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Simultaneous Bilateral Diffuse Melanocytic Uveal Hyperplasia
Simultaneous Bilateral Diffuse Melanocytic Uveal Hyperplasia Jens M. Rohrbach, M.D., Wolfgang Roggendorf, M.D., Solon Thanos, M.D., Klaus-Peter Steuhl, M.D., and Hans-jurgen Thiel, M.D. A 52-year-old woman noted loss of vision in August 1984. Clinical examination disclosed iris cysts and ciliary body cysts, macular edema, and uveal nevi. Cataract extraction and pressure-lowering operations were required in both eyes because of a tumor-induced angle-closure glaucoma. Vision, however, progressively decreased to light perception in each eye. Both eyes were finally enucleated because a malignant melanoma could not be ruled out, though iris tissue obtained in 1985 suggested a nevuslike process. Histologic study indicated a bilateral uveal hyperplasia. Results of light and electron microscopy, immunologic studies, and suspension cell culture suggested that the uveal hyperplasia was more likely a melanoma of low malignancy than a nevuslike process. We could not detect an extraocular primary tumor and assumed that this condition constituted an oncogenic syndrome.
T HE INCIDENCE of bilateral, endophytic uveal melanoma was estimated in 1977 to be one per 50 million whites.' Published reports since 1977 indicate, however, a higher incidence."! Disseminating cutaneous melanoma should be ruled out in cases of bilateral uveal melanoma'< because metastasis or extension of a primary uveal melanoma to the fellow eye is rare." Simultaneous, bilateral, diffuse melanocytic hyperplasia is a rare but well-defined entity that differs from bilateral endophytic uveal Accepted for publication April 26, 1990. From the University Eye Hospital Tubingen, Department of General Ophthalmology (Drs. Rohrbach, Thanos, Steuhl, and Thiel), and the Institute of Neuropathology, University of Tubingen (Dr. Roggendorf), Tubingen, West Germany. This study was supported in part by a grant from Pharmacia. Reprint requests to [ens M. Rohrbach, M.D., Universitas Augenklinik, Schleichstrasse 12, 0-7400 Tubingen, West Germany.
melanoma and involvement of the fellow eye in malignant melanoma.P'" Because diffuse melanocytic hyperplasia did not metastasize, investigators do not know whether to call it a melanoma l 2-l 4 or a nevuslike Iesion.P:" We used light and electron microscopy, immunologic techniques, and tissue culture to estimate the biologic characteristics of this condition in the patient we studied.
Case Report In August 1984, a 52-year-old woman sought our advice because of blurred vision in both eyes for two weeks. Family and personal (general and ophthalmologic) histories were noncontributory. Corrected visual acuity was 20/40 in both eyes. The anterior chambers were flat because of iris cysts and ciliary body cysts, which had the typical appearance when seen with a Goldmann contact lens with the pupil dilated. No solid tumor was noted at that time. The lenses showed the beginning of cataractous changes. Ophthalmoscopic examination disclosed pigmented uveal spots, which were initially interpreted as uveal nevi, and a bilateral macular edema. Fluorescein angiography disclosed breaks in the retinal pigment epithelium without subretinal neovascularization. The cataracts increased in density and were extracted a few months later (right eye, February 1985 and left eye, March 1985) without complications. The supposed uveal nevi increased in number and diameter (Figs. 1 and 2). With time, visual acuity was reduced and the visual field progressively narrowed. These conditions were attributable to macular degeneration and glaucomatous optic atrophy. In May 1985, a solid tumor was found in the chamber angle of the left eye, and the glaucoma was therefore considered tumor-induced. The iris cysts and ciliary body cysts were thought to have an additional pressure-increasing effect
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Fig. 1 (Rohrbach and associates). Right eye, August 1985. Note multiple supposed uveal nevi, which correspond to circumscribed hyperpigmentations of the diffuse uveal process. Macular gliosis and optic atrophy as a consequence of a chronic angle closure glaucoma have developed.
because penetration with a Nd:YAG laser resulted in a deepening of the anterior chambers and a temporary reduction of intraocular pressure. Sector iridectomy (right eye, June 1985 and left eye, July 1985), a filtering procedure
(right eye, March 1986 and left eye, April 1986), and cydocryocoagulation (right eye, September 1986 and left eye, May, September, and October 1986), had to be performed to lower the intraocular pressure, which often had risen
Fig. 2 (Rohrbach and associates). Left eye, August 1985, is similar to the right eye (Fig. 1).
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to more than 40 mm Hg and could not be controlled by timolol maleate 0.5% twice daily and pilocarpine 2% three times daily, nor by acetazolamide (500 mg Zday}, Histologic examination of the iris excised in 1985 showed interspersed nevuslike cells in the stroma (Fig. 3). A definitive diagnosis was not made, but the lesion was assumed to be benign. In March 1986, the electroretinogram showed a marked reduction of all potentials, and the flicker response indicated advanced cone damage. Computed tomography in November 1986 showed no orbital extension of the tumor. In January 1987, visual acuity had decreased to R.E.: 2/40 and L.E.: light perception, and an extrascleral pigmented tumor, which was sub-
sequently partially removed was seen on the left eye (Fig. 4). Histologic examination again showed a tumor of mostly uniform nevuslike cells with few mitoses and numerous pigmentladen macrophages. Because the extrascleral tumor recurred and enlarged within eight weeks (Fig. 5), enucleation of the left eye was performed in April 1987. In 1988, the intraocular pressure in the right eye was normal. Exudative detachment of the whole retina and progressive macular degeneration, in addition to the glaucomatous optic cupping, decreased vision to bare light perception. As in the left eye, the tumor could not be demonstrated echographically. Although extrascleral extension was not observed, enucleation of the right eye was advised because of the uncertain nature of the tumor and occasional pain. The patient underwent enucleation in December 1988. In 1984, results of general medical, gynecologic, and dermatologic examinations were normal except that the patient was overweight with hyperlipidemia and mild arterial hypertension. There was no evidence of a primary or secondary tumor. In 1988, pigmented spots were found in the vulva and in the rectum. Melanoma was suspected, but the histologic diagnosis was a benign pigmented skin lesion. A medical check-up, which included abdominal computed tomography and echography, showed no evidence of a primary or secondary neoplasm. A mild type II diabetes was detected. The isolated rise of gamma glutamyl transpeptidase was attributed to the use of 100 mg/day of fenofibrate. The patient was healthy at her last examination April 1990.
Fig. 4 (Rohrbach and associates). Left eye, January 1987. Note extrascleral nodules of pigmented tumor.
Fig. 5 (Rohrbach and associates). Left eye. Despite excision and scleral patch, extrascleral tumor (arrow) recurred within eight weeks.
Fig. 3 (Rohrbach and associates). Iris specimen obtained from the left eye in July 1985. The iris stroma is interspersed with round-to-spindled, nevuslike cells (arrows). Note iris vessel with erythrocytes (star) (hematoxylin and eosin, x 600).
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Histologic examination disclosed similar features in both eyes. Macroscopic and light microscopic examinations showed that the choroid, ciliary body, and iris were evenly thickened (Fig. 6) by an infiltration ofround-tospindled, uniform cells with only occasional nucleoli (Fig. 7). Mitotic figures were scarce. Some cells had a nuclear fold like the spindle A-cell type described by Callender" (Fig. 7). Tumor cells could be found outside the sclera in the left eye (Fig. 8) and within the sclera along a ciliary nerve in the right eye. Circumscribed hyperpigmentations corresponded to the clinically observed uveal nevi. Vessels within the tumor were sparse, but there were no necrotic areas within the tumor. Bone formation had begun at the posterior pole of the left eye, possibly because of tumor-induced chronic damage to the retinal pigment epithelium." The chamber angles were completely occluded by tumor cells, which grew partly on the inner
Fig. 6 (Rohrbach and associates). Right eye prepared for light microscopy. Note diffuse thickening of choroid, and especially of the ciliary body and iris. The retina is completely detached and partly absent because of an artifact. The left eye had similar features.
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corneal surface, indicating loss of contact inhibition. Iris cysts and ciliary body cysts-probably tumor-induced degeneration productswere lined by pigmented or nonpigmented epithelium (Fig. 9). They were adjacent to regenerating lens masses. Loss of ganglion cells and of retinal photoreceptors, submacular and supramacular gliosis, and advanced excavation of the optic nerve heads were the cause of the visual loss. The retina was detached in the right eye only. Electron microscopic examination disclosed that the tumor cell nuclei had relatively scant chromatin. Many nuclei were folded, some showed intranuclear vacuoles as a consequence of cytoplasmic invagination, and some had a nucleolus. Well-differentiated mitochondria and rough endoplasmic reticulum, but only few golgi apparatuses (Figs. 10 and 11), were found in the cytoplasm, which had villous processes (Fig. 11). Some tumor cells appeared lighter than others (Fig. 10). Cytoplasmic pigment granules (melanosomes) of different sizes, degrees of pigmentation, and densities seemed not to be coated by a membranous envelope (Figs. 10 and 11). Some tumor cells had cytoplasmic filaments. A few were lined by collagen fibers and a discrete band of homogenous material, which was probably basement membrane. Desmosomes were lacking. Some cells were believed to be pigment-laden macrophages. Immunologic studies showed that the tumor cells stained positive for S-100 protein indicating a neural crest origin. The tumor cell stains indicated no cytokeratin, nerve filaments, or glial fibrillary acidic protein, making an epithelial or neuroglial process unlikely. Dividing
Fig. 7 (Rohrbach and associates). Tumor cells of left eye. Note round-to-spindled cells with rare nucleoli and occasional nuclear folds (arrowheads) (hematoxylin and eosin, x 600).
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Fig. 8 (Rohrbach and associates). Extrascleral (subconjunctival) pigmented tumor in the area of former excision (left eye). Arrow indicates conjunctiva (hematoxylin and eosin, x 25). tumor cells accounted for less than 1% of all tumor cells; less than 1% of cells stained red with the monoclonal antibody Ki-67, which marks all cells outside the Go-phase of the cell-cycle." To perform the suspension cell culture, a 3 x 5-mm piece of the posterior segment was excised under aseptic conditions and transferred into Hank's balanced salt solution. Sclera and tumor were separated. Because the neoplasm did not invade the sclera, it could easily be separated from it. The tumor was transferred into Hank's buffer, which contained 0.1 % trypsin (GIBCO, Berlin, West Germany) and 0.025% collagenase. It was incubated for one hour and dissociated mechanically by repeated suctioning in a Pasteur pipette. After repeated washing in Hank's solution (three times, ten-minute centrifugation at 1,000 revolutions per minute with a centrifuge), the dissociated cells (eight petriperm dishes coated with polylysin and laminin) were transferred to a F12-medium (GIBCO) containing 5% fetal calf serum and incubated in a cell culture incubator at 37 C and in an atmosphere containing 5% CO 2, The medium was exchanged every three days. Cells were observed with an inverted Zeiss microscope and photographed on a black and white TX-pan 400 film. The initial density of the dissociated cells was about 0.4 x 105 to 0.5 X 105 (4 X 104 to 5 X 104). Four dishes were contaminated after one week and discarded. Over an observation period of five weeks, the cells remained in suspension and were spherical without any tendency to attach to the matrix. The cells were uniformly round to oval, black, and varied in size. The largest cells showed typical melanin granulation. The cell
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Fig. 9 (Rohrbach and associates). Anterior segment of the right eye. Note tumor-induced cystic degeneration of the ciliary epithelium (arrows) (hematoxylin and eosin, x 75). density increased over five weeks to 1.1 x 105 to 1.3 X 105 in the four remaining dishes). This increase was continuously observed over the time of culture and was not affected by the addition of basic fibroblast growth factor (prepared from bovine pituitary gland) at concentrations of up to 10 pgjml of medium. The shape and size of the cultured cells remained unchanged throughout the period of observation.
Discussion
Simultaneous bilateral uveal melanocytic hyperplasia is a rare, but well-defined process that affects middle-aged and elderly white patients and has a female preponderance.P'" It has not led to metastasis, and it was arbitrarily classified as a melanoma or as nevus. Because the patients described in published reports had primary extraocular malignant tumor (mostly carcinoma of the abdomen or bowel), a new, oncogenic syndrome was postulated.lo,ll,13,14 We know, for example, that cells of skin fibroblasts from patients with hereditary adenomatosis of the colon and rectum behave more like malignant cells in tissue culture. IS Moreover, nonmetastatic diffuse" or endophytic'-" uveal melanomas have been seen in patients with a preceding cutaneous melanoma or another primary tumor,7,20 whereas uveal melanoma patients may have an increased risk of developing a second tumor." The conjunction of cutaneous and uveal melanomas is part of the dysplastic nevus syndrome or B-K-mole syndrome. 7,2o,21
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Fig. 10 (Rohrbach and associates). Electron micrograph of a less-pigmented tumor cell (star) from the right eye with pigment granules of different size and scattered rough endoplasmic reticulum. Only few mitochondria (X 4,800).
Fig. 11 (Rohrbach and associates). Electron micrograph shows a less-pigmented tumor cell from the right eye with some mitochondria, pigment granules, scattered rough endoplasmic reticulum, and a golgi apparatus (arrow). Cytoplasm shows villous processes (arrowhead) (X 4,800).
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Therefore, a neoplasm or a neoplastic disposition may alter cells at other sites of the body such that malignant transformations may occur. No extraocular primary tumor could be detected in our patient five years after the onset of visual symptoms. In most reported cases, the associated extraocular tumor caused death within three years of diagnosis of the bilateral, diffuse, uveal process. IO,12,13 It could be, therefore, that the patients' survival time had been too short for the development of metastases from the uveal lesion. In our patient, the cytologic characteristics were similar to those of patients described previously; there were mostly uniform spindle cells with only rare nucleoli and mitotic figures, and some eyes had varying amounts of epithelioid cells).JO,12-14 The small amount of tumor cells outside the Go-phase of the cell cycle as demonstrated with the monoclonal antibody Ki-67, and the absence of metastases after five years of observation (diffuse melanomas usually have a poor prognosis's), indicate, though are not proof of, a benign, nevuslike process. Alternatively, infiltrative growth (in the chamber angle l O,I2,I4 and on the posterior corneal surface), scleral invasion10,12.14 and perforation," (Figs. 4, 5, and 8) as well as growth of tumor cells in suspension tissue culture make a malignant tumor more probable. Our final diagnosis was simultaneous, bilateral, diffuse uveal melanoma of low growth potential. We conclude that because the bilateral diffuse uveal melanocytic lesions, whether they are melanomas or not, grow simultaneously in much the same way and because they are often associated with an extraocular primary tumor (carcinoma), the assumption of an oncogenic process is justifiable. Additionally, the diffuse tumor could be a consequence of diffuse melanocytic transformation (except in areas such as the chamber angle or posterior corneal surface, where normally no melanocytes exist) rather than of a diffuse, invasive growth. Even an extrascleral tumor may be caused by extrascleral transformation (for example, Schwann cells of ciliary nerves) and not by a real scleral penetration of the tumor extending from the interior of the globe.12 The boundary between benignancy and malignancy is not a sharp line but a broad zone, and whether a tumor is benign or malignant sometimes cannot be determined with the methods available. At present, therefore, the biologic character of certain tumors in the transition zone between nevi and
melanomas can be ascertained only by the clinical course. The challenge of future work in this field is in the development of new techniques such as immunologic detection of malignancyspecific antigens and molecular probes.
References 1. Shammas, H. F., and Watzke, R. c.: Bilateral choroidal melanomas. Arch. Ophthalmol. 95:617, 1977. 2. G611nitz, R., and Lommatzsch, P. K.: Die prognostische Relevanz histopathologischer Parameter beim malignen Melanom der Aderhaut unter Anwendung der pTNM-Klassifikation. Klin. Monatsbl. Augenheilkd. 192:296, 1988. 3. Lau, T.: Das primar doppelseitige maligne Melanom der Chorioidea. Klin. Monatsbl. Augenheilkd. 179:333,1981. 4. Migdal, c., and Macfarlane, A.: Bilateral primary choroidal melanoma. Br. J. Ophthalmol. 68:268, 1984. 5. Seregard, S., Daunius, C,; Kock, E., and Popovic, V.: Two cases of primary bilateral malignant melanoma of the choroid. Br. J. Ophthalmol. 72:244, 1988. 6. Waterhouse, W. J., Fries, P. D., Char, D. H., Crawford, J. B., and Howes, E. L., [r.: Bilateral ciliary body melanomas. Can. J. Ophthalmol. 24:125, 1989. 7. Turner, B. J., Siatkowski, R. M., Augsburger, J. J., Shields, J. A., Lustbader, E., and Mastrangelo, M. J.: Other cancers in uveal melanoma patients and their families. Am. J. Ophthalmol. 107:601, 1989. 8. De Bustros, S., Augsburger, J. J., Shields, J. A., Shakin, E. P., and Pryor, c.c., II: Intraocular metastases from cutaneous malignant melanoma. Arch. Ophthalmol. 103:937, 1985. 9. Shields, J. A., Shields, C. L., Shakin, E. P., and Kobetz, L. E.: Metastasis of choroidal melanoma to the contralateral choroid, orbit, and eyelid. Br. J. Ophthalmol. 72:456, 1988. 10. Barr, C. c., Zimmerman, L. E., Curtin, V. T., and Font, R. L.: Bilateral diffuse melanocytic uveal tumors associated with systemic malignant neoplasms. Arch. Ophthalmol. 100:249, 1982. 11. Zimmerman, L. E.: Malignant melanoma. In Spencer, W. H.: Ophthalmic Pathology. An Atlas and Textbook, ed. 3, vol. 3. Philadelphia, W. B. Saunders, 1986, pp. 2072-2139. 12. Machemer, R.: Zur Pathogenese des flachenhaften malignen Melanoms. Klin. Monatsbl. Augenheilkd. 148:641, 1966. 13. Mullaney, J., Mooney, D., O'Connor, M., and McDonald, G. S. A.: Bilateral ovarian carcinoma with bilateral uveal melanoma. Br. J. Ophthalmol. 68:261, 1984. 14. Tsukahara, S., Wakui, K., and Ohzeki, S.: Si-
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multaneous bilateral primary diffuse malignant uveal melanoma. Case report with pathological examination. Br. J. Ophthalmol. 70:33, 1986. 15. Callender, G. R.: Malignant melanotic tumors of the eye. A study of histologic types in 111 cases. Trans. Am. Acad. Ophthalmol. Otolaryngol. 36:131, 1931. 16. Rohrbach, J. M., Liesenhoff, E., and Steuhl, K. P.: Prinzipien der intraokularen Ossifikation am Beispiel der sekundaren Aderhautverknocherung. Klin. Monatsbl. Augenheilkd. In press. 17. Roggendorf, W., Schuster, T., and Peiffer, J.: Proliferative potential of meningiomas determined with the monoclonal antibody Ki-67. Acta Neuropathol. (Berlin) 73:361,1987. 18. Kopelovich, L.: Hereditary adenomatosis of the colon and rectum. A model of tumor progression. In Day, S. B. (ed.): Cancer Invasion and Metastasis.
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Biologic Mechanisms and Therapy. New York, Raven Press, 1977, pp. 383-395. 19. Augsburger, J. J., Shields, J. A., Mastrangelo, J. M., and Frank, P. E.: Diffuse primary malignant melanoma after prior primary cutaneous malignant melanoma. Arch. Ophthalmol. 98:1261, 1980. 20. Gilbert, C. N., EI Baba, F., Schachat, A. P., Grossniklaus, H., and Green, W. R.: Nonsimultaneous primary choroidal and cutaneous melanomas. Ophthalmology 94:1169, 1987. 21. Oosterhuis, J. A., Went, L. N., and Lynch, H. T.: Primary choroidal and cutaneous melanomas, bilateral choroidal melanomas, and familial occurrence of melanomas. Br. J. Ophthalmol. 66:230, 1982. 22. Sassani, J. W., Weinstein, J. M., and Graham, W. P.: Massively invasive diffuse choroidal melanoma. Arch. Ophthalmol. 103:945, 1985.
OPHTHALMIC MINIATURE
"Wonderful dark eyes," he said. She didn't know where to look. His pale eyes held her like a pinned butterfly. Looking into them was like looking up at the sky, trying to see through wispy clouds to the end of it. Once she'd tried that, lying on her back for hours until her eyes smarted and she felt dizzy. She was feeling dizzy now. Johanna Kingsley, Faces New York, Bantam Books, 1987, p. 26
T HE INCIDENCE of bilateral, endophytic uveal melanoma was estimated in 1977 to be one per 50 million whites.' Published reports since 1977 indicate, however, a higher incidence."! Disseminating cutaneous melanoma should be ruled out in cases of bilateral uveal melanoma'< because metastasis or extension of a primary uveal melanoma to the fellow eye is rare." Simultaneous, bilateral, diffuse melanocytic hyperplasia is a rare but well-defined entity that differs from bilateral endophytic uveal Accepted for publication April 26, 1990. From the University Eye Hospital Tubingen, Department of General Ophthalmology (Drs. Rohrbach, Thanos, Steuhl, and Thiel), and the Institute of Neuropathology, University of Tubingen (Dr. Roggendorf), Tubingen, West Germany. This study was supported in part by a grant from Pharmacia. Reprint requests to [ens M. Rohrbach, M.D., Universitas Augenklinik, Schleichstrasse 12, 0-7400 Tubingen, West Germany.
melanoma and involvement of the fellow eye in malignant melanoma.P'" Because diffuse melanocytic hyperplasia did not metastasize, investigators do not know whether to call it a melanoma l 2-l 4 or a nevuslike Iesion.P:" We used light and electron microscopy, immunologic techniques, and tissue culture to estimate the biologic characteristics of this condition in the patient we studied.
Case Report In August 1984, a 52-year-old woman sought our advice because of blurred vision in both eyes for two weeks. Family and personal (general and ophthalmologic) histories were noncontributory. Corrected visual acuity was 20/40 in both eyes. The anterior chambers were flat because of iris cysts and ciliary body cysts, which had the typical appearance when seen with a Goldmann contact lens with the pupil dilated. No solid tumor was noted at that time. The lenses showed the beginning of cataractous changes. Ophthalmoscopic examination disclosed pigmented uveal spots, which were initially interpreted as uveal nevi, and a bilateral macular edema. Fluorescein angiography disclosed breaks in the retinal pigment epithelium without subretinal neovascularization. The cataracts increased in density and were extracted a few months later (right eye, February 1985 and left eye, March 1985) without complications. The supposed uveal nevi increased in number and diameter (Figs. 1 and 2). With time, visual acuity was reduced and the visual field progressively narrowed. These conditions were attributable to macular degeneration and glaucomatous optic atrophy. In May 1985, a solid tumor was found in the chamber angle of the left eye, and the glaucoma was therefore considered tumor-induced. The iris cysts and ciliary body cysts were thought to have an additional pressure-increasing effect
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Fig. 1 (Rohrbach and associates). Right eye, August 1985. Note multiple supposed uveal nevi, which correspond to circumscribed hyperpigmentations of the diffuse uveal process. Macular gliosis and optic atrophy as a consequence of a chronic angle closure glaucoma have developed.
because penetration with a Nd:YAG laser resulted in a deepening of the anterior chambers and a temporary reduction of intraocular pressure. Sector iridectomy (right eye, June 1985 and left eye, July 1985), a filtering procedure
(right eye, March 1986 and left eye, April 1986), and cydocryocoagulation (right eye, September 1986 and left eye, May, September, and October 1986), had to be performed to lower the intraocular pressure, which often had risen
Fig. 2 (Rohrbach and associates). Left eye, August 1985, is similar to the right eye (Fig. 1).
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to more than 40 mm Hg and could not be controlled by timolol maleate 0.5% twice daily and pilocarpine 2% three times daily, nor by acetazolamide (500 mg Zday}, Histologic examination of the iris excised in 1985 showed interspersed nevuslike cells in the stroma (Fig. 3). A definitive diagnosis was not made, but the lesion was assumed to be benign. In March 1986, the electroretinogram showed a marked reduction of all potentials, and the flicker response indicated advanced cone damage. Computed tomography in November 1986 showed no orbital extension of the tumor. In January 1987, visual acuity had decreased to R.E.: 2/40 and L.E.: light perception, and an extrascleral pigmented tumor, which was sub-
sequently partially removed was seen on the left eye (Fig. 4). Histologic examination again showed a tumor of mostly uniform nevuslike cells with few mitoses and numerous pigmentladen macrophages. Because the extrascleral tumor recurred and enlarged within eight weeks (Fig. 5), enucleation of the left eye was performed in April 1987. In 1988, the intraocular pressure in the right eye was normal. Exudative detachment of the whole retina and progressive macular degeneration, in addition to the glaucomatous optic cupping, decreased vision to bare light perception. As in the left eye, the tumor could not be demonstrated echographically. Although extrascleral extension was not observed, enucleation of the right eye was advised because of the uncertain nature of the tumor and occasional pain. The patient underwent enucleation in December 1988. In 1984, results of general medical, gynecologic, and dermatologic examinations were normal except that the patient was overweight with hyperlipidemia and mild arterial hypertension. There was no evidence of a primary or secondary tumor. In 1988, pigmented spots were found in the vulva and in the rectum. Melanoma was suspected, but the histologic diagnosis was a benign pigmented skin lesion. A medical check-up, which included abdominal computed tomography and echography, showed no evidence of a primary or secondary neoplasm. A mild type II diabetes was detected. The isolated rise of gamma glutamyl transpeptidase was attributed to the use of 100 mg/day of fenofibrate. The patient was healthy at her last examination April 1990.
Fig. 4 (Rohrbach and associates). Left eye, January 1987. Note extrascleral nodules of pigmented tumor.
Fig. 5 (Rohrbach and associates). Left eye. Despite excision and scleral patch, extrascleral tumor (arrow) recurred within eight weeks.
Fig. 3 (Rohrbach and associates). Iris specimen obtained from the left eye in July 1985. The iris stroma is interspersed with round-to-spindled, nevuslike cells (arrows). Note iris vessel with erythrocytes (star) (hematoxylin and eosin, x 600).
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Histologic examination disclosed similar features in both eyes. Macroscopic and light microscopic examinations showed that the choroid, ciliary body, and iris were evenly thickened (Fig. 6) by an infiltration ofround-tospindled, uniform cells with only occasional nucleoli (Fig. 7). Mitotic figures were scarce. Some cells had a nuclear fold like the spindle A-cell type described by Callender" (Fig. 7). Tumor cells could be found outside the sclera in the left eye (Fig. 8) and within the sclera along a ciliary nerve in the right eye. Circumscribed hyperpigmentations corresponded to the clinically observed uveal nevi. Vessels within the tumor were sparse, but there were no necrotic areas within the tumor. Bone formation had begun at the posterior pole of the left eye, possibly because of tumor-induced chronic damage to the retinal pigment epithelium." The chamber angles were completely occluded by tumor cells, which grew partly on the inner
Fig. 6 (Rohrbach and associates). Right eye prepared for light microscopy. Note diffuse thickening of choroid, and especially of the ciliary body and iris. The retina is completely detached and partly absent because of an artifact. The left eye had similar features.
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corneal surface, indicating loss of contact inhibition. Iris cysts and ciliary body cysts-probably tumor-induced degeneration productswere lined by pigmented or nonpigmented epithelium (Fig. 9). They were adjacent to regenerating lens masses. Loss of ganglion cells and of retinal photoreceptors, submacular and supramacular gliosis, and advanced excavation of the optic nerve heads were the cause of the visual loss. The retina was detached in the right eye only. Electron microscopic examination disclosed that the tumor cell nuclei had relatively scant chromatin. Many nuclei were folded, some showed intranuclear vacuoles as a consequence of cytoplasmic invagination, and some had a nucleolus. Well-differentiated mitochondria and rough endoplasmic reticulum, but only few golgi apparatuses (Figs. 10 and 11), were found in the cytoplasm, which had villous processes (Fig. 11). Some tumor cells appeared lighter than others (Fig. 10). Cytoplasmic pigment granules (melanosomes) of different sizes, degrees of pigmentation, and densities seemed not to be coated by a membranous envelope (Figs. 10 and 11). Some tumor cells had cytoplasmic filaments. A few were lined by collagen fibers and a discrete band of homogenous material, which was probably basement membrane. Desmosomes were lacking. Some cells were believed to be pigment-laden macrophages. Immunologic studies showed that the tumor cells stained positive for S-100 protein indicating a neural crest origin. The tumor cell stains indicated no cytokeratin, nerve filaments, or glial fibrillary acidic protein, making an epithelial or neuroglial process unlikely. Dividing
Fig. 7 (Rohrbach and associates). Tumor cells of left eye. Note round-to-spindled cells with rare nucleoli and occasional nuclear folds (arrowheads) (hematoxylin and eosin, x 600).
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Fig. 8 (Rohrbach and associates). Extrascleral (subconjunctival) pigmented tumor in the area of former excision (left eye). Arrow indicates conjunctiva (hematoxylin and eosin, x 25). tumor cells accounted for less than 1% of all tumor cells; less than 1% of cells stained red with the monoclonal antibody Ki-67, which marks all cells outside the Go-phase of the cell-cycle." To perform the suspension cell culture, a 3 x 5-mm piece of the posterior segment was excised under aseptic conditions and transferred into Hank's balanced salt solution. Sclera and tumor were separated. Because the neoplasm did not invade the sclera, it could easily be separated from it. The tumor was transferred into Hank's buffer, which contained 0.1 % trypsin (GIBCO, Berlin, West Germany) and 0.025% collagenase. It was incubated for one hour and dissociated mechanically by repeated suctioning in a Pasteur pipette. After repeated washing in Hank's solution (three times, ten-minute centrifugation at 1,000 revolutions per minute with a centrifuge), the dissociated cells (eight petriperm dishes coated with polylysin and laminin) were transferred to a F12-medium (GIBCO) containing 5% fetal calf serum and incubated in a cell culture incubator at 37 C and in an atmosphere containing 5% CO 2, The medium was exchanged every three days. Cells were observed with an inverted Zeiss microscope and photographed on a black and white TX-pan 400 film. The initial density of the dissociated cells was about 0.4 x 105 to 0.5 X 105 (4 X 104 to 5 X 104). Four dishes were contaminated after one week and discarded. Over an observation period of five weeks, the cells remained in suspension and were spherical without any tendency to attach to the matrix. The cells were uniformly round to oval, black, and varied in size. The largest cells showed typical melanin granulation. The cell
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Fig. 9 (Rohrbach and associates). Anterior segment of the right eye. Note tumor-induced cystic degeneration of the ciliary epithelium (arrows) (hematoxylin and eosin, x 75). density increased over five weeks to 1.1 x 105 to 1.3 X 105 in the four remaining dishes). This increase was continuously observed over the time of culture and was not affected by the addition of basic fibroblast growth factor (prepared from bovine pituitary gland) at concentrations of up to 10 pgjml of medium. The shape and size of the cultured cells remained unchanged throughout the period of observation.
Discussion
Simultaneous bilateral uveal melanocytic hyperplasia is a rare, but well-defined process that affects middle-aged and elderly white patients and has a female preponderance.P'" It has not led to metastasis, and it was arbitrarily classified as a melanoma or as nevus. Because the patients described in published reports had primary extraocular malignant tumor (mostly carcinoma of the abdomen or bowel), a new, oncogenic syndrome was postulated.lo,ll,13,14 We know, for example, that cells of skin fibroblasts from patients with hereditary adenomatosis of the colon and rectum behave more like malignant cells in tissue culture. IS Moreover, nonmetastatic diffuse" or endophytic'-" uveal melanomas have been seen in patients with a preceding cutaneous melanoma or another primary tumor,7,20 whereas uveal melanoma patients may have an increased risk of developing a second tumor." The conjunction of cutaneous and uveal melanomas is part of the dysplastic nevus syndrome or B-K-mole syndrome. 7,2o,21
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Fig. 10 (Rohrbach and associates). Electron micrograph of a less-pigmented tumor cell (star) from the right eye with pigment granules of different size and scattered rough endoplasmic reticulum. Only few mitochondria (X 4,800).
Fig. 11 (Rohrbach and associates). Electron micrograph shows a less-pigmented tumor cell from the right eye with some mitochondria, pigment granules, scattered rough endoplasmic reticulum, and a golgi apparatus (arrow). Cytoplasm shows villous processes (arrowhead) (X 4,800).
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Therefore, a neoplasm or a neoplastic disposition may alter cells at other sites of the body such that malignant transformations may occur. No extraocular primary tumor could be detected in our patient five years after the onset of visual symptoms. In most reported cases, the associated extraocular tumor caused death within three years of diagnosis of the bilateral, diffuse, uveal process. IO,12,13 It could be, therefore, that the patients' survival time had been too short for the development of metastases from the uveal lesion. In our patient, the cytologic characteristics were similar to those of patients described previously; there were mostly uniform spindle cells with only rare nucleoli and mitotic figures, and some eyes had varying amounts of epithelioid cells).JO,12-14 The small amount of tumor cells outside the Go-phase of the cell cycle as demonstrated with the monoclonal antibody Ki-67, and the absence of metastases after five years of observation (diffuse melanomas usually have a poor prognosis's), indicate, though are not proof of, a benign, nevuslike process. Alternatively, infiltrative growth (in the chamber angle l O,I2,I4 and on the posterior corneal surface), scleral invasion10,12.14 and perforation," (Figs. 4, 5, and 8) as well as growth of tumor cells in suspension tissue culture make a malignant tumor more probable. Our final diagnosis was simultaneous, bilateral, diffuse uveal melanoma of low growth potential. We conclude that because the bilateral diffuse uveal melanocytic lesions, whether they are melanomas or not, grow simultaneously in much the same way and because they are often associated with an extraocular primary tumor (carcinoma), the assumption of an oncogenic process is justifiable. Additionally, the diffuse tumor could be a consequence of diffuse melanocytic transformation (except in areas such as the chamber angle or posterior corneal surface, where normally no melanocytes exist) rather than of a diffuse, invasive growth. Even an extrascleral tumor may be caused by extrascleral transformation (for example, Schwann cells of ciliary nerves) and not by a real scleral penetration of the tumor extending from the interior of the globe.12 The boundary between benignancy and malignancy is not a sharp line but a broad zone, and whether a tumor is benign or malignant sometimes cannot be determined with the methods available. At present, therefore, the biologic character of certain tumors in the transition zone between nevi and
melanomas can be ascertained only by the clinical course. The challenge of future work in this field is in the development of new techniques such as immunologic detection of malignancyspecific antigens and molecular probes.
References 1. Shammas, H. F., and Watzke, R. c.: Bilateral choroidal melanomas. Arch. Ophthalmol. 95:617, 1977. 2. G611nitz, R., and Lommatzsch, P. K.: Die prognostische Relevanz histopathologischer Parameter beim malignen Melanom der Aderhaut unter Anwendung der pTNM-Klassifikation. Klin. Monatsbl. Augenheilkd. 192:296, 1988. 3. Lau, T.: Das primar doppelseitige maligne Melanom der Chorioidea. Klin. Monatsbl. Augenheilkd. 179:333,1981. 4. Migdal, c., and Macfarlane, A.: Bilateral primary choroidal melanoma. Br. J. Ophthalmol. 68:268, 1984. 5. Seregard, S., Daunius, C,; Kock, E., and Popovic, V.: Two cases of primary bilateral malignant melanoma of the choroid. Br. J. Ophthalmol. 72:244, 1988. 6. Waterhouse, W. J., Fries, P. D., Char, D. H., Crawford, J. B., and Howes, E. L., [r.: Bilateral ciliary body melanomas. Can. J. Ophthalmol. 24:125, 1989. 7. Turner, B. J., Siatkowski, R. M., Augsburger, J. J., Shields, J. A., Lustbader, E., and Mastrangelo, M. J.: Other cancers in uveal melanoma patients and their families. Am. J. Ophthalmol. 107:601, 1989. 8. De Bustros, S., Augsburger, J. J., Shields, J. A., Shakin, E. P., and Pryor, c.c., II: Intraocular metastases from cutaneous malignant melanoma. Arch. Ophthalmol. 103:937, 1985. 9. Shields, J. A., Shields, C. L., Shakin, E. P., and Kobetz, L. E.: Metastasis of choroidal melanoma to the contralateral choroid, orbit, and eyelid. Br. J. Ophthalmol. 72:456, 1988. 10. Barr, C. c., Zimmerman, L. E., Curtin, V. T., and Font, R. L.: Bilateral diffuse melanocytic uveal tumors associated with systemic malignant neoplasms. Arch. Ophthalmol. 100:249, 1982. 11. Zimmerman, L. E.: Malignant melanoma. In Spencer, W. H.: Ophthalmic Pathology. An Atlas and Textbook, ed. 3, vol. 3. Philadelphia, W. B. Saunders, 1986, pp. 2072-2139. 12. Machemer, R.: Zur Pathogenese des flachenhaften malignen Melanoms. Klin. Monatsbl. Augenheilkd. 148:641, 1966. 13. Mullaney, J., Mooney, D., O'Connor, M., and McDonald, G. S. A.: Bilateral ovarian carcinoma with bilateral uveal melanoma. Br. J. Ophthalmol. 68:261, 1984. 14. Tsukahara, S., Wakui, K., and Ohzeki, S.: Si-
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multaneous bilateral primary diffuse malignant uveal melanoma. Case report with pathological examination. Br. J. Ophthalmol. 70:33, 1986. 15. Callender, G. R.: Malignant melanotic tumors of the eye. A study of histologic types in 111 cases. Trans. Am. Acad. Ophthalmol. Otolaryngol. 36:131, 1931. 16. Rohrbach, J. M., Liesenhoff, E., and Steuhl, K. P.: Prinzipien der intraokularen Ossifikation am Beispiel der sekundaren Aderhautverknocherung. Klin. Monatsbl. Augenheilkd. In press. 17. Roggendorf, W., Schuster, T., and Peiffer, J.: Proliferative potential of meningiomas determined with the monoclonal antibody Ki-67. Acta Neuropathol. (Berlin) 73:361,1987. 18. Kopelovich, L.: Hereditary adenomatosis of the colon and rectum. A model of tumor progression. In Day, S. B. (ed.): Cancer Invasion and Metastasis.
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Biologic Mechanisms and Therapy. New York, Raven Press, 1977, pp. 383-395. 19. Augsburger, J. J., Shields, J. A., Mastrangelo, J. M., and Frank, P. E.: Diffuse primary malignant melanoma after prior primary cutaneous malignant melanoma. Arch. Ophthalmol. 98:1261, 1980. 20. Gilbert, C. N., EI Baba, F., Schachat, A. P., Grossniklaus, H., and Green, W. R.: Nonsimultaneous primary choroidal and cutaneous melanomas. Ophthalmology 94:1169, 1987. 21. Oosterhuis, J. A., Went, L. N., and Lynch, H. T.: Primary choroidal and cutaneous melanomas, bilateral choroidal melanomas, and familial occurrence of melanomas. Br. J. Ophthalmol. 66:230, 1982. 22. Sassani, J. W., Weinstein, J. M., and Graham, W. P.: Massively invasive diffuse choroidal melanoma. Arch. Ophthalmol. 103:945, 1985.
OPHTHALMIC MINIATURE
"Wonderful dark eyes," he said. She didn't know where to look. His pale eyes held her like a pinned butterfly. Looking into them was like looking up at the sky, trying to see through wispy clouds to the end of it. Once she'd tried that, lying on her back for hours until her eyes smarted and she felt dizzy. She was feeling dizzy now. Johanna Kingsley, Faces New York, Bantam Books, 1987, p. 26