Short Reports Successful treatment of juvenile xanthogranuloma using bevacizumab Noy Ashkenazy, MS,a Christopher R. Henry, MD,a Ashkan M. Abbey, MD,b Craig A. McKeown, MD,a Audina M. Berrocal, MD,a and Timothy G. Murray, MD, MBAc Juvenile xanthogranuloma (JXG) is an uncommon non-Langerhans cell histiocytic disorder that occurs predominantly in infants. Traditional treatment of ocular JXG involves the administration of topical or local corticosteroids. We treated 2 children with JXG refractory to local corticosteroid therapy with off-label intraocular bevacizumab. To our knowledge, this is the first report of successful use of bevacizumab for ocular JXG.
Case 1
A
4-year-old boy presented with complaints of pain and decreased vision in his right eye. On examination, visual acuity was 20/30 in the right eye and 20/20 in the left eye. Pupils were equal, round, and reactive to light. Extraocular motility was full; there was no evidence of strabismus or nystagmus. Intraocular pressure (IOP) was 17 mm Hg in the right eye and 14 mm Hg in the left eye. Anterior segment examination revealed a 1 mm boat-shaped hyphema in the right eye. The patient was initially managed with topical atropine 1% eyedrops twice daily in the right eye, and the hyphema improved. One week later, the patient returned with visual acuity decreased to 20/200 and pain in his right eye. Microcystic corneal edema and 3 1 cells were noted in the anterior chamber. An irregular elevation of the iris was identified superotemporally, and gonioscopy revealed the presence of a yellow-white mass on the surface of the iris (Figure 1A). Anterior segment optical coherence tomography revealed a hyperreflective, heterogenous mass on the surface of the peripheral iris and abutting the trabecular meshwork (Figure 1B). Topical prednisolone acetate 1% eyedrops 4 times daily was added. During serial examinations under anesthesia, he was noted to have Author affiliations: aBascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida; bAssociated Retinal Consultants, William Beaumont Hospital, Royal Oak, Michigan; cMurray Ocular Oncology and Retina, Miami Submitted November 1, 2013. Revision accepted January 12, 2014. Correspondence: Christopher R. Henry, MD, Bascom Palmer Eye Institute, 900 N.W. 17th Street, Miami, Florida 33136 (email: [email protected]). J AAPOS 2014;-:1-3. Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.01.007
Journal of AAPOS
resolution of anterior chamber cellular reaction and stabilization of the iris lesion; visual acuity improved to 20/20 in the right eye. A taper of prednisolone acetate and atropine eyedrops was attempted. One month after discontinuation of topical steroids, the patient again presented with decreased visual acuity (20/80) in the right eye. A recurrent, spontaneous hyphema was noted. Growth of the hypopigmented iris mass with intrinsic vascularity and overlying focal hemorrhage was noted (Figure 1C). Repeat examination under anesthesia was performed, and a fine-needle aspiration biopsy of the iris lesion was obtained using a 27-gauge needle on a syringe. Intravitreal bevacizumab (1.25 mg/0.05 mL) was injected via the pars plana using a 30-gauge, half-inch needle. Prednisolone acetate eyedrops were resumed. Fine-needle aspiration specimens revealed granulomatous inflammation comprising a mixture of histiocytes and lymphocytes consistent with a diagnosis of JXG. Over the ensuing months, prednisolone acetate eyedrops were tapered. Visual acuity at 18 months’ follow-up was 20/20 in the right eye and IOP was 15 mm Hg; there was complete involution of the lesion, without recurrence of hyphema or iritis (Figure 1D).
Case 2 A 6-month-old girl with a history of multifocal cutaneous lesions on her forehead and scalp was referred to our institute with a history of recurrent subconjunctival hemorrhages in the right eye. Visual acuity was 9.8 cycles/cm at 55 cm in each eye. Cycloplegic refraction was 10.75 1 1.00 080 in the right eye and 11.50 1 0.50 115 in the left eye. Pupils were equal, round, and reactive to light, extraocular motility was full, and there was no evidence of strabismus or nystagmus. The patient had a 4 mm yellow-orange, elevated, inferotemporal episcleral lesion that was concerning for JXG (Figure 2A). On gonioscopy, during examination under anesthesia, the lesion was noted to involve the posterior peripheral aspect of the cornea, angle, and iris (Figure 2B). B-scan ultrasonography revealed abnormal thickening of the iris and ciliary body complex. The patient underwent initial treatment with a sub-Tenon’s injection of triamcinolone acetonide (40 mg/1 ml) and was started on topical prednisolone acetate 1% eyedrops 4 times daily in the right eye. Examination under anesthesia was repeated 3 weeks later and revealed enlargement of the lesion. A sub-Tenon’s injection of triamcinolone acetonide was repeated. She was observed for an additional month, with no noted improvement of the lesion. Treatment with intracameral bevacizumab (1.25 mg/0.05 mL), using a 30-gauge needle, was instituted. The patient was started on topical dorzolomide 2% with timolol 0.5% eyedrops twice daily in the right eye due to an elevated IOP of 22 mm Hg. Topical steroid eyedrops were tapered. Three months following bevacizumab treatment, flattening and reduced vascularity of the epibulbar component of the JXG lesion was observed (Figure 2C). Gonioscopy revealed significant involution
1
2
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FIG 1. Anterior segment optical coherence tomography and gonioscopic images of case 1. A, One week after initial presentation, a yellow-white mass with intrinsic vascularity on the iris surface. B, A hyperreflective, heterogenous mass on the surface of the peripheral iris and abutting the trabecular meshwork. C, Spontaneous hyphema and focal hemorrhage over the JXG lesion following attempted taper of topical steroid 3 months after initial presentation. D, Complete involution of the iris lesion 5 months after intravitreal bevaciumab.
and reduced vascularity of the intraocular JXG component (Figure 2D). There were no recurrent hemorrhages during 36-months of follow-up. Dermatopathology specimens from an outside dermatologist confirmed the diagnosis of systemic JXG. Best-corrected visual acuity at final follow-up was 20/30 in the right eye (Allen picture eye chart). Repeat cycloplegic refraction was 11.25 sphere in the right eye, demonstrating reduced astigmatism following therapy. IOP improved to 13 mm Hg in the right eye, with no evidence of optic nerve cupping and without requiring glaucoma eyedrops.
Discussion Ocular lesions are reported as the most frequent noncutaneous finding in JXG but are seen in only 0.4% of patients.1 While JXG uncommonly occurs as isolated ocular lesions, absence of skin involvement does not exclude a diagnosis of JXG. Cutaneous JXG typically follows a benign self-limited course, but ocular lesions are less frequently transitory and can lead to significant adverse sequelae. Such complications include spontaneous hyphema, iris heterochromia, uveitis, vitreous hemorrhage, glaucoma, cataract, and blindness.1-10 Iris lesions are notoriously difficult to treat, and recurrent spontaneous hyphema is a classically recognized manifestation.2 Unlike cutaneous JXG, limbal and uveal JXG lesions often do not resolve without treatment.6 There is presently no standard of care for the ophthalmic manifestations of JXG. Surgical resection of local, noninfiltrating uveal lesions, by iridectomy or iridocyclectomy, has
Volume - Number - / - 2014
FIG 2. Anterior segment photographs and gonioscopic images of case 2. A, At time of initial examination under anesthesia, a 4 mm, yelloworange, elevated inferotemporal epibulbar component of the JXG lesion. B, The JXG lesion involving the posterior peripheral aspect of the cornea, angle, and iris; intrinsic vascularity of the lesion is evident. C, Flattening and reduced vascularity of the epibulbar component of the JXG lesion 3 months after treatment. D, Partial involution of intraocular component of the JXG lesion and reduction in the intrinsic vascularity of the lesion.
been reported.2 However, nonsurgical approaches are preferred because they pose less risk of intraocular bleeding. Initial medical management often consists of topical or local corticosteroid therapy, which can be successful.7 Localized radiotherapy has been associated with a risk of cataract formation.8 Parmley and colleagues9 described an adult patient who responded well to low-dose weekly methotrexate after failed management with topical corticosteroids, subconjunctival corticosteroids, systemic corticosteroids, and 3 sessions of radiotheraphy. Pollono and colleagues10 reported the case of a 2-month-old boy with bilateral ocular and skin involvement who was managed with systemic vinblastine following failed treatment with corticosteroids. To our knowledge, this is the first report of off-label intraocular bevacizumab for ocular JXG lesions. We hypothesize that bevacizumab modulates the intrinsic vascularity of JXG lesions via its anti-VEGF mechanism, contributing to regression. Shields and colleagues11 have reported use of bevacizumab in a 6-year-old boy with systemic and intraocular Langerhans cell histiocytosis. For the management of iris neovascularization, anterior uveitis, and an iridociliochoroidal mass, the patient was treated with an intracameral injection of 1.25 mg/0.05 mL bevacizumab in addition to low-dose plaque radiotherapy of 35 Gy over 4 days. Follow-up at 10 months revealed a regressed, flat scar with no evidence of radiation-induced retinopathy, secondary glaucoma, or disease recurrence. In theory, intraocular bevacizumab carries a lower risk of cataract formation and secondary glaucoma than local corticosteroid therapy or radiation. Additionally, it spares
Journal of AAPOS
Volume - Number - / - 2014 children from potentially adverse systemic effects of methotrexate or other chemotherapeutic agents.
Literature Search A PubMed search was performed in November 2013 using the following keywords: juvenile xanthogranuloma AND (bevacizumab OR ranibizumab OR aflibercept OR pegaptanib OR anti-VEGF). References 1. Chang MW, Frieden IJ, Good W. The risk of intraocular juvenile xanthogranuloma: survey of current practices and assessment of risk. J Am Acad Dermatol 1996;34:445-9. 2. Zimmerman LE. Ocular lesions of juvenile xanthogranuloma, Nevoxanthoendothelioma. Trans Am Acad Ophthalmol Otolaryngol 1965; 69:412-42. 3. Zamir E, Wang RC, Krishnakumar S, Leverant AA, Dugel PU, Rao NA. Juvenile xanthogranuloma masquerading as pediatric chronic uveitis: a clinicopathologic study. Surv Ophthalmol 2001; 46:164-71.
Journal of AAPOS
Ashkenazy et al
3
4. Wertz FD, Zimmerman LE, McKeown CA, Croxatto JO, Whitmore PV, LaPaina FG. Juvenile xanthogranuloma of the optic nerve, disc, retina, and choroid. Ophthalmology 1982;89:1331-5. 5. Vendal Z, Walton D, Chen T. Glaucoma in juvenile xathogranuloma. Semin Ophthalmol 2006;21:191-4. 6. Chaudhry IA, Al-Jishi Z, Shamsi FA, Riley F. Juvenile xanthogranuloma of the corneoscleral limbus: case report and review of the literature. Surv Opthalmol 2004;49:608-14. 7. Cadera W, Silver MM, Burt L. Juvenile xanthogranuloma. J Can Ophthalmol 1983;18:169-74. 8. MacLeod PM. Case report: juvenile xanthogranuloma of the iris managed with superficial radiotherapy. Clin Radiol 1986;37:295-6. 9. Parmley VC, George DP, Fannin LA. Juvenile xanthogranuloma of the iris in an adult. Arch Ophthalmol 1998;116:377-9. 10. Pollono D, Galan M, Curuchet A, Drut R, Pollono A, Rodriguez J. Juvenile xanthogranuloma with bilateral ocular involvement: complete response after treatment with vinblastine: case report. Eur J Ophthalmol 2009;19:1069-72. 11. Shields CL, Hogarty MD, Kligman BE, Christian C, Ehya H, Shields JA. Langerhans cell histiocytosis of the uvea with neovascular glaucoma: diagnosis by fine-needle aspiration biopsy and management with intraocular bevacizumab and brachytherapy. J AAPOS 2010;14:534-7.
Case 1
A
4-year-old boy presented with complaints of pain and decreased vision in his right eye. On examination, visual acuity was 20/30 in the right eye and 20/20 in the left eye. Pupils were equal, round, and reactive to light. Extraocular motility was full; there was no evidence of strabismus or nystagmus. Intraocular pressure (IOP) was 17 mm Hg in the right eye and 14 mm Hg in the left eye. Anterior segment examination revealed a 1 mm boat-shaped hyphema in the right eye. The patient was initially managed with topical atropine 1% eyedrops twice daily in the right eye, and the hyphema improved. One week later, the patient returned with visual acuity decreased to 20/200 and pain in his right eye. Microcystic corneal edema and 3 1 cells were noted in the anterior chamber. An irregular elevation of the iris was identified superotemporally, and gonioscopy revealed the presence of a yellow-white mass on the surface of the iris (Figure 1A). Anterior segment optical coherence tomography revealed a hyperreflective, heterogenous mass on the surface of the peripheral iris and abutting the trabecular meshwork (Figure 1B). Topical prednisolone acetate 1% eyedrops 4 times daily was added. During serial examinations under anesthesia, he was noted to have Author affiliations: aBascom Palmer Eye Institute, Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida; bAssociated Retinal Consultants, William Beaumont Hospital, Royal Oak, Michigan; cMurray Ocular Oncology and Retina, Miami Submitted November 1, 2013. Revision accepted January 12, 2014. Correspondence: Christopher R. Henry, MD, Bascom Palmer Eye Institute, 900 N.W. 17th Street, Miami, Florida 33136 (email: [email protected]). J AAPOS 2014;-:1-3. Copyright Ó 2014 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2014.01.007
Journal of AAPOS
resolution of anterior chamber cellular reaction and stabilization of the iris lesion; visual acuity improved to 20/20 in the right eye. A taper of prednisolone acetate and atropine eyedrops was attempted. One month after discontinuation of topical steroids, the patient again presented with decreased visual acuity (20/80) in the right eye. A recurrent, spontaneous hyphema was noted. Growth of the hypopigmented iris mass with intrinsic vascularity and overlying focal hemorrhage was noted (Figure 1C). Repeat examination under anesthesia was performed, and a fine-needle aspiration biopsy of the iris lesion was obtained using a 27-gauge needle on a syringe. Intravitreal bevacizumab (1.25 mg/0.05 mL) was injected via the pars plana using a 30-gauge, half-inch needle. Prednisolone acetate eyedrops were resumed. Fine-needle aspiration specimens revealed granulomatous inflammation comprising a mixture of histiocytes and lymphocytes consistent with a diagnosis of JXG. Over the ensuing months, prednisolone acetate eyedrops were tapered. Visual acuity at 18 months’ follow-up was 20/20 in the right eye and IOP was 15 mm Hg; there was complete involution of the lesion, without recurrence of hyphema or iritis (Figure 1D).
Case 2 A 6-month-old girl with a history of multifocal cutaneous lesions on her forehead and scalp was referred to our institute with a history of recurrent subconjunctival hemorrhages in the right eye. Visual acuity was 9.8 cycles/cm at 55 cm in each eye. Cycloplegic refraction was 10.75 1 1.00 080 in the right eye and 11.50 1 0.50 115 in the left eye. Pupils were equal, round, and reactive to light, extraocular motility was full, and there was no evidence of strabismus or nystagmus. The patient had a 4 mm yellow-orange, elevated, inferotemporal episcleral lesion that was concerning for JXG (Figure 2A). On gonioscopy, during examination under anesthesia, the lesion was noted to involve the posterior peripheral aspect of the cornea, angle, and iris (Figure 2B). B-scan ultrasonography revealed abnormal thickening of the iris and ciliary body complex. The patient underwent initial treatment with a sub-Tenon’s injection of triamcinolone acetonide (40 mg/1 ml) and was started on topical prednisolone acetate 1% eyedrops 4 times daily in the right eye. Examination under anesthesia was repeated 3 weeks later and revealed enlargement of the lesion. A sub-Tenon’s injection of triamcinolone acetonide was repeated. She was observed for an additional month, with no noted improvement of the lesion. Treatment with intracameral bevacizumab (1.25 mg/0.05 mL), using a 30-gauge needle, was instituted. The patient was started on topical dorzolomide 2% with timolol 0.5% eyedrops twice daily in the right eye due to an elevated IOP of 22 mm Hg. Topical steroid eyedrops were tapered. Three months following bevacizumab treatment, flattening and reduced vascularity of the epibulbar component of the JXG lesion was observed (Figure 2C). Gonioscopy revealed significant involution
1
2
Ashkenazy et al
FIG 1. Anterior segment optical coherence tomography and gonioscopic images of case 1. A, One week after initial presentation, a yellow-white mass with intrinsic vascularity on the iris surface. B, A hyperreflective, heterogenous mass on the surface of the peripheral iris and abutting the trabecular meshwork. C, Spontaneous hyphema and focal hemorrhage over the JXG lesion following attempted taper of topical steroid 3 months after initial presentation. D, Complete involution of the iris lesion 5 months after intravitreal bevaciumab.
and reduced vascularity of the intraocular JXG component (Figure 2D). There were no recurrent hemorrhages during 36-months of follow-up. Dermatopathology specimens from an outside dermatologist confirmed the diagnosis of systemic JXG. Best-corrected visual acuity at final follow-up was 20/30 in the right eye (Allen picture eye chart). Repeat cycloplegic refraction was 11.25 sphere in the right eye, demonstrating reduced astigmatism following therapy. IOP improved to 13 mm Hg in the right eye, with no evidence of optic nerve cupping and without requiring glaucoma eyedrops.
Discussion Ocular lesions are reported as the most frequent noncutaneous finding in JXG but are seen in only 0.4% of patients.1 While JXG uncommonly occurs as isolated ocular lesions, absence of skin involvement does not exclude a diagnosis of JXG. Cutaneous JXG typically follows a benign self-limited course, but ocular lesions are less frequently transitory and can lead to significant adverse sequelae. Such complications include spontaneous hyphema, iris heterochromia, uveitis, vitreous hemorrhage, glaucoma, cataract, and blindness.1-10 Iris lesions are notoriously difficult to treat, and recurrent spontaneous hyphema is a classically recognized manifestation.2 Unlike cutaneous JXG, limbal and uveal JXG lesions often do not resolve without treatment.6 There is presently no standard of care for the ophthalmic manifestations of JXG. Surgical resection of local, noninfiltrating uveal lesions, by iridectomy or iridocyclectomy, has
Volume - Number - / - 2014
FIG 2. Anterior segment photographs and gonioscopic images of case 2. A, At time of initial examination under anesthesia, a 4 mm, yelloworange, elevated inferotemporal epibulbar component of the JXG lesion. B, The JXG lesion involving the posterior peripheral aspect of the cornea, angle, and iris; intrinsic vascularity of the lesion is evident. C, Flattening and reduced vascularity of the epibulbar component of the JXG lesion 3 months after treatment. D, Partial involution of intraocular component of the JXG lesion and reduction in the intrinsic vascularity of the lesion.
been reported.2 However, nonsurgical approaches are preferred because they pose less risk of intraocular bleeding. Initial medical management often consists of topical or local corticosteroid therapy, which can be successful.7 Localized radiotherapy has been associated with a risk of cataract formation.8 Parmley and colleagues9 described an adult patient who responded well to low-dose weekly methotrexate after failed management with topical corticosteroids, subconjunctival corticosteroids, systemic corticosteroids, and 3 sessions of radiotheraphy. Pollono and colleagues10 reported the case of a 2-month-old boy with bilateral ocular and skin involvement who was managed with systemic vinblastine following failed treatment with corticosteroids. To our knowledge, this is the first report of off-label intraocular bevacizumab for ocular JXG lesions. We hypothesize that bevacizumab modulates the intrinsic vascularity of JXG lesions via its anti-VEGF mechanism, contributing to regression. Shields and colleagues11 have reported use of bevacizumab in a 6-year-old boy with systemic and intraocular Langerhans cell histiocytosis. For the management of iris neovascularization, anterior uveitis, and an iridociliochoroidal mass, the patient was treated with an intracameral injection of 1.25 mg/0.05 mL bevacizumab in addition to low-dose plaque radiotherapy of 35 Gy over 4 days. Follow-up at 10 months revealed a regressed, flat scar with no evidence of radiation-induced retinopathy, secondary glaucoma, or disease recurrence. In theory, intraocular bevacizumab carries a lower risk of cataract formation and secondary glaucoma than local corticosteroid therapy or radiation. Additionally, it spares
Journal of AAPOS
Volume - Number - / - 2014 children from potentially adverse systemic effects of methotrexate or other chemotherapeutic agents.
Literature Search A PubMed search was performed in November 2013 using the following keywords: juvenile xanthogranuloma AND (bevacizumab OR ranibizumab OR aflibercept OR pegaptanib OR anti-VEGF). References 1. Chang MW, Frieden IJ, Good W. The risk of intraocular juvenile xanthogranuloma: survey of current practices and assessment of risk. J Am Acad Dermatol 1996;34:445-9. 2. Zimmerman LE. Ocular lesions of juvenile xanthogranuloma, Nevoxanthoendothelioma. Trans Am Acad Ophthalmol Otolaryngol 1965; 69:412-42. 3. Zamir E, Wang RC, Krishnakumar S, Leverant AA, Dugel PU, Rao NA. Juvenile xanthogranuloma masquerading as pediatric chronic uveitis: a clinicopathologic study. Surv Ophthalmol 2001; 46:164-71.
Journal of AAPOS
Ashkenazy et al
3
4. Wertz FD, Zimmerman LE, McKeown CA, Croxatto JO, Whitmore PV, LaPaina FG. Juvenile xanthogranuloma of the optic nerve, disc, retina, and choroid. Ophthalmology 1982;89:1331-5. 5. Vendal Z, Walton D, Chen T. Glaucoma in juvenile xathogranuloma. Semin Ophthalmol 2006;21:191-4. 6. Chaudhry IA, Al-Jishi Z, Shamsi FA, Riley F. Juvenile xanthogranuloma of the corneoscleral limbus: case report and review of the literature. Surv Opthalmol 2004;49:608-14. 7. Cadera W, Silver MM, Burt L. Juvenile xanthogranuloma. J Can Ophthalmol 1983;18:169-74. 8. MacLeod PM. Case report: juvenile xanthogranuloma of the iris managed with superficial radiotherapy. Clin Radiol 1986;37:295-6. 9. Parmley VC, George DP, Fannin LA. Juvenile xanthogranuloma of the iris in an adult. Arch Ophthalmol 1998;116:377-9. 10. Pollono D, Galan M, Curuchet A, Drut R, Pollono A, Rodriguez J. Juvenile xanthogranuloma with bilateral ocular involvement: complete response after treatment with vinblastine: case report. Eur J Ophthalmol 2009;19:1069-72. 11. Shields CL, Hogarty MD, Kligman BE, Christian C, Ehya H, Shields JA. Langerhans cell histiocytosis of the uvea with neovascular glaucoma: diagnosis by fine-needle aspiration biopsy and management with intraocular bevacizumab and brachytherapy. J AAPOS 2010;14:534-7.
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