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Juvenile Xanthogranuloma Masquerading as Pediatric Chronic Uveitis
SURVEY OF OPHTHALMOLOGY VOLUME 46 • NUMBER 2 • SEPTEMBER–OCTOBER 2001
CLINICAL PATHOLOGICAL REVIEW MILTON BONIUK AND STEFAN SEREGARD, EDITORS
Juvenile Xanthogranuloma Masquerading as Pediatric Chronic Uveitis: A Clinicopathologic Study Ehud Zamir, MD,1 Robert C. Wang, MD,1 Subramanian Krishnakumar, MD,1 Amy Aiello Leverant, MD,2 Pravin U. Dugel, MD,3 and Narsing A. Rao, MD1 1
Doheny Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, Arizona Pediatric Eye Specialists, Phoenix, Arizona, and 3Retinal Consultants of Arizona, Phoenix, Arizona, USA
2
Abstract. Juvenile xanthogranuloma (JXG) is a rare, pediatric histiocytic skin disorder that may affect the eye. It can present with protean ocular manifestations, including masquerade uveitis, heterochromia, hyphema, or glaucoma. It very rarely involves the retina and posterior segment; indeed, posterior involvement has been documented histopathologically in only one case. We present the case of a 2-year-old child with ocular JXG presenting as chronic, refractive uveitis, without skin or systemic findings. The blind, painful eye was enucleated and found to harbor a diffuse histiocytic process that involved both the anterior and posterior segments, including the retina and subretinal space. Histological, immunohistochemical, and electron microscopic studies confirmed the diagnosis of JXG. The pathologic classification and differential diagnosis of systemic histiocytic disorders are discussed. Since JXG can present as masquerade pediatric uveitis, this entity should be considered in children with atypical uveitis. In rare instances, JXG may involve the posterior segment and the retina, leading to retinal detachment and blindness. (Surv Ophthalmol 46:164–171, 2001. © 2001 by Elsevier Science Inc. All rights reserved.) Key words. electron microscopy • histiocytic disorders • immunohistochemistry xanthogranuloma • masquerade syndromes • pediatric uveitis
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juvenile
retinoblastoma, medulloepithelioma, and leukemia. An array of laboratory diagnostic techniques is often required to reach a final diagnosis. We present an unusual case of ocular JXG in a 2-year-old girl with masquerade uveitis and no skin lesions. The disease progressed rapidly despite antiinflammatory therapy; the diagnosis was finally confirmed by enucleation of the blind, painful eye. In addition to the classic anterior segment involvement, the globe showed extensive retinal involvement. Retinal and posterior segment involvement is extremely rare in JXG.6,10,22 Although 3 such cases
Juvenile xanthogranuloma (JXG) is a benign, non–Langerhans cell histiocytic skin disorder that affects children during the first 2 years of life.23 The eye is the most commonly involved extracutaneous organ, but the incidence of such involvement is only 0.3–0.5%.4 In Zimmerman’s series of ocular JXG,23 the diverse intraocular manifestations included heterochromia, spontaneous hyphema, iris and ciliary body masses, unilateral glaucoma, cataract, and uveitis. When JXG manifests only in the eyes, clinical diagnosis is often difficult. Differential diagnosis is wide, ranging from juvenile rheumatoid arthritis to 164 © 2001 by Elsevier Science Inc. All rights reserved.
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have been reported, histologic documentation of retinal involvement was available in only one case.22 In this report, we review the current pathologic classification of systemic histiocytosis syndromes and discuss the histopathology, emphasizing the immunohistochemical and ultrastructural characteristics that assist in classifying JXG as a distinct histiocytosis syndrome. Although two earlier reports used either immunohistochemical analysis6 or electron microscopy22 to assist in the diagnosis, this is the first comprehensive pathological report of ocular JXG, in which both these diagnostic modalities were combined with histopathologic evaluation of an enucleated globe, and correlated with the recent classification of histiocytic lesions.
Case Report A 2-year-old girl was examined because of heterochromia, anisocoria, and a squint that had been present since she was 1 year old. She was the product of a normal pregnancy and normal delivery and was otherwise healthy. Examination revealed good fixation and following with the right eye, but no fixation with the left eye, which was esotropic. Slit-lamp examination and funduscopy of the right eye were unremarkable. The left eye revealed white conjunctiva, anterior uveitis, and band keratopathy. The anterior chamber was shallow, with 270 posterior synechiae and a pupillary membrane. No fundus details could be seen. Ultrasound examination showed vitreous debris and an attached retina. The tentative diagnosis was rheumatoid arthritis. Despite therapy with topical prednisolone and cyclopentolate, the patient became more photophobic over the following month. Examination under anesthesia revealed an intraocular pressure of 18 mm Hg in the right eye (OD) and 13 mm Hg in the left (OS). The left fundus could not be visualized properly. An injection of triamcinolone acetonide was given in the posterior sub-Tenon space. Laboratory workup, including a complete blood count, sedimentation rate, anti-nuclear antibody, rheumatoid factor, and knee X-rays, was normal. When no response was noted to the steroid therapy, the patient underwent a left pars plana lensectomy and vitrectomy. During surgery, the anterior chamber was found to be very shallow, leading the surgeon to suspect pupillary block and angle-closure glaucoma. The vitreous cavity contained membranes and blood. The optic nerve head appeared glaucomatous with fibrous membranes on its surface. Two months after surgery, the patient had a spontaneous hyphema in the left eye. One month later, the iris was noted to have gray elevations with fine vascularity in its nasal half. There was a grayish, organized mass at the six o’clock position. The iris le-
sions were thought to be cystic, and another examination under anesthesia was performed. Prominent episcleral vessels were noted on the temporal side. Five gray iris cysts were described on the nasal iris. The nerve appeared atrophic; the retina was flat, but no details could be seen because of the vitreous debris. The patient was then referred to the Doheny Eye Institute. No skin lesions were noted on examination. Her right eye was normal. The left eye did not fix. The pupil was unresponsive to light, and did not elicit a consensual response. There was a prominent episcleral blood vessel on the temporal side. Marked heterochromia was noted, with brown discoloration of the left iris (Fig. 1). The intraocular pressure was 14 mm Hg OD and 6 mm Hg OS. The cornea had slight band keratopathy. The anterior chamber was deep, with 3 cell and flare. There were a few confluent, darkly pigmented nodules on the superonasal side of the iris. There was a yellowish lesion in the 6-o’clock position and flocculent debris over the entire iris surface (Fig. 2). The eye was aphakic. No details could be seen in the fundus. Transillumination did not reveal a focal mass in the ciliary body region. At this point, masquerade uveitis was suspected, with the differential diagnosis of juvenile xanthogranuloma versus ciliary body medulloepithelioma. The patient sought a second opinion in another hospital, where an ultrasound biomicroscopic examination of the iris demonstrated diffuse thickening with no cystic lesions. A fine needle aspiration biopsy revealed few histiocytic cells, increasing the suspicion of juvenile xanthogranuloma. Because the eye was blind, hypotonous, and irritated, and because the possibility of intraocular malignancy had still not been ruled out, the patient’s parents favored an enucleation.
Pathological Examination The eye was fixed in 4% formaldehyde solution and processed for pathological examination. Gross examination revealed a globe measuring 21 18 18 mm. There was a yellowish-brown iris mass, and the iris was markedly thickened. There was organized material underneath the detached retina (Fig. 3). Microscopic examination showed multiple foci of histiocytes distributed on the anterior iris surface (Figs. 4 and 5). Some of these cells were seen infiltrating the iris stroma and the ciliary epithelium. Admixed with the histiocytes were a few eosinophils, lymphocytes, and plasma cells. The trabecular meshwork also was infiltrated by histiocytes. Occasional Touton and other giant cells could be detected (Fig. 5). There was an organized, cellular collection around the ciliary body (Fig. 4). The retina was detached and disorganized, with areas of gliosis and occasional intraretinal micro-abscesses containing neu-
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Fig. 1. Clinical photograph showing left esotropia and marked heterochromia. The left eye is smaller, as indicated by a narrowed interpalpebral fissure.
trophils, eosinophils, and histiocytes. The detached retina showed epiretinal membrane with traction (Fig. 6). The subretinal space was infiltrated with foamy histiocytes and multinculeated giant cells, similar to those found on the iris (Fig. 7). Oil-red-O stain revealed multiple lipid-positive cells on the iris and the trabecular meshwork, within the epiretinal membrane extending along the internal limiting membrane, and under the retina (Figs. 5 and 7).
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Fig. 2. Prominent episcleral vessels are evident on the temporal side of the globe. The iris shows an inferior yellowish mass and flocculent debris on its surface, as evident on the pupillary margin. Three raised, cyst-like structures are seen in the peripheral iris at 9–11 o’clock.
with diffuse, cytoplasmic staining (Fig. 8). All cells were negative for CD1a, a Langerhans cell marker. TRANSMISSION ELECTRON MICROSCOPY (TEM) STUDIES
Paraffin-embedded sections were subjected to standard immunohistochemical protocols, using biotin-streptavidin-peroxidase detection (DAKO Corporation, Carpinteria, CA). Immunohistochemically, the histiocytes were S-100 negative, and were strongly positive for CD-68 (a macrophage marker),
The tissue was fixed in Karnovsky’s fixative (2% paraformaldehyde, 2.5% glutaraldehyde in 0.1 M cacodylate buffer at pH 7.4) and processed for embedding in epoxy resin. Thin sections (70–80 nm) were examined with transmission electron microscopy (TEM). Several electron dense intracytoplasmic granules were seen in the histiocytes. These round-to-oval membrane-bound granules, measuring approximately 100 nm in diameter, were diffusely scattered in the histiocyte cytoplasm. The granules had two
Fig. 3. A gross photograph of the sectioned enucleation specimen. The lesion on the inferior iris is indicated by an orange arrow. The eye is aphakic. The ciliary body area is occupied by a thick membrane that causes tractional retinal detachment. Note retinal thickening and subretinal material (green arrow).
Fig. 4. Histologic section through the peripheral iris shows thickening of the iris, with collections of histiocytes, lymphocytes, and plasma cells on the iris surface. Similar cells, as well as membranes, are seen between the ciliary processes (hematoxylin and eosin).
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Fig. 5. A higher magnification shows a mound of histiocytes on the iris surface. Notice a Touton giant cell (arrow [hematoxylin and eosin]). Inset shows an oilred-O-positive cell in the same location.
Fig. 6. The retina reveals a thick epiretinal membrane (between arrows), composed of cells similar to those seen in the anterior segment (hematoxylin and eosin).
Fig. 7. A photomicrograph of the subretinal space, showing infiltration of foamy histiocytes (hematoxylin and eosin). Inset: Oil-red-O staining, showing strong lipid-positivity in the subretinal histiocytes.
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Fig. 9. A transmission electron microscope photomicrograph showing a histiocyte with a kidney-shaped nucleus and several intermediate sized, electron-dense granules (arrows). Birbeck granules are absent.
Fig. 8. Immunostaining with CD-68 shows strong positivity of the cells covering the iris, indicating their macrophage origin. Positive cells appear brown (biotin-streptavidin-peroxidase detection).
electron-dense membranes, seperated by a slight gap. Birbeck granules were absent (Fig. 9).
Discussion Differentiating chronic pediatric uveitis from more esoteric conditions that mimic it is often difficult. The case reported here initially presented with severe chronic “uveitis” and band keratopathy in a female baby with a quiet eye. The presentation led to a presumptive diagnosis of juvenile rheumatoid arthritis. When it later became evident that corticosteroid therapy was ineffective, and when mass lesions appeared on the iris, alternative diagnoses were entertained. In retrospect, clinical clues such as the occurrence of hyphema could have raised the suspicion of JXG earlier. However, the postoperative timing may have implied a surgical complication, rather than a truly spontaneous hyphema. The lack of skin lesions also contributed to the delay in diagnosis. When a masquerade syndrome was suspected, the diagnosis of JXG could not be made with cer-
tainty on clinical or cytological grounds alone. The diagnosis was suggested by cytologic examination of a needle aspiration biopsy. However, because of the massive infiltration of the iris and the refractory nature of the lesion, we could not exclude with certainty other potentially malignant diseases, in particular medulloepithelioma. JXG is a benign histiocytic/inflammatory lesion that primarily affects the skin and the eyes, although visceral involvement may also occur. It usually regresses spontaneously within 3 to 6 years.5 The characteristic raised, reddish-yellowish skin lesions appear in infancy or early childhood. The incidence of ocular involvement in a patient with cutaneous JXG was estimated to be only 0.3% to 0.5%.4 Of reported patients with ocular JXG, 41% have had multiple cutaneous lesions.4 However, the disease may present in the eye only, without the characteristic skin lesions. Skin lesions may follow the ocular findings, with a delay of as much as 8 to 10 months.4 The lesions are typically reddish-yellow papules with a predilection for the facial skin. Our patient did not present skin lesions, and her disease seems to have been limited to the eye. In Zimmerman’s series of 53 patients with ocular JXG, 85% presented before 1 year of age.23 Similarly, in the present case, the onset of disease was at age 1 year. However, JXG may rarely be seen in adults.18
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Ocular JXG lesions typically involve the iris, where they appear as yellowish nodules. Iris involvement may also present as diffuse thickening with a muddy color. In cases of diffuse involvement of the iris, heterochromia may be seen (Fig. 1).23 The iris lesions are vascular, tending to bleed and to cause spontaneous hyphema; the hyphema, in turn, may be complicated by secondary glaucoma and corneal opacification. Rarely, JXG involves the choroid, ciliary body, retina, or optic nerve.6,10,22 Epibulbar lesions can be found at the corneoscleral limbus, conjunctiva, episclera, or orbit.23 The skin of the eyelids may be involved, in which case the globe is usually spared. The lesions typically show histologic evidence of large histiocytes with foamy cytoplasm and Toutontype giant cells. These cells contain fat, which can be demonstrated by oil-red-O staining. The lipid component in a case of JXG reported by DeBarge et al was shown to contain apolipoprotein A, the major apolipoprotein of high density lipoprotein.6 There is a large group of benign and malignant histiocytic disorders with a complex pathological classification. The term M-PIRE (mononuclear phagocyte and immuno-regulatory effector cells) system has been suggested as an encompassing designation for histiocytes.8 The Writing Group of the Histiocyte Society1 suggested the following classification: Class I, Langerhans cell histiocytosis (LCH); class II, nonLangerhans cell histiocytosis (non-LCH); and class III, malignant histiocytosis. The common denominator of LCH is a distinct cell with a typical kidneyshaped nucleus. It is immunoreactive with CD1a and S 100 protein. Birbeck granules can be seen by electron microscopy. In contrast, class II, non-Langerhans cell histiocytosis (non-LCH) syndromes, are characterized by the presence of monocyte/macrophage-derived cells. Therefore, the cells are positive for CD68, an intracytoplasmic, lysosome-associated glycoprotein used as a macrophage marker. They may appear vacuolated, xanthomatized, spindleshaped, oncocytic, or multinucleated. Touton and foreign body giant cells may be present. The former cells are characterized by a wreath of nuclei arranged around a homogenous eosinophilic cytoplasmic center. Histiocytes of iris lesions are less likely to show the foamy cytoplasm seen in skin lesions. Also, fewer Touton giant cells are seen in the iris than in the skin lesions.6,19,23 This was the case with our patient, who demonstrated only a few Touton giant cells (Fig. 5). Each of the above non-LCH morphologic types has characteristic immunohistochemical and ultrastructural features. Therefore, there is no definitive diagnostic marker for non-LCH.15 Juvenile xanthogranuloma is a class II or non-LCH disorder. It typically contains proliferating histiocytes that are
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negative for S100 and MAC 387, and positive for HAM 56, HHF35, KP1, KiM1P, and vimentin.15 Factor XIIIa is also positive. Although CD1a (OKT-6) is generally considered a specific marker for Langerhans cells, a case of JXG with CD1 positivity has been reported.2 Similarly, our case showed CD68 positivity that proved those cells to be histiocytes, while negative S100 and CD-1a staining excluded the possibility of LCH. Beyond morphologic and immunohistochemical examination, electron microscopy has an important role in the differential diagnosis of histiocytic disorders. Ultrastructurally, Langerhans cells are characterized by the presence of distinctive, granular intracytoplasmic inclusions called Birbeck granules or racket bodies. These bodies are absent in non-LCH, which contain variable amounts of nonspecific organelles. These organelles may appear as commashaped, dense, regularly laminated or myeloid bodies, or as pleomorphic cytoplasmic inclusions. Their function is unknown.7,11,14 Variations within these findings are attributable to the predominant cell type. Our case showed the presence of intermediatesized, intracytoplasmic, electron-dense granules, but no Birbeck granules were seen. Ocular disease may present as iris heterochromia, unilateral glaucoma, uveitis, hyphema, or an isolated iris tumor.12,19,23 Rarely, the orbit and optic nerve may be involved.6,22 Retinal involvement, such as was seen in our case, is extremely rare. We were able to find only three documented cases in the MEDLINEcited literature where such involvement was suspected.6,10,22 DeBarge et al described a 12-year-old patient with no skin lesions, painful proptosis, and a solitary, orange subretinal mass that resolved after treatment with oral and periocular corticosteroids. The lesion recurred over a 2-year period, resolving with each course of corticosteroids. The patient had biopsy-proven JXG iris lesions. However, the subretinal lesion was not biopsied. Godde-Jolly et al10 similarly described an 8-month-old infant with iris, ciliary body, and subretinal involvement by JXG, again without histologic evidence of the subretinal component. We are aware of only one report of a posterior segment JXG proven by histologic analysis: Wertz et al described a 20-month-old child with involvement of the optic nerve and massive contiguous spread to the peripapillary choroid and retina.22 Our case was interesting in that there was extensive involvement of the iris, ciliary body, angle, retina, and subretinal space. Immunohistochemical analysis confirmed the macrophage origin of the cells, which stained positive for CD68. Negative S-100 staining helped differentiate the histiocytic cells from Langerhans cells. Focal weak positivity for CD1a was seen in a few iris cells. These probably represented dendritic cells,
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which are normally present in the iris and the anterior chamber angle.16 Ocular JXG can be diagnosed by a skin biopsy if the typical skin lesions are present. Otherwise, an anterior chamber paracentesis may provide the diagnosis by revealing foamy histiocytes.20 Iris biopsy may be required and may be diagnostic in cases where paracenthesis is equivocal or uninformative.6 We did not consider an iris biopsy in our case, as the eye was blind, painful, and hypotonous. We could not rule out a malignant tumor, such as medulloepithelioma, on clinical grounds. Under these circumstances, enucleation provided symptomatic relief and complete diagnostic information, while obviating the risks of inducing sympathetic ophthalmia or spread of a possible malignancy. Simple iris JXG lesions may regress with topical, periocular, or systemic steroid therapy.9,21 However, some cases are refractive to corticosteroids and may require therapy with local irradiation or immunosuppressive drugs.3,13,17,18 Low-dose weekly methotrexate was used to treat a patient with a JXG iris lesion that was refractory to regional steroid injections.18 Resolution of the lesion resulted in diffuse iris atrophy without residual tumor. In our case, the disease was refractory to both topical and regional steroid therapy. At the time of diagnosis, it was clear that the eye had no favorable visual or anatomic prognosis; therefore, further medical therapy was not indicated. This case demonstrates the need for accurate etiologic diagnosis in atypical or refractory pediatric uveitis cases. The possibility of a masquerade syndrome has to be borne in mind for any child with atypical uveitis. In such cases, evaluation by a specialist in uveitis or ocular oncology is recommended. If retinoblastoma or medulloepithelioma can be ruled out on clinical grounds, obtaining intraocular material for diagnosis should be considered. Early tissue diagnosis is critical in JXG since untreated intraocular lesions can result in blindness. Involvement of the retina is a rare complication of JXG that may lead to chronic retinal detachment and appears to indicate a poor ocular prognosis.
Method of Literature Search We searched Medline, using keywords such as histiocytosis, juvenile xanthogranuloma, intraocular, histopathology, immunohistochemistry, electron microscopy and various boolean combinations of the above, for the years 1966–2000. We searched both English and foreign languages. Some references, including those from pre-Medline years, were retrieved from citations in the reference lists of Medline articles. There was 1 German reference (Muller and Junemann),
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and its English abstract was used for the necessary information. A French article by Godde-Jolly et al was translated.
References 1. ___: Histiocytosis syndromes in children. Writing Group of the Histiocyte Society. Lancet 1:208–9, 1987 2. Andersen WK, Knowles DM, Silvers DN: CD1 (OKT6)-positive juvenile xanthogranuloma. OKT6 is not specific for Langerhans cell histiocytosis (histiocytosis X). J Am Acad Dermatol 26:850–4, 1992 3. Cadera W, Silver MM, Burt L: Juvenile xanthogranuloma. Can J Ophthalmol 18:169–74, 1983 4. Chang MW, Frieden IJ, Good W: The risk intraocular juvenile xanthogranuloma: survey of current practices and assessment of risk. J Am Acad Dermatol 34:445–9, 1996 5. Cohen BA, Hood A: Xanthogranuloma: report on clinical and histologic findings in 64 patients. Pediatr Dermatol 6: 262–6, 1989 6. DeBarge LR, Chan CC, Greenberg SC, et al: Chorioretinal, iris, and ciliary body infiltration by juvenile xanthogranuloma masquerading as uveitis. Surv Ophthalmol 39:65–71, 1994 7. Enzinger FM, Weiss SW: Juvenile xanthogranuloma, in Enzinger FM, Weiss SW (eds): Soft Tissue Tumors. St Louis, Mosby, 1983, pp 135–40 8. Foucar K, Foucar E: The mononuclear phagocyte and immunoregulatory effector (M-PIRE) system: evolving concepts. Semin Diagn Pathol 7:4–18, 1990 9. Gass JDM: Management of juvenile xanthogranuloma of the iris. Arch Ophthalmol 71:344–7, 1964 10. Godde-Jolly D, Rozenbaum J, Chazalon T: [2 cases of juvenile xanthogranuloma. Diagnostic and therapeutic problems posed by the iridic localization of the disease]. Bull Soc Ophtalmol Fr 85:889–93, 1985 11. Gonzalez-Crussi F, Campbell RJ: Juvenile xanthogranuloma: ultrastructural study. Arch Pathol 89:65–72, 1970 12. Harley RD, Romayananda N, Chan GH: Juvenile xanthogranuloma. J Pediatr Ophthalmol Strabismus 19:33–9, 1982 13. Karcioglu ZA, Mullaney PB: Diagnosis and management of iris juvenile xanthogranuloma. J Pediatr Ophthalmol Strabismus 34:44–51, 1997 14. Lever WF, Schaumberg-Lever G: Histopathology of the skin. Philadelphia, JB Lippincott, 1991, pp 442–3 15. Marrogi AJ, Dehner LP, Coffin CM, Wick MR: Benign cutaneous histiocytic tumors in childhood and adolescence, excluding Langerhans cell proliferations. A clinicopathologic and immunohistochemical analysis. Am J Dermatopathol 14: 8–18, 1992 16. McMenamin PG, Crewe J, Morrison S, Holt PG: Immunomorphologic studies of macrophages and MHC class II-positive dendritic cells in the iris and ciliary body of the rat, mouse, and human eye. Invest Ophthalmol Vis Sci 35:3234– 50, 1994 17. Muller RP, Junemann G: [Results of radiotherapy in case of juvenile xanthogranuloma of the iris]. Strahlentherapie 159: 277–82, 1983 18. Parmley VC, George DP, Fannin LA: Juvenile xanthogranuloma of the iris in an adult. Arch Ophthalmol 116:377–9, 1998 19. Sanders TE: Intraocular juvenile xanthogranuloma (nevoxanthogranuloma): a survey of 20 cases. Trans Am Ophthalmol Soc 58:59–74, 1960 20. Schwartz LW, Rodrigues MM, Hallett JW: Juvenile xanthogranuloma diagnosed by paracentesis. Am J Ophthalmol 77:243–6, 1974 21. Treacy KW, Letson RD, Summers CG: Subconjunctival steroid in the management of uveal juvenile xanthogranuloma: a case report. J Pediatr Ophthalmol Strabismus 27:126–8, 1990 22. Wertz FD, Zimmerman LE, McKeown CA, et al: Juvenile xan-
JUVENILE XANTHOGRANULOMA thogranuloma of the optic nerve, disc, retina, and choroid. Ophthalmology 89:1331–5, 1982 23. Zimmerman LE: Ocular lesions of juvenile xanthogranuloma. Nevoxanthoendothelioma. Trans Am Acad Ophthalmol Otolaryngol 69:412–442, 1965 Supported in part by National Institutes of Health core grant EY03040 and by an unrestricted grant from Research to Prevent Blindness, New York, New York.
171 Dr. Zamir is the recipient of a fellowship grant from the American Physicians Fellowship for Medicine in Israel, Boston, MA. The authors have no commercial or proprietary interest in any product or idea discussed in this article. Presented in part at the American Uveitis Society Meeting, Dallas, Texas, October 2000. Reprint address: Narsing A. Rao, MD, Doheny Eye Institute, University of Southern California, Keck School of Medicine, 1450 San Pablo Street, DVRC 211, Los Angeles, CA 90033. E-mail: [email protected]
CLINICAL PATHOLOGICAL REVIEW MILTON BONIUK AND STEFAN SEREGARD, EDITORS
Juvenile Xanthogranuloma Masquerading as Pediatric Chronic Uveitis: A Clinicopathologic Study Ehud Zamir, MD,1 Robert C. Wang, MD,1 Subramanian Krishnakumar, MD,1 Amy Aiello Leverant, MD,2 Pravin U. Dugel, MD,3 and Narsing A. Rao, MD1 1
Doheny Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, California, Arizona Pediatric Eye Specialists, Phoenix, Arizona, and 3Retinal Consultants of Arizona, Phoenix, Arizona, USA
2
Abstract. Juvenile xanthogranuloma (JXG) is a rare, pediatric histiocytic skin disorder that may affect the eye. It can present with protean ocular manifestations, including masquerade uveitis, heterochromia, hyphema, or glaucoma. It very rarely involves the retina and posterior segment; indeed, posterior involvement has been documented histopathologically in only one case. We present the case of a 2-year-old child with ocular JXG presenting as chronic, refractive uveitis, without skin or systemic findings. The blind, painful eye was enucleated and found to harbor a diffuse histiocytic process that involved both the anterior and posterior segments, including the retina and subretinal space. Histological, immunohistochemical, and electron microscopic studies confirmed the diagnosis of JXG. The pathologic classification and differential diagnosis of systemic histiocytic disorders are discussed. Since JXG can present as masquerade pediatric uveitis, this entity should be considered in children with atypical uveitis. In rare instances, JXG may involve the posterior segment and the retina, leading to retinal detachment and blindness. (Surv Ophthalmol 46:164–171, 2001. © 2001 by Elsevier Science Inc. All rights reserved.) Key words. electron microscopy • histiocytic disorders • immunohistochemistry xanthogranuloma • masquerade syndromes • pediatric uveitis
•
juvenile
retinoblastoma, medulloepithelioma, and leukemia. An array of laboratory diagnostic techniques is often required to reach a final diagnosis. We present an unusual case of ocular JXG in a 2-year-old girl with masquerade uveitis and no skin lesions. The disease progressed rapidly despite antiinflammatory therapy; the diagnosis was finally confirmed by enucleation of the blind, painful eye. In addition to the classic anterior segment involvement, the globe showed extensive retinal involvement. Retinal and posterior segment involvement is extremely rare in JXG.6,10,22 Although 3 such cases
Juvenile xanthogranuloma (JXG) is a benign, non–Langerhans cell histiocytic skin disorder that affects children during the first 2 years of life.23 The eye is the most commonly involved extracutaneous organ, but the incidence of such involvement is only 0.3–0.5%.4 In Zimmerman’s series of ocular JXG,23 the diverse intraocular manifestations included heterochromia, spontaneous hyphema, iris and ciliary body masses, unilateral glaucoma, cataract, and uveitis. When JXG manifests only in the eyes, clinical diagnosis is often difficult. Differential diagnosis is wide, ranging from juvenile rheumatoid arthritis to 164 © 2001 by Elsevier Science Inc. All rights reserved.
0039-6257/01/$–see front matter PII S0039-6257(01)00253-3
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have been reported, histologic documentation of retinal involvement was available in only one case.22 In this report, we review the current pathologic classification of systemic histiocytosis syndromes and discuss the histopathology, emphasizing the immunohistochemical and ultrastructural characteristics that assist in classifying JXG as a distinct histiocytosis syndrome. Although two earlier reports used either immunohistochemical analysis6 or electron microscopy22 to assist in the diagnosis, this is the first comprehensive pathological report of ocular JXG, in which both these diagnostic modalities were combined with histopathologic evaluation of an enucleated globe, and correlated with the recent classification of histiocytic lesions.
Case Report A 2-year-old girl was examined because of heterochromia, anisocoria, and a squint that had been present since she was 1 year old. She was the product of a normal pregnancy and normal delivery and was otherwise healthy. Examination revealed good fixation and following with the right eye, but no fixation with the left eye, which was esotropic. Slit-lamp examination and funduscopy of the right eye were unremarkable. The left eye revealed white conjunctiva, anterior uveitis, and band keratopathy. The anterior chamber was shallow, with 270 posterior synechiae and a pupillary membrane. No fundus details could be seen. Ultrasound examination showed vitreous debris and an attached retina. The tentative diagnosis was rheumatoid arthritis. Despite therapy with topical prednisolone and cyclopentolate, the patient became more photophobic over the following month. Examination under anesthesia revealed an intraocular pressure of 18 mm Hg in the right eye (OD) and 13 mm Hg in the left (OS). The left fundus could not be visualized properly. An injection of triamcinolone acetonide was given in the posterior sub-Tenon space. Laboratory workup, including a complete blood count, sedimentation rate, anti-nuclear antibody, rheumatoid factor, and knee X-rays, was normal. When no response was noted to the steroid therapy, the patient underwent a left pars plana lensectomy and vitrectomy. During surgery, the anterior chamber was found to be very shallow, leading the surgeon to suspect pupillary block and angle-closure glaucoma. The vitreous cavity contained membranes and blood. The optic nerve head appeared glaucomatous with fibrous membranes on its surface. Two months after surgery, the patient had a spontaneous hyphema in the left eye. One month later, the iris was noted to have gray elevations with fine vascularity in its nasal half. There was a grayish, organized mass at the six o’clock position. The iris le-
sions were thought to be cystic, and another examination under anesthesia was performed. Prominent episcleral vessels were noted on the temporal side. Five gray iris cysts were described on the nasal iris. The nerve appeared atrophic; the retina was flat, but no details could be seen because of the vitreous debris. The patient was then referred to the Doheny Eye Institute. No skin lesions were noted on examination. Her right eye was normal. The left eye did not fix. The pupil was unresponsive to light, and did not elicit a consensual response. There was a prominent episcleral blood vessel on the temporal side. Marked heterochromia was noted, with brown discoloration of the left iris (Fig. 1). The intraocular pressure was 14 mm Hg OD and 6 mm Hg OS. The cornea had slight band keratopathy. The anterior chamber was deep, with 3 cell and flare. There were a few confluent, darkly pigmented nodules on the superonasal side of the iris. There was a yellowish lesion in the 6-o’clock position and flocculent debris over the entire iris surface (Fig. 2). The eye was aphakic. No details could be seen in the fundus. Transillumination did not reveal a focal mass in the ciliary body region. At this point, masquerade uveitis was suspected, with the differential diagnosis of juvenile xanthogranuloma versus ciliary body medulloepithelioma. The patient sought a second opinion in another hospital, where an ultrasound biomicroscopic examination of the iris demonstrated diffuse thickening with no cystic lesions. A fine needle aspiration biopsy revealed few histiocytic cells, increasing the suspicion of juvenile xanthogranuloma. Because the eye was blind, hypotonous, and irritated, and because the possibility of intraocular malignancy had still not been ruled out, the patient’s parents favored an enucleation.
Pathological Examination The eye was fixed in 4% formaldehyde solution and processed for pathological examination. Gross examination revealed a globe measuring 21 18 18 mm. There was a yellowish-brown iris mass, and the iris was markedly thickened. There was organized material underneath the detached retina (Fig. 3). Microscopic examination showed multiple foci of histiocytes distributed on the anterior iris surface (Figs. 4 and 5). Some of these cells were seen infiltrating the iris stroma and the ciliary epithelium. Admixed with the histiocytes were a few eosinophils, lymphocytes, and plasma cells. The trabecular meshwork also was infiltrated by histiocytes. Occasional Touton and other giant cells could be detected (Fig. 5). There was an organized, cellular collection around the ciliary body (Fig. 4). The retina was detached and disorganized, with areas of gliosis and occasional intraretinal micro-abscesses containing neu-
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Fig. 1. Clinical photograph showing left esotropia and marked heterochromia. The left eye is smaller, as indicated by a narrowed interpalpebral fissure.
trophils, eosinophils, and histiocytes. The detached retina showed epiretinal membrane with traction (Fig. 6). The subretinal space was infiltrated with foamy histiocytes and multinculeated giant cells, similar to those found on the iris (Fig. 7). Oil-red-O stain revealed multiple lipid-positive cells on the iris and the trabecular meshwork, within the epiretinal membrane extending along the internal limiting membrane, and under the retina (Figs. 5 and 7).
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Fig. 2. Prominent episcleral vessels are evident on the temporal side of the globe. The iris shows an inferior yellowish mass and flocculent debris on its surface, as evident on the pupillary margin. Three raised, cyst-like structures are seen in the peripheral iris at 9–11 o’clock.
with diffuse, cytoplasmic staining (Fig. 8). All cells were negative for CD1a, a Langerhans cell marker. TRANSMISSION ELECTRON MICROSCOPY (TEM) STUDIES
Paraffin-embedded sections were subjected to standard immunohistochemical protocols, using biotin-streptavidin-peroxidase detection (DAKO Corporation, Carpinteria, CA). Immunohistochemically, the histiocytes were S-100 negative, and were strongly positive for CD-68 (a macrophage marker),
The tissue was fixed in Karnovsky’s fixative (2% paraformaldehyde, 2.5% glutaraldehyde in 0.1 M cacodylate buffer at pH 7.4) and processed for embedding in epoxy resin. Thin sections (70–80 nm) were examined with transmission electron microscopy (TEM). Several electron dense intracytoplasmic granules were seen in the histiocytes. These round-to-oval membrane-bound granules, measuring approximately 100 nm in diameter, were diffusely scattered in the histiocyte cytoplasm. The granules had two
Fig. 3. A gross photograph of the sectioned enucleation specimen. The lesion on the inferior iris is indicated by an orange arrow. The eye is aphakic. The ciliary body area is occupied by a thick membrane that causes tractional retinal detachment. Note retinal thickening and subretinal material (green arrow).
Fig. 4. Histologic section through the peripheral iris shows thickening of the iris, with collections of histiocytes, lymphocytes, and plasma cells on the iris surface. Similar cells, as well as membranes, are seen between the ciliary processes (hematoxylin and eosin).
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Fig. 5. A higher magnification shows a mound of histiocytes on the iris surface. Notice a Touton giant cell (arrow [hematoxylin and eosin]). Inset shows an oilred-O-positive cell in the same location.
Fig. 6. The retina reveals a thick epiretinal membrane (between arrows), composed of cells similar to those seen in the anterior segment (hematoxylin and eosin).
Fig. 7. A photomicrograph of the subretinal space, showing infiltration of foamy histiocytes (hematoxylin and eosin). Inset: Oil-red-O staining, showing strong lipid-positivity in the subretinal histiocytes.
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Fig. 9. A transmission electron microscope photomicrograph showing a histiocyte with a kidney-shaped nucleus and several intermediate sized, electron-dense granules (arrows). Birbeck granules are absent.
Fig. 8. Immunostaining with CD-68 shows strong positivity of the cells covering the iris, indicating their macrophage origin. Positive cells appear brown (biotin-streptavidin-peroxidase detection).
electron-dense membranes, seperated by a slight gap. Birbeck granules were absent (Fig. 9).
Discussion Differentiating chronic pediatric uveitis from more esoteric conditions that mimic it is often difficult. The case reported here initially presented with severe chronic “uveitis” and band keratopathy in a female baby with a quiet eye. The presentation led to a presumptive diagnosis of juvenile rheumatoid arthritis. When it later became evident that corticosteroid therapy was ineffective, and when mass lesions appeared on the iris, alternative diagnoses were entertained. In retrospect, clinical clues such as the occurrence of hyphema could have raised the suspicion of JXG earlier. However, the postoperative timing may have implied a surgical complication, rather than a truly spontaneous hyphema. The lack of skin lesions also contributed to the delay in diagnosis. When a masquerade syndrome was suspected, the diagnosis of JXG could not be made with cer-
tainty on clinical or cytological grounds alone. The diagnosis was suggested by cytologic examination of a needle aspiration biopsy. However, because of the massive infiltration of the iris and the refractory nature of the lesion, we could not exclude with certainty other potentially malignant diseases, in particular medulloepithelioma. JXG is a benign histiocytic/inflammatory lesion that primarily affects the skin and the eyes, although visceral involvement may also occur. It usually regresses spontaneously within 3 to 6 years.5 The characteristic raised, reddish-yellowish skin lesions appear in infancy or early childhood. The incidence of ocular involvement in a patient with cutaneous JXG was estimated to be only 0.3% to 0.5%.4 Of reported patients with ocular JXG, 41% have had multiple cutaneous lesions.4 However, the disease may present in the eye only, without the characteristic skin lesions. Skin lesions may follow the ocular findings, with a delay of as much as 8 to 10 months.4 The lesions are typically reddish-yellow papules with a predilection for the facial skin. Our patient did not present skin lesions, and her disease seems to have been limited to the eye. In Zimmerman’s series of 53 patients with ocular JXG, 85% presented before 1 year of age.23 Similarly, in the present case, the onset of disease was at age 1 year. However, JXG may rarely be seen in adults.18
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Ocular JXG lesions typically involve the iris, where they appear as yellowish nodules. Iris involvement may also present as diffuse thickening with a muddy color. In cases of diffuse involvement of the iris, heterochromia may be seen (Fig. 1).23 The iris lesions are vascular, tending to bleed and to cause spontaneous hyphema; the hyphema, in turn, may be complicated by secondary glaucoma and corneal opacification. Rarely, JXG involves the choroid, ciliary body, retina, or optic nerve.6,10,22 Epibulbar lesions can be found at the corneoscleral limbus, conjunctiva, episclera, or orbit.23 The skin of the eyelids may be involved, in which case the globe is usually spared. The lesions typically show histologic evidence of large histiocytes with foamy cytoplasm and Toutontype giant cells. These cells contain fat, which can be demonstrated by oil-red-O staining. The lipid component in a case of JXG reported by DeBarge et al was shown to contain apolipoprotein A, the major apolipoprotein of high density lipoprotein.6 There is a large group of benign and malignant histiocytic disorders with a complex pathological classification. The term M-PIRE (mononuclear phagocyte and immuno-regulatory effector cells) system has been suggested as an encompassing designation for histiocytes.8 The Writing Group of the Histiocyte Society1 suggested the following classification: Class I, Langerhans cell histiocytosis (LCH); class II, nonLangerhans cell histiocytosis (non-LCH); and class III, malignant histiocytosis. The common denominator of LCH is a distinct cell with a typical kidneyshaped nucleus. It is immunoreactive with CD1a and S 100 protein. Birbeck granules can be seen by electron microscopy. In contrast, class II, non-Langerhans cell histiocytosis (non-LCH) syndromes, are characterized by the presence of monocyte/macrophage-derived cells. Therefore, the cells are positive for CD68, an intracytoplasmic, lysosome-associated glycoprotein used as a macrophage marker. They may appear vacuolated, xanthomatized, spindleshaped, oncocytic, or multinucleated. Touton and foreign body giant cells may be present. The former cells are characterized by a wreath of nuclei arranged around a homogenous eosinophilic cytoplasmic center. Histiocytes of iris lesions are less likely to show the foamy cytoplasm seen in skin lesions. Also, fewer Touton giant cells are seen in the iris than in the skin lesions.6,19,23 This was the case with our patient, who demonstrated only a few Touton giant cells (Fig. 5). Each of the above non-LCH morphologic types has characteristic immunohistochemical and ultrastructural features. Therefore, there is no definitive diagnostic marker for non-LCH.15 Juvenile xanthogranuloma is a class II or non-LCH disorder. It typically contains proliferating histiocytes that are
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negative for S100 and MAC 387, and positive for HAM 56, HHF35, KP1, KiM1P, and vimentin.15 Factor XIIIa is also positive. Although CD1a (OKT-6) is generally considered a specific marker for Langerhans cells, a case of JXG with CD1 positivity has been reported.2 Similarly, our case showed CD68 positivity that proved those cells to be histiocytes, while negative S100 and CD-1a staining excluded the possibility of LCH. Beyond morphologic and immunohistochemical examination, electron microscopy has an important role in the differential diagnosis of histiocytic disorders. Ultrastructurally, Langerhans cells are characterized by the presence of distinctive, granular intracytoplasmic inclusions called Birbeck granules or racket bodies. These bodies are absent in non-LCH, which contain variable amounts of nonspecific organelles. These organelles may appear as commashaped, dense, regularly laminated or myeloid bodies, or as pleomorphic cytoplasmic inclusions. Their function is unknown.7,11,14 Variations within these findings are attributable to the predominant cell type. Our case showed the presence of intermediatesized, intracytoplasmic, electron-dense granules, but no Birbeck granules were seen. Ocular disease may present as iris heterochromia, unilateral glaucoma, uveitis, hyphema, or an isolated iris tumor.12,19,23 Rarely, the orbit and optic nerve may be involved.6,22 Retinal involvement, such as was seen in our case, is extremely rare. We were able to find only three documented cases in the MEDLINEcited literature where such involvement was suspected.6,10,22 DeBarge et al described a 12-year-old patient with no skin lesions, painful proptosis, and a solitary, orange subretinal mass that resolved after treatment with oral and periocular corticosteroids. The lesion recurred over a 2-year period, resolving with each course of corticosteroids. The patient had biopsy-proven JXG iris lesions. However, the subretinal lesion was not biopsied. Godde-Jolly et al10 similarly described an 8-month-old infant with iris, ciliary body, and subretinal involvement by JXG, again without histologic evidence of the subretinal component. We are aware of only one report of a posterior segment JXG proven by histologic analysis: Wertz et al described a 20-month-old child with involvement of the optic nerve and massive contiguous spread to the peripapillary choroid and retina.22 Our case was interesting in that there was extensive involvement of the iris, ciliary body, angle, retina, and subretinal space. Immunohistochemical analysis confirmed the macrophage origin of the cells, which stained positive for CD68. Negative S-100 staining helped differentiate the histiocytic cells from Langerhans cells. Focal weak positivity for CD1a was seen in a few iris cells. These probably represented dendritic cells,
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which are normally present in the iris and the anterior chamber angle.16 Ocular JXG can be diagnosed by a skin biopsy if the typical skin lesions are present. Otherwise, an anterior chamber paracentesis may provide the diagnosis by revealing foamy histiocytes.20 Iris biopsy may be required and may be diagnostic in cases where paracenthesis is equivocal or uninformative.6 We did not consider an iris biopsy in our case, as the eye was blind, painful, and hypotonous. We could not rule out a malignant tumor, such as medulloepithelioma, on clinical grounds. Under these circumstances, enucleation provided symptomatic relief and complete diagnostic information, while obviating the risks of inducing sympathetic ophthalmia or spread of a possible malignancy. Simple iris JXG lesions may regress with topical, periocular, or systemic steroid therapy.9,21 However, some cases are refractive to corticosteroids and may require therapy with local irradiation or immunosuppressive drugs.3,13,17,18 Low-dose weekly methotrexate was used to treat a patient with a JXG iris lesion that was refractory to regional steroid injections.18 Resolution of the lesion resulted in diffuse iris atrophy without residual tumor. In our case, the disease was refractory to both topical and regional steroid therapy. At the time of diagnosis, it was clear that the eye had no favorable visual or anatomic prognosis; therefore, further medical therapy was not indicated. This case demonstrates the need for accurate etiologic diagnosis in atypical or refractory pediatric uveitis cases. The possibility of a masquerade syndrome has to be borne in mind for any child with atypical uveitis. In such cases, evaluation by a specialist in uveitis or ocular oncology is recommended. If retinoblastoma or medulloepithelioma can be ruled out on clinical grounds, obtaining intraocular material for diagnosis should be considered. Early tissue diagnosis is critical in JXG since untreated intraocular lesions can result in blindness. Involvement of the retina is a rare complication of JXG that may lead to chronic retinal detachment and appears to indicate a poor ocular prognosis.
Method of Literature Search We searched Medline, using keywords such as histiocytosis, juvenile xanthogranuloma, intraocular, histopathology, immunohistochemistry, electron microscopy and various boolean combinations of the above, for the years 1966–2000. We searched both English and foreign languages. Some references, including those from pre-Medline years, were retrieved from citations in the reference lists of Medline articles. There was 1 German reference (Muller and Junemann),
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and its English abstract was used for the necessary information. A French article by Godde-Jolly et al was translated.
References 1. ___: Histiocytosis syndromes in children. Writing Group of the Histiocyte Society. Lancet 1:208–9, 1987 2. Andersen WK, Knowles DM, Silvers DN: CD1 (OKT6)-positive juvenile xanthogranuloma. OKT6 is not specific for Langerhans cell histiocytosis (histiocytosis X). J Am Acad Dermatol 26:850–4, 1992 3. Cadera W, Silver MM, Burt L: Juvenile xanthogranuloma. Can J Ophthalmol 18:169–74, 1983 4. Chang MW, Frieden IJ, Good W: The risk intraocular juvenile xanthogranuloma: survey of current practices and assessment of risk. J Am Acad Dermatol 34:445–9, 1996 5. Cohen BA, Hood A: Xanthogranuloma: report on clinical and histologic findings in 64 patients. Pediatr Dermatol 6: 262–6, 1989 6. DeBarge LR, Chan CC, Greenberg SC, et al: Chorioretinal, iris, and ciliary body infiltration by juvenile xanthogranuloma masquerading as uveitis. Surv Ophthalmol 39:65–71, 1994 7. Enzinger FM, Weiss SW: Juvenile xanthogranuloma, in Enzinger FM, Weiss SW (eds): Soft Tissue Tumors. St Louis, Mosby, 1983, pp 135–40 8. Foucar K, Foucar E: The mononuclear phagocyte and immunoregulatory effector (M-PIRE) system: evolving concepts. Semin Diagn Pathol 7:4–18, 1990 9. Gass JDM: Management of juvenile xanthogranuloma of the iris. Arch Ophthalmol 71:344–7, 1964 10. Godde-Jolly D, Rozenbaum J, Chazalon T: [2 cases of juvenile xanthogranuloma. Diagnostic and therapeutic problems posed by the iridic localization of the disease]. Bull Soc Ophtalmol Fr 85:889–93, 1985 11. Gonzalez-Crussi F, Campbell RJ: Juvenile xanthogranuloma: ultrastructural study. Arch Pathol 89:65–72, 1970 12. Harley RD, Romayananda N, Chan GH: Juvenile xanthogranuloma. J Pediatr Ophthalmol Strabismus 19:33–9, 1982 13. Karcioglu ZA, Mullaney PB: Diagnosis and management of iris juvenile xanthogranuloma. J Pediatr Ophthalmol Strabismus 34:44–51, 1997 14. Lever WF, Schaumberg-Lever G: Histopathology of the skin. Philadelphia, JB Lippincott, 1991, pp 442–3 15. Marrogi AJ, Dehner LP, Coffin CM, Wick MR: Benign cutaneous histiocytic tumors in childhood and adolescence, excluding Langerhans cell proliferations. A clinicopathologic and immunohistochemical analysis. Am J Dermatopathol 14: 8–18, 1992 16. McMenamin PG, Crewe J, Morrison S, Holt PG: Immunomorphologic studies of macrophages and MHC class II-positive dendritic cells in the iris and ciliary body of the rat, mouse, and human eye. Invest Ophthalmol Vis Sci 35:3234– 50, 1994 17. Muller RP, Junemann G: [Results of radiotherapy in case of juvenile xanthogranuloma of the iris]. Strahlentherapie 159: 277–82, 1983 18. Parmley VC, George DP, Fannin LA: Juvenile xanthogranuloma of the iris in an adult. Arch Ophthalmol 116:377–9, 1998 19. Sanders TE: Intraocular juvenile xanthogranuloma (nevoxanthogranuloma): a survey of 20 cases. Trans Am Ophthalmol Soc 58:59–74, 1960 20. Schwartz LW, Rodrigues MM, Hallett JW: Juvenile xanthogranuloma diagnosed by paracentesis. Am J Ophthalmol 77:243–6, 1974 21. Treacy KW, Letson RD, Summers CG: Subconjunctival steroid in the management of uveal juvenile xanthogranuloma: a case report. J Pediatr Ophthalmol Strabismus 27:126–8, 1990 22. Wertz FD, Zimmerman LE, McKeown CA, et al: Juvenile xan-
JUVENILE XANTHOGRANULOMA thogranuloma of the optic nerve, disc, retina, and choroid. Ophthalmology 89:1331–5, 1982 23. Zimmerman LE: Ocular lesions of juvenile xanthogranuloma. Nevoxanthoendothelioma. Trans Am Acad Ophthalmol Otolaryngol 69:412–442, 1965 Supported in part by National Institutes of Health core grant EY03040 and by an unrestricted grant from Research to Prevent Blindness, New York, New York.
171 Dr. Zamir is the recipient of a fellowship grant from the American Physicians Fellowship for Medicine in Israel, Boston, MA. The authors have no commercial or proprietary interest in any product or idea discussed in this article. Presented in part at the American Uveitis Society Meeting, Dallas, Texas, October 2000. Reprint address: Narsing A. Rao, MD, Doheny Eye Institute, University of Southern California, Keck School of Medicine, 1450 San Pablo Street, DVRC 211, Los Angeles, CA 90033. E-mail: [email protected]