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5. Hensey OJ, Hart CA, Cooke RW. Skin abscesses caused by candida albicans: unusual presentation of c. albicans disease. J Clin Microbiol 1980;12:44–5. 6. Feldman WE, Hedaya E, O’Brien M. Candida albicans skin abscesses. Arch Dis Child. 1984;59:479–80. 7. Tuon FF, Nicodemo AC. Candida albicans skin abscess. Rev Inst Med Trop Sao Paulo 2006;48:301–2. 8. Celik AD, Yulugkural Z, Kuloglu F, et al. Candida glabrata: etiologic agent of soft tissue abscess in a diabetic patient. Indian J Pathol Microbiol 2010;53:590–1. 9. Weston WL. Cutaneous manifestations of defective host defenses. Pediatr Clin North Am 1977;24:395–407.

IgG4-Related Dacryoadenitis in a 13-Year-Old Girl Gregory Notz, D.O.*, Alessandra Intili, M.D.*, and Jurij R. Bilyk, M.D.† Abstract: IgG4-related disease is a recently described fibroinflammatory condition, often with systemic involvement. Several authors have reported IgG4-related orbital inflammation in adults. Pediatric cases of IgG4related disease have been reported in the literature involving other areas of the body, with only 1 recent report of probable orbital involvement. The first case of probable IgG4-related dacryoadenitis is reported in a child.

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gG4-related disease is a recently described fibroinflammatory condition typified by lymphoplasmacytic infiltration of soft tissues by IgG4+ plasma cells, often with systemic involvement.1 Several authors have reported IgG4-related orbital inflammation (OI) in adults.2–7 Pediatric cases of IgG4-related disease have been reported in the literature involving other areas of the body.8,9 This is the first reported case of probable IgG4related dacryoadenitis in a child. This report is Health Insurance Portability and Accountability Act complaint.

CASE DESCRIPTION A 13-year-old girl was evaluated by her pediatrician for complaints of left eyelid swelling and mild discomfort for 1 to 2 weeks duration. She was initially diagnosed with a possible chalazion associated with preseptal cellulitis and started on a 2-week course of oral cephalexin with no improvement. She was subsequently seen by her ophthalmologist and treated with ampicillin/clavulinic acid and sufacetamide/prednisolone drops. Although this resulted in modest improvement, the patient’s symptoms of eyelid edema and erythema recurred within 1 week of completion of therapy. An MRI of the orbits revealed a uniformly enlarged left lacrimal gland with displacement of the left lateral rectus (Fig. 1). There was no evidence of bony destruction or globe distortion. The patient was diagnosed with idiopathic orbital inflammatory syndrome (IOIS) and treated with oral corticosteroids (prednisone 40 mg/d) for 2 months with nearly complete improvement of her eyelid findings. Three months after *Wills Eye Hospital, U.S.A.; †Skull Base Division, Neuro-Ophthalmology Service, Wills Eye Hospital, Philadelphia Pennsylvania, U.S.A. Accepted for publication August 21, 2013. The authors disclose no financial or conflict of interest. Address correspondence and reprint requests to Jurij R. Bilyk, M.D., Skull Base Division, Neuro-Ophthalmology Service Wills Eye Hospital, 840 Walnut St., Suite 930 Philadelphia, PA 19107. E-mail: [email protected] DOI: 10.1097/IOP.0000000000000016

Case Reports

completion of corticosteroid therapy, her eyelid symptoms and pain returned, and the patient underwent 2 additional imaging studies, which continued to show enlargement of the left lacrimal gland. She was referred for further management after being symptomatic for 10 months. Initial examination showed visual acuity of 20/25 in each eye with no afferent pupillary defect. Extraocular motility was normal. Nontender eyelid edema was present on the left with no resistance to retropulsion and no proptosis noted by Hertel exophthalmometry (Fig. 2). The lacrimal glands were not palpable or tender. There was no evidence of keratic precipitates or posterior synechiae on slit lamp examination. Dilated fundus examination was also unremarkable. The patient arrived with serologic results, including an angiotensin-converting enzyme, antineutrophil cytoplasmic antibody, Lyme titers, complete blood count, Westergren sedimentation rate, c-reactive protein, antinuclear antibody, and acetylcholine receptor antibody, all which were within normal limits. Chest x-ray was normal with no evidence of hilar adenopathy. A subtotal excision of the left orbital lobe of the lacrimal gland was performed through a standard upper eyelid crease incision. Intraoperatively, the gland was found to be densely fibrotic with mild erosion of the lacrimal gland fossa. Final histopathology revealed intense staining for IgG4 plasma cells (>50 per high power field (HPF) in at least 3 HPF). An IgG4:IgG ratio was not performed. Marked fibrosis and presence of lymphoid follicles were also noted with minimal residual native lacrimal gland present in the specimen (Fig. 3). There was no evidence of granulomatous inflammation, an increased number of eosinophils, or phlebitis. No histiocytes with emperipolesis suggestive of RosaiDorfman disease were present. Postoperative serum IgG4 levels were normal at 23.9. Flow cytometry did not reveal a monoclonal B-cell population. A diagnosis of IgG4-related dacryoadenitis was made.10 The patient was referred to a gastroenterologist and hematologist for further evaluation. No evidence of systemic disease was noted. She remains asymptomatic 10 months after completion of a 3-month course of corticosteroid therapy, with no evidence of systemic disease. Repeat MRI showed near complete resolution of the lacrimal gland mass.

DISCUSSION IgG4-related disease is a newly described diagnosis defined by its typical histopathological and immunohistochemical features.1,11 Despite the myriad systemic manifestations, the histopathology remains relatively constant regardless of involved viscera, akin to other inflammatory processes such as sarcoidosis.1,11 Orbital involvement was initially described in 20073,4. The histopathological features of IgG4-related disease include >10 IgG4+ plasma cells/HPF, varying degrees of “storiform” fibrosis, a lymphoplasmacytic infiltrate, and obliterative phlebitis; the presence of granulomatous inflammation or neutrophilical microabscesses excludes this diagnosis.11,12 Flow cytometry lacks monoclonality. Elevated serum IgG4 levels are seen in most cases but may be normal in up to 40%.2,11 In this patient, serum IgG4 levels were within normal range, but this finding must be tempered by the possibility that serum IgG4 levels were blunted by chronic systemic corticosteroid therapy.7 Considerable controversy exists regarding the sensitivity and specificity of IgG4 staining and IgG4 serum levels in making the diagnosis of IgG4-related disease. As mentioned earlier, a finding of >10 IgG4+ plasma cells/HPF appears to be acceptable for making this diagnosis overall and was a criterion for diagnosis in the most recent study regarding IgG4-related OI.2,12 The finding of >50 IgG4+ plasma cells/HPF, as noted in this patient, is considered highly specific overall.11 That said, a

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FIG. 1.  Initial MRI. Top left: Axial, precontrast T1-weighted image. Top right: Axial, postcontrast T1-weighted image with fat suppression. Bottom: Coronal, postcontrast T1-weighted images. Note the left lacrimal gland mass with diffuse and relatively homogenous enhancement.

FIG. 2.  External photo at presentation. Note the left hypoglobus and mild left upper eyelid swelling without erythema.

recent consensus statement on IgG4-related disease has proposed a nomogram of site-specific IgG+ plasma cell staining, in part because the varying amounts of native plasma cells present in different tissues.11 For the lacrimal gland, >100 IgG4+ cells/HPF is the recommended threshold, with the caveat that other criteria must also be considered and that IgG4+ staining may be related to the stage of the disease process at the time of diagnosis. As an example, if tissue biopsy is performed once a significant amount of fibrosis has occurred, the residual inflammatory component may not manifest a robust IgG4+ staining pattern.13 Furthermore, it remains unclear if IgG4+ staining patterns are affected significantly by prior corticosteroid therapy, as occurred in this patient. As already mentioned, attainment of the cutoff value of IgG4+ plasma cell staining as an isolated finding does not constitute a

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FIG. 3.  Histo- and immunopathology. Top, low magnification view showing large areas of fibrosis with lymphoplasmacytic infiltration (hematoxylin-eosin). Bottom, high magnification image demonstrates the transition zone between the lymphoplasmacytic infiltrate and fibrosis (hematoxylin-eosin).

definitive diagnosis of IgG4-related disease.11 Because of its wide range of clinical presentation, the diagnosis of IgG4-related disease requires an integration of clinical, radiographic, serologic, histopathologic, and immunohistochemical data. Based on the

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recent consensus statement, this patient is best characterized as “histologically possible/probable of IgG4-related disease.”11 Other disease processes may mimick IgG4-related disease, manifesting both serologic and histopathological features of increased IgG4, including pr3-related granulomatosis with polyangiitis (formerly Wegener granulomatosis), rheumatoid arthritis, Castleman disease, rhinosinusitis, and low-grade lymphoma, among others.11,14,15 However, in most cases, differentiation can be made by reviewing other histopathological and immunohistochemical staining and flow cytometry, when necessary. In this patient, the histopathology was consistent with IgG4-related disease and showed no features of other pathologic processes. Several small series on IgG4-related OI have been published in the literature, most recently by Plaza et al.,2 who described 11 adult cases.2–6 It appears that IgG4-related OI has a particular propensity for lacrimal gland involvement (IgG4related dacryoadenitis), occurring in 90% of cases in 1 series, although infiltration of orbital fat and extraocular muscle has been reported.2,7,16 Of note, the typical storiform pattern of fibrosis and obliterative phlebitis may not be seen in the lacrimal gland due to the idiosyncrasies of this tissue.11 Unlike IOIS, IgG4-related OI presents in an indolent fashion, usually over weeks to months with little or no associated pain. IgG4related OI should be considered as a separate entity and not as part of the spectrum of IOIS.2,10 Bilateral orbital involvement may occur in 55%.2 An associated history of atopic disease (eczema, asthma, chronic sinusitis) is common;2 this patient had no history of atopy but did experience chronic rhinosinusitis. Gastrointestinal involvement (sclerosing cholangitis, autoimmune pancreatitis, etc.) may also occur either simultaneously or sequentially. In addition, IgG4-related disease has been linked to a 16-fold increased risk of subsequent lymphoma and a 3.5-fold higher lifetime risk of malignancy.17,18 Such an association is also postulated anecdotally with IgG4-related OI (including IgG4-related dacryoadenitis), with 2 cases of extranodal marginal zone lymphoma and 1 case of follicular lymphoma reported after the initial IgG4 diagnosis.7,19,20 However, it remains unclear whether the associations of future malignancy found in the adult population are apropos for the pediatric age group: the paucity of reported pediatric cases of IgG4-related disease makes any conclusion on this matter difficult at present. IgG4-related disease has been described in the pediatric population in scattered case reports involving the joints, pancreas, mediastinum, submandibular gland, pituitary gland, and pachymeninges.8,9,21,22 Masaki et al.23 reported on 64 cases of IgG4-related disease involving the parotid, submandibular, or lacrimal gland, with the youngest age of 17 years; it is unclear from the manuscript whether this patient had lacrimal gland involvement. After initial submission of this manuscript, 1 case of IgG4-related disease presenting as an orbital mass in a 5-yearold child was published.24 Extraconal soft tissue infiltration of the inferior orbit was identified on imaging. Histopathology showed >30 IgG4+ plasma cells/HPF along with a mildly elevated serum IgG4 level and an elevated pANCA titer. The management of IgG4-related OI typically begins with systemic corticosteroids and, when necessary, progresses to antimetabolite or biologic agents.2,9 One major point of contention is the extent of initial workup and long-term follow up15. Biliary and pancreatic disease is often screened with serologic and radiographic testing such as abdominal MRI. An initial referral to a hematologist may also be prudent. However, there is no consensus on long-term systemic surveillance in IgG4related disease and at present appears to remain at the discretion of the treating physicians. In summary, a 13-year-old girl presented with a lacrimal gland mass initially misdiagnosed as IOIS. Subsequent biopsy

Case Reports

revealed probable IgG4-related dacryoadenitis. The possibility of IgG4-related OI should be considered in children who present with features that are atypical for IOIS.

REFERENCES 1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539–51. 2. Plaza JA, Garrity JA, Dogan A, et al. Orbital inflammation with IgG4-positive plasma cells: manifestation of IgG4 systemic disease. Arch Ophthalmol 2011;129:421–8. 3. Cheuk W, Yuen HK, Chan JK. Chronic sclerosing dacryoadenitis: part of the spectrum of IgG4-related Sclerosing disease? Am J Surg Pathol 2007;31:643–5. 4. Takahira M, Kawano M, Zen Y, et al. IgG4-related chronic sclerosing dacryoadenitis. Arch Ophthalmol 2007;125:1575–8. 5. Mehta M, Jakobiec F, Fay A. Idiopathic fibroinflammatory disease of the face, eyelids, and periorbital membrane with immunoglobulin G4-positive plasma cells. Arch Pathol Lab Med 2009;133:1251–5. 6. Sato Y, Ohshima K, Ichimura K, et al. Ocular adnexal IgG4-related disease has uniform clinicopathology. Pathol Int 2008;58:465–70. 7. Lindfield D, Attfield K, McElvanney A. Systemic immunoglobulin G4 (IgG4) disease and idiopathic orbital inflammation; removing ‘idiopathic’ from the nomenclature? Eye (Lond) 2012;26:623–9. 8. Hufnagel M, Henneke P, Schmitt-Graeff A. IgG4-related disease. N Engl J Med 2012;366:1643–4; author reply 1646–7. 9. Mannion M, Cron RQ. Successful treatment of pediatric IgG4 related systemic disease with mycophenolate mofetil: case report and a review of the pediatric autoimmune pancreatitis literature. Pediatr Rheumatol Online J 2011;9:1. 10. Stone JH, Khosroshahi A, Deshpande V, et al. Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthritis Rheum 2012;64:3061–7. 11. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol 2012;25:1181–92. 12. Chari ST. Diagnosis of autoimmune pancreatitis using its five cardinal features: introducing the Mayo Clinic’s HISORt criteria. J Gastroenterol 2007;42 (suppl 18):39–41. 13. Masaki Y, Kurose N, Yamamoto M, et al. Cutoff values of serum IgG4 and histopathological IgG4+ plasma cells for diagnosis of patients with IgG4-related disease. Int J Rheumatol 2012;2012:580814. 14. Yamamoto M, Tabeya T, Naishiro Y, et al. Value of serum IgG4 in the diagnosis of IgG4-related disease and in differentiation from rheumatic diseases and other diseases. Mod Rheumatol 2012;22:419–25. 15. Berry-Brincat A, Rose GE. Idiopathic orbital inflammation: a new dimension with the discovery of immunoglobulin G4-related disease. Curr Opin Ophthalmol 2012;23:415–9. 16. Castillo F, Garrity JA, Kravitz DJ. Intractable graves ophthalmopathy? JAMA Ophthalmol 2013;131:269–70. 17. Yamamoto M, Takahashi H, Shinomura Y. IgG4-related disease and malignancy. Intern Med 2012;51:349–50. 18. Yamamoto M, Takahashi H, Tabeya T, et al. Risk of malignancies in IgG4-related disease. Mod Rheumatol 2012;22:414–8. 19. Cheuk W, Yuen HK, Chan AC, et al. Ocular adnexal lymphoma associated with IgG4+ chronic sclerosing dacryoadenitis: a previously undescribed complication of IgG4-related sclerosing disease. Am J Surg Pathol 2008;32:1159–67. 20. Yamada K, Kawano M, Inoue R, et al. Clonal relationship between infiltrating immunoglobulin G4 (IgG4)-positive plasma cells in lacrimal glands and circulating IgG4-positive lymphocytes in Mikulicz’s disease. Clin Exp Immunol 2008;152:432–9. 21. Fukumori K, Shakado S, Miyahara T, et al. Atypical manifestations of pancreatitis with autoimmune phenomenon in an adolescent female. Intern Med 2005;44:886–91. 22. Melo JC, Kitsko D, Reyes-Múgica M. Pediatric chronic sclerosing sialadenitis: Küttner tumor. Pediatr Dev Pathol 2012;15:165–9. 23. Masaki Y, Dong L, Kurose N, et al. Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis 2009;68:1310–5. 24. Kalapesi FB, Garrott HM, Moldovan C, et al. IgG4 orbital inflammation in a 5-year-old child presenting as an orbital mass. Orbit 2013;32:137–40.

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IgG4-related dacryoadenitis in a 13-year-old girl.

IgG4-related disease is a recently described fibroinflammatory condition, often with systemic involvement. Several authors have reported IgG4-related ...
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