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대한안과학회지 2018 년제 59 권제 11 호 J Korean Ophthalmol Soc 2018;59(11):1071-1076 ISSN 0378-6471 (Print) ISSN 2092-9374 (Online) https://doi.org/10.3341/jkos.2018.59.11.1071 Case Report 황색육아종과동반된면역글로불린 G4 관련안질환 1 예 IgG4-related Ophthalmic Disease Associated with Adult Xanthogranulomatous Disease 이승현 1 정석중 1 허진형 2 유혜린 1 Seunghyun Lee, MD 1, Sokjoong Chung, MD 1, Jinhyung Heo, MD, PhD 2, Helen Lew, MD, PhD 1 차의과학대학교분당차병원안과학교실 1, 차의과학대학교분당차병원병리학교실 2 Department of Ophthalmology, CHA Bundang Medical Center 1, Seongnam, Korea Department of Pathology, CHA Bundang Medical Center 2, Seongnam, Korea Purpose: To report a case of immunoglobulin G4 (IgG4)-related ophthalmic disease associated with adult xanthogranulomatous disease. Case summary: A 38-year-old male with a history of cholecystectomy visited our clinic for bilateral periorbital swelling. Histopathology of the orbital biopsy showed diffuse infiltration of foamy histiocytes with Touton giant cells and lymphoid follicles, with a diagnosis of adult-onset xanthogranuloma. After excisional biopsy, he was treated with azathioprine and prednisolone. Four years after treatment, he again visited the clinic due to bilateral, yellowish eyelid masses. Serological examinations were all nonspecific findings, except for elevation of IgG and IgG4 levels. Magnetic resonance imaging showed bilateral symmetric soft tissue enlargement with slightly heterogeneous T1/T2 isosignal intensity, with contrast enhancement at the superolateral aspect of extraconal spaces. Excisional biopsy and blepharoplasty were performed. Immunohistochemical sections showed that the IgG4+/IgG plasma cell ratio was 10-20% and the IgG4 plasma cell count was 22/high power field (HPF). His past sections of 2013 from the pathology department were again stained and showed that the IgG4+/IgG plasma cell ratio was 40-50% and the IgG4 plasma cell count was 59/HPF. Thus, he was definitely diagnosed with IgG4-related ophthalmic disease. Conclusions: If there is recurrent eyelid swelling, IgG4-related ophthalmic disease should be considered as a differential diagnosis. And the patient with adult xanthogranulomatous disease can be diagnosed with IgG4-related ophthalmic disease. J Korean Ophthalmol Soc 2018;59(11):1071-1076 Keywords: Adult xanthogranulomatous disease, IgG4-related ophthalmic disease, Xanthogranuloma 면역글로불린G4관련질환 (immunoglobulin G4 [IgG4]-related disease) 은면역반응으로유발되는림프구와형질세포가침윤된조직의비대와조직학적으로섬유화와면역글로 Received: 2018. 7. 12. Revised: 2018. 8. 20. Accepted: 2018. 10. 21. Address reprint requests to Helen Lew, MD, PhD Department of Ophthalmology, CHA Bundang Medical Center, #59 Yatap-ro, Bundang-gu, Seongnam 13496, Korea Tel: 82-31-780-5330, Fax: 82-31-780-5336 E-mail: eye@cha.ac.kr * Conflicts of Interest: The authors have no conflicts to disclose. 불린G4 형질세포가관찰되는질환으로전신모든장기에영향을줄수있다고알려져있으며병인은아직명확하지않다. 1 과거에는 IgG4 연관경화성질환, IgG4 연관자가면역질환등다양한명칭으로불려왔지만 2012년 Research Program for Intractable disease of the Ministry of Health, Labor, and Welfare (MHLW) 에서면역글로불린G4관련질환이라고명명하였고, 진단기준을제시하였다. 2 2015년에 Goto et al 3 은면역글로불린G4관련질환중타기관의침범없이안와에만국한되는경우를면역글로불린 G4관련안질환 (IgG4 related ophthalmic disease) 이라명명하였고영상학적검사, 병리조직학적검사, 전신혈액검사세가지기준에따르는 c2018 The Korean Ophthalmological Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 1071

- 대한안과학회지 2018 년제 59 권제 11 호 - 새로운진단기준을발표하였다. 성인황색육아종은안와를침범하는질환으로양안눈꺼풀의노란색조변화및부종을주증상으로하는질환으로치료가잘되지않고자주재발하며, 조직학적으로포말조직구와토우튼거대세포가관찰되고 S100 및 CD1 염색에음성소견을보이는특징을가지고있다. 4 최근국외에서황색육아종환자에서추후면역글로불린G4관련질환이발병한사례가보고되어있으며, 5,6 본원안과에서과거에성인황색육아종진단후치료및경과관찰중이던환자가최근의면역글로불린G4관련안질환의진단기준에부합하여두가지동반진단이가능했던사례를경험하여보고하고자한다. 증례보고 4개월간지속된양안의눈꺼풀부종및노란종괴를주소로 38세남자환자가본원안과에내원하였다. 담낭절제술을시행받은과거력이있었으며현재복용하는경구약은없었다 (Fig. 1A, B). 양안교정시력은 1.0, 안압은비접촉안압계검사상 15/17 mmhg였으며세극등검사상전안부및후극부에는특이소견이관찰되지않았다. 안구운동장애및안구돌출또한관찰되지않았다. 외부에서촬영한안와컴퓨터단층촬영검사에서양측안와상외측에서연부조직비대가관찰되었다 (Fig. 2A, B). 경구프레드니솔론 20 mg 을 2주복용하였으나증상변화없어국소마취하양안눈꺼풀종괴절제, 조직검사및상안검교정술을시행하였다. 조직검사결과, 피부와눈둘레근에포말조직구및토우튼거대세포의침윤과림프여포가확인되었고 (Fig. 3A), S-100 및 CD1 염색에서음성소견을보여성인안와황색육아종으로진단하였다. 이후혈액종양내과에서아자씨오프린및프레드니솔론으로 6개월간치료를받았다. 4년뒤다시시작되는양안의노란색눈꺼풀종괴및부종을주소로본원안과에다시내원하였으며, 양안교정시력 1.0/0.8, 비접촉안압계검사상 15/15 mmhg였고안구운동장애및안구돌출은관찰되지않았다 (Fig. 1C, D). 혈청단백전기영동검사에서상승된 IgG (1,680.0 mg/dl) 및 IgG4 (1,385.0 mg/l) 값을확인했으며흉부단순촬영, 심전도및다른전신검사소견에서특이소견은관찰되지않았다. 안와자기공명영상검사에서양측성안와연부조직비대가관찰되었고안와상외측에서 T1/T2에서불균질하게등신호강도를보이며조영증강되는소견을보였다 (Fig. 2C, D). 윗눈꺼풀성형술, 연부조직절제및조직검사를시행하였고다시포말조직구및토우튼거대세포의침윤과림프여포가확인되었으며 (Fig. 3D), 검체의면역화학염색에서 IgG4+/IgG+ 는 10-20%, IgG4+ 세포수 22/high power field (HPF) 가확인되었다 (Fig. 3E, F). 4년전에절제했던조직을본원병리학교실에의뢰하여다시면역화학염색한결과 IgG4+/IgG+ 는 40-50%, IgG4+ 세포수 59/HPF로확인되어 (Fig. 3B, C) 전형적인면역글로불린G4관련안질환으로진단하였다. 고찰 성인황색육아종은아직까지원인및진단, 치료가잘알려지지않은질환으로비랑게르한스조직구질환 (non-langerhans cell histiocytosis type 2) 에속하며, 포말조직구, 토우튼거대세포, 다양한섬유화및괴사등의조직학적소견이진단에큰도움이된다. 황색육아종 (adult onset xanthogranuloma), 생괴사성황색육아종 (necrobiotic xanthogranuloma), 에드하임체스터병 (Erdheim-Chester disease), 성인천식동반눈주변황색육아종 (adult onset asthma and periocular xanthogranuloma) 등네가지로분류되며아직까지각종연구에서조직학적진단이전에진단할수있는특이적인방법은알려져있지않고, 수술, 항암요법, 방사선치료, 스테로이드치료를비롯하여다양한치료법들이알려져있지만, 명확하게정해진치료법역시현재알려져있지않다. 7,8 2012년 MHLW에서면역글로불린G4 연관경화성질환, 면역글로불린G4 연관자가면역질환등다양한명칭으로불리던질환을면역글로불린G4관련질환이라고명명하였고, 진단기준을제시하였다. 하지만침범장기마다임상양상과, 병리학적특징이다르기때문에면역글로불린G4관련질환진단기준과더불어각각의기관의특징에부합하는세부적인진단기준이필요하며신장과췌장에해당하는세부진단기준은이미발표된바있다. 2 최근성인안와황색육아종과전신성면역글로불린G4관련질환사이의연관성이보고되고있다. 9-11 두질환은임상적, 영상의학적, 조직병리학적으로공통점을가지며면역글로불린G4 형질세포, 지방괴사, 림프구소포, 섬유화등이이에해당하고정확환연관관계를알기위해서는병리학적으로안와황색육아종의확진과타장기에서면역글로불린 G4관련질환의조직학적근거가확인되어야한다. 2017년 McKelvie et al 10 의보고에따르면, 성인황색육아종의경우눈꺼풀과안와앞부분에주로병변이나타나며면역글로불린G4관련안질환에서눈꺼풀에병변이나타나는경우는극히드물고안와아랫부분이나얼굴신경에 30% 정도발병한다. 안구외장기침범으로는성인황색육아종의경우에드하임테스터병에서만타장기침범이보고 1072

- 이승현외 : 황색육아종과면역글로불린 G4 관련안질환 - A B C D Figure 1. Clinical photographs of the patient s eyelid with the diagnosis of adult xanthogranulomatous disease. The patient visited clinic with bilateral eyelid swelling and yellowish mass (A, B). Four years later, he was re-visited with the same symptoms (C, D). A C B D Figure 2. Orbital computed tomography on the first visit demonstrated bilateral soft tissue swelling with no bone invasions (A, B). Coronal image (A), Axial image (B), magnetic resonance imaging on 4 years later demonstrated bilateral soft tissue swelling with no bone invasions (C, D). T2 axial image show diffuse swelling with heterogenous signal intensities at bilateral lacrimal glands (C). T1 axial image show heterogenous soft tissue swelling at bilateral eyelids and preseptal areas (D). A B C D E F Figure 3. Histologic findings of orbital mass on the first excisional biopsy. (A) Variable germinal centers and nodular lymphoid infiltrates in the lacrimal gland and the touton giant cells (arrow) and many foamy histiocytes in the subcutaneous layer (Hematoxylin and eosin [H&E] stain, 200). (B, C) Immunohistochemical stain of orbital mass 4 years later, immunoglobulin G4 [IgG4]+/IgG+ plasma cell ratio of 40-50% and 59 IgG4+ plasma cells per high power field (HPF). IgG plasma cells ( 100) (B), IgG4 plasma cells ( 100) (C). Histologic findings of orbital mass on relapse (D). Diffuse infiltration of foamy histiocytes (arrow) and a few lymphoplasma cells (dash arrow) (H&E stain, 100). (E, F) Immunohistochemical stain of orbital mass on relapse, IgG4+/IgG+plasma cell ratio of 10-20%and 22 IgG4+ plasma cells per HPF. IgG plasma cells ( 100) (E), IgG4 plasma cells ( 100) (F). 1073

- 대한안과학회지 2018 년제 59 권제 11 호 - 되었다. 면역글로불린G4관련안질환에서만악성림프종으로의진행이보고되었고, 타연구에서는성인안와황색육아종과단세포군감마글로불린병증, 형질세포질환등의악성질환과의관련이보고되었다. McKelvie et al 10 의보고에따르면, 과거생괴사성황색육아종으로진단받은환자가 4년후췌장염이발병하였고이후양안상안검부종과췌장염이호전과재발을반복하였다. 안와조직검사가반복되어시행되었지만섬유화가동반된급성및만성염증이외에특이소견은관찰되지않았다. 췌장염발병 10년후초기췌장의조직을다시검사하였고고배율현미경검사상 150 개의 IgG4+ 형질세포, IgG4+/IgG+ 비율이 200% 관찰되었으며, 면역글로불린G4관련자가면역림프구경화췌장염소견을보였다. 이후이전에조직검사를시행한안검, 안와조직을다시검사하였고고배율현미경검사상 70개의 IgG4+ 형질세포, IgG4+/IgG+ 비율은 58% 가관찰되었으며, 생괴사를동반한명확한황색육아종소견을보였다. 따라서이환자는안와에증가한 IgG4+ 형질세포와함께생괴사성황색육아종을가지며, 이후면역글로불린G4관련자가면역췌장염이동반된사례였다. 면역글로불린G4관련질환은전신염증성섬유화질환으로거의모든장기를침범할수있는것으로알려져있으며, 전신증상으로는갑상선염, 특발비대성심막염, 심낭침범, 폐가성종양, 제1형자가면역췌장염, 세균성췌장염, 세뇨관간질신염, 막성신병증, 신장의가성종양, 후복막섬유증, 대동맥염, 림프절병증등이보고되고있다. 12 안와에나타나는대표적인증상으로는눈물샘염 (62.0%), 안와근염 (19.0%), 공막염 (4.8%) 및비루관폐쇄 (4.8%) 등이보고되고있다. 면역글로불린G4관련질환은신체의여러기관에서발생할수있지만반드시여러장기에서동시적으로발생하는것은아니다. 하지만안와병변이발견되어진단될때다른기관에서이상을발견하는것은드문일이아니며 (71.0%), 특히혈청 IgG4가현저하게상승한경우 (900 mg/dl 이상 ) 타액선이나림프절과같은안와외병소가동시에발생할가능성이높다는보고도있다. 13 면역글로불린G4관련질환중타기관의침범없이안와만침범한경우를면역글로불린G4관련안질환이라명명하며, 2015년 Goto et al 3 은안와침범만있는경우에한하여적용할수있는면역글로불린G4관련안질환진단기준을제시하였다. 진단기준은세가지로, 이를만족하는정도에따라 definitive, probable, possible로분류하였다. 첫번째진단기준은영상검사에서눈물샘, 삼차신경, 외안근을포함한다양한안와조직의종양이나비대소견을보이는것이다. 두번째는병리조직학적검사에서저명한림프구와형질세포의침윤이나경화를보이거나종자중심이관찰되며, IgG4 +/IgG+ 세포비율 40% 이상또는고배율현미경관찰시 IgG4+ 세포가 50개이상보이는것이다. 세번째는혈액검사에서혈청 IgG4가 135 mg/dl 이상인것이다. 세가지기준모두를만족하면 definitive, 첫번째와두번째조건만만족할시 probable, 첫번째와세번째조건만만족할시 possible 면역글로불린G4관련안질환으로진단한다. 14 면역글로불린 G4관련안질환관련유병율은아직명확하게알려져있지않으나최근일본의다기관조사에따르면안와림프증식성질환 1,014예중 mucosa-associated lymphoid tissue (MALT) 림프종이 39.8% 로가장많았고, 면역글로불린G4관련안질환이 21.6% 로보고되었다. 안와가성종양, 특발성안와염등의진단하스테로이드를반복적으로사용하는환자중실제로많은수가면역글로불린G4관련안질환과관련성이있음을고려해보아야할것이며안와근염, 특발시신경병증또는후공막염등의경우에도면역글로불린 G4관련안질환과구별이어려울수있다. 15 국내에서면역글로불린 G4관련질환에대한보고는 2010년 Kim et al 16 의 Hyper-IgG4 증후군 3예, 2012년 Cho et al 17 의시신경을침범한면역글로불린G4 연관경화성질환 1 예, 2013년 Yoon et al 18 의특발경화성외안근염환자에서발생한눈꺼풀면역글로불린G4 연관경화병증 1예등이있으며, 전신침범이없이 2015년면역글로불린G4관련안질환에부합하는증례는 2017년 Chung et al 14 의 definitive 면역글로불린G4관련안질환이최초보고된증례가있었다. 본증례의환자는 2013년조직학적으로성인황색육아종진단후면역억제제및스테로이드치료를지속적으로받았으나안와연부조직의부종이재발하였고, 이후전신혈액검사및조직병리검사등을통해, 2015년발표된 definitive 면역글로불린G4관련안질환으로확진되었다. 즉진단의시기는달랐지만, 환자가처음내원했을때부터두질환이같이있었음을확인할수있었다. 따라서반복되는눈꺼풀부종및종괴가있는환자를진단할때안와종양, 안와자가면역질환, 특발안와염과더불어면역글로불린G4관련질환을감별질환에반드시고려해야할것이며, 황색육아종과면역글로불린G4관련질환이동시에있을수있다는사실도염두에두어야할것이다. 진단에있어전신혈액검사, 영상검사및조직검사가도움될것으로사료된다. 또두질환이단독으로있을때와함께병발했을때각각의예후나치료방법의차이에대한연구가앞으로필요할것으로생각된다. REFERENCES 1) Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med 2012;366:539-51. 1074

- 이승현외 : 황색육아종과면역글로불린 G4 관련안질환 - 2) Umehara H, Okazaki K, Masaki Y, et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol 2012;22:21-30. 3) Goto H, Takahira M, Azumi A. Diagnostic criteria for IgG4-related ophthalmic disease. Jpn J Ophthalmol 2015;59:1-7. 4) Guo J, Wang J. Adult orbital xanthogranulomatous disease: review of the literature. Arch Pathol Lab Med 2009;133:1994-7. 5) Burris CK, Rodriguez ME, Raven ML, et al. Adult-onset asthma and periocular xanthogranulomas associated with systemic IgG4- related disease. Am J Ophthalmol Case Rep 2016;1:34-7. 6) Honda Y, Nakamizo S, Dainichi T, et al. Adult onset asthma and periocular xanthogranuloma associated with IgG4 related disease with infiltration of regulatory T cells. J Eur Acad Dermatol Venereol 2017;31:e124-5. 7) Vick VL, Wilson MW, Fleming JC, Haik BG. Orbital and eyelid manifestations of xanthogranulomatous diseases. Orbit 2006;25:221-5. 8) Sivak-Callcott JA, Rootman J, Rasmussen SL, et al. Adult xanthogranulomatous disease of the orbit and ocular adnexa: new immunohistochemical findings and clinical review. Br J Ophthalmol 2006;90:602-8. 9) Singh K, Rajan KD, Eberhart C. Orbital necrobiotic xanthogranuloma associated with systemic IgG4 disease. Ocul Immunol Inflamm 2010;18:373-8. 10) McKelvie P, McNab AA, Hardy T, Rathi V. Comparative study of clinical, pathological, radiological, and genetic features of patients with adult ocular adnexal xanthogranulomatous disease, Erdheim- Chester Disease, and IgG4-related disease of the orbit/ocular adnexa. Ophthalmic Plast Reconstr Surg 2017;33:112-9. 11) Mudhar HS, Bhatt R, Sandramouli S. Xanthogranulomatous variant of immunoglobulin G4 sclerosing disease presenting as ptosis, proptosis and eyelid skin plaques. Int Ophthalmol 2011;31:245-8. 12) Wallace ZS, Deshpande V, Stone JH. Ophthalmic manifestations of IgG4-related disease: single-center experience and literature review. Semin Arthritis Rheum 2014;43:806-17. 13) Kubota T, Katayama M, Moritani S, Yoshino T. Serologic factors in early relapse of IgG4-related orbital inflammation after steroid treatment. Am J Ophthalmol 2013;155:373-9.e1. 14) Chung SR, Lee TE, You IC, et al. A typical case of IgG4-related ophthalmic disease satisfying diagnostic criteria. J Korean Ophthalmol Soc 2017;58:852-6. 15) Japanese study group of IgG4-related ophthalmic disease. A prevalence study of IgG4-related ophthalmic disease in Japan. Jpn J Ophthalmol 2013;57:573-9. 16) Kim K, Lee MJ, Kim NJ, et al. Three cases of hyper-igg4 syndrome involving ocular adnexa. J Korean Ophthalmol Soc 2010; 51:1133-8. 17) Cho HS, Choi JY, Yum JH. A case of IgG4-related sclerosing disease involving the optic nerve. J Korean Ophthalmol Soc 2012;53: 1879-84. 18) Yoon JH, Jung JW, Chi MJ. A case of IgG4-related sclerosing disease involving the eyelid in an idiopathic sclerosing myositis patient. J Korean Ophthalmol Soc 2013;54:160-4. 1075

- 대한안과학회지 2018 년제 59 권제 11 호 - = 국문초록 = 황색육아종과동반된면역글로불린 G4 관련안질환 1 예 목적 : 기존안와황색육아종이진단되었던환자에서재발된피부황색육아종을통하여면역글로불린 G4 관련안질환이동반진단된증례를보고하고자한다. 증례요약 : 양안의눈꺼풀부종을주소로 38 세남성이내원하였다. 전안부및후극부에서특이소견이관찰되지않았다. 조직검사상포말조직구및토우튼거대세포가관찰되며 S100 및 CD1 염색에음성소견을보여성인황색육아종진단하경구아자씨오프린과프레드리솔론치료를받았다. 4 년뒤양안의노란색눈꺼풀종괴를주소로재내원하였다. 자기공명영상에서양안안와상외측의대칭적인연부조직부종이관찰되었고, 혈액검사상 immunoglobulin G (IgG) 및 IgG4 수치가상승되었다. 조직검사후면역화학염색에서 IgG4+/IgG+ 10-20%, IgG4+ 22/ 고배율시야가확인되었으며과거조직을재염색하여 IgG4+/IgG+ 40-50%, IgG4+ 59/ 고배율시야를확인하여전형적인면역글로불린 G4 관련안질환으로새롭게진단하였다. 결론 : 비특이적인눈꺼풀부종환자에서면역글로불린 G4 관련안질환을고려해야하며, 기존황색육아종환자에서도면역글로불린 G4 관련안질환이동반될수있다. < 대한안과학회지 2018;59(11):1071-1076> 이승현 / Seunghyun Lee 차의과학대학교분당차병원안과학교실 Department of Ophthalmology, CHA Bundang Medical Center 1076