1040-5488/15/9206-e126/0 VOL. 92, NO. 6, PP. e126Ye133 OPTOMETRY AND VISION SCIENCE Copyright * 2015 American Academy of Optometry
CLINICAL CASE
Ocular Juvenile Xanthogranuloma Liangliang Niu*, Chaoran Zhang*, Fanrong Meng*, Rongrong Cai*, Yingwen Bi*, Yan Wang†, and Jianjiang Xu*
ABSTRACT Purpose. To report the clinical and histopathologic characteristics and prognoses of three ocular juvenile xanthogranuloma (JXG) cases. Case Reports. Three cases were included in this study. The first case involved a 5-year-old girl with an enlarging yellowish mass at the limbus with corneal involvement. Ultrasound biomicroscopy showed a poorly demarcated mass involving the underlying cornea and sclera. The mass was excised in combination with a lamellar keratoplasty procedure. No recurrence was seen at the 2-year follow-up. The second case involved a 2-year-old boy with an enlarging yellowish mass on the conjunctiva, without limbal involvement. The mass was excised with no recurrence noted 1 year later. The third case involved a 7-month-old girl with unilateral eye redness and photophobia combined with multiple orange-red, raised nodular lesions on the skin. Examination under general anesthesia revealed a gray-yellow mass in the inferior and temporal iridocorneal angles. The intraocular pressure and corneal diameter were normal. Examination using ultrasound biomicroscopy showed a high-level echo lump in the inferior and temporal angles. There was no treatment for this case. At the 1-year follow up, the eye symptoms had resolved and the skin lesions were flat. Histopathologic examinations were completed on all three cases. The presence of Touton giant cells in hematoxylin-eosin staining, positive CD68 staining, and negative S-100 and CD1a staining confirmed the diagnosis of JXG. Conclusions. We report three histopathologically confirmed ocular JXG cases involving the corneoscleral limbus, conjunctiva, and iris with angle involvement, respectively. Ultrasound biomicroscopy performed on two cases demonstrated no obvious division between the mass and the surrounding structures. The cases with ocular surface involvement were successfully treated by excision and the case with iris involvement spontaneously regressed without any treatment. Early excision may be the better choice for ocular surface lesions, especially when corneal involvement is a possibility. (Optom Vis Sci 2015;92:e126Ye133) Key Words: juvenile xanthogranuloma, ocular, UBM, Touton cells, CD68, S-100
J
uvenile xanthogranuloma (JXG) is a rare nonYLangerhans cell histiocytosis (LCH) that usually presents in children as nodular skin lesions. It also can affect one or more extracutaneous sites, however, including the central nervous system, the liver/ spleen, the lungs, and the eyes, among other sites. In this article, we report three ocular JXG cases involving the corneoscleral limbus, conjunctiva, and iris, respectively. We report the clinical and histopathologic characteristics and the outcome of our cases, and a review of the literature. Written consent was obtained from all patients.
*MD † MD, PhD Departments of Ophthalmology (LN, CZ, FM, YW, JX) and Pathology (RC, YB), Eye and ENT Hospital of Fudan University, Shanghai, China.
CASE REPORT Case 1 A 5-year-old girl who had had an enlarged mass on her right eye for 3 months was referred to our clinic. She was otherwise healthy and had an unremarkable family history. Slit-lamp examination showed an 8-mm-diameter yellowish mass on the nasal inferior limbus with corneal, conjunctival, and scleral involvement (Fig. 1A). Ultrasound biomicroscopy (UBM) was performed and a mass with moderate internal reflectivity was noted. There was no distinct demarcation between the mass and the underlying cornea and sclera (Fig. 1C, D). Examination of the left eye was normal, as were the intraocular structures of the right eye. Magnetic resonance imaging and chest x-ray revealed no positive findings. Topical corticosteroid eye drops were used for 2 weeks. There was no change in the size of the mass and a secondary increase in the intraocular pressure (IOP) was noted.
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FIGURE 1. The slit-lamp photograph, UBM, histopathologic, and immunohistochemical examinations of case 1. (A) The slit-lamp photograph of case 1. An 8-mm-diameter mass appeared on the ocular surface involving the inferior nasal corneal limbus. (B) Slit-lamp anterior segment photograph showing 2 years after the surgery for case 1. (C, D) UBM of case 1 showed the mass presented as a middle-level echo. There was no obvious demarcation found between the mass and cornea (AC, anterior chamber; SC, sclera; COR, cornea). (E) Hematoxylin-eosin staining of case 1 demonstrated the subepithelial infiltration of histiocytes with pale cytoplasm and vacuoles. Typical multinucleated Touton giant cells were absent (400). (F) Immunohistochemical staining for case 1 showed a positive staining for CD68 (200). Optometry and Vision Science, Vol. 92, No. 6, June 2015
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e128 Ocular Juvenile XanthogranulomaVNiu et al.
The IOP returned to normal after discontinuation of the topical corticosteroid. Under general anesthesia, the lesion was excised combined with lamellar corneal transplantation. The portion of the lesion involving the cornea was unable to be completely excised because of the depth of corneal involvement as well as the soft nature of the lesion. Hematoxylin-eosin staining of the excised specimen demonstrated subepithelial infiltration of histiocytes with pale cytoplasm and vacuoles. No obvious Touton giant cells were found. Immunohistochemical staining was also performed. Positive staining for CD68 and negative staining for protein S-100 and CD1a confirmed the diagnosis of JXG (Fig. 1E, F). No recurrence was noted at the 2-year follow-up (Fig. 1B).
Case 2 A 2-year-old boy presented with a yellow-orange enlarged lesion on the conjunctiva of the right eye, which had been noticed by his parents 5 months previously. The parents denied any history of trauma. The patient’s medical and family histories were noncontributory. Slit-lamp examination showed a yellowish mass close to the inferior nasal limbus without corneal involvement, measuring about 5 by 6 mm (Fig. 2A). The intraocular structures of both eyes were normal. The lesion was fully excised, and the sclera under the mass was found to be intact. Numerous typical Touton giant cells were found with hematoxylin-eosin staining (Fig. 2C). Immunohistochemical staining showed positive staining for CD68 and negative staining for proteins S-100 and CD1a (Fig. 2D, E). No signs of recurrence or complication were evident at either the 1-month (Fig. 2B) or 1-year follow-up visits.
Case 3 The third case involved a 7-month-old girl who developed multiple orange-red, hard, and raised papulonodular skin lesions 4 months previously, accompanied by unilateral eye redness and photophobia. The skin lesions, located mainly on the head, neck, and trunk regions, were about 5 to 15 mm in diameter (Fig. 3A). Magnetic resonance imaging, chest x-ray, and abdominal ultrasound testing revealed no abnormal findings. An examination under general anesthesia was performed. A diffuse gray-yellow mass was found in the inferior periphery of the iris (Fig. 3B). The corneal diameter of both eyes was 10 mm, and the IOP was 12 and 13 mm Hg in the right and left eyes, respectively. Ultrasound biomicroscopy was also performed. A mass with mid- to high internal reflectivity was evident in the iris, extending into the posterior aspects of the inferior and temporal iridocorneal angles (Fig. 3C). The mass had contact with the cornea, although no corneal invasion was evident. A biopsy performed on the skin lesions by a dermatologist confirmed the diagnosis of JXG. No treatment was administered because of the mild nature of the ocular symptoms and normal IOP. Although the patient’s family was unable to travel to Shanghai for the 1-year follow up visit, they reported via telephone that most of the skin lesions had spontaneously regressed and that the ocular symptoms of redness and photophobia had fully resolved themselves.
DISCUSSION Juvenile xanthogranuloma is an uncommon nonYLangerhans cell histiocytic inflammatory disorder that is characterized by the proliferation of macrophages together with multinucleated giant cells (Touton cells).1 The diagnosis of JXG is dependent on histopathologic and immunohistochemical examinations. In JXG, immunohistochemical staining for histiocytic markers Ki-M1P and CD68 is generally positive, whereas staining for CD1a and S-100 (Langerhans cells markers) is negative.2,3 This point is crucial to distinguish JXG from LCH. In LCH, immunohistochemical staining for CD1a and S-100 is consistently positive.4 Janssen and Harms2 classified conventionally stained JXG lesions into four morphologic subtypes. Early JXG was characterized by a large amount of monomorphic histiocytic infiltration without multinuclear giant cells. Classic JXG featured histiocytic infiltration with a mass of fully developed Touton cells. In transitional JXG, Touton giant cells were either absent or only seldom found. Touton cells are usually considered a typical marker of JXG, but in some JXG cases, very few or no Touton cells are apparent. As in our first case, no Touton cells were found and the diagnosis of JXG was dependent on immunohistochemical staining. Juvenile xanthogranuloma occurs mainly in infants younger than 1 year and less commonly in older children and adults.2 The usual presentation of JXG is in infancy with one or more nodular skin lesions, but one or more systemic (extracutaneous) sites may also be affected, including the central nervous system, the liver/ spleen, the lungs, the eyes/orbits, oropharynx, and muscles.5 We performed a Medline search from 1965 to the present. In total, 34 ocular cases were reported, with 23 of the cases being under 2 years (Table 1). Ocular JXG appears to occur more commonly at an isolated site, although the sites were numerous, including the corneoscleral limbus, iris, conjunctiva, cornea, choroid, optic nerve, eyelid, and orbit. The corneoscleral limbus and iris were the sites most often involved in ocular JXG. Of the 34 reported cases of ocular JXG, 15 had corneoscleral limbal involvement, 12 had iris involvement, and only 10 had skin involvement. In our current study, we report two isolated cases of ocular JXG, one with corneoscleral involvement at the limbus, and one with conjunctival involvement. We also report one case with both systemic skin lesions and iris involvement. We performed UBM for two of our cases. We found UBM to be a very helpful tool for understanding the relationship of the JXG mass and the surrounding tissues. In the first case, UBM showed a mass at the limbus without a clearly demarcated border separating it from the underlying cornea and sclera. It was especially difficult to distinguish the mass from the surrounding cornea, which suggested that excision would be difficult. As a result, we were able to plan on performing a lamellar keratoplasty at the time of excision. In another case, UBM clearly demonstrated invasion by the mass of the inferior and nasal iridocorneal angles. This alerted us to check closely for any signs of secondary glaucoma. These findings also demonstrated the ability of ocular JXG lesions to involve surrounding tissues. As mentioned previously, many studies that did not use UBM have found JXG to occur at isolated ocular sites. Based on our findings, as UBM becomes more commonplace in the evaluation of JXG lesions, we believe that future studies will find that the prevalence of JXG
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FIGURE 2. The slit-lamp photograph, histopathologic, and immunohistochemical stainings of case 2. (A) The slit-lamp anterior segment photograph of case 2 showing a yellowish mass close to the inferior nasal limbus without cornea involvement, which was about 5 by 6 mm. (B) The mass of case 2 was completely removed and there was no obvious injection at the 1-month follow-up. (C) Histopathology for case 2 demonstrating large quantities of foamy histiocytes infiltrating in subconjunctival layer, with an abundance of typical Touton giant cells (arrows) (400). (D, E) Immunohistochemical staining of case 2 showed a positive staining for CD68 (histiocytic marker) and a negative staining for CD1a (Langerhans cell marker) (200). Optometry and Vision Science, Vol. 92, No. 6, June 2015
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e130 Ocular Juvenile XanthogranulomaVNiu et al.
FIGURE 3. Juvenile xanthogranuloma with iris, skin involvement, and UBM examination of case 3. (A) Close-up view of case 3 with orange-red nodular lesions in the head. (B) The slit-lamp anterior segment photograph of case 3 showed that the iris texture was unclear; a diffused gray-yellow mass was found on the inferior periphery of the iris and anterior chamber angle, which made contact with the cornea of the right eye. (C) Ultrasound biomicroscopy for case 3 demonstrated middle- to high-echo lump located at the lower and temporal anterior chamber angle, which made contact with the peripheral cornea.
lesions involving multiple sites is higher than previously reported. To our knowledge, this is the first case series of UBM findings in ocular JXG. Juvenile xanthogranuloma should also be distinguished from other limbal lesions in young children, for instance, limbal dermoids, nodular anterior scleritis, and sclerokeratitis. Limbal dermoids exist at birth and grow along with the eyes; fine hairs may protrude from the lesion surface. Limbal dermoids are characterized by keratinized epithelium, hairs, and sebaceous and sudoriferous glands in histopathology.29 In addition, the scleritis usually causes obvious pain and responds well to immunosuppressive treatment. Juvenile xanthogranuloma is a self-limiting disorder in some cases, especially in cases of cutaneous lesions. Unlike the cutaneous
form, systemic JXG has been reported to possibly cause significant complications requiring aggressive medical care.30 There is currently no standard treatment of ocular JXG. Glucocorticoids, immunosuppressive agents, radiation therapy, and surgery have been reported as possible ocular JXG treatments (Table 1). Topical corticosteroids were reported to successfully treat one case of conjunctival JXG. In our case, there was no improvement after 2 weeks of topical steroid treatment, however, and treatment was discontinued because of IOP elevation. Radiation for iris JXG lesions has also been reported,5,28 but complications such as cataract and retinal detachment make this option less desirable. Juvenile xanthogranuloma usually occurs in young children or infants, and treatment should be selected to minimize toxic effects. In our study,
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TABLE 1.
Reported cases of ocular juvenile xanthogranulomatosis Patient no. Age, y 1
43
Sex (M/F)
Ocular involvement
Extraocular involvement
M
Conjunctiva
None
Conjunctivectomy, cryotherapy Sub-Tenon injection of TA and topical prednisolone acetate Excision
2
0.5
F
Iris
Skin
3
2
M
Conjunctiva
None
4
1.2
M
Corneoscleral limbus, iris, choroid
None
5
0.75
M
Corneoscleral limbus
None
6
4
F
Corneoscleral limbus
None
7
1.3
M
Optic nerve
Skin
8
2
F
Eyelid
None
Sub-Tenon injection of triamcinolone, topical and systemic prednisolone, systemic MTX Excision, subconjunctival betamethasone injection, topical prednisolone Excision, subconjunctival betamethasone injection, topical prednisolone Pulse high-dose methylprednisolone with systemic prednisolone Excision
9
2
M
Iris
Skin
Systemic vinblastine
10
18 d
None
11
0.6
M
Eyelid
Skin
12
0.6
F
Corneoscleral limbus
None
Intralesional steroid injections and oral prednisolone Topical betamethasone eye drops Excision
13
7
M
None
Excision and topical fluorometholone
14
0.83
F
Conjunctiva, corneoscleral limbus Eyelid
None
15
1
F
16
1.5
F
None
Excision with intralesional steroid injections Excision with lamellar graft Excision
17
5
M
None
Excision
18
0.67
M
Unknown Eyelid
Corneoscleral limbus Corneoscleral limbus Corneoscleral limbus Multifocal uveal sites
None
Follow-up results
Therapy
Skin, CNS, Topical dexamethasone, kidney, lung, systemic corticotherapy liver, spleen
Reference Lee et al.3
No recurrence at 2-mo follow-up Involution of iris and skin lesions at 1-mo follow-up No recurrence at 20-mo follow-up A new skin lesion developed at 3-y follow-up
Manjandavida et al.6 Olmo et al.7 Longmuir et al.8
No recurrence at 1-y follow-up
De Keyser et al.9
No recurrence at 6-mo follow-up
De Keyser et al.9
Vision improved, skin lesions decreased
Daien et al.10
No recurrence at 4-mo follow-up No recurrence at 1-y follow-up No recurrence at 3.5-mo follow-up
Lim et al.11
Unknown
Liang et al.14
Pollono et al.12 Kuruvilla et al.13
Mocan et al.15 Recurrence at 4-mo follow-up. After intralesional injection of triamcinolone acetonide, no recurrence at 1-y follow-up No recurrence at Mocan et al.15 3-y follow-up No recurrence at 8-mo follow-up
Kaur et al.16
No recurrence at 12-mo follow-up No recurrence at 14-mo follow-up Unknown
Lim-I-Linn and Li17 Chaudhry et al.18 Park et al.19
Labalette Recurrence of ocular et al.20 and systemic lesions. After chemotherapy with vinblastine and oral corticosteroids, no additional lesions at 4-y follow-up (continued on next page)
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e132 Ocular Juvenile XanthogranulomaVNiu et al. TABLE 1. (Continued) Patient no. Age, y 19 0.5
Sex (M/F) M
Ocular involvement Corneoscleral limbus, iris
Extraocular involvement Skin
Therapy Topical betamethasone
20
2
F
Uvea
None
Enucleation of eyeball Topical and systemic steroids Topical steroids
21
1.58
M
Iris
Skin
22
0.33
M
Iris
None
23
3
M
Iris
None
24
0.17
M
Iris
None
Corneoscleral limbus Iris, choroid, retina, ciliary body Corneoscleral limbus Corneoscleral limbus
None
Topical and systemic steroids Topical and systemic steroids Excision
None
Topical corticosteroid
None
Excision
None
Excision
25
17
M
26
12
M
27
16
F
28
16
M
29
5
F
Corneoscleral limbus
None
Excision
30
18
M
Corneoscleral limbus
None
Excision
F
Iris
Skin
Excision, topical and systemic steroids Topical and systemic steroids Excision, topical and systemic steroids Radiation therapy
31
1.08
32
0.92 Unknown Conjunctiva
Skin
33
0.67 Unknown Iris
Skin
34
0.17
None
M
Corneoscleral limbus, iris
Follow-up results Enlarged iris lesion with no change in skin lesions at 6-mo follow-up Unknown
Reference Rad and Kheradvar21
Zamir et al.22
No recurrence at 5-y follow-up No recurrence at 9-mo follow-up No recurrence at 6-mo follow-up No recurrence at 3-y follow-up No recurrence at 1-mo follow-up Unknown
Karcioglu and Mullaney23 Karcioglu and Mullaney23 Karcioglu and Mullaney23 Karcioglu and Mullaney23 Yanoff and Perry24 DeBarge et al.25
No recurrence at 2-y follow-up Recurrence at 6 mo after excision. After lamellar graft, no recurrence at 5-y follow-up Lamellar graft done after recurrence at 1 y after excision Recurrence at 1 mo after excision. After lamellar graft, no recurrence at 5-y follow-up No recurrence at 1-y follow-up No recurrence
Collum et al.26
The patient was lost to follow-up No recurrence at 2-mo follow-up
Harley et al.27
Collum et al.26
Collum et al.26
Collum et al.26
Harley et al.27 Harley et al.27
Fischbach and Sause28
In the above cases, case 14 developed secondary astigmatism and amblyopia; cases 19, 23, 24, 31, and 33 developed hyphema; cases 11 and 19 developed secondary glaucoma; and case 18 developed vitreous hemorrhage. Additionally, case 22 was found to have retinoblastoma. These conditions were all treated accordingly. TA, triamcinolone; MTX, methotrexate; CNS, central nervous system.
UBM demonstrated that the JXG lesions have the ability to invade surrounding tissues. A lesion on the ocular surface may have potential to invade the cornea and subsequently cause a decrease in vision. When feasible for such cases, surgical excision of lesions may be a better option. Recently, excision has been a treatment method chosen by many doctors.7,9,11,15Y19,24,26,27 For an ocular JXG lesion not amenable to resection, however, aggressive treatment may not be necessary unless severe complications such as glaucoma arise. In our case of iris and angle involvement where
secondary glaucoma was a concern, the skin lesions and ocular symptoms spontaneously regressed without treatment. There is no standard treatment of ocular JXG; thus, the site, any potential complications, and the safety of treatment should be considered on a case-by-case basis. In summary, we report three cases of histopathologically confirmed ocular JXG. Each case affected different ocular sites. One case involved the corneoscleral limbus. Another case had only conjunctival involvement. The final case had iris, angle, and
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Ocular Juvenile XanthogranulomaVNiu et al.
extraocular skin involvement. Our experience shows UBM to be a very useful tool for observing the relationship of the JXG mass with any contiguous tissues. Serial UBM measurements can provide valuable information regarding any changes in size and location after treatment. In our study, the two cases treated by excision remained tumor free at the 1-year follow up. The case with both iris and skin involvement had spontaneous regression of ocular symptoms and skin lesions 1 year after the initial examination. Juvenile xanthogranuloma is a rare non-LCH usually occurring in infants and young children with no accepted standard treatment. Treatment should be personalized to each specific case.
ACKNOWLEDGMENTS Research was supported by the National Science Foundation for Young Scientists of China (No. 81100636), the Shanghai Rising-Star program (No. 12QH1400500), and the Fund for the Development of Talents in Shanghai City (No. 2012049). The authors declare no conflict of interest. Received November 16, 2014; accepted March 26, 2015.
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12. 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;19:1069Y72. 13. Kuruvilla R, Escaravage GK, Jr., Finn AJ, Dutton JJ. Infiltrative subcutaneous juvenile xanthogranuloma of the eyelid in a neonate. Ophthal Plast Reconstr Surg 2009;25:330Y2. 14. Liang S, Liu YH, Fang K. Juvenile xanthogranuloma with ocular involvement. Pediatr Dermatol 2009;26:232Y4. 15. Mocan MC, Bozkurt B, Orhan D, Kuzey G, Irkec M. Juvenile xanthogranuloma of the corneal limbus: report of two cases and review of the literature. Cornea 2008;27:739Y42. 16. Kaur H, Cameron JD, Mohney BG. Severe astigmatic amblyopia secondary to subcutaneous juvenile xanthogranuloma of the eyelid. J AAPOS 2006;10:277Y8. 17. Lim-I-Linn Z, Li L. Juvenile xanthogranuloma of the corneoscleral limbus. Cornea 2005;24:745Y7. 18. Chaudhry IA, Al-Jishi Z, Shamsi FA, Riley F. Juvenile xanthogranuloma of the corneoscleral limbus: case report and review of the literature. Surv Ophthalmol 2004;49:608Y14. 19. Park SH, Rah SH, Kim YH. Juvenile xanthogranuloma as an isolated corneoscleral limbal mass: a case report. Korean J Ophthalmol 2003; 17:63Y6. 20. Labalette P, Guilbert F, Jourdel D, Nelken B, Cuvellier JC, Maurage CA. Bilateral multifocal uveal juvenile xanthogranuloma in a young boy with systemic disease. Graefes Arch Clin Exp Ophthalmol 2002;240:506Y9. 21. Rad AS, Kheradvar A. Juvenile xanthogranuloma: concurrent involvement of skin and eye. Cornea 2001;20:760Y2. 22. 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;46:164Y71. 23. Karcioglu ZA, Mullaney PB. Diagnosis and management of iris juvenile xanthogranuloma. J Pediatr Ophthalmol Strabismus 1997;34:44Y51. 24. Yanoff M, Perry HD. Juvenile xanthogranuloma of the corneoscleral limbus. Arch Ophthalmol 1995;113:915Y7. 25. DeBarge LR, Chan CC, Greenberg SC, McLean IW, Yannuzzi LA, Nussenblatt RB. Chorioretinal, iris, and ciliary body infiltration by juvenile xanthogranuloma masquerading as uveitis. Surv Ophthalmol 1994;39:65Y71. 26. Collum LM, Power WJ, Mullaney J, Farrell M. Limbal xanthogranuloma. J Pediatr Ophthalmol Strabismus 1991;28:157Y9. 27. Harley RD, Romayananda N, Chan GH. Juvenile xanthogranuloma. J Pediatr Ophthalmol Strabismus 1982;19:33Y9. 28. Fischbach J, Sause W. Radiation therapy in the management of ocular juvenile xanthogranuloma. Int J Radiat Oncol Biol Phys 1982;8:959Y60. 29. Golubovic S, Latkovic Z, Horvatic-Obradovic M. Surgical treatment of large corneal dermoid. Doc Ophthalmol 1995;91:25Y32. 30. Chantranuwat C. Systemic form of juvenile xanthogranuloma: report of a case with liver and bone marrow involvement. Pediatr Dev Pathol 2004;7:646Y8.
Yan Wang Eye and ENT Hospital of Fudan University 83 Fenyang Rd Shanghai 200031 China e-mail: [email protected]
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CLINICAL CASE
Ocular Juvenile Xanthogranuloma Liangliang Niu*, Chaoran Zhang*, Fanrong Meng*, Rongrong Cai*, Yingwen Bi*, Yan Wang†, and Jianjiang Xu*
ABSTRACT Purpose. To report the clinical and histopathologic characteristics and prognoses of three ocular juvenile xanthogranuloma (JXG) cases. Case Reports. Three cases were included in this study. The first case involved a 5-year-old girl with an enlarging yellowish mass at the limbus with corneal involvement. Ultrasound biomicroscopy showed a poorly demarcated mass involving the underlying cornea and sclera. The mass was excised in combination with a lamellar keratoplasty procedure. No recurrence was seen at the 2-year follow-up. The second case involved a 2-year-old boy with an enlarging yellowish mass on the conjunctiva, without limbal involvement. The mass was excised with no recurrence noted 1 year later. The third case involved a 7-month-old girl with unilateral eye redness and photophobia combined with multiple orange-red, raised nodular lesions on the skin. Examination under general anesthesia revealed a gray-yellow mass in the inferior and temporal iridocorneal angles. The intraocular pressure and corneal diameter were normal. Examination using ultrasound biomicroscopy showed a high-level echo lump in the inferior and temporal angles. There was no treatment for this case. At the 1-year follow up, the eye symptoms had resolved and the skin lesions were flat. Histopathologic examinations were completed on all three cases. The presence of Touton giant cells in hematoxylin-eosin staining, positive CD68 staining, and negative S-100 and CD1a staining confirmed the diagnosis of JXG. Conclusions. We report three histopathologically confirmed ocular JXG cases involving the corneoscleral limbus, conjunctiva, and iris with angle involvement, respectively. Ultrasound biomicroscopy performed on two cases demonstrated no obvious division between the mass and the surrounding structures. The cases with ocular surface involvement were successfully treated by excision and the case with iris involvement spontaneously regressed without any treatment. Early excision may be the better choice for ocular surface lesions, especially when corneal involvement is a possibility. (Optom Vis Sci 2015;92:e126Ye133) Key Words: juvenile xanthogranuloma, ocular, UBM, Touton cells, CD68, S-100
J
uvenile xanthogranuloma (JXG) is a rare nonYLangerhans cell histiocytosis (LCH) that usually presents in children as nodular skin lesions. It also can affect one or more extracutaneous sites, however, including the central nervous system, the liver/ spleen, the lungs, and the eyes, among other sites. In this article, we report three ocular JXG cases involving the corneoscleral limbus, conjunctiva, and iris, respectively. We report the clinical and histopathologic characteristics and the outcome of our cases, and a review of the literature. Written consent was obtained from all patients.
*MD † MD, PhD Departments of Ophthalmology (LN, CZ, FM, YW, JX) and Pathology (RC, YB), Eye and ENT Hospital of Fudan University, Shanghai, China.
CASE REPORT Case 1 A 5-year-old girl who had had an enlarged mass on her right eye for 3 months was referred to our clinic. She was otherwise healthy and had an unremarkable family history. Slit-lamp examination showed an 8-mm-diameter yellowish mass on the nasal inferior limbus with corneal, conjunctival, and scleral involvement (Fig. 1A). Ultrasound biomicroscopy (UBM) was performed and a mass with moderate internal reflectivity was noted. There was no distinct demarcation between the mass and the underlying cornea and sclera (Fig. 1C, D). Examination of the left eye was normal, as were the intraocular structures of the right eye. Magnetic resonance imaging and chest x-ray revealed no positive findings. Topical corticosteroid eye drops were used for 2 weeks. There was no change in the size of the mass and a secondary increase in the intraocular pressure (IOP) was noted.
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FIGURE 1. The slit-lamp photograph, UBM, histopathologic, and immunohistochemical examinations of case 1. (A) The slit-lamp photograph of case 1. An 8-mm-diameter mass appeared on the ocular surface involving the inferior nasal corneal limbus. (B) Slit-lamp anterior segment photograph showing 2 years after the surgery for case 1. (C, D) UBM of case 1 showed the mass presented as a middle-level echo. There was no obvious demarcation found between the mass and cornea (AC, anterior chamber; SC, sclera; COR, cornea). (E) Hematoxylin-eosin staining of case 1 demonstrated the subepithelial infiltration of histiocytes with pale cytoplasm and vacuoles. Typical multinucleated Touton giant cells were absent (400). (F) Immunohistochemical staining for case 1 showed a positive staining for CD68 (200). Optometry and Vision Science, Vol. 92, No. 6, June 2015
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e128 Ocular Juvenile XanthogranulomaVNiu et al.
The IOP returned to normal after discontinuation of the topical corticosteroid. Under general anesthesia, the lesion was excised combined with lamellar corneal transplantation. The portion of the lesion involving the cornea was unable to be completely excised because of the depth of corneal involvement as well as the soft nature of the lesion. Hematoxylin-eosin staining of the excised specimen demonstrated subepithelial infiltration of histiocytes with pale cytoplasm and vacuoles. No obvious Touton giant cells were found. Immunohistochemical staining was also performed. Positive staining for CD68 and negative staining for protein S-100 and CD1a confirmed the diagnosis of JXG (Fig. 1E, F). No recurrence was noted at the 2-year follow-up (Fig. 1B).
Case 2 A 2-year-old boy presented with a yellow-orange enlarged lesion on the conjunctiva of the right eye, which had been noticed by his parents 5 months previously. The parents denied any history of trauma. The patient’s medical and family histories were noncontributory. Slit-lamp examination showed a yellowish mass close to the inferior nasal limbus without corneal involvement, measuring about 5 by 6 mm (Fig. 2A). The intraocular structures of both eyes were normal. The lesion was fully excised, and the sclera under the mass was found to be intact. Numerous typical Touton giant cells were found with hematoxylin-eosin staining (Fig. 2C). Immunohistochemical staining showed positive staining for CD68 and negative staining for proteins S-100 and CD1a (Fig. 2D, E). No signs of recurrence or complication were evident at either the 1-month (Fig. 2B) or 1-year follow-up visits.
Case 3 The third case involved a 7-month-old girl who developed multiple orange-red, hard, and raised papulonodular skin lesions 4 months previously, accompanied by unilateral eye redness and photophobia. The skin lesions, located mainly on the head, neck, and trunk regions, were about 5 to 15 mm in diameter (Fig. 3A). Magnetic resonance imaging, chest x-ray, and abdominal ultrasound testing revealed no abnormal findings. An examination under general anesthesia was performed. A diffuse gray-yellow mass was found in the inferior periphery of the iris (Fig. 3B). The corneal diameter of both eyes was 10 mm, and the IOP was 12 and 13 mm Hg in the right and left eyes, respectively. Ultrasound biomicroscopy was also performed. A mass with mid- to high internal reflectivity was evident in the iris, extending into the posterior aspects of the inferior and temporal iridocorneal angles (Fig. 3C). The mass had contact with the cornea, although no corneal invasion was evident. A biopsy performed on the skin lesions by a dermatologist confirmed the diagnosis of JXG. No treatment was administered because of the mild nature of the ocular symptoms and normal IOP. Although the patient’s family was unable to travel to Shanghai for the 1-year follow up visit, they reported via telephone that most of the skin lesions had spontaneously regressed and that the ocular symptoms of redness and photophobia had fully resolved themselves.
DISCUSSION Juvenile xanthogranuloma is an uncommon nonYLangerhans cell histiocytic inflammatory disorder that is characterized by the proliferation of macrophages together with multinucleated giant cells (Touton cells).1 The diagnosis of JXG is dependent on histopathologic and immunohistochemical examinations. In JXG, immunohistochemical staining for histiocytic markers Ki-M1P and CD68 is generally positive, whereas staining for CD1a and S-100 (Langerhans cells markers) is negative.2,3 This point is crucial to distinguish JXG from LCH. In LCH, immunohistochemical staining for CD1a and S-100 is consistently positive.4 Janssen and Harms2 classified conventionally stained JXG lesions into four morphologic subtypes. Early JXG was characterized by a large amount of monomorphic histiocytic infiltration without multinuclear giant cells. Classic JXG featured histiocytic infiltration with a mass of fully developed Touton cells. In transitional JXG, Touton giant cells were either absent or only seldom found. Touton cells are usually considered a typical marker of JXG, but in some JXG cases, very few or no Touton cells are apparent. As in our first case, no Touton cells were found and the diagnosis of JXG was dependent on immunohistochemical staining. Juvenile xanthogranuloma occurs mainly in infants younger than 1 year and less commonly in older children and adults.2 The usual presentation of JXG is in infancy with one or more nodular skin lesions, but one or more systemic (extracutaneous) sites may also be affected, including the central nervous system, the liver/ spleen, the lungs, the eyes/orbits, oropharynx, and muscles.5 We performed a Medline search from 1965 to the present. In total, 34 ocular cases were reported, with 23 of the cases being under 2 years (Table 1). Ocular JXG appears to occur more commonly at an isolated site, although the sites were numerous, including the corneoscleral limbus, iris, conjunctiva, cornea, choroid, optic nerve, eyelid, and orbit. The corneoscleral limbus and iris were the sites most often involved in ocular JXG. Of the 34 reported cases of ocular JXG, 15 had corneoscleral limbal involvement, 12 had iris involvement, and only 10 had skin involvement. In our current study, we report two isolated cases of ocular JXG, one with corneoscleral involvement at the limbus, and one with conjunctival involvement. We also report one case with both systemic skin lesions and iris involvement. We performed UBM for two of our cases. We found UBM to be a very helpful tool for understanding the relationship of the JXG mass and the surrounding tissues. In the first case, UBM showed a mass at the limbus without a clearly demarcated border separating it from the underlying cornea and sclera. It was especially difficult to distinguish the mass from the surrounding cornea, which suggested that excision would be difficult. As a result, we were able to plan on performing a lamellar keratoplasty at the time of excision. In another case, UBM clearly demonstrated invasion by the mass of the inferior and nasal iridocorneal angles. This alerted us to check closely for any signs of secondary glaucoma. These findings also demonstrated the ability of ocular JXG lesions to involve surrounding tissues. As mentioned previously, many studies that did not use UBM have found JXG to occur at isolated ocular sites. Based on our findings, as UBM becomes more commonplace in the evaluation of JXG lesions, we believe that future studies will find that the prevalence of JXG
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FIGURE 2. The slit-lamp photograph, histopathologic, and immunohistochemical stainings of case 2. (A) The slit-lamp anterior segment photograph of case 2 showing a yellowish mass close to the inferior nasal limbus without cornea involvement, which was about 5 by 6 mm. (B) The mass of case 2 was completely removed and there was no obvious injection at the 1-month follow-up. (C) Histopathology for case 2 demonstrating large quantities of foamy histiocytes infiltrating in subconjunctival layer, with an abundance of typical Touton giant cells (arrows) (400). (D, E) Immunohistochemical staining of case 2 showed a positive staining for CD68 (histiocytic marker) and a negative staining for CD1a (Langerhans cell marker) (200). Optometry and Vision Science, Vol. 92, No. 6, June 2015
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FIGURE 3. Juvenile xanthogranuloma with iris, skin involvement, and UBM examination of case 3. (A) Close-up view of case 3 with orange-red nodular lesions in the head. (B) The slit-lamp anterior segment photograph of case 3 showed that the iris texture was unclear; a diffused gray-yellow mass was found on the inferior periphery of the iris and anterior chamber angle, which made contact with the cornea of the right eye. (C) Ultrasound biomicroscopy for case 3 demonstrated middle- to high-echo lump located at the lower and temporal anterior chamber angle, which made contact with the peripheral cornea.
lesions involving multiple sites is higher than previously reported. To our knowledge, this is the first case series of UBM findings in ocular JXG. Juvenile xanthogranuloma should also be distinguished from other limbal lesions in young children, for instance, limbal dermoids, nodular anterior scleritis, and sclerokeratitis. Limbal dermoids exist at birth and grow along with the eyes; fine hairs may protrude from the lesion surface. Limbal dermoids are characterized by keratinized epithelium, hairs, and sebaceous and sudoriferous glands in histopathology.29 In addition, the scleritis usually causes obvious pain and responds well to immunosuppressive treatment. Juvenile xanthogranuloma is a self-limiting disorder in some cases, especially in cases of cutaneous lesions. Unlike the cutaneous
form, systemic JXG has been reported to possibly cause significant complications requiring aggressive medical care.30 There is currently no standard treatment of ocular JXG. Glucocorticoids, immunosuppressive agents, radiation therapy, and surgery have been reported as possible ocular JXG treatments (Table 1). Topical corticosteroids were reported to successfully treat one case of conjunctival JXG. In our case, there was no improvement after 2 weeks of topical steroid treatment, however, and treatment was discontinued because of IOP elevation. Radiation for iris JXG lesions has also been reported,5,28 but complications such as cataract and retinal detachment make this option less desirable. Juvenile xanthogranuloma usually occurs in young children or infants, and treatment should be selected to minimize toxic effects. In our study,
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TABLE 1.
Reported cases of ocular juvenile xanthogranulomatosis Patient no. Age, y 1
43
Sex (M/F)
Ocular involvement
Extraocular involvement
M
Conjunctiva
None
Conjunctivectomy, cryotherapy Sub-Tenon injection of TA and topical prednisolone acetate Excision
2
0.5
F
Iris
Skin
3
2
M
Conjunctiva
None
4
1.2
M
Corneoscleral limbus, iris, choroid
None
5
0.75
M
Corneoscleral limbus
None
6
4
F
Corneoscleral limbus
None
7
1.3
M
Optic nerve
Skin
8
2
F
Eyelid
None
Sub-Tenon injection of triamcinolone, topical and systemic prednisolone, systemic MTX Excision, subconjunctival betamethasone injection, topical prednisolone Excision, subconjunctival betamethasone injection, topical prednisolone Pulse high-dose methylprednisolone with systemic prednisolone Excision
9
2
M
Iris
Skin
Systemic vinblastine
10
18 d
None
11
0.6
M
Eyelid
Skin
12
0.6
F
Corneoscleral limbus
None
Intralesional steroid injections and oral prednisolone Topical betamethasone eye drops Excision
13
7
M
None
Excision and topical fluorometholone
14
0.83
F
Conjunctiva, corneoscleral limbus Eyelid
None
15
1
F
16
1.5
F
None
Excision with intralesional steroid injections Excision with lamellar graft Excision
17
5
M
None
Excision
18
0.67
M
Unknown Eyelid
Corneoscleral limbus Corneoscleral limbus Corneoscleral limbus Multifocal uveal sites
None
Follow-up results
Therapy
Skin, CNS, Topical dexamethasone, kidney, lung, systemic corticotherapy liver, spleen
Reference Lee et al.3
No recurrence at 2-mo follow-up Involution of iris and skin lesions at 1-mo follow-up No recurrence at 20-mo follow-up A new skin lesion developed at 3-y follow-up
Manjandavida et al.6 Olmo et al.7 Longmuir et al.8
No recurrence at 1-y follow-up
De Keyser et al.9
No recurrence at 6-mo follow-up
De Keyser et al.9
Vision improved, skin lesions decreased
Daien et al.10
No recurrence at 4-mo follow-up No recurrence at 1-y follow-up No recurrence at 3.5-mo follow-up
Lim et al.11
Unknown
Liang et al.14
Pollono et al.12 Kuruvilla et al.13
Mocan et al.15 Recurrence at 4-mo follow-up. After intralesional injection of triamcinolone acetonide, no recurrence at 1-y follow-up No recurrence at Mocan et al.15 3-y follow-up No recurrence at 8-mo follow-up
Kaur et al.16
No recurrence at 12-mo follow-up No recurrence at 14-mo follow-up Unknown
Lim-I-Linn and Li17 Chaudhry et al.18 Park et al.19
Labalette Recurrence of ocular et al.20 and systemic lesions. After chemotherapy with vinblastine and oral corticosteroids, no additional lesions at 4-y follow-up (continued on next page)
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e132 Ocular Juvenile XanthogranulomaVNiu et al. TABLE 1. (Continued) Patient no. Age, y 19 0.5
Sex (M/F) M
Ocular involvement Corneoscleral limbus, iris
Extraocular involvement Skin
Therapy Topical betamethasone
20
2
F
Uvea
None
Enucleation of eyeball Topical and systemic steroids Topical steroids
21
1.58
M
Iris
Skin
22
0.33
M
Iris
None
23
3
M
Iris
None
24
0.17
M
Iris
None
Corneoscleral limbus Iris, choroid, retina, ciliary body Corneoscleral limbus Corneoscleral limbus
None
Topical and systemic steroids Topical and systemic steroids Excision
None
Topical corticosteroid
None
Excision
None
Excision
25
17
M
26
12
M
27
16
F
28
16
M
29
5
F
Corneoscleral limbus
None
Excision
30
18
M
Corneoscleral limbus
None
Excision
F
Iris
Skin
Excision, topical and systemic steroids Topical and systemic steroids Excision, topical and systemic steroids Radiation therapy
31
1.08
32
0.92 Unknown Conjunctiva
Skin
33
0.67 Unknown Iris
Skin
34
0.17
None
M
Corneoscleral limbus, iris
Follow-up results Enlarged iris lesion with no change in skin lesions at 6-mo follow-up Unknown
Reference Rad and Kheradvar21
Zamir et al.22
No recurrence at 5-y follow-up No recurrence at 9-mo follow-up No recurrence at 6-mo follow-up No recurrence at 3-y follow-up No recurrence at 1-mo follow-up Unknown
Karcioglu and Mullaney23 Karcioglu and Mullaney23 Karcioglu and Mullaney23 Karcioglu and Mullaney23 Yanoff and Perry24 DeBarge et al.25
No recurrence at 2-y follow-up Recurrence at 6 mo after excision. After lamellar graft, no recurrence at 5-y follow-up Lamellar graft done after recurrence at 1 y after excision Recurrence at 1 mo after excision. After lamellar graft, no recurrence at 5-y follow-up No recurrence at 1-y follow-up No recurrence
Collum et al.26
The patient was lost to follow-up No recurrence at 2-mo follow-up
Harley et al.27
Collum et al.26
Collum et al.26
Collum et al.26
Harley et al.27 Harley et al.27
Fischbach and Sause28
In the above cases, case 14 developed secondary astigmatism and amblyopia; cases 19, 23, 24, 31, and 33 developed hyphema; cases 11 and 19 developed secondary glaucoma; and case 18 developed vitreous hemorrhage. Additionally, case 22 was found to have retinoblastoma. These conditions were all treated accordingly. TA, triamcinolone; MTX, methotrexate; CNS, central nervous system.
UBM demonstrated that the JXG lesions have the ability to invade surrounding tissues. A lesion on the ocular surface may have potential to invade the cornea and subsequently cause a decrease in vision. When feasible for such cases, surgical excision of lesions may be a better option. Recently, excision has been a treatment method chosen by many doctors.7,9,11,15Y19,24,26,27 For an ocular JXG lesion not amenable to resection, however, aggressive treatment may not be necessary unless severe complications such as glaucoma arise. In our case of iris and angle involvement where
secondary glaucoma was a concern, the skin lesions and ocular symptoms spontaneously regressed without treatment. There is no standard treatment of ocular JXG; thus, the site, any potential complications, and the safety of treatment should be considered on a case-by-case basis. In summary, we report three cases of histopathologically confirmed ocular JXG. Each case affected different ocular sites. One case involved the corneoscleral limbus. Another case had only conjunctival involvement. The final case had iris, angle, and
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Ocular Juvenile XanthogranulomaVNiu et al.
extraocular skin involvement. Our experience shows UBM to be a very useful tool for observing the relationship of the JXG mass with any contiguous tissues. Serial UBM measurements can provide valuable information regarding any changes in size and location after treatment. In our study, the two cases treated by excision remained tumor free at the 1-year follow up. The case with both iris and skin involvement had spontaneous regression of ocular symptoms and skin lesions 1 year after the initial examination. Juvenile xanthogranuloma is a rare non-LCH usually occurring in infants and young children with no accepted standard treatment. Treatment should be personalized to each specific case.
ACKNOWLEDGMENTS Research was supported by the National Science Foundation for Young Scientists of China (No. 81100636), the Shanghai Rising-Star program (No. 12QH1400500), and the Fund for the Development of Talents in Shanghai City (No. 2012049). The authors declare no conflict of interest. Received November 16, 2014; accepted March 26, 2015.
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Yan Wang Eye and ENT Hospital of Fudan University 83 Fenyang Rd Shanghai 200031 China e-mail: [email protected]
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![[Localized eruptive juvenile xanthogranuloma].](/assets/img/hold.png)
