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Diffuse Uveal Melanoma in a 5-Year-Old Child
Diffuse Uveal Melanoma in a 5-Year-Old Child Pearl S. R o s e n b a u m , M . D . , M i l t o n B o n i u k , M . D . , and Ramon L. Font, M . D .
A 5-year-old white boy developed a gray-tan discoloration with nodular thickening of the iris stroma in his left eye six weeks earlier. Ophthalmologic examination demonstrated keratic precipitates, peripheral anterior synechiae, and several pale-tan choroidal infiltrates in the involved eye. Cytologie examination of the aqueous humor and results of iris biopsy were interpreted as malignant melanoma of the iris, predominantly of the epithelioid cell type. The globe was enucleated one week later. Histopathologic examination disclosed a diffuse malignant melanoma of the uvea, mixed cell type, with multiple cysts of the ciliary epithelium. Study by electron microscopy indicated bizarre neoplastic melanocytes containing numerous immature melanosomes in various stages of melanogenesis, as well as fully melanized mature melanosomes. Eight months after enucleation the patient developed metastasis to the nasopharynx and base of the skull. DIFFUSE OR FLAT malignant melanoma of the
uvea is rare. In a review of 6,358 uveal melano mas in the Registry of Ophthalmic Pathology at the Armed Forces Institute of Pathology, Barr, McLean, and Zimmerman 1 found only 101 (1.6%) in patients less than 20 years of age. Sufficient clinical and pathologic data were available on 78 of the 101 patients, and none showed diffuse uveal involvement. Reese and Howard 2 and Font, Spaulding, and Zimmerman 3 showed that 4.5% and 5%, respec tively, of all uveal melanomas were of the diffuse type. There is often a delay in the diagnosis and treatment of these tumors as they are generally
Accepted for publication Aug. 1, 1988. From the Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas. This study was supported in part by grants from the Retina Research Foundation and the Lions Eye Bank, Houston, Texas. Reprint requests to Ramon L. Font, M.D., Ophthalmic Pathology Laboratory, Cullen Eye Institute, Baylor Col lege of Medicine, 6501 Fannin, Houston, TX 77030.
not included in the clinical differential diagno sis. Reese and Howard 2 noted a delay in diag nosis ranging from two months to nine years in 17 of 28 patients with diffuse uveal melanomas. This, coupled with the tendency for extraocular extension to occur early, 24 accounts* for the generally poor prognosis for patients with this lesion.
Case Report A 5-year-old white, blue-eyed boy was re ferred in August 1987 for the management of an iris abnormality of the left eye. Six weeks earli er, the child's mother had noted that the tem poral portion of his left iris was darker blue than usual, and the boy complained of blurred vision in this eye. His ocular history included excision of a dermoid cyst from the superotemporal aspect of the left orbit at 6 months of age. The operation was performed elsewhere and the diagnosis was not confirmed histopathologically by u s . The patient's natural father was homosexual and abused drugs; the boy lived with his mother and stepfather. Best-corrected visual acuity was R.E.: 20/20 with +1.00 +0.50 x 148 and L.E.: 20/20-2 with -1.50 +0.25 x 143. Intraocular tension by applanation tonometry was R.E.: 16 mm Hg and L.E.: 30 mm Hg. Results of slit-lamp examina tion of the right eye were unremarkable. The left eye showed keratic precipitates on the infe rior portion of the cornea. The temporal iris stroma appeared thickened and blue-gray (Fig. 1); the nasal peripheral iris contained several slightly elevated gray-tan nodules. Gonioscopy showed thickening of the peripheral iris stroma superonasally as well as scattered peripheral anterior synechiae. The lenses were clear. The left globe transilluminated evenly. The vitreous was clear in both eyes. Indirect ophthalmoscopy demonstrated a cup/disk ratio of 0.2 and retinal pigment epithelial mottling in the midperiphery of the right eye. A cup/disk ratio of 0.4 and multiple pale-tan choroidal infiltrates ranging from 1 to 2 disk diameters were ob-
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Fig. 1 (Rosenbaum, Boniuk, and Font). The left eye shows mild conjunctival injection as well as hyperpigmentation of the peripheral iris and generalized effacement of the iris crypt structure. The right eye was normal. served in the peripapillary region and along the inferotemporal arcade of the left fundus. Results of a complete clinical and roentgenographic examination showed no evidence of metastatic disease, and results of serum pro tein electrophoresis, rapid plasma reaginmicrohemagglutination inhibition for Treponema pallidum, and serologie studies for rubella, Toxoplasma, hepatitis, and HIV were negative. The differential diagnosis included diffuse mel anoma of the iris, medulloepithelioma, juve nile xanthogranuloma, and a metastatic neo plasm. A diagnostic sector iridectomy from the nasal portion of the iris was performed and aqueous humor was removed for cytologie examination. Multiple cysts of the ciliary body were ob served posterior to the iridectomy site. Cyto logie examination of clear aqueous fluid showed clusters of malignant cells suggestive of epithelioid malignant melanoma cells. Histopathologic examination of the iridectomy speci men disclosed a diffuse infiltrate of predomi nantly large epithelioid malignant melanoma cells, intermixed with spindle-shaped cells, dif fusely infiltrating the iris stroma. FontanaMasson and S-100 protein stains of the iridecto my specimen demonstrated a small amount of melanin pigment within the cytoplasm of some
Fig. 2 (Rosenbaum, Boniuk, and Font). Gross ap pearance of the enucleated left eye. Top, View of anterior segment depicting diffuse thickening of the ciliary body on both sides as well as slight thickening and irregularity of the iris stroma. Numerous cysts of the pars plicata are clearly seen nasally (arrow). Bottom, View of posterior segment showing diffuse thickening (up to 2 mm) of the choroid with scat tered, mottled, tan-brown areas of pigmentation.
of the neoplastic cells. A histopathologic diag nosis of diffuse malignant melanoma of the iris, predominantly of the epithelioid cell type, was made. The eye was enucleated one week later. Macroscopically, the firm left globe mea sured 22 x 22.5 x 22.5 mm and had 2.0 mm of optic nerve attached. The clear cornea mea sured 11.5 x 10.5 mm. The iris was blue and a coloboma at the iridectomy site was present nasally between the 8 and 10:30 o'clock meridi ans. No shadows were seen on transillumination of the globe, which was sectioned horizon tally. The anterior chamber was shallow and peripheral anterior synechiae were observed. Multiple cysts of the pars plicata, filled with semitranslucent material, were noted. The cili ary body on both sides and the entire choroid were tan-brown and the choroid was diffusely thickened, measuring up to 2 mm (Fig. 2). The
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Fig. 4 (Rosenbaum, Boniuk, and Font). Multiple cysts of the pigmented and nonpigmented ciliary epithelium of the pars plicata containing proteina ceous material. A cellular tumor diffusely infiltrates the iris stroma and ciliary processes (hematoxylin and eosin, x30). Fig. 3 (Rosenbaum, Boniuk, and Font). Highpower view of the ciliary body disclosing bizarre multinucleated epithelioid melanoma cells inter mixed with spindle-shaped cells and scattered mononuclear cells (hematoxylin and eosin, x!80). vitreous was clear and the retina was attached. The optic disk was flat, with a cup/disk ratio of 0.4. Microscopically, a diffuse infiltrate of neoplastic cells containing hyperchromatic, pleomorphic nuclei and prominent red-purple nu cleoli were seen throughout the iris, chamber angle structures (including Schlemm's canal), and ciliary body (Fig. 3). Several of the tumor cells contained intracytoplasmic melanin gran ules. Numerous cysts lined by pigmented and nonpigmented ciliary epithelium and contain ing proteinaceous material were seen (Fig. 4). Alcian blue stains failed to demonstrate mucopolysaccharides within the cysts. Nasally, the choroid contained foci of fumor cells inter mixed with scattered lymphoplasmacytic infil trates, whereas the choroid temporally was diffusely infiltrated by melanoma cells that ex hibited epithelioid features and scattered bi zarre multinucleated cells (Fig. 5). Mild to mod erate mitotic activity was noted. Extensive gliosis of the retina was observed. No evidence of intrascleral or intravascular invasion was present. The histopathologic diagnosis was dif fuse malignant melanoma of the uvea, mixed cell type, with multiple cysts of the ciliary epithelium. Electron microscopy showed bi zarre neoplastic melanocytes containing nu-
merous melanosomes and premelanosomes in various stages of melanogenesis (Figs. 6 and 7). Eight months after enucleation, the patient developed headaches, nausea, and vomiting.
Fig. 5 (Rosenbaum, Boniuk, and Font). The cho roid is diffusely thickened and contains an admixture of epithelioid and spindle-shaped melanoma cells. Bizarre multinucleated tumor cells are occasionally observed (arrows). A moderate lymphoplasmacytic cell infiltrate is scattered throughout. The choriocapillaris is focally obliterated. The retinal pigment epithelium is intact (hematoxylin and eosin, x 115).
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Fig. 6 (Rosenbaum, Boniuk, and Font). Electron micrograph showing melanoma cells with irregular, convoluted nuclei. The cytoplasm contains scattered mitochondria, short dilated profiles of rough-surfaced endoplasmic reticulum, and numerous melanosomes (x 9,200). Inset depicts a premelanosome (asterisk) (x 36,400). Computed tomography disclosed a large mass involving the base of the skull, and destroying the floor of the middle cranial fossa and the sphenoidal and posterior ethmoidal sinuses, with extension to the cavernous sinuses. Biop sy of the mass showed a malignant neoplasm displaying similar histopathologic features to those observed in the primary uveal tumor. Immunohistochemical studies of the metastatic tumor were also positive for melanin. Immedi ately after the results of the biopsy, chemother apy was initiated. Shortly thereafter, the pa tient was transferred to another hospital for possible radical craniofacial surgery. Unfortu nately, the patient was lost to follow-up.
Discussion Our patient was examined by an ophthalmol ogist because of the astute observations of his mother who noted iris discoloration in the involved eye. Initial ophthalmologic examina tion showed evidence of anterior uveitis, graytan iris nodules, and secondary glaucoma. While in juvenile xanthogranuloma, the intra ocular pressure may be increased, the iris nod ules are typically brown-yellow and not gray. Furthermore, no cutaneous nodules character istic of juvenile xanthogranuloma were ob served. A thorough clinical and roentgeno-
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Fig. 7 (Rosenbaum, Boniuk, and Font). Electron micrograph of tumor cell demonstrating different melanosomes in various stages of melanogenesis: premelanosome (1), early immature melanosome (2), late imma ture melanosome (rodlet type) (3), and almost fully melanized granule (4) (x 36,400).
graphic examination showed no evidence of metastatic lesion. Although a diffuse melanoma of the iris was the presumed clinical diagnosis initially, the nature of the retinal pigment epithelial mot tling in the fundus of the right eye and the posterior choroidal infiltrates in the left were intriguing. In retrospect, we believe the choroi dal infiltrates represented neoplastic infiltra tion by malignant melanoma cells. Given the father's homosexuality and drug abuse, an in fectious process was considered but then ex cluded based on the negative results of serolog ie testing for HIV infection. Cysts of the ciliary epithelium in children are a feature suggestive of cystic medulloepithelioma.5,6 Such cysts have been documented histopathologically in a 26-year-old white woman with metastatic malignant melanoma of the skin to the ciliary body 7 and in the case of a primary ciliary body melanoma in a 5-year-old white boy (G. K. Klintworth, unpublished data, May 1969). In these two cases, the cysts con tained a proteinaceous fluid. The cysts occur ring in cystic medulloepitheliomas contain hyaluronidase-sensitive mucopolysaccharides, resembling primary vitreous. The failure of the proteinaceous material within the ciliary epi thelial cysts to stain with Alcian blue in our case serves to illustrate this distinction.
It is now recognized that flat uveal melanocytomas may occur in children. 8 Any portion of the uveal tract may be involved; if anterior segment involvement is present, secondary glaucoma may ensue. Our patient, however, did not demonstrate the jet-black pigmentation characteristic of uveal melanocytoma. Transillumination defects have been variably reported (ranging from approximately 4% 3 to 87% 2 of cases). In our patient, no transillumination shadows were noted either on clinical ex amination or on gross examination of the enu cleated globe. In our case, the choroid displayed scattered lymphoplasmacytic infil trates but no foci of necrosis or areas of postnecrotic scarring were observed. The significance of this chronic nongranulomatous choroiditis remains uncertain but might reflect activation of the child's immune system by the neoplastic cells. We classified histopathologically this diffuse uveal melanoma as Callender's mixed cell type; this cell type comprises from 13% 2 to 76%3 of all diffuse uveal melanomas. Diffuse uveal mela nomas show a marked tendency for early me tastasis, as previously noted in two large se ries. 2,3 Tumor cells typically permeate the anterior intrascleral plexuses, the long and short posterior intrascleral canals, and along the nerve fibers of the optic nerve. One of these
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series 3 d e m o n s t r a t e d a five-year t u m o r d e a t h rate of 73% (19 of 26 p a t i e n t s ) ; all of t h e s e p a t i e n t s d i e d of m e t a s t a t i c d i s e a s e w i t h i n 48 m o n t h s of e n u c l e a t i o n , w i t h a m e d i a n s u r v i v a l time of 20 m o n t h s . A l t h o u g h o u r case failed to s h o w a n y h i s t o p a t h o l o g i c e v i d e n c e of intrascleral or extraocular e x t e n s i o n of the t u m o r , t h e r e w a s m a r k e d i n v o l v e m e n t of t h e c h a m b e r angle s t r u c t u r e s ( i n c l u d i n g S c h l e m m ' s canal). Metastatic i n v o l v e m e n t limited to t h e n a s o p h a r y n x a n d b a s e of the skull is u n u s u a l ; w i d e s p r e a d m é t a s t a s e s or p r e d o m i n a n t liver in v o l v e m e n t is m o r e c o m m o n . 3 Except for t h e p r e s e n c e of bizarre m u l t i n u c l e a t e d m e l a n o m a cells, t h e h i s t o p a t h o l o g i c features of t h e diffuse u v e a l m a s s in o u r p a t i e n t w e r e n o t different from t h o s e c o m m o n l y o b s e r v e d in o t h e r diffuse uveal melanomas. T h e d e v e l o p m e n t of m e t a s t a t i c d i s e a s e in this child, e i g h t m o n t h s after e n u c l e a t i o n , r e e m p h a s i z e s the p o o r p r o g n o s i s r e l a t e d to this a g g r e s s i v e t u m o r a n d t h e n e e d to i n c l u d e dif fuse u v e a l m e l a n o m a in t h e differential d i a g n o sis of p a t i e n t s of all age g r o u p s .
References 1. Barr, C. C , McLean, I. W., and Zimmerman, L. E.: Uveal melanoma in children and adolescents. Arch. Ophthalmol. 99:2133, 1981. 2. Reese, A. B., and Howard, G. M.: Flat uveal melanomas. Am. J. Ophthalmol. 64:1021, 1967. 3. Font, R. L., Spaulding, A. G., and Zimmerman, L. E.: Diffuse malignant melanoma of the uveal tract. A clinicopathologic report of 54 cases. Trans. Am. Acad. Ophthalmol. Otolarygol. 72:877, 1968. 4. Parsons, J. H.: Diffuse sarcomata of the uveal tract. Arch. Ophthalmol. 33:101, 1904. 5. Gifford, H.: A cystic diktyoma. Surv. Ophthal mol. 11:557, 1966. 6. Broughton, W. L., and Zimmerman, L. E.: A clinicopathologic study of 56 cases of intraocular medulloepitheliomas. Am. J. Ophthalmol. 85:407, 1978. 7. Font, R. L., Naumann, G., and Zimmerman, L. E.: Primary malignant melanoma of the skin meta static to the eye and orbit. Report of ten cases and review of the literature. Am. J. Ophthalmol. 63:738, 1967. 8. Haas, B. D., Jakobiec, F. A., Iwamoto, T., Cox, M., Bernacki, E. G., and Pokorny, K. L.: Diffuse choroidal melanocytoma in a child. Ophthalmology 93:1632, 1986.
O P H T H A L M I C MINIATURE
They have p r o p p e d my head between the pillow and the sheet-cuff Like an eye between two white lids that will not shut. Stupid pupil, it has to take everything in. Sylvia Plath, "Tulips," 1962
A 5-year-old white boy developed a gray-tan discoloration with nodular thickening of the iris stroma in his left eye six weeks earlier. Ophthalmologic examination demonstrated keratic precipitates, peripheral anterior synechiae, and several pale-tan choroidal infiltrates in the involved eye. Cytologie examination of the aqueous humor and results of iris biopsy were interpreted as malignant melanoma of the iris, predominantly of the epithelioid cell type. The globe was enucleated one week later. Histopathologic examination disclosed a diffuse malignant melanoma of the uvea, mixed cell type, with multiple cysts of the ciliary epithelium. Study by electron microscopy indicated bizarre neoplastic melanocytes containing numerous immature melanosomes in various stages of melanogenesis, as well as fully melanized mature melanosomes. Eight months after enucleation the patient developed metastasis to the nasopharynx and base of the skull. DIFFUSE OR FLAT malignant melanoma of the
uvea is rare. In a review of 6,358 uveal melano mas in the Registry of Ophthalmic Pathology at the Armed Forces Institute of Pathology, Barr, McLean, and Zimmerman 1 found only 101 (1.6%) in patients less than 20 years of age. Sufficient clinical and pathologic data were available on 78 of the 101 patients, and none showed diffuse uveal involvement. Reese and Howard 2 and Font, Spaulding, and Zimmerman 3 showed that 4.5% and 5%, respec tively, of all uveal melanomas were of the diffuse type. There is often a delay in the diagnosis and treatment of these tumors as they are generally
Accepted for publication Aug. 1, 1988. From the Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, Texas. This study was supported in part by grants from the Retina Research Foundation and the Lions Eye Bank, Houston, Texas. Reprint requests to Ramon L. Font, M.D., Ophthalmic Pathology Laboratory, Cullen Eye Institute, Baylor Col lege of Medicine, 6501 Fannin, Houston, TX 77030.
not included in the clinical differential diagno sis. Reese and Howard 2 noted a delay in diag nosis ranging from two months to nine years in 17 of 28 patients with diffuse uveal melanomas. This, coupled with the tendency for extraocular extension to occur early, 24 accounts* for the generally poor prognosis for patients with this lesion.
Case Report A 5-year-old white, blue-eyed boy was re ferred in August 1987 for the management of an iris abnormality of the left eye. Six weeks earli er, the child's mother had noted that the tem poral portion of his left iris was darker blue than usual, and the boy complained of blurred vision in this eye. His ocular history included excision of a dermoid cyst from the superotemporal aspect of the left orbit at 6 months of age. The operation was performed elsewhere and the diagnosis was not confirmed histopathologically by u s . The patient's natural father was homosexual and abused drugs; the boy lived with his mother and stepfather. Best-corrected visual acuity was R.E.: 20/20 with +1.00 +0.50 x 148 and L.E.: 20/20-2 with -1.50 +0.25 x 143. Intraocular tension by applanation tonometry was R.E.: 16 mm Hg and L.E.: 30 mm Hg. Results of slit-lamp examina tion of the right eye were unremarkable. The left eye showed keratic precipitates on the infe rior portion of the cornea. The temporal iris stroma appeared thickened and blue-gray (Fig. 1); the nasal peripheral iris contained several slightly elevated gray-tan nodules. Gonioscopy showed thickening of the peripheral iris stroma superonasally as well as scattered peripheral anterior synechiae. The lenses were clear. The left globe transilluminated evenly. The vitreous was clear in both eyes. Indirect ophthalmoscopy demonstrated a cup/disk ratio of 0.2 and retinal pigment epithelial mottling in the midperiphery of the right eye. A cup/disk ratio of 0.4 and multiple pale-tan choroidal infiltrates ranging from 1 to 2 disk diameters were ob-
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Fig. 1 (Rosenbaum, Boniuk, and Font). The left eye shows mild conjunctival injection as well as hyperpigmentation of the peripheral iris and generalized effacement of the iris crypt structure. The right eye was normal. served in the peripapillary region and along the inferotemporal arcade of the left fundus. Results of a complete clinical and roentgenographic examination showed no evidence of metastatic disease, and results of serum pro tein electrophoresis, rapid plasma reaginmicrohemagglutination inhibition for Treponema pallidum, and serologie studies for rubella, Toxoplasma, hepatitis, and HIV were negative. The differential diagnosis included diffuse mel anoma of the iris, medulloepithelioma, juve nile xanthogranuloma, and a metastatic neo plasm. A diagnostic sector iridectomy from the nasal portion of the iris was performed and aqueous humor was removed for cytologie examination. Multiple cysts of the ciliary body were ob served posterior to the iridectomy site. Cyto logie examination of clear aqueous fluid showed clusters of malignant cells suggestive of epithelioid malignant melanoma cells. Histopathologic examination of the iridectomy speci men disclosed a diffuse infiltrate of predomi nantly large epithelioid malignant melanoma cells, intermixed with spindle-shaped cells, dif fusely infiltrating the iris stroma. FontanaMasson and S-100 protein stains of the iridecto my specimen demonstrated a small amount of melanin pigment within the cytoplasm of some
Fig. 2 (Rosenbaum, Boniuk, and Font). Gross ap pearance of the enucleated left eye. Top, View of anterior segment depicting diffuse thickening of the ciliary body on both sides as well as slight thickening and irregularity of the iris stroma. Numerous cysts of the pars plicata are clearly seen nasally (arrow). Bottom, View of posterior segment showing diffuse thickening (up to 2 mm) of the choroid with scat tered, mottled, tan-brown areas of pigmentation.
of the neoplastic cells. A histopathologic diag nosis of diffuse malignant melanoma of the iris, predominantly of the epithelioid cell type, was made. The eye was enucleated one week later. Macroscopically, the firm left globe mea sured 22 x 22.5 x 22.5 mm and had 2.0 mm of optic nerve attached. The clear cornea mea sured 11.5 x 10.5 mm. The iris was blue and a coloboma at the iridectomy site was present nasally between the 8 and 10:30 o'clock meridi ans. No shadows were seen on transillumination of the globe, which was sectioned horizon tally. The anterior chamber was shallow and peripheral anterior synechiae were observed. Multiple cysts of the pars plicata, filled with semitranslucent material, were noted. The cili ary body on both sides and the entire choroid were tan-brown and the choroid was diffusely thickened, measuring up to 2 mm (Fig. 2). The
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Fig. 4 (Rosenbaum, Boniuk, and Font). Multiple cysts of the pigmented and nonpigmented ciliary epithelium of the pars plicata containing proteina ceous material. A cellular tumor diffusely infiltrates the iris stroma and ciliary processes (hematoxylin and eosin, x30). Fig. 3 (Rosenbaum, Boniuk, and Font). Highpower view of the ciliary body disclosing bizarre multinucleated epithelioid melanoma cells inter mixed with spindle-shaped cells and scattered mononuclear cells (hematoxylin and eosin, x!80). vitreous was clear and the retina was attached. The optic disk was flat, with a cup/disk ratio of 0.4. Microscopically, a diffuse infiltrate of neoplastic cells containing hyperchromatic, pleomorphic nuclei and prominent red-purple nu cleoli were seen throughout the iris, chamber angle structures (including Schlemm's canal), and ciliary body (Fig. 3). Several of the tumor cells contained intracytoplasmic melanin gran ules. Numerous cysts lined by pigmented and nonpigmented ciliary epithelium and contain ing proteinaceous material were seen (Fig. 4). Alcian blue stains failed to demonstrate mucopolysaccharides within the cysts. Nasally, the choroid contained foci of fumor cells inter mixed with scattered lymphoplasmacytic infil trates, whereas the choroid temporally was diffusely infiltrated by melanoma cells that ex hibited epithelioid features and scattered bi zarre multinucleated cells (Fig. 5). Mild to mod erate mitotic activity was noted. Extensive gliosis of the retina was observed. No evidence of intrascleral or intravascular invasion was present. The histopathologic diagnosis was dif fuse malignant melanoma of the uvea, mixed cell type, with multiple cysts of the ciliary epithelium. Electron microscopy showed bi zarre neoplastic melanocytes containing nu-
merous melanosomes and premelanosomes in various stages of melanogenesis (Figs. 6 and 7). Eight months after enucleation, the patient developed headaches, nausea, and vomiting.
Fig. 5 (Rosenbaum, Boniuk, and Font). The cho roid is diffusely thickened and contains an admixture of epithelioid and spindle-shaped melanoma cells. Bizarre multinucleated tumor cells are occasionally observed (arrows). A moderate lymphoplasmacytic cell infiltrate is scattered throughout. The choriocapillaris is focally obliterated. The retinal pigment epithelium is intact (hematoxylin and eosin, x 115).
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Fig. 6 (Rosenbaum, Boniuk, and Font). Electron micrograph showing melanoma cells with irregular, convoluted nuclei. The cytoplasm contains scattered mitochondria, short dilated profiles of rough-surfaced endoplasmic reticulum, and numerous melanosomes (x 9,200). Inset depicts a premelanosome (asterisk) (x 36,400). Computed tomography disclosed a large mass involving the base of the skull, and destroying the floor of the middle cranial fossa and the sphenoidal and posterior ethmoidal sinuses, with extension to the cavernous sinuses. Biop sy of the mass showed a malignant neoplasm displaying similar histopathologic features to those observed in the primary uveal tumor. Immunohistochemical studies of the metastatic tumor were also positive for melanin. Immedi ately after the results of the biopsy, chemother apy was initiated. Shortly thereafter, the pa tient was transferred to another hospital for possible radical craniofacial surgery. Unfortu nately, the patient was lost to follow-up.
Discussion Our patient was examined by an ophthalmol ogist because of the astute observations of his mother who noted iris discoloration in the involved eye. Initial ophthalmologic examina tion showed evidence of anterior uveitis, graytan iris nodules, and secondary glaucoma. While in juvenile xanthogranuloma, the intra ocular pressure may be increased, the iris nod ules are typically brown-yellow and not gray. Furthermore, no cutaneous nodules character istic of juvenile xanthogranuloma were ob served. A thorough clinical and roentgeno-
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Fig. 7 (Rosenbaum, Boniuk, and Font). Electron micrograph of tumor cell demonstrating different melanosomes in various stages of melanogenesis: premelanosome (1), early immature melanosome (2), late imma ture melanosome (rodlet type) (3), and almost fully melanized granule (4) (x 36,400).
graphic examination showed no evidence of metastatic lesion. Although a diffuse melanoma of the iris was the presumed clinical diagnosis initially, the nature of the retinal pigment epithelial mot tling in the fundus of the right eye and the posterior choroidal infiltrates in the left were intriguing. In retrospect, we believe the choroi dal infiltrates represented neoplastic infiltra tion by malignant melanoma cells. Given the father's homosexuality and drug abuse, an in fectious process was considered but then ex cluded based on the negative results of serolog ie testing for HIV infection. Cysts of the ciliary epithelium in children are a feature suggestive of cystic medulloepithelioma.5,6 Such cysts have been documented histopathologically in a 26-year-old white woman with metastatic malignant melanoma of the skin to the ciliary body 7 and in the case of a primary ciliary body melanoma in a 5-year-old white boy (G. K. Klintworth, unpublished data, May 1969). In these two cases, the cysts con tained a proteinaceous fluid. The cysts occur ring in cystic medulloepitheliomas contain hyaluronidase-sensitive mucopolysaccharides, resembling primary vitreous. The failure of the proteinaceous material within the ciliary epi thelial cysts to stain with Alcian blue in our case serves to illustrate this distinction.
It is now recognized that flat uveal melanocytomas may occur in children. 8 Any portion of the uveal tract may be involved; if anterior segment involvement is present, secondary glaucoma may ensue. Our patient, however, did not demonstrate the jet-black pigmentation characteristic of uveal melanocytoma. Transillumination defects have been variably reported (ranging from approximately 4% 3 to 87% 2 of cases). In our patient, no transillumination shadows were noted either on clinical ex amination or on gross examination of the enu cleated globe. In our case, the choroid displayed scattered lymphoplasmacytic infil trates but no foci of necrosis or areas of postnecrotic scarring were observed. The significance of this chronic nongranulomatous choroiditis remains uncertain but might reflect activation of the child's immune system by the neoplastic cells. We classified histopathologically this diffuse uveal melanoma as Callender's mixed cell type; this cell type comprises from 13% 2 to 76%3 of all diffuse uveal melanomas. Diffuse uveal mela nomas show a marked tendency for early me tastasis, as previously noted in two large se ries. 2,3 Tumor cells typically permeate the anterior intrascleral plexuses, the long and short posterior intrascleral canals, and along the nerve fibers of the optic nerve. One of these
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November, 1988
AMERICAN JOURNAL OF OPHTHALMOLOGY
series 3 d e m o n s t r a t e d a five-year t u m o r d e a t h rate of 73% (19 of 26 p a t i e n t s ) ; all of t h e s e p a t i e n t s d i e d of m e t a s t a t i c d i s e a s e w i t h i n 48 m o n t h s of e n u c l e a t i o n , w i t h a m e d i a n s u r v i v a l time of 20 m o n t h s . A l t h o u g h o u r case failed to s h o w a n y h i s t o p a t h o l o g i c e v i d e n c e of intrascleral or extraocular e x t e n s i o n of the t u m o r , t h e r e w a s m a r k e d i n v o l v e m e n t of t h e c h a m b e r angle s t r u c t u r e s ( i n c l u d i n g S c h l e m m ' s canal). Metastatic i n v o l v e m e n t limited to t h e n a s o p h a r y n x a n d b a s e of the skull is u n u s u a l ; w i d e s p r e a d m é t a s t a s e s or p r e d o m i n a n t liver in v o l v e m e n t is m o r e c o m m o n . 3 Except for t h e p r e s e n c e of bizarre m u l t i n u c l e a t e d m e l a n o m a cells, t h e h i s t o p a t h o l o g i c features of t h e diffuse u v e a l m a s s in o u r p a t i e n t w e r e n o t different from t h o s e c o m m o n l y o b s e r v e d in o t h e r diffuse uveal melanomas. T h e d e v e l o p m e n t of m e t a s t a t i c d i s e a s e in this child, e i g h t m o n t h s after e n u c l e a t i o n , r e e m p h a s i z e s the p o o r p r o g n o s i s r e l a t e d to this a g g r e s s i v e t u m o r a n d t h e n e e d to i n c l u d e dif fuse u v e a l m e l a n o m a in t h e differential d i a g n o sis of p a t i e n t s of all age g r o u p s .
References 1. Barr, C. C , McLean, I. W., and Zimmerman, L. E.: Uveal melanoma in children and adolescents. Arch. Ophthalmol. 99:2133, 1981. 2. Reese, A. B., and Howard, G. M.: Flat uveal melanomas. Am. J. Ophthalmol. 64:1021, 1967. 3. Font, R. L., Spaulding, A. G., and Zimmerman, L. E.: Diffuse malignant melanoma of the uveal tract. A clinicopathologic report of 54 cases. Trans. Am. Acad. Ophthalmol. Otolarygol. 72:877, 1968. 4. Parsons, J. H.: Diffuse sarcomata of the uveal tract. Arch. Ophthalmol. 33:101, 1904. 5. Gifford, H.: A cystic diktyoma. Surv. Ophthal mol. 11:557, 1966. 6. Broughton, W. L., and Zimmerman, L. E.: A clinicopathologic study of 56 cases of intraocular medulloepitheliomas. Am. J. Ophthalmol. 85:407, 1978. 7. Font, R. L., Naumann, G., and Zimmerman, L. E.: Primary malignant melanoma of the skin meta static to the eye and orbit. Report of ten cases and review of the literature. Am. J. Ophthalmol. 63:738, 1967. 8. Haas, B. D., Jakobiec, F. A., Iwamoto, T., Cox, M., Bernacki, E. G., and Pokorny, K. L.: Diffuse choroidal melanocytoma in a child. Ophthalmology 93:1632, 1986.
O P H T H A L M I C MINIATURE
They have p r o p p e d my head between the pillow and the sheet-cuff Like an eye between two white lids that will not shut. Stupid pupil, it has to take everything in. Sylvia Plath, "Tulips," 1962