LABORATORY SCIENCE
Orbital Immunoglobulin G4YRelated Disease: A Systematic Review Kaustubh Mulay, DNB* and Santosh G. Honavar, MS, FACSÞ
Abstract: Immunoglobulin G4Yrelated disease (IgG4-RD) is a clinically distinct systemic condition that can involve the orbital tissue. Characterized by a triad of a mass-forming lesion, infiltration by IgG4-positive plasma cells, and elevated serum IgG4 titers in many cases, IgG4-RD has clinicopathologic features that overlap with ocular adnexal lymphomas and orbital inflammatory conditions. Although most cases of orbital IgG4-RD respond well to steroids, it may become necessary to include supplemental immunosuppressant therapy in the management. Key Words: orbit, IgG4, lacrimal gland, steroids (Asia Pac J Ophthalmol 2014;3: 322Y325)
I
mmunoglobulin G4Yrelated disease (IgG4-RD) is a recently described fibroinflammatory entity characterized by a massforming lesion in the affected organ, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, and elevated serum titers of IgG4 in some cases. Autoimmune pancreatitis, which is considered to be the prototype of this disease, was associated with elevated serum titers of IgG4 in the beginning of this century.1 Since then, IgG4-RD has been described in several organs of the human body such as lymph nodes, lungs, skin, aorta, biliary tract, salivary glands, thyroid, and so on.2Y8 Orbital involvement in IgG4-RD is not uncommon. The purpose of this review was to summarize the epidemiology, clinicopathologic features, laboratory findings, and management of patients with orbital IgG4-RD (Fig. 1).
Nomenclature Immunoglobulin G4Yrelated disease was recognized as a systemic condition in 2003.9 Various terminologies such as IgG4-associated disease, IgG4-related systemic disease, IgG4related sclerosing disease, IgG4-related systemic sclerosing disease, IgG4-related autoimmune disease, hyper-IgG4 disease, IgG4-related multiorgan lymphoproliferative syndrome, systemic IgG4-related plasmacytic syndrome, and IgG4 syndrome have been used to describe this disease.9 In 2011, researchers agreed to use the term ‘‘IgG4-related disease’’ for this condition.10 This is now the preferred terminology. Table 1 tabulates various terminologies used for orbital manifestations of IgG4-RD.
From the *National Reporting Centre for Ophthalmic Pathology (NRCOP) and †Ophthalmic and Facial Plastic Surgery and Ocular Oncology, Centre for Sight, Hyderabad, India. Received for publication January 13, 2014; accepted September 15, 2014. The authors have no funding or conflicts of interest to declare. Reprints: Kaustubh Mulay, DNB, National Reporting Centre for Ophthalmic Pathology, Centre for Sight, Ashoka Capitol Building, Road No. 2, Banjara Hills, Hyderabad 500 034, India. E-mail: [email protected]. Copyright * 2014 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000077
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Epidemiology Although most of the cases of IgG4-RD have been reported in adults, children as young as 5-year-olds may also be affected.11Y15
Clinical Features IgG4-RD usually presents as a gradually developing, painless proptosis or eyelid swelling, which can be unilateral or bilateral.12,14,16 Visual disturbances are not a feature of IgG4RD unless it is complicated by neural involvement.17 The disease can involve ocular adnexae, including the lacrimal gland, orbital fat, extraocular muscles, eyelids, nasolacrimal duct, lacrimal sac, trigeminal nerve branch, infraorbital nerve, and the periorbita.12,14,17Y20 Although lacrimal gland involvement is the most frequent ophthalmic manifestation of orbital IgG4RD, recent reports in literature describe lacrimal glandYsparing IgG4-RD.21
Radiological Findings IgG4-RD masses often appear on Computed tomography (CT) as diffused and heterogeneous masses, which may appear hypointense, isointense, or hyperintense on T2- weighted magnetic resonance imaging.12,22 Positron emission tomorgraphy (PET) shows lesions to be hypermetabolic and may also show demineralization of the orbital wall.22 The extraocular muscles appear enlarged when involved.16,22
Systemic Associations Involvement of other organs such as salivary glands, lymph nodes, lungs, kidney, para-aorta, and pancreas has been described in association with orbital IgG4-RD.23,24 Immunoglobulin G4Yrelated disease is frequently associated with allergic conditions such as atopic dermatitis and asthma.14,15
Laboratory Findings The majority of patients with IgG4-RD have elevated titers of IgG4 in the serum, which can be as many as 25 times the normal value or even higher.9 The cutoff value of serum IgG4 has been set at 135 mg/dL.11 However, approximately 30% to 40% patients with IgG4-RD can have a normal serum IgG4 titer despite having light microscopic and immunohistochemical features characteristic of this disease.10,25 Elevated serum IgG4 titers are not specific of IgG4-RD and can be present in conditions such as multicentric Castleman disease, Wegener granulomatosis, Churg-Strauss syndrome, and even pancreatic adenocarcinoma.26 Serum IgE titers may be low, normal, or elevated.12Y14 Hypergammaglobulinemia, elevated soluble interleukin 2 levels, and hypocomplementemia have been reported in association with IgG4-RD.12Y14,27 The role of serum IgG4 titers as indicators of disease activity and response to treatment has not been clearly defined.28 Serum IgG4 titers remain high in most patients even after treatment with glucocorticoids.29
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Orbital IgG4-RD
FIGURE 1. Clinicopathologic features of IgG4-RD. A, IgG4-related dacryoadenitis presenting as an upper lid swelling in a 55-year-old woman. B, Computed tomography scan in a 7-year-old boy showing a homogenous and diffuse orbital mass. C, Fibrosis with a dense lymphoplasmacytic infiltrate and lymphoid follicles (hematoxylin-eosin stain, original magnification 40). D, Immunoglobulin G4 dacryoadenitis showing fibrosis and lymphoplasmacytic inflammatory infiltrate (hematoxylin-eosin stain, original magnification 40). E, Aggregates of plasma cells (hematoxylin-eosin stain, original magnification 400) and [F] IgG4-positive plasma cells.
Light Microscopic Features
Immunoglobulin G4-Positive Plasma Cells
Light microscopic examination is the key to the diagnosis of IgG4-RD. Although confirmatory, neither elevated serum IgG4 titers nor increased IgG4-positive plasma cells in tissue are specific for the disease. Major light microscopic features characteristic of IgG4-RD are as follows28: (1) dense lymphoplasmacytic infiltrate, (2) fibrosis that has a storiform pattern at least focally, and (3) obliterative phlebitis.
Immunostaining with IgG4 to identify and quantify IgG4-positive plasma cells is quintessential in the diagnosis of IgG4-RD. Guidelines in the current literature for quantifying IgG4-positive plasma cells are not specific or standardized. IgGand IgG4-positive plasma cells can be counted using photographs or directly under a microscope using a 40 objective. Both methods are considered acceptable.28 It is recommended that quantification be performed in areas where the density of IgG4positive plasma cells is maximum in order to avoid underestimation in rare cases where the distribution of IgG4-positive plasma cells is not uniform. Some authors suggest counting of plasma cells in 3 fields of 40 magnification as suggested above.28
Two of these features are required for a confident diagnosis.28 Exceptions include minor salivary glands, lacrimal glands, lymph nodes, and lungs in which storiform fibrosis or obliterative phlebitis can be absent or inconspicuous.28 The lymphocytes are predominantly of T-cell type, whereas B cells are either scattered or seen in aggregates. Plasma cells are essential and may be seen in aggregates. Spindle cells are either of fibroblastic or myofibroblastic nature. Phlebitis, when present, can be of obliterative or nonobliterative type. In the former, lymphocytes and plasma cells are seen in the walls and lumina of the vessels. Minor light microscopic findings associated with IgG4-RD include presence of eosinophils, macrophages containing eosinophilic material, and Touton giant cells.12,30 Epithelioid cell granulomas and a prominent neutrophilic infiltrate are features inconsistent with diagnosis of IgG4-RD.31 * 2014 Asia Pacific Academy of Ophthalmology
TABLE 1. Preferred Nomenclature for Involvement of Orbital Tissue in IgG4-RD9 Tissue Lacrimal gland Orbital soft tissue Extraocular muscles Orbit with involvement of multiple anatomical structures
Terminology Preferred IgG4-related dacryoadenitis IgG4-related orbital inflammation IgG4-related orbital myositis IgG4-related pan-orbital inflammation
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A minimum of 10 IgG4-plasma cells per high-power field (HPF) is required for the diagnosis of IgG4-RD. However, finding of more than 30 such cells per HPF gives a respectable sensitivity, and presence of more than 50 IgG4-positive plasma cells per HPF is highly specific.32Y34 For lesions involving the lacrimal gland, presence of 100 IgG4-positive plasma cells per HPF is recommended.28 NonYIgG4-RD conditions may have a large number of IgG4-positive plasma cells only because of an abundance of plasma cells, and the IgG4-positive plasma-cell count may not be helpful in making a diagnosis. In this situation, an IgG4-positive to IgG-positive plasma cell ratio can be useful. A ratio greater than 40% is an accepted criterion in the diagnosis of IgG4-RD.35
Differential Diagnosis Clinically, differentials of IgG4-RD include nonspecific orbital inflammatory diseases (NSOID), lymphomas, idiopathic orbital myositis, and antineutrophil cytoplasmic antibody (ANCA)Y associated vasculitis such as Wegener granulomatosis. Unlike IgG4-RD, NSOIDs and idiopathic myositis present with pain, redness, and restriction of ocular motility.36 A proper histopathologic and immunohistochemical evaluation is eventually required to distinguish IgG4-RD from these lesions. On light microscopy, IgG4-RD may appear similar to conditions such as ANCA-associated vasculitis, multicentric Castleman disease, orbital xanthogranulomatous disease, and lymphomas, all of which may have increased IgG4-positive plasma cells.37Y40 A thorough laboratory workup including coagulation studies, serum calcium, muscle enzymes, erythrocyte sedimentation rate, antiYdoublestranded DNA, lupus anticoagulant, C-reactive proteins, antinuclear antibody, antiextractable nuclear antigen (anti-ENA), antiYsignal recognition particle, ANCA, and serum complement levels is essential to exclude vasculitis and other autoimmune disorders. Lymphoma can not only mimic but also develop in tissue affected by IgG4-RD.39 Presence of a predominant B-cell population (seen in lymphomas) as opposed to a predominant T-cell population (seen in IgG4-RD) is one of the clues to the diagnosis of B-cell lymphomas.25 Demonstration of monoclonality and immunoglobulin gene H rearrangement also supports the diagnosis of lymphoma.
Treatment There are no standard protocols for the treatment of IgG4-RD. Most patients of IgG4-RD respond well to systemic glucocorticoids. Prednisolone in a dose of 5 to 10 mg per day is suggested for orbital involvement.41 However, IgG4-RD may relapse after discontinuation of glucocorticoid treatment or may even be refractory to glucocorticoid therapy.42,43 Immunosuppressants such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate have been used in maintenance therapy and during relapses. However, reports on their use are mixed.12,42Y45 Recently, rituximab has been tried in patients with IgG4-RD, especially in steroidrefractory and recurrent cases. Rituximab helps by depleting the subset of CD20-positive B lymphocytes that differentiate into short-lived plasma cells, which produce the disease-associated IgG4.46 Use of rituximab has been reported to be successful with serum IgG4 titers decreasing to normal values.47,48 Patients with IgG4-RD need long-term follow-up because of a risk of recurrence of the disease and development of lymphoma.
Distinction From Nonspecific Orbital Inflammation: Is It Important? Although a considerable overlap exists in the clinical presentation and histopathology of IgG4-RD and NSOIDs, IgG4-RD
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is now identified as a distinct entity. HLA-DRB1 and HLADQA1-57 are associated with increased susceptibility and relapse, respectively, in patients with IgG4-RD.49,50 No such observations have been described in NSOIDs so far. The exact etiology and pathogenesis of IgG4-RD are unclear. However, autoimmunity may be the initial stimulus leading to increased production of type 2 helper T cells and regulatory T-cell cytokines associated with IgG4-RD.25 On the contrary, very rarely are NSOIDs associated with autoimmunity.51 In addition, allergic conditions such as atopy, raised levels of soluble interleukin 2 receptor, and serum IgE have been reported in patients with IgG4-RD along with instances of polyclonal hypergammaglobulinemia.13 Thus, finding of IgG4-positive plasma cells in inflammatory lesions of the orbit warrants the screening of patients for possible presence of systemic diseases. Although treatment for sclerosing orbital inflammations and IgG4-RD is similar in published literature, refractoriness to glucocorticoids and relapse on withdrawal of glucocorticoids are frequent in IgG4-RD.42,43 Nonspecific orbital inflammatory diseases often respond well to steroids, but patients with IgG4-RD may require additional use of immunosuppressants.42Y45 Longterm follow-up in patients with IgG4-RD is necessary as these patients are at a risk of developing a malignant lymphoma.39 Immunoglobulin G4Yrelated disease is a novel and distinct clinicopathologic entity that shares several clinicopathologic features with other conditions involving the orbit. Presence of a large number of plasma cells in the affected tissue should prompt the pathologists to include IgG4-RD in their differential diagnoses. A diagnosis of IgG4-RD should be followed by a thorough workup for systemic involvement. A long-term follow up is essential in these patients due to both the risk of relapse and risk of developing lymphoma. REFERENCES 1. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732Y738. 2. Cheuk W, Chan JK. Lymphadenopathy of IgG4-related disease: an underdiagnosed and overdiagnosed entity. Semin Diagn Pathol. 2012;29:226Y234. 3. Wibmer T, Kropf-Sanchen C, Ru¨diger S, et al. Isolated IgG4-related interstitial lung disease: unusual histological and radiological features of a pathologically proven case. Multidiscip Respir Med. 2013;8:22. 4. Ikeda T, Oka M, Shimizu H, et al. IgG4-related skin manifestations in patients with IgG4-related disease. Eur J Dermatol. 2013;23:241Y245. 5. Stone JH, Khosroshahi A, Hilgenberg A, et al. IgG4-related systemic disease and lymphoplasmacytic aortitis. Arthritis Rheum. 2009;60:3139Y3145. 6. Harrison JD, Rodriguez-Justo M. IgG4-related sialadenitis is rare: histopathological investigation of 129 cases of chronic submandibular sialadenitis. Histopathology. 2013;63:96Y102. 7. Al-Dhahab H, McNabb-Baltar J, Al-Busafi S, et al. Immunoglobulin G4Yrelated pancreatic and biliary diseases. Can J Gastroenterol. 2013;27:523Y530. 8. Watanabe T, Maruyama M, Ito T, et al. Clinical features of a new disease concept, IgG4-related thyroiditis. Scand J Rheumatol. 2013;42:325Y330. 9. Stone JH. IgG4-related disease: nomenclature, clinical features, and treatment. Semin Diagn Pathol. 2012;29:177Y190. 10. Stone JH, Khosroshahi A, Deshpande V, et al. IgG4-related disease: recommendations for the nomenclature of this condition and its individual organ system manifestations. Arthritis Rheum. 2012;64:3061Y3067.
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11. Kalapesi FB1, Garrott HM, Moldovan C, Williams M, Ramanan A, Herbert HM. IgG4 orbital inflammation in a 5-year-old child presenting as an orbital mass. Orbit. 2013;32:137Y140.
33. Zhang L, Notohara K, Levy MJ, et al. IgG4-positive plasma cell infiltration in the diagnosis of autoimmune pancreatitis. Mod Pathol. 2007;20:23Y28.
12. Mulay K, Aggarwal E, Jariwala M, et al. Orbital immunoglobulin G4Yrelated disease: case series and literature review. Clin Exp Ophthalmol. 2013.
34. Deshpande V, Chicano S, Finkelberg D, et al. Autoimmune pancreatitis: a systemic immune complex mediated disease. Am J Surg Pathol. 2006;30:1537Y1545.
13. Kubota T, Moritani S, Katayama M, et al. Ocular adnexal IgG4-related lymphoplasmacytic infiltrative disorder. Arch Ophthalmol. 2010;128:577Y584.
35. Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012;22:21Y30.
14. Sato Y, Ohshima KI, Ichimura K, et al. Ocular adnexal IgG4-related disease has uniform clinicopathology. Pathol Int. 2008;58:465Y470.
36. Kubota T. Orbital myositis. In: Gran JT, ed. Idiopathic Inflammatory MyopathiesVRecent Developments. InTech 2011:123Y142. Available at: http://www.intechopen.com/books/ idiopathic-inflammatory-myopathies-recent-developments/ orbital-myositis. Accessed 15 July, 2014.
15. Kubota T, Moritani S. Orbital IgG4-related disease: clinical features and diagnosis. ISRN Rheumatol. 2012;2012:412896. 16. Shin YU, Oh YH, Lee YJ. Unusual involvement of IgG4-related sclerosing disease in lacrimal and submandibular glands and extraocular muscles. Korean J Ophthalmol. 2012;26:216Y221. 17. Sogabe Y, Miyatani K, Goto R, et al. Pathological findings of infraorbital nerve enlargement in IgG4-related ophthalmic disease. Jpn J Ophthalmol. 2012;56:511Y514. 18. Sogabe Y, Ohshima KI, Azumi A, et al. Location and frequency of lesions in patients with IgG4-related ophthalmic diseases [published online ahead of print]. Graefes Arch Clin Exp Ophthalmol. 2014;252:531Y538. 19. Batra R, Mudhar HS, Sandramouli S. A unique case of IgG4 sclerosing dacryocystitis. Ophthal Plast Reconstr Surg. 2012;28:e70Ye72. 20. Mehta M, Jakobiec F, Fay A. Idiopathic fibroinflammatory disease of the face, eyelids, and periorbital membrane with immunoglobulin G4Ypositive plasma cells. Arch Pathol Lab Med. 2009;133:1251Y1255. 21. Khan TT, Halat SK, Al Hariri AB. Lacrimal gland sparing IgG4-related disease in the orbit. Ocul Immunol Inflamm. 2013;21:220Y224. 22. Ginat DT, Freitag SK, Kieff D, et al. Radiographic patterns of orbital involvement in IgG4-related disease. Ophthal Plast Reconstr Surg. 2013;24:471Y476. 23. Hagiya C, Tsuboi H, Yokosawa M, et al. Clinicopathological features of IgG4-related disease complicated with orbital involvement diseases [published online ahead of print]. Mod Rheumatol. 2013;24:471Y476. 24. Dı´az AC, Arfenoni BA, Semelka RC, et al. Case report of systemic IgG-related disease affecting the pancreas and orbit. Clin Imaging. 2012;36:615Y618. 25. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366:539Y551. 26. Ebbo M, Grados A, Bernit E, et al. Pathologies associated with serum IgG4 elevation. Int J Rheumatol. 2012;2012:602809. 27. Takahira M, Kawano M, Zen Y, et al. IgG4-related chronic sclerosing dacryoadenitis. Arch Ophthalmol. 2007;125:1575Y1578. 28. Deshpande V, Zen Y, Ferry JA, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25:1181Y1192. 29. Sah RP, Chari ST. Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis. Curr Opin Rheumatol. 2011;23:108Y113. 30. Mudhar HS, Bhatt R, Sandramouli S. Xanthogranulomatous variant of immunoglobulin G4 sclerosing disease presenting as ptosis, proptosis and eyelid skin plaques. Int Ophthalmol. 2011;31:245Y248.
37. Verdijk RM, Heidari P, Verschooten R, et al. Raised numbers of IgG4-positive plasma cells are a common histopathological finding in orbital xanthogranulomatous disease. Orbit. 2014;33:17Y22. 38. Chang SY, Keogh KA, Lewis JE, et al. IgG4-positive plasma cells in granulomatosis with polyangiitis (Wegener’s): a clinicopathologic and immunohistochemical study on 43 granulomatosis with polyangiitis and 20 control cases. Hum Pathol. 2013;44:2432Y2437. 39. Kase S, Noda M, Ishijima K, et al. IgG4-related inflammation of the orbit simulating malignant lymphoma. Anticancer Res. 2013;33:2779Y2783. 40. Karamchandani JR, Younes SF, Warnke RA, et al. IgG4-related systemic sclerosing disease of the ocular adnexa: a potential mimic of ocular lymphoma. Am J Clin Pathol. 2012;137:699Y711. 41. Yamamoto M, Takahashi H, Ohara M, et al. A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Mod Rheumatol. 2006;16:335Y340. 42. Khosroshahi A, Stone JH. A clinical overview of IgG4-related systemic disease. Curr Opin Rheumatol. 2011;23:57Y66. 43. Hsuan JD, Selva D, McNab AA, et al. Idiopathic sclerosing orbital inflammation. Arch Ophthalmol. 2006;124:1244Y1250. 44. Bosco JJ, Suan D, Varikatt W, et al. Extra-pancreatic manifestations of IgG4-related systemic disease: a single-centre experience of treatment with combined immunosuppression. Intern Med J. 2013;43:417Y423. 45. Palazzo E, Palazzo C, Palazzo M. IgG4-related disease [published online ahead of print]. Joint Bone Spine. 2013;81:27Y31. 46. Khosroshahi A, Carruthers MN, Deshpande V, et al. Rituximab for the treatment of IgG4-related disease. Lessons from 10 consecutive patients. Medicine (Baltimore). 2012;91:57Y66. 47. Sedyshev SKh, Vasil’ev VI, Kovrigina AM, et al. IgG4-related disease: patient group characterization and rituximab therapy [in Russian]. Ter Arkh. 2013;85:48Y53. 48. Murakami J, Matsui S, Ishizawa S, et al. Recurrence of IgG4-related disease following treatment with rituximab. Mod Rheumatol. 2013;23:1226Y1230. 49. Sodikoff JB, Keilin S, Cai Q, et al. Mycophenolate mofetil for maintenance of remission in steroid8dependent autoimmune pancreatitis. World J Gastroenterol. 2012;18:2287Y2290.
31. Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol. 2010;34:1812Y1819.
50. Kawa S, Ota M, Yoshizawa K, et al. HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology. 2002;122:1264Y1269.
32. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38:982Y984.
51. Kubota T, Moritani S. High incidence of autoimmune disease in Japanese patients with ocular adnexal reactive lymphoid hyperplasia. Am J Ophthalmol. 2007;144:148Y149.
* 2014 Asia Pacific Academy of Ophthalmology
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Orbital Immunoglobulin G4YRelated Disease: A Systematic Review Kaustubh Mulay, DNB* and Santosh G. Honavar, MS, FACSÞ
Abstract: Immunoglobulin G4Yrelated disease (IgG4-RD) is a clinically distinct systemic condition that can involve the orbital tissue. Characterized by a triad of a mass-forming lesion, infiltration by IgG4-positive plasma cells, and elevated serum IgG4 titers in many cases, IgG4-RD has clinicopathologic features that overlap with ocular adnexal lymphomas and orbital inflammatory conditions. Although most cases of orbital IgG4-RD respond well to steroids, it may become necessary to include supplemental immunosuppressant therapy in the management. Key Words: orbit, IgG4, lacrimal gland, steroids (Asia Pac J Ophthalmol 2014;3: 322Y325)
I
mmunoglobulin G4Yrelated disease (IgG4-RD) is a recently described fibroinflammatory entity characterized by a massforming lesion in the affected organ, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, and elevated serum titers of IgG4 in some cases. Autoimmune pancreatitis, which is considered to be the prototype of this disease, was associated with elevated serum titers of IgG4 in the beginning of this century.1 Since then, IgG4-RD has been described in several organs of the human body such as lymph nodes, lungs, skin, aorta, biliary tract, salivary glands, thyroid, and so on.2Y8 Orbital involvement in IgG4-RD is not uncommon. The purpose of this review was to summarize the epidemiology, clinicopathologic features, laboratory findings, and management of patients with orbital IgG4-RD (Fig. 1).
Nomenclature Immunoglobulin G4Yrelated disease was recognized as a systemic condition in 2003.9 Various terminologies such as IgG4-associated disease, IgG4-related systemic disease, IgG4related sclerosing disease, IgG4-related systemic sclerosing disease, IgG4-related autoimmune disease, hyper-IgG4 disease, IgG4-related multiorgan lymphoproliferative syndrome, systemic IgG4-related plasmacytic syndrome, and IgG4 syndrome have been used to describe this disease.9 In 2011, researchers agreed to use the term ‘‘IgG4-related disease’’ for this condition.10 This is now the preferred terminology. Table 1 tabulates various terminologies used for orbital manifestations of IgG4-RD.
From the *National Reporting Centre for Ophthalmic Pathology (NRCOP) and †Ophthalmic and Facial Plastic Surgery and Ocular Oncology, Centre for Sight, Hyderabad, India. Received for publication January 13, 2014; accepted September 15, 2014. The authors have no funding or conflicts of interest to declare. Reprints: Kaustubh Mulay, DNB, National Reporting Centre for Ophthalmic Pathology, Centre for Sight, Ashoka Capitol Building, Road No. 2, Banjara Hills, Hyderabad 500 034, India. E-mail: [email protected]. Copyright * 2014 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000077
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Epidemiology Although most of the cases of IgG4-RD have been reported in adults, children as young as 5-year-olds may also be affected.11Y15
Clinical Features IgG4-RD usually presents as a gradually developing, painless proptosis or eyelid swelling, which can be unilateral or bilateral.12,14,16 Visual disturbances are not a feature of IgG4RD unless it is complicated by neural involvement.17 The disease can involve ocular adnexae, including the lacrimal gland, orbital fat, extraocular muscles, eyelids, nasolacrimal duct, lacrimal sac, trigeminal nerve branch, infraorbital nerve, and the periorbita.12,14,17Y20 Although lacrimal gland involvement is the most frequent ophthalmic manifestation of orbital IgG4RD, recent reports in literature describe lacrimal glandYsparing IgG4-RD.21
Radiological Findings IgG4-RD masses often appear on Computed tomography (CT) as diffused and heterogeneous masses, which may appear hypointense, isointense, or hyperintense on T2- weighted magnetic resonance imaging.12,22 Positron emission tomorgraphy (PET) shows lesions to be hypermetabolic and may also show demineralization of the orbital wall.22 The extraocular muscles appear enlarged when involved.16,22
Systemic Associations Involvement of other organs such as salivary glands, lymph nodes, lungs, kidney, para-aorta, and pancreas has been described in association with orbital IgG4-RD.23,24 Immunoglobulin G4Yrelated disease is frequently associated with allergic conditions such as atopic dermatitis and asthma.14,15
Laboratory Findings The majority of patients with IgG4-RD have elevated titers of IgG4 in the serum, which can be as many as 25 times the normal value or even higher.9 The cutoff value of serum IgG4 has been set at 135 mg/dL.11 However, approximately 30% to 40% patients with IgG4-RD can have a normal serum IgG4 titer despite having light microscopic and immunohistochemical features characteristic of this disease.10,25 Elevated serum IgG4 titers are not specific of IgG4-RD and can be present in conditions such as multicentric Castleman disease, Wegener granulomatosis, Churg-Strauss syndrome, and even pancreatic adenocarcinoma.26 Serum IgE titers may be low, normal, or elevated.12Y14 Hypergammaglobulinemia, elevated soluble interleukin 2 levels, and hypocomplementemia have been reported in association with IgG4-RD.12Y14,27 The role of serum IgG4 titers as indicators of disease activity and response to treatment has not been clearly defined.28 Serum IgG4 titers remain high in most patients even after treatment with glucocorticoids.29
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Volume 3, Number 5, September/October 2014
Orbital IgG4-RD
FIGURE 1. Clinicopathologic features of IgG4-RD. A, IgG4-related dacryoadenitis presenting as an upper lid swelling in a 55-year-old woman. B, Computed tomography scan in a 7-year-old boy showing a homogenous and diffuse orbital mass. C, Fibrosis with a dense lymphoplasmacytic infiltrate and lymphoid follicles (hematoxylin-eosin stain, original magnification 40). D, Immunoglobulin G4 dacryoadenitis showing fibrosis and lymphoplasmacytic inflammatory infiltrate (hematoxylin-eosin stain, original magnification 40). E, Aggregates of plasma cells (hematoxylin-eosin stain, original magnification 400) and [F] IgG4-positive plasma cells.
Light Microscopic Features
Immunoglobulin G4-Positive Plasma Cells
Light microscopic examination is the key to the diagnosis of IgG4-RD. Although confirmatory, neither elevated serum IgG4 titers nor increased IgG4-positive plasma cells in tissue are specific for the disease. Major light microscopic features characteristic of IgG4-RD are as follows28: (1) dense lymphoplasmacytic infiltrate, (2) fibrosis that has a storiform pattern at least focally, and (3) obliterative phlebitis.
Immunostaining with IgG4 to identify and quantify IgG4-positive plasma cells is quintessential in the diagnosis of IgG4-RD. Guidelines in the current literature for quantifying IgG4-positive plasma cells are not specific or standardized. IgGand IgG4-positive plasma cells can be counted using photographs or directly under a microscope using a 40 objective. Both methods are considered acceptable.28 It is recommended that quantification be performed in areas where the density of IgG4positive plasma cells is maximum in order to avoid underestimation in rare cases where the distribution of IgG4-positive plasma cells is not uniform. Some authors suggest counting of plasma cells in 3 fields of 40 magnification as suggested above.28
Two of these features are required for a confident diagnosis.28 Exceptions include minor salivary glands, lacrimal glands, lymph nodes, and lungs in which storiform fibrosis or obliterative phlebitis can be absent or inconspicuous.28 The lymphocytes are predominantly of T-cell type, whereas B cells are either scattered or seen in aggregates. Plasma cells are essential and may be seen in aggregates. Spindle cells are either of fibroblastic or myofibroblastic nature. Phlebitis, when present, can be of obliterative or nonobliterative type. In the former, lymphocytes and plasma cells are seen in the walls and lumina of the vessels. Minor light microscopic findings associated with IgG4-RD include presence of eosinophils, macrophages containing eosinophilic material, and Touton giant cells.12,30 Epithelioid cell granulomas and a prominent neutrophilic infiltrate are features inconsistent with diagnosis of IgG4-RD.31 * 2014 Asia Pacific Academy of Ophthalmology
TABLE 1. Preferred Nomenclature for Involvement of Orbital Tissue in IgG4-RD9 Tissue Lacrimal gland Orbital soft tissue Extraocular muscles Orbit with involvement of multiple anatomical structures
Terminology Preferred IgG4-related dacryoadenitis IgG4-related orbital inflammation IgG4-related orbital myositis IgG4-related pan-orbital inflammation
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A minimum of 10 IgG4-plasma cells per high-power field (HPF) is required for the diagnosis of IgG4-RD. However, finding of more than 30 such cells per HPF gives a respectable sensitivity, and presence of more than 50 IgG4-positive plasma cells per HPF is highly specific.32Y34 For lesions involving the lacrimal gland, presence of 100 IgG4-positive plasma cells per HPF is recommended.28 NonYIgG4-RD conditions may have a large number of IgG4-positive plasma cells only because of an abundance of plasma cells, and the IgG4-positive plasma-cell count may not be helpful in making a diagnosis. In this situation, an IgG4-positive to IgG-positive plasma cell ratio can be useful. A ratio greater than 40% is an accepted criterion in the diagnosis of IgG4-RD.35
Differential Diagnosis Clinically, differentials of IgG4-RD include nonspecific orbital inflammatory diseases (NSOID), lymphomas, idiopathic orbital myositis, and antineutrophil cytoplasmic antibody (ANCA)Y associated vasculitis such as Wegener granulomatosis. Unlike IgG4-RD, NSOIDs and idiopathic myositis present with pain, redness, and restriction of ocular motility.36 A proper histopathologic and immunohistochemical evaluation is eventually required to distinguish IgG4-RD from these lesions. On light microscopy, IgG4-RD may appear similar to conditions such as ANCA-associated vasculitis, multicentric Castleman disease, orbital xanthogranulomatous disease, and lymphomas, all of which may have increased IgG4-positive plasma cells.37Y40 A thorough laboratory workup including coagulation studies, serum calcium, muscle enzymes, erythrocyte sedimentation rate, antiYdoublestranded DNA, lupus anticoagulant, C-reactive proteins, antinuclear antibody, antiextractable nuclear antigen (anti-ENA), antiYsignal recognition particle, ANCA, and serum complement levels is essential to exclude vasculitis and other autoimmune disorders. Lymphoma can not only mimic but also develop in tissue affected by IgG4-RD.39 Presence of a predominant B-cell population (seen in lymphomas) as opposed to a predominant T-cell population (seen in IgG4-RD) is one of the clues to the diagnosis of B-cell lymphomas.25 Demonstration of monoclonality and immunoglobulin gene H rearrangement also supports the diagnosis of lymphoma.
Treatment There are no standard protocols for the treatment of IgG4-RD. Most patients of IgG4-RD respond well to systemic glucocorticoids. Prednisolone in a dose of 5 to 10 mg per day is suggested for orbital involvement.41 However, IgG4-RD may relapse after discontinuation of glucocorticoid treatment or may even be refractory to glucocorticoid therapy.42,43 Immunosuppressants such as azathioprine, methotrexate, cyclophosphamide, and mycophenolate have been used in maintenance therapy and during relapses. However, reports on their use are mixed.12,42Y45 Recently, rituximab has been tried in patients with IgG4-RD, especially in steroidrefractory and recurrent cases. Rituximab helps by depleting the subset of CD20-positive B lymphocytes that differentiate into short-lived plasma cells, which produce the disease-associated IgG4.46 Use of rituximab has been reported to be successful with serum IgG4 titers decreasing to normal values.47,48 Patients with IgG4-RD need long-term follow-up because of a risk of recurrence of the disease and development of lymphoma.
Distinction From Nonspecific Orbital Inflammation: Is It Important? Although a considerable overlap exists in the clinical presentation and histopathology of IgG4-RD and NSOIDs, IgG4-RD
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is now identified as a distinct entity. HLA-DRB1 and HLADQA1-57 are associated with increased susceptibility and relapse, respectively, in patients with IgG4-RD.49,50 No such observations have been described in NSOIDs so far. The exact etiology and pathogenesis of IgG4-RD are unclear. However, autoimmunity may be the initial stimulus leading to increased production of type 2 helper T cells and regulatory T-cell cytokines associated with IgG4-RD.25 On the contrary, very rarely are NSOIDs associated with autoimmunity.51 In addition, allergic conditions such as atopy, raised levels of soluble interleukin 2 receptor, and serum IgE have been reported in patients with IgG4-RD along with instances of polyclonal hypergammaglobulinemia.13 Thus, finding of IgG4-positive plasma cells in inflammatory lesions of the orbit warrants the screening of patients for possible presence of systemic diseases. Although treatment for sclerosing orbital inflammations and IgG4-RD is similar in published literature, refractoriness to glucocorticoids and relapse on withdrawal of glucocorticoids are frequent in IgG4-RD.42,43 Nonspecific orbital inflammatory diseases often respond well to steroids, but patients with IgG4-RD may require additional use of immunosuppressants.42Y45 Longterm follow-up in patients with IgG4-RD is necessary as these patients are at a risk of developing a malignant lymphoma.39 Immunoglobulin G4Yrelated disease is a novel and distinct clinicopathologic entity that shares several clinicopathologic features with other conditions involving the orbit. Presence of a large number of plasma cells in the affected tissue should prompt the pathologists to include IgG4-RD in their differential diagnoses. A diagnosis of IgG4-RD should be followed by a thorough workup for systemic involvement. A long-term follow up is essential in these patients due to both the risk of relapse and risk of developing lymphoma. REFERENCES 1. Hamano H, Kawa S, Horiuchi A, et al. High serum IgG concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732Y738. 2. Cheuk W, Chan JK. Lymphadenopathy of IgG4-related disease: an underdiagnosed and overdiagnosed entity. Semin Diagn Pathol. 2012;29:226Y234. 3. Wibmer T, Kropf-Sanchen C, Ru¨diger S, et al. Isolated IgG4-related interstitial lung disease: unusual histological and radiological features of a pathologically proven case. Multidiscip Respir Med. 2013;8:22. 4. Ikeda T, Oka M, Shimizu H, et al. IgG4-related skin manifestations in patients with IgG4-related disease. Eur J Dermatol. 2013;23:241Y245. 5. Stone JH, Khosroshahi A, Hilgenberg A, et al. IgG4-related systemic disease and lymphoplasmacytic aortitis. Arthritis Rheum. 2009;60:3139Y3145. 6. Harrison JD, Rodriguez-Justo M. IgG4-related sialadenitis is rare: histopathological investigation of 129 cases of chronic submandibular sialadenitis. Histopathology. 2013;63:96Y102. 7. Al-Dhahab H, McNabb-Baltar J, Al-Busafi S, et al. Immunoglobulin G4Yrelated pancreatic and biliary diseases. Can J Gastroenterol. 2013;27:523Y530. 8. Watanabe T, Maruyama M, Ito T, et al. Clinical features of a new disease concept, IgG4-related thyroiditis. Scand J Rheumatol. 2013;42:325Y330. 9. Stone JH. IgG4-related disease: nomenclature, clinical features, and treatment. Semin Diagn Pathol. 2012;29:177Y190. 10. Stone JH, Khosroshahi A, Deshpande V, et al. IgG4-related disease: recommendations for the nomenclature of this condition and its individual organ system manifestations. Arthritis Rheum. 2012;64:3061Y3067.
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11. Kalapesi FB1, Garrott HM, Moldovan C, Williams M, Ramanan A, Herbert HM. IgG4 orbital inflammation in a 5-year-old child presenting as an orbital mass. Orbit. 2013;32:137Y140.
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37. Verdijk RM, Heidari P, Verschooten R, et al. Raised numbers of IgG4-positive plasma cells are a common histopathological finding in orbital xanthogranulomatous disease. Orbit. 2014;33:17Y22. 38. Chang SY, Keogh KA, Lewis JE, et al. IgG4-positive plasma cells in granulomatosis with polyangiitis (Wegener’s): a clinicopathologic and immunohistochemical study on 43 granulomatosis with polyangiitis and 20 control cases. Hum Pathol. 2013;44:2432Y2437. 39. Kase S, Noda M, Ishijima K, et al. IgG4-related inflammation of the orbit simulating malignant lymphoma. Anticancer Res. 2013;33:2779Y2783. 40. Karamchandani JR, Younes SF, Warnke RA, et al. IgG4-related systemic sclerosing disease of the ocular adnexa: a potential mimic of ocular lymphoma. Am J Clin Pathol. 2012;137:699Y711. 41. Yamamoto M, Takahashi H, Ohara M, et al. A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Mod Rheumatol. 2006;16:335Y340. 42. Khosroshahi A, Stone JH. A clinical overview of IgG4-related systemic disease. Curr Opin Rheumatol. 2011;23:57Y66. 43. Hsuan JD, Selva D, McNab AA, et al. Idiopathic sclerosing orbital inflammation. Arch Ophthalmol. 2006;124:1244Y1250. 44. Bosco JJ, Suan D, Varikatt W, et al. Extra-pancreatic manifestations of IgG4-related systemic disease: a single-centre experience of treatment with combined immunosuppression. Intern Med J. 2013;43:417Y423. 45. Palazzo E, Palazzo C, Palazzo M. IgG4-related disease [published online ahead of print]. Joint Bone Spine. 2013;81:27Y31. 46. Khosroshahi A, Carruthers MN, Deshpande V, et al. Rituximab for the treatment of IgG4-related disease. Lessons from 10 consecutive patients. Medicine (Baltimore). 2012;91:57Y66. 47. Sedyshev SKh, Vasil’ev VI, Kovrigina AM, et al. IgG4-related disease: patient group characterization and rituximab therapy [in Russian]. Ter Arkh. 2013;85:48Y53. 48. Murakami J, Matsui S, Ishizawa S, et al. Recurrence of IgG4-related disease following treatment with rituximab. Mod Rheumatol. 2013;23:1226Y1230. 49. Sodikoff JB, Keilin S, Cai Q, et al. Mycophenolate mofetil for maintenance of remission in steroid8dependent autoimmune pancreatitis. World J Gastroenterol. 2012;18:2287Y2290.
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