 1978; 572-82. 35. Zimmerman LE. The histogenesis of conjunctival melanomas. In: Jakobiec FA, ed. Ocular and Adnexal tumors. Birmingham, AL: Aesculapius Publishing, 1978; 600 - 30. 36. Shields JA. Current approaches to the diagnosis and management of choroidal melanomas. Surv Ophthalmol 1977; 21 :443-63.
Malignant Melanoma of the Choroid Associated with Oculodermal MeIano cytosis JOHN R. GONDER, MD, JERRY A. SHIELDS, MD,* DANIEL M. ALBERT, MDt
Abstract: A 66-year-old white woman with oculodermal melanocytosis developed a malignant melanoma of the choroid in the right eye. The association of uveal melanoma with ocular and oculodermal melanocytosis is discussed. A differential diagnosis of ocular and oculodermal melanocytosis with emphasis on primary acquired melanosis is presented. Accurate diagnosis of ocular and oculodermal melanocytosis is important as these conditions have been reported to develop malignant melanoma of the skin, uveal tract, orbit, meninges, and brain. [Key words: malignant melanoma, ocular melanocytosis, oculodermal melanocytosis.] Ophthalmology 88:372-376, 1981
Ocular and oculodermal melanocytosis are usually congenital pigmentations. Pigmentation of the uvea, episclera and periorbital skin is called oculodermal melanocytosis (nevus of Ota1 ), whereas pigmentation of the uvea and episclera without skin involvement is termed ocular melanocytosis (melanosis oculi). Pigmentation of the skin without globe involvement is termed dermal melanocytosis. Hulke,2 in 1861, recorded a malignant melanoma arising in the eye of a patient with oculodermal melanocytosis. Subsequently, other reports have further documented the relationship between uveal melanoma and ocular and oculodermal melanocytosis 3 -1 4 and have led to specuFrom the Wills Eye Hospital and Research Institute, Thomas Jefferson University: Philadelphia, and the Harvard Medical School, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary: Boston. Dr. Gonder was a Fellow in Ophthalmic Pathology at Harvard Medical School and is now a Fellow in vitreoretinal diseases on the Retina Service at Wills Eye Hospital. Supported in part by the R. Samuel McLaughlin Foundation and National Eye Institute grant EY01917, The Retina Research and Development Foundation, Philadelphia, the Pennsylvania Lions Sight Conservation and Eye Research Foundation and the Ocular Oncology Fund, Wills Eye Hospital. Reprint requests to Jerry A. Shields, MD, Ocular Oncology Service, Wills Eye Hospital, Ninth and Walnut Streets, Philadelphia, PA 19107.
372
lation regarding the malignant potential of ocular and oculodermal melanocytosis. In this article, we report and illustrate a typical case of oculodermal melanocytosis to help the clinician be more aware of this condition and differentiate it from other ocular pigmentations. The occurrence of a malignant melanoma of the choroid in our patient emphasizes the need for an accurate clinical diagnosis and follow-up of persons with ocular and oculodermal melanocytosis.
CASE REPORT A 66-year-old white woman was referred to the Oncology Service of Wills Eye Hospital for evaluation of a tumor of the choroid in the right eye. One week prior to presentation, the patient noted decreased vision in the right eye. She had been aware of photopsia and floaters for four weeks. Her past ocular history revealed that the pigmentation of the periocular skin and episclera on the right side had been present from birth, but more noticeable since age 12. The patient's family history and past medical history were unremarkable. External ocular examination revealed cutaneous pigmentation of the periocular region of the right eye (Fig 1). Visual acuity with correction was hand movements and 6/9-1 in the right and left eyes, respectively. The intraocular pressure by applanation was 16 mm Hg bilaterally. Slit-lamp examination confirmed episcleral pigmentation (Fig. 2). Funduscopic 0161-6420/8110400/0372/$00.95
© American Academy of Ophthalmology
GONDER, et al • OCULAR PATHOLOGY FOR CLINICIANS
Fig 1. Left, facial view of the patient demonstrating the pigmentation of the right periorbital ski n in oculodermal melanoc ytosis. Fig 2. Right, a closeup picture of the right globe of the patient demonstrating the patches of episcleral pigmentation.
Fig 3. Left, a low-power photomicrograph of the enucleated right eye demonstrating a moderately pigmented choroidal melanoma adjacent to the optic nerve (hematoxy lin and eosin , original magnification x 10). Fig 4. Right , a highpower photomicrograph of the choroidal melanoma demonstrating both small epithelioid and plump spindle-B melanoma cells. Note the pigment in some melanoma cells (hematoxylin and eosin . original magnification x 100).
examination of the right eye showed a pigmented choroidal tumor partially obscured by a vitreous hemorrhage. Fluorescein angiography and ultrasonography were compatible with the diagnosis of malign ant melanoma of the choroid and it was elected to perform an incisional P-32 test and to enucleate the eye if the test res ults were positive. At the time of surgery transillumination showed a shadow adjacent to the optic disc. The P-32 uptake result was 364% increase over the control. 15 The patient underwent enucleation of the right eye . Pathology. The enucleated eye meas ured 24 x 24 x 24 mm. The episclera showed fairly well defined patches of tlat pigmentation, extending from the limbal region to the posterior pole. The globe was opened obliquely, revealing a large. mushroom-shaped choroidal tumor meas uring 9 x \0 x 9
mm . The anterior segment, lens , iris and ciliary body were unremarkable. Low-power microscopic examination revealed a large, moderately pigmented tumor (Fig. 3). It was diagno sed as a mixed-cell type malignant melanoma (Fig. 4). The limbal conjunctiva and episclera showed pigmented dendritic melanoc ytes. Hyperpigmented melanocytes were present in the iri s, ciliary body , and choroid . Similar melanocytes were also observed in the sc lera, in emissary canals. and along the posterior ciliary arteries (Fig 5). The retina adjacent to the tumor was detached by an accumulation of blood. The retina overlying the tumor apex was invaded by the tumor. Vitreou s hemorrhage was present. Pathologic diagnoses were (I) malignant melanoma of the choroid of the mixed-cell type with no extrascl eral exten-
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DISCUSSION Ocular and oculodermal melanocytosis develop as congenital pigmentations in the majority of persons. However, others can acquire or show increased pigmentation· at puberty (as with this patient) or during
pregnancy.16,17 Oculodermal melanocytosis is common in the Oriental race, with a reported prevalence of 0.5%.18 In ocular and oculodermal melanocytosis, the pigmentation can involve the conjunctiva, episclera, uveal tract and optic disc. 19 - 22 Oculodermal melanocytosis, in addition, may have pigmentation of the skin, of the eyelid, temple, forehead, cheek,
Fig S. Left. a low-power photomicrograph of the anterior chamber angle demonstrating heavily pigmented melanocytes in the iris, ciliary body, trabecular meshwork, Schlemn's canal and episclera (hematoxylin and eosin, original magnification x 40). Right. a ol w-power photomicrograph demonstrating the heavily pigmented choroid superiorly . The underlying sclera contains melanocytes. A short posterior ciliary artery can be seen to exit posteriorly from the sclera. Note the pigmented melanocytes associated with this vessel (hematoxylin and eosin, original magnification x 16). Fig 6. Top , an external eye photograph of idiopathic primary acquired melanosis showing diffuse pigmentation of the conjunctiva and hyperpigmented nodules at the limbus (Courtesy of Dr. J . Ballantyne). Bottom, an external eye photograph of the right globe of a patient with ocular melanocytosis demonstrating the episcleral pigmentation . Contrast with Fig 6 (top) .
Fig 7. Left, a photomicrograph of primary acquired melanosis demonstrating melanocytes along the basal layer of the epithelium . Note the nesting of these melanocytes. The pigmented cells below the basal layer are melanophages (periodic-Acid-Schiff, original magnification x \(0). Right. a photomicrograph of ocular melanocytosis involving the conjunctiva. The basal layer of the epithelium is uninvolved. An increased number of pigmented melanocytes can be seen in the substantia propria (hematoxylin and eosin, original magnification x 1(0).
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the orbit, the meninges, and the oral and nasal mucosa. 16 ,17,23-25 Histopathologic study, as illustrated in our case, shows an increased number of hyperpigmented melanocytes in the involved tissues. A similar histologic picture is seen in the blue nevus and mongolian spot26 and the melanocytoma. 3,27 Abnormalities of migration of the neural crest cells (which are the embryologic precursors of the melanocyte) may account for the development of ocular melanocytosis, oculodermal melanocytosis, and other similar conditions. 28 Both ocular and oculodermal melanocytosis have been described in association with the development of malignant melanoma. The statement that ocular melanocytosis is a premalignant condition predisposing to uveal melanomas, while oculodermal melanocytosis rarely gives rise to uveal melanoma has been challenged. 3 Ocular and oculodermal melanocytosis most likely represent different degrees of the same pigmentary abnormality, and both should have equal predisposition to the development of melanoma. A review of the literature shows uveal melanomas to arise in both conditions. 2- 14 In fact, uveal melanomas have occurred in cases of bilateral, ocular,9 and oculodermal melanocytosis. 8 Melanomas have also been reported to occur in the orbit,29,30 the central nervous system,14,31.32 and skin 26 in oculodermal melanocytosis. Coats,5 Reese,lO and Yanoff and Zimmerman3 have stated that there is an increased incidence of malignant melanoma in ocular and oculodermal melanocytosis. Blodp3 has challenged this belief, citing a case of malignant melanoma of the choroid in the uninvolved eye of a patient with ocular melanocytosis. The definitive answer to this question could possibly be obtained by a prospective study of patients with ocular or oculodermal melanocytosis. The pigmentation of ocular and oculodermal melanocytosis is to be differentiated from other real or apparent pigmentary disturbances of the globe, conjunctiva, and skin. The blue to black appearance of the globe associated with thin sclera occurring in osteogenesis imperfecta and staphylomas may be confused with the episcleral pigmentation of ocular melanocytosis. Ochronosis produces a brown discoloration of the sclera that usually occurs in the palpebral fissure and results from the oxidation of homogentistic acid. An Axenfeld's intrascleral nerve loop and other emissary canals may demonstrate pigmentation of the adjacent episclera and if the pigmentation is extensive, it may be difficult to differentiate from ocular melanocytosis. Simple heterochromia of the iris lacks the conjunctival, episcleral, or choroidal hyperpigmentation of ocular melanocytosis. Other pigmentary disturbances of the conjunctiva may be difficult to differentiate from the conjunctival pigmentation of ocular melanocytosis. Racial conjunctival pigmentation is most commonly found at the limbus and is more frequent in the non-Caucasian races. The pigmentation does not involve the episclera
as in ocular melanocytosis. On histopathologic study, the basal layer of the epithelium is hyperpigmented and does not demonstrate the increased hyperpigmented melanocytes of the substantia propria seen in ocular melanocytosis. Secondary benign acquired conjunctival melanosis shows a similar hyperpigmentation of the basal layer of the epithelium. 34 This type of melanosis can be secondary to irradiation, pregnancy, or Addison's disease. Clinically, secondary benign acquired conjunctival melanosis is a flat conjunctival hyperpigmentation. It may be confused with and must be differentiated from both ocular melanocytosis and the primary idiopathic acquired melanosis. 35 Primary idiopathic acquired melanosis is a disease of persons ages 40 to 50 years. It is usually unilateral and characteristically a flat, diffuse brown lesion of the conjunctiva (Fig 6). It spreads in a waxing and waning fashion. The lesion has a definite malignant potential for the development of a conjunctival melanoma but not for the development of choroidal melanomas as in ocular melanocytosis. Primary acquired melanosis may represent the conjunctival counterpart of lentigo maligna and superficial spreading melanoma in situ of the skin. 35 .36 When primary acquired melanosis of the conjunctiva occurs simultaneously with lentigo malign a of the skin of the lid, it must be differentiated from the oculodermal melanocytosis. On histopathologic study, primary acquired melanosis shows activity of the melanocytes near the basal layer of the epithelium. In distinction, oculodermal melanocytosis that involves the conjunctiva has hyperpigmented dendritic melanocytes deep in the substantia propria (Fig 7). However, the pigmentation in ocular and oculodermal melanocytosis is more often episcleral than conjunctival, and this can be clinically confirmed by the fact that the bulbar conjunctiva can be moved freely over the pigmentation. Management of ocular and oculodermal melanocytosis depends, of course, on an accurate clinical diagnosis. The dermal pigmentation can be subtle, remote from the lids, and may be overlooked. It has been pointed out that this may result in an underdiagnosis of oculodermal melanocytosis. 3 As persons with melanocytosis have been documented to develop malignant melanomas of the globe, skin, orbit and central nervous system, they should be carefully examined and have regular follow-up examinations for evidence of such tumors. In particular, all examinations should include a fundus examination by indirect ophthalmoscopy. The management of a malignant melanoma developing in such a person is no different than the management of melanoma in patients without melanocytosis. 36
REFERENCES 1. Ota M. Navus fusco-caeruleus ophthalmomaxillaris. Tokyo Med J 1939; 63:1243-5. 2. Hulke JW. A series of cases of carcinoma of the eyeball. Royal London Ophthalmic Hosp Rep 1861; 3:279-86.
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