Pigmented Adenoma of the Optic Nerve Head Simulating a Melanocytoma Jerry A. Shields, MD,l Ralph C. Eagle, Jr., MD,2 Carol L. Shields, MD, I Patrick De Potter, MDI Purpose: The purpose of this report is to describe a clinicopathologic correlation of an unusual pigmented tumor of the optic nerve head, to point out that such a lesion can simulate clinically a melanocytoma of the optic disc, and to discuss the differential diagnosis of pigmented epipapillary lesions. Findings: Histopathologic studies of the affected eye showed a peculiar pigmented tumor of the optic disc that was compatible with an adenoma arising from the juxtapapillary retinal pigment epithelium. Conclusions: Adenoma of the retinal pigment epithelium can closely simulate a melanocytoma of the optic disc. There are some clinical features that may serve to differentiate the two lesions. Ophthalmology 1992;99:1705-1708

The melanocytoma of the optic nerve is a distinct tumor that has characteristic clinical and pathological features. I- 5 It is usually a dark brown to black lesion that involves the optic disc. The typical ophthalmoscopic and fluorescein angiographic features of a melanocytoma serve to differentiate this benign tumor from a juxtapapillary malignant melanoma. In rare instances, an optic nerve melanocytoma has apparently evolved into an malignant melanoma. 6 Tumors and related lesions of the retinal pigment epithelium (RPE) include congenital hypertrophy, reactive hyperplasia, combined hamartoma, adenoma, and adenocarcinoma. 7 These lesions are generally benign in their

Originally received: April 6, 1992. Revision accepted: June 15 . 1992. 'Ocular Oncology Service, Wills Eye Hospital, Jefferson Medical College, Thomas Jefferson University, Philadelphia. 2 Pathology Department, Wills Eye Hospital, Jefferson Medical College, Thomas Jefferson University, Philadelphia.

Presented at the Atlantic Coast Fluorescein Club Annual Meeting, Wilmer Ophthalmological Institute, Baltimore, January 1992. Supported in part by the Eye Tumor Research Foundation, Inc, Philadelphia, Pennsylvania, and in part by the Macula Foundation, New York, New York. Reprint requests to Jerry A. Shields, MD, Director, Ocular Oncology Service. Wills Eye Hospital, 900 Walnut St, Philadelphia. PA 19107.

biologic behavior and have little or no potential for true malignant transformation. 7 - '6 Even those with malignant cytologic features (adenocarcinomas) do not tend to exhibit distant metastasis. 17 We report a clinicopathologic correlation of an adenoma or hyperplasia of the RPE that clinically simulated a melanocytoma of the optic disc.

Clinical History A 76-year-old asymptomatic woman with visual acuity of 20/20 and normal pupillary reactions in both eyes was found on routine ophthalmologic examination in October 1980 to have a heavily pigmented lesion of her left optic disc. The black lesion covered the inferonasal two thirds of the optic disc and extended into the adjacent nerve fiber layer of the retina (Fig I). Fluorescein angiography showed the lesion to be hypofluorescent throughout the angiogram (Fig 2). Based on its clinical appearance, the lesion was diagnosed as a melanocytoma of the optic disc with involvement of the juxtapapillary retina. The patient was followed annually on the Oncology Service at Wills Eye Hospital for 10 years. At the time of her last examination in March 1991, her visual acuity remained 20/20 in each eye, there had been no apparent change in the lesion, and the pupillary reactions were normal. She died of a myocardial infarction in November 1991, and the affected eye was obtained after death and promptly fixed in buffered formalin.

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Top left, Figure 1. Fundus photograph taken in 1980 shows deeply pigmented, minimally elevated lesion of the optic disc. Top right, Figure 2. Fluorescein angiogram in recirculation phase shows hypofluorescence of the lesion. The mass was hypofluorescent throughout the entire angiogram. Center left, Figure 3. Low-magnification photomicrograph of the optic disc region shows irregular pigmentation involving the optic nerve anterior to the lamina cribrosa with slight extension into the juxtapapillary retina. Notice that the adjacent choroid is normal (hematoxylin-eosin; original magnification, X 10). Center right, Figure 4. Photomicrograph of the margin of lesion shows cords of pigmented tumor cells apparently originating from the posterior termination of the RPE (arrow) (hematoxylin-eosin; original magnification, X2S). Bottom left, Figure 5. Photomicrograph of the central portion of the tumor shows irregular cords of deeply pigmented cells with intervening fibrous tissue and eosinophilic basement membrane material (hematoxylin-eosin; original magnification, xl 00). Bottom right, Figure 6. Bleached preparation shows the tumor cells to be cuboidal to columnar with uniform, small, round nuclei (hematoxylineosin; original magnification, X100).

Shields et al . Adenoma of RPE

Pathology The globe was normal externally and showed no recognizable shadow on transillumination. The sectioned eye contained a deeply pigmented tumor that obscured most of the optic disc (Fig 3). The lesion was approximately 2 mm in diameter and 0.25 mm in elevation and had a slightly irregular surface. Microscopically, the optic nerve head anterior to the lamina cribrosa was enlarged by a tumor (Fig 3) composed of infiltrating cords, cylinders, and tubules of deeply pigmented retinal pigment epithelial cells. At the peripheral portion of the tumor, there was direct continuity between the cells constituting the lesion and the juxtapapillary RPE (Fig 4). The cells comprising both the lesion and the contiguous segment of juxtapapillary RPE appeared somewhat like those seen in congenital hypertrophy of the RPE in that they were taller than normal and contained large amounts of jet-black pigment including macromelanosomes (Fig 5).18 Bleached sections disclosed that the nuclei of the tumor cells were small and uniform (Fig 6). No mitotic figures were present on close scrutiny of 40 highpower fields. Within the substance of the disc, the proliferating RPE had elaborated large amounts of extracellular matrix material including periodic acid-Schiff-positive basement membrane, which formed an intricate interweaving array of sinuous folds and tubules. In some areas, the RPE cells were enclosed within round and oval segments of basement membrane material. Elsewhere, linear segments of neoplastic RPE and associated connective tissue matrix were observed. Tumor cells were seen on the surface of the lesion where they had extended laterally on the internal limiting membrane. Gliosis was not observed on the tumor's anterior surface. A small focus of gliosis was confined to the outer layers of the peripapillary retina where the photoreceptors had been displaced laterally by the swollen optic nerve. The tumor contained sparse vessels. The central retinal artery and vein were unremarkable. The retrolaminar optic nerve showed moderate to severe atrophy.

Discussion The case reported here proved to be an unusual diagnostic problem both from clinical and histopathologic standpoints. Clinically, the lesion was believed to be a melanocytoma of the optic disc, based on the ophthalmoscopic appearance, fluorescein angiographic features, and clinical course. 1-5 A retrospective review of the stereoscopic fundus photographs and fluorescein angiograms suggested that the margins of the lesion were more well defined and not fibrillated like many melanocytomas. However, this subtle difference was only recognized on careful retrospective assessment. It is quite possible that other similar lesions that are diagnosed clinically as melanocytomas could represent adenoma or hyperplasia of the RPE. This may be of little clinical importance since both lesions are benign and are

best managed by periodic observation. However, the uveal melanocytes comprising melanocytomas have low-grade tendency to transform into melanoma, which does have metastatic potential, I,2.6.19,20 whereas RPE tumors have no known potential to exhibit metastasis.7. 10. I1,13 On histopathologic examination, we were surprised to find that the lesion was a tumor of the RPE that assumed an intrapapillary location. From a histopathologic standpoint, the differential diagnosis included an adenoma of the RPE, adenocarcinoma of the RPE, reactive hyperplasia of the RPE, and combined hamartoma of the RPE and sensory retina. Adenocarcinoma 17 was not a serious consideration because the cells were uniform, without nuclear pleomorphism or mitotic activity. Reactive hyperplasia of the RPE may be almost identical to adenoma of the RPE. However, we considered reactive hyperplasia to be unlikely because there was no history, clinical signs, or histopathologic signs of ocular trauma or inflammation. 7.8- '0 Also included in the differential diagnosis is combined hamartoma.I.2I ,22 However, our tumor lacked the superficial fibroglial tissue that is present in combined hamartoma both clinically and histopathologically. In addition, the RPE cells in combined hamartoma typically surround intrinsic abnormal blood vessels, a finding that was not present in our case. Although most RPE tumors have occurred in the retina, ciliary body, or iris,7 our literature review disclosed a few other adenomas and reactive hyperplasias of the RPE that partially affected the optic disc. 9 . ' 1.21 One reported case was remarkably similar to the one reported here.23 In that report, a 76-year-old woman underwent enucleation for suspected choroidal melanoma that, retrospectively, had ophthalmoscopic features similar to a melanocytoma. 23 Histopathologically, it proved to be an adenoma or perhaps reactive hyperplasia of the RPE. The pathogenesis of the lesion in our case is speculative. Even though it was first diagnosed later in life, it is possible that the lesion represents a congenital malformation that may have been present since birth. The fact that the lesion remained stable through 10 years of follow-up further supports that concept, although there is a possibility that the lesion could have been acquired after birth. Other similar lesions of the RPE, such as hypertrophy and combined hamartoma, are believed to be congenitallesions. 7 In summary, a clinicopathologic correlation is presented of an unusual adenoma (or possibly reactive hyperplasia) of the RPE that apparently originated in the juxtapapillary RPE and extended to involve the tissue of the optic disc. Clinically, the lesion had features that strongly suggested the diagnosis of melanocytoma. We speculate that such pigmented lesions of the optic disc may be more common than generally believed, but that they are misdiagnosed clinically as melanocytomas.

References 1. Shields lA, Shields CL. Intraocular Tumors: A Text and Atlas. Philadelphia, WB Saunders, 1992, chap 7.

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Ophthalmology Volume 99, Number 11, November 1992 2. Zimmerman LE. Melanocytes, melanocytic nevi, and melanocytomas. The Jonas S. Friedenwald Memorial Lecture. Invest Ophthalmol 1965;4: 11-40. 3. Zimmerman LE, Garron LK. Melanocytoma of the optic disc. Int Ophthalmol Clin 1962;2:431-40. 4. Joffe L, Shields JA, Osher RH, et al. Clinical and follow-up studies ofmelanocytomas of the optic disc. Ophthalmology 1979;86: 1067-78. 5. Osher RH, Shields JA, Layman PRo Pupillary and visual field evaluation in patients with melanocytoma of the optic disc. Arch Ophthalmol 1979;97:1096-9. 6. Shields JA, Shields CL, Eagle RC Jr, et al. Malignant melanoma associated with melanocytoma of the optic disc. Ophthalmology 1990;97:225-30. 7. Shields JA, Shields CL. Intraocular Tumors: A Text and Atlas. Philadelphia, WB Saunders, 1992; chap 25. 8. Greer CH. Epithelial tumours of the retinal pigment epithelium. Trans Ophthalmol Soc UK 1952;72:265-77. 9. Fair JR. Tumors of the retinal pigment epithelium. Am J Ophthalmol 1958;45:495-505. 10. Gamer A. Tumours of the retinal pigment epithelium. Br J Ophthalmol 1970;54:715-23. 11. Stow MN. Hyperplasia of the pigment epithelium of the retina simulating a neoplasm. Trans Am Acad Ophthalmol Otolaryngol 1949;53:674-77. 12. Streeten BW, McGraw JL. Tumor of the ciliary pigment epithelium. Am J Ophthalmol 1972;74:420-9. 13. Font RL, Zimmerman LE, Fine BS. Adenoma of the retinal pigment epithelium: histochemical and electronmicroscopic observations. Am J Ophthalmol 1972;73:544-54.

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14. Chang M, Shields JA, Wachtel DL. Adenoma ofthe pigment epithelium of the ciliary body simulating a malignant melanoma. Am J Ophthalmol 1979;88:40-4. 15. Lieb WE, Shields JA, Eagle RC Jr, et al. Cystic adenoma of the pigmented ciliary epithelium. Clinical, pathologic, and immunohistopathologic findings. Ophthalmology 1990;97: 1489-93. 16. Vogel MH, Zimmerman LE, Gass JDM. Proliferation of the juxtapapillary retinal pigment epithelium simulating malignant melanoma. Doc Ophthalmol 1969;26:461-81. 17. Minckler D, Allen AW Jr. Adenocarcinoma of the retinal pigment epithelium. Arch Ophthalmol 1978;96:2252-4. 18. Lloyd WC III, Eagle RC Jr, Shields JA, et al. Congenital hypertrophy of the retinal pigment epithelium. Electron microscopic and morphometric observations. Ophthalmology 1990;97: 1052-60. 19. Zografos L, Uffer S, Gailloud C, Kohli M. Le melanome de la papille, nouvelle observation. Klin Monatsbl Augenheilkd 1982; 180:503-9. 20. Apple DJ, Craythom JM, Reidy JJ, et al. Malignant transformation of an optic nerve melanocytoma. Can J Ophthalmol 1984;19:320-5. 21. Gass JDM. An unusual hamartoma of the pigment epithelium and retina simulating choroidal melanoma and retinoblastoma. Trans Am Ophthalmol Soc 1973;71:171-85. 22. Schachat AP, Shields JA, Fine SL, et al. Combined hamartomas of the retina and retinal pigment epithelium. Ophthalmology 1984;91: 1609-15. 23. Blodi FC, Reuling H, Somson ET. Pseudomelanocytoma at the optic nervehead. An adenoma of the retinal pigment epithelium. Arch Ophthalmol 1965;73:353-5.

Pigmented adenoma of the optic nerve head simulating a melanocytoma.

The purpose of this report is to describe a clinicopathologic correlation of an unusual pigmented tumor of the optic nerve head, to point out that suc...
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