Adult Orbital Xanthogranulomatous Disease: a retrospective analysis on clinical characteristics, serological examination and immunohistochemical findings of different subtypes

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Here we summarized characteristics of 20 AOXGD patients to explore the ethnic features of these disease. Methods: Patients of definite AOXGD diagnosis undergoing treatment were reviewed. Clinical characteristics were collected and analyzed. Results: 20 AOXGD patients were composed of 10 adult-onset asthma and periocular xanthogranuloma (AAPOX), 7 necrobiotic xanthogranuloma (NBX), 3 adult-onset xanthogranuloma (AOX). All cases were bilateral involved with symptoms of nodularity, yellow discoloration, eyelid swelling and mechanical ptosis. 10 patients (45%) had elevated serum IgG4 with average of 2.97±2.29g/L, which was significantly associated with relative eyelid thickness (RET) and orbital involvement (dominant in AAPOX subtype, P<0.05). The ratio of IgG4/IgG positive plasma cells in tissues was from 2.9% to 33.4%. Based on the IgG4 related disease (IgG4-RD) diagnostic criteria, no AOXGD patients met the definitive diagnostic criteria of IgG4-RD. All patients underwent surgeries to remove most lesions and obtain definite pathological diagnosis, then following methylprednisolone and methotrexate administration. After the treatment, ptosis and swelling were significantly corrected without local recurrence. The immunohistochemistry results showed that the TIMP- 1 protein level was higher in AOXGD tissues than in normal tissues. Conclusions: In our cases AOXGD is a rare and special disease characterized by elevated serum IgG4 alone, especially in AAPOX subtype. Degree of eyelid swelling and orbital involvement in AOXGD is significantly associated with serum IgG4 level, which serves as a potent indicator to choose the therapeutic regimen and operation opportunity. Surgery assisted with methylprednisolone and methotrexate administration is an effective therapy for AOXGD. Inflammatory processes participated in the development of AOXGD and thus AOXGD may be a kind of inflammatory disease. Adult orbital xanthogranulomatous disease (AOXGD) IgG4 Therapy Figures Figure 1 Figure 2 Figure 3 Figure 4 1 Introduction Adult orbital xanthogranulomatous disease (AOXGD) is a rare non-Langerhans cell histiocytosis comprising four syndromes: adult-onset xanthogranuloma (AOX), adult-onset asthma and periocular xanthogranuloma (AAPOX)[ 1 ], necrobiotic xanthogranuloma (NBX)[ 2 ] and Erdheim-Chester disease (ECD)[ 3 ]. AOX is an isolated xanthogranuloma located subcutaneously around the eyelid without systemic involvement. AAPOX is a syndrome showing yellow, swelling and indurated xanthomatous eyelids and/or periorbital masses[ 4 , 5 ]. It always combined with asthma, extraocular muscle and lacrimal gland involvement. NBX is characterized by subcutaneous lesions tending to ulcerated and fibrose[ 6 ]. ECD is the severest type of AOXGD together with progressive lymphohistiocytic infiltration in the orbit and internal organs including mediastinum, pericardium and pleural, perinephric and other tissues[ 7 , 8 ]. The histopathologic features ofAOXGD are mononucleated foamy histiocytes accompanied by lymphocytes, plasma cells and Touton giant cells[ 4 ]. The diagnosis of each type of AOXGD is difficult to subclassify on the basis of histopathology alone and usually requires the correlation of systemic involvement. There were some evidences suggesting a strong link between IgG4 related disease (IgG4-RD) and AOXGD[ 9 , 10 ]. IgG4-RD is an immune-mediated tumor-like swelling of involved organs, fibrosis and the lymphocytic infiltration dominant for IgG4-positive plasma cells[ 11 ]. However, because of the low incidence, these findings were mainly from case reports and lack of substantial evidences. This study collected 20 AOXGD patients to summarize the clinical features, to expound the association between characteristics and IgG4, additionally to propose the appropriate therapeutic regimen. 2 Methods 20 patients of definite AOXGD diagnosis who presented to Department of Ophthalmology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine were reviewed from January 2015 to January 2019. Basic information included age, gender, disease duration, medication, previous surgical procedure and local recurrence. The evaluative clinic features included nodularity, yellow discoloration, laterality of involvement, margin reflex distance 1(MRD1), relative eyelid thickness (RET), orbital involvement, systemic diseases, serum immunoglobulin level (IgG, IgA, IgM, IgE, IgG4). The degree of mechanical ptosis and eyelid swelling was assessed by MRD1 and RET respectively. RET was determined in the lateral view and defined as the most swelling eyelid site to the cornea compared with the lateral corneal height which was set as 1 (Fig. 1 ). The orbital involvement was measured through CT or MRI images including periorbital masses, enlargement of lacrimal gland and extraocular muscle ( Fig. 2 A ). Thoracoabdominal CT, X-ray or ultrasound examinations were collected to estimate systemic diseases. All patients underwent surgeries to remove most lesions and obtain definite pathological diagnosis. Then following methylprednisolone and methotrexate administration. Methylprednisolone was taken orally according to weight (0.5mg/kg) and tapered regularly (5mg reduction per month). Methotrexate was administrated concomitantly with dose of 10mg/d and tapered in 9 months (2.5mg reduction every 3 months). The IgG4 and IgG positive plasma cells in AOXGD tissues were examined in immumohistochemical staining assay. The evaluations and operative procedures were performed by the same surgical team. A minimum follow-up of 6 month was required. SPSS (IBM Statistics Software Version 22) was used for Statistical analysis. The gender distribution and orbital involvement between groups was analyzed using the X2 test. Other characteristics between groups was analysed using one-way ANOVA. Correlation of IgG4, IgE and clinical characteristics was analyzed by Spearman rank correlation test. Evaluation values of pre-operation and post-operation was analyzed by independent-samples T test. The average was present as mean ± SD. A P value less than 0.05 was considered significant. Informed consent for treatment, clinical and radiographic photographs was obtained for all patients. This study was approved by Shanghai Ninth People’s Hospital Ethical Committee. 3 Results 3.1 Clinical characteristics of AOXGD The clinical characteristics of 22 AOXGD patients were summarized in Table 1 (as shown in Supplemental Table 1). Based on the biopsy (distinctive Touton giant cells, Fig. 2 C), imaging features and medical history, all AOXGD patients were classified into three subtypes: 10 AAPOX patients, 7 NBX patients and 3 AOX patients. There was no ECD in these patients. 7 of 20 patients were male (35%) and the other 13 were female (65%). The average age was 48.74 ± 7.65 years old (range from 27 to 64 years old). The average duration ofAOXGD before presentation was 6.77 ± 4.07 years and no patient had self-limited tendency. There was no previous medical or surgical procedure before presentation in all patients. All cases were bilateral involved (40 eyes) with typical symptoms of nodularity, yellow discoloration and eyelid swelling (Fig. 2 B). RET, the index of evaluating eyelid swelling, was from 1.08 to 2.1 (average RET was 1.58 ± 0.35). Because of eyelid swelling, the patients displayed various degrees of ptosis. MRD1, index of evaluating ptosis, ranged from 0.5 to 3.5mm (average MRD1was 2.05 ± 0.75mm). The orbital involvement was present in 12 cases (60%) through CT or MRI, including lacrimal gland enlargement in 8 patients, lacrimal gland prolapse in 2 patients, extraocular muscle enlargement in 4 patients. Five AAPOX patients had the adult-onset asthma history, nine AAPOX patients had diffuse enlargement of bilateral salivary glands, one NBX patient had leukoderma history and no systemic diseases were found in the other 16 patients. The mean serum IgG4 level was 2.97 ± 2.29g/L (range from 0.17 to 7.31g/L, normal: 0.03g/L ~ 1.35g/L). The mean serum IgE level was 94.86 ± 53.85IU/ml (range from 18 to 267IU/ml, normal: 0 ~ 100IU/ml). 3.2 Clinical characteristics of AOXGD subtypes To investigate the features of three types of AAPOX in our study, the difference analysis of variance was performed in Table 1 (as shown in Supplemental Table 1). There was no difference of age, gender, duration and serum IgE level among three groups. However, serum IgG4 level, MRD1, RET and orbital involvement displayed significant difference in three groups (P < 0.05). 55 percent of patients showed high serum IgG4 including 8 AAPOX, 2 NBX and 1 AOX. Elevated serum IgG4 was significantly distributed in AAPOX group with average of 4.63 ± 2.21g/L (P < 0.05) compared with average of 1.78 ± 1.27g/L and 1.04 ± 0.9g/L in NBX and AOX respectively. AAPOX subtype was also prone to have decreased MRD1 and increased RET with average of 1.65 ± 0.58mm and 1.86 ± 0.21 respectively (P < 0.05). Because of the definition ofAAPOX, the orbital involvement was mainly present in all AAPOX patients and 2 out of 7 (28.6%) in NBX. 3.3 High Serum IgG4 is the feature of AOXGD As mentioned above, 55% AOXGD had the elevated serum IgG4 especially in AAPOX subtype (Fig. 3 B). To further explore the association of IgG4 and AOXGD, tissues IgG4 examination was performed through immumohistochemical staining assay. The results showed that AOXGD tissues had various degrees of IgG4 staining (Fig. 3 A). The ratio of IgG4/IgG positive plasma cells in tissues was from 2.9–33.4%, with average of 15.9 ± 8.7%. According to 2012 comprehensive clinical diagnostic criteria for IgG4-RD: (1) single or multiple swelling organs, (2) high serum IgG4 level and (3) a ratio of IgG4/IgG positive plasma cells > 40%[ 12 ], the definite diagnosis for IgG4-RD should meet three items of criteria. Both (1) and (3) was the more probable histological diagnosis for IgG4-RD. Both (1) and (3) was the possible diagnosis for IgG4-RD. All AOXGD patients presented swelling organs of eyelid masses or enlarged lacrimal gland. However, none of the patients fulfill the histological diagnostic criteria for IgG4-RD. Base on the diagnostic criteria, these 20 AOXGD patients failed to confirm to definite IgG4-RD diagnosis. These results suggested that AOXGD was not considered to be definite IgG4-RD. AOXGD, especially AAPOX, was a special disease characterized by high serum IgG4 alone. 3.4 Association of serum IgG4 and AOXGD characteristics Elevated serum IgG4 was common in AOXGD, herein correlation analysis was performed to explore the association between clinical characteristics and serum IgG4 (as shown in Supplemental Table 2). The serum IgG4 level was significant associated with RET and orbital involvement (P < 0.05), but shared no correlation with age, gender, duration and MRD1. Although the MRD1 and RET displayed negative correlation (P < 0.05), the serum IgG4 did not share correlation with MRD1 directly. It was indicated that AOXGD patients with elevated serum IgG4 was prone to have symptoms of severe swelling eyelid, together with orbital involvement. Additionally, serum IgE was also examined, which was reported abnormal in some previous study. 8 patients (40%) showed increased serum IgE. However, no correlation was observed between serum IgE level and all clinical characteristics. 3.5 Treatment of surgery combined with methylprednisolone and methotrexate All patients received the resection of palpebral masses and most of orbital lesions. Methylprednisolone and methotrexate was concomitantly administrated the day after the operation. The average follow-up was 11.32 ± 4.69 mouths. After the treatment ptosis was corrected obviously with significantly increased MRD1 (as shown in Supplemental Table 3). Postoperative mean MRD1 was 3.45 ± 0.65mm (range from 3.5 to 4 mm, P < 0.01). Compared with pre-operation, the eyelid swelling was improved remarkably with significantly decreased RET value (Fig. 2 D). Postoperative mean RET was 0.88 ± 0. 17 (range from 0.66 to 1.41, P < 0.01). Until the last follow-up, no local recurrence was observed in all cases. 3.6 Immunohistochemistry analysis of AOXGD tissues Additional paraffin-embedded samples were collected, and silanized slides containing 3-µm-thick tissue sections were divided for immunohistochemistry analysis. Immunohistochemistry was performed using antibodies against TIMP- 1. The immunohistochemistry results showed that the TIMP- 1 protein level was higher in AOXGD tissues (Fig. 4 ). 4 Discussion Adult orbital xanthogranulomatous disease (AOXGD) is a rare non-Langerhans cell histiocytosis comprised of four subtypes: AOX, AAPOX[ 1 ], NBX[ 2 ] and ECD[ 3 ]. AOX is an isolated xanthogranuloma located subcutaneously around the eyelid without orbital and systemic involvement. AAPOX is a syndrome with yellow, swelling and indurated xanthomatous eyelids and periorbital masses[ 4 , 5 ]. It always combined with adult-onset asthma, extraocular muscle and lacrimal gland involvement. NBX is characterized by subcutaneous lesions tending to ulcerated and fibrose[ 6 ]. ECD is the severest type of AOXGD together with progressive lymphohistiocytic infiltration in the orbit and internal organs including mediastinum, pericardium and pleural, perinephric and other tissues[ 7 , 8 ]. The histopathologic features ofAOXGD are mononucleated foamy histiocytes accompanied by lymphocytes, plasma cells and specific Touton giant cells (Fig. 2 C)[ 4 ]. The diagnosis of each type of AOXGD is difficult to subclassify on the basis of histopathology alone and usually requires the correlation of systemic involvement. Because of the rarity, majority of previous researches were case reports or overviews of reference literature and few studies were carried in patients. In present study, 20 patients of definite AOXGD diagnosis were reviewed and classified into three categories: 10 AAPOX patients, 7 NBX patients and 3 AOX patients. Among four subtypes of AOXGD, AOX was considered to be the least common and NBX was considered to be the most common[ 13 ]. However, our results showed the proportion of 210 50% AAPOX and 35%NBX. No ECD patient was in our study, because ECD patients were always combined with severe systemic involvement which made them not to preferentially visit to Ophthalmology. In reviews there was no sex preference in AOX and NBX[ 4 , 14 ], but male preferential in AAPOX and ECD (male to female ratio, 2:1)[ 6 , 15 ]. Our gender distribution was different from the that of literature. There was female preferential in NBX (male to female ratio, 1:6), but no difference was observed between three groups. Although the sample number here was far bigger than that of previous studies, it still belonged to small sample leading to bias. The clinical manifestations of AOXGD were palpebral nodularity, yellow discoloration, eyelid swelling and mechanical ptosis. The degree of AOXGD severity was always declarative alone in most study[ 16 – 18 ] and there was lack of appropriate and quantitative outcome measures to evaluate the effects of treatment. Here we used MRD1 and RET as the before-and-after treatment outcome measures to assess the degree of mechanical ptosis and eyelid swelling respectively. RET was determined in the lateral view and defined as the most swelling eyelid site to the cornea compared with the lateral corneal height which was set as 1 (Fig. 1 A). These two important indexes helped us to better analyze in this study. There is a viewpoint that AOXGD, AAPOX or NBX, is associated with IgG4-related disease (IgG4-RD)[ 10 , 19 – 22 ]. IgG4-RD is a systemic inflammatory fibrosing disorder frequently with elevated serum IgG4 level, which may involve almost every organ[ 23 ]. Ophthalmic manifestations include: dacryoadenitis, orbital pseudotumor, orbital myositis, scleritis, and nasolacrimal duct obstruction. The main histopathological characteristics are an association of lymphoplasmacytic infiltrate with increased number of IgG4-positive plasma cells, storiform-type fibrosis, and obliterative phlebitis. IgG4-RD is diagnosed by 2012 comprehensive clinical diagnostic criteria: (1) single or multiple swelling organs, (2) high serum IgG4 level and (3) a ratio of IgG4/IgG positive plasma cells > 40%[ 12 ]. The definite diagnosis for IgG4-RD should meet three items of criteria. Both (1) and (3) is the more probable histological diagnosis for IgG4-RD. Both (1) and (3) is the possible diagnosis for IgG4-RD. It was reported that significant infiltration of IgG4-positive plasma cells and elevated IgG4 serology were observed in part of AOXGD cases. In our results 55 percent of patients (11 of 20) had high serum IgG4 including 8 AAPOX, 2 NBX and 1 AOX. The ratio of IgG4/IgG positive plasma cells in tissues was from 2.9–33.4%. None of the patients fulfill the histological diagnostic criteria for IgG4-RD. Base on the diagnostic criteria, these AOXGD patients were not considered to be definite IgG4-RD. Elevated serum IgG4 was significantly distributed in AAPOX group with average of 4.63 ± 2.21g/L, but not in NBX and AOX. AAPOX subtype was also prone to have decreased MRD1 and increased RET. To further investigate the association between IgG4 and AOXGD, we performed the correlation analysis between serum IgG4 level and clinical characteristics. Orbital involvement and eyelid swelling were significantly associated with the increased serum lgG4 level. It is reminded in the future that examination of serum IgG4 level is indispensable in AOXGD patients present with the swelling appearance. It is suggested that AOXGD, especially AAPOX, was a special disease characterized by high serum IgG4 alone. Tissue inhibitors of metalloproteinases (TIMPs) have been described to be related with a wide range of inflammatory and pathological processes. Of 4 paralogous genes in human genome encoding TIMPs, TIMP-1 is the most important in the regulation of the extracellular matrix which is proved to exist in various pathological processes such as inflammation and tumor invasion. According to the immunohistochemistry result that TIMP-1 protein level in AOXGD tissues was higher than that in normal tissues, inflammatory processes participated in the development of AOXGD and thus AOXGD may be a kind of inflammatory disease. A myriad of therapies has been attempted including administration of corticosteroid[ 24 ] (topical, intralesional, and systemic), alkylating agents[ 25 ], antimetabolites and interferon[ 26 ], radiotherapy, plasmapheresis and surgical debulking[ 27 ]. The effect of each therapy is still controversial and amphibolous. Some study claimed only observation for AOX patients because of self-limited tendency. However, we failed to observe this tendency in our 3 AOX patients and it was suggested that treatment should be required on the early phase because of possible scarring or necrosis[ 27 ]. By now there is no uniform standard for AOXGD treatment. In our study, surgery was the first step of sequential treatment. The aim of surgery is not only to remove most of lesions, but also to obtain definite pathological diagnosis. Based on pathological features and the abnormal serum IgG4, methylprednisolone and methotrexate was administrated in our study after the operation. The methylprednisolone was available for relieve edema, inflammation and enlargement of orbital involvement in addition to debulking. Methotrexate is a folate antagonist that affects T cells and macrophage recruitment and function. It has anti-inflammatory properties and is the most frequently reported in the treatment of IgG4-ROD. Methotrexate can be initiated as a steroid-sparing agent. This sequential therapy achieved satisfactory outcomes with remarkable correction of ptosis, improved eyelid fullness and satisfactory contour. Until the last follow-up, no local recurrence was observed in all cases. The prognosis in AOXGD is also different from that of IgG4-RD, which always has a high recurrence rate. It is demonstrated that surgery combined with methylprednisolone and methotrexate is effective. 5 Conclusion In our cases AOXGD is a rare and special disease characterized by elevated serum IgG4 alone, especially in AAPOX subtype. Degree of eyelid swelling and orbital involvement in AOXGD is significantly associated with serum IgG4 level. Surgery assisted with methylprednisolone and methotrexate is an effective therapy for AOXGD. Declarations Funding: This work was supported by the National Natural Science Foundation of China (grants 81870688, 81970834 and 82371067), the Science and Technology Commission of Shanghai Municipality (grants 19441900800) and the Clinical Research Program of 9th People's Hospital, Shanghai Jiao Tong University School of Medicine (JYLJ202418). The funders had no role in study design, data collection and analysis, decision to publish,or preparation of the manuscript. Conflict of Interest: This study has no commercial or propriety interest. The authors report no conflict of interest. Availability of data and material: The datasets used or analysed during the current study are available from the corresponding author on reasonable request. Code availability: Not applicable. Ethical Approval: Ethical approval was given by Shanghai Ninth People’s Hospital Ethical Committee. Consent to participate: Patient consent was obtained to publish the clinical photographs. All figures in the manuscript were drawn and composed by ourselves. Consent for publication: Written informed consent for publication was obtained from all participants. References Jakobiec FA, MD Mills, AA Hidayat, and etc. Periocular xanthogranulomas associated with severe adult-onset asthma. Trans Am Ophthalmol Soc, 1993. 91: p. 99-125; discussion 125-9. Robertson, D.M. and R.K. Winkelmann. Ophthalmicfeatures of necrobiotic xanthogranuloma with paraproteinemia. Am J Ophthalmol, 1984. 97(2): p. 173-83. Alper, M.G., L.E. Zimmerman, and F.G. Piana. Orbital manifestations of Erdheim-Chesterdisease. Trans Am Ophthalmol Soc, 1983. 81: p. 64-85. Sivak-Callcott, J.A., J. Rootman, S.L. 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Elner VM, R Mintz, H Demirci, and etc. Local corticosteroid treatment of eyelid and orbital xanthogranuloma. Ophthal Plast Reconstr Surg, 2006. 22(1): p. 36-40. Torabian SZ, N Fazel, and R Knuttle. Necrobiotic xanthogranuloma treated with chlorambucil. Dermatol Online J, 2006. 12(5): p. 11. Liszewski W, JD Wisniewski, H Safah, and etc. Treatment of refractory necrobiotic xanthogranulomas with extracorporeal photopheresis and intravenous immunoglobulin. Dermatol Ther, 2014.27(5): p. 268-71. Miguel D, J Lukacs, T Illing, and etc. Treatment of necrobiotic xanthogranuloma - a systematic review. J Eur Acad Dermatol Venereol,2017. 31(2): p. 221-235. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6225843","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":452584110,"identity":"89645ecf-c4f1-4fae-8a78-e562365241ab","order_by":0,"name":"Rui Li","email":"","orcid":"","institution":"Shanghai Ninth People ’ s Hospital, Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Li","suffix":""},{"id":452584111,"identity":"7add6c8d-5db4-4d3c-8615-ee2ab0993e17","order_by":1,"name":"Xia Ding","email":"","orcid":"","institution":"Shanghai Ninth People ’ s Hospital, Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xia","middleName":"","lastName":"Ding","suffix":""},{"id":452584112,"identity":"38aa5a16-e3b3-4c4e-9536-1b48fc434b9c","order_by":2,"name":"Yu Yu","email":"","orcid":"","institution":"Shanghai Ninth People ’ s Hospital, Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Yu","suffix":""},{"id":452584113,"identity":"5a741605-81b8-459a-ba59-04e844649869","order_by":3,"name":"Dai Su","email":"","orcid":"","institution":"Shanghai Ninth People ’ s Hospital, Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Dai","middleName":"","lastName":"Su","suffix":""},{"id":452584114,"identity":"196cade8-3959-4452-b0a7-d1ac5c52c226","order_by":4,"name":"Lin Li","email":"","orcid":"","institution":"Shanghai Ninth People ’ s Hospital, Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Lin","middleName":"","lastName":"Li","suffix":""},{"id":452584115,"identity":"6a18cafa-90d1-4e3d-91da-8eee8f2baa69","order_by":5,"name":"Yue Xing","email":"","orcid":"","institution":"Shanghai Ninth People ’ s Hospital, Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Xing","suffix":""},{"id":452584116,"identity":"5bd986ca-034d-496d-971c-72fe4b1e2e7e","order_by":6,"name":"Jin Li","email":"data:image/png;base64,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","orcid":"","institution":"Shanghai Ninth People ’ s Hospital, Shanghai Jiaotong University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Jin","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2025-03-14 11:38:24","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6225843/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6225843/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82309139,"identity":"099e5d5f-f579-4a7f-8557-d6468f9ebb19","added_by":"auto","created_at":"2025-05-09 01:41:42","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":416180,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDefinition of relative eyelid thickness (RET)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRET was determined in the lateral view and defined as the most swelling eyelid site to the cornea (red line) compared with the lateral corneal height (yellow line) which was set as 1.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6225843/v1/679576d7dd99deb056fb10e6.png"},{"id":82309143,"identity":"cfd80cb4-233f-49b8-a660-e25e099dac0f","added_by":"auto","created_at":"2025-05-09 01:41:42","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":596152,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAOXGD clinical manifestation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA. Contrast-enhanced along with fat-suppression on MRI T1WI imaging. It showed clearly the enlargement of bilateral lacrimal gland and extraocular muscle;\u003c/p\u003e\n\u003cp\u003eB. Pre-operative external photograph showed typical bilateral nodularity, yellow discoloration, upper eyelid swelling and mechanical ptosis;\u003c/p\u003e\n\u003cp\u003eC. Histology of xanthogranuloma tissue revealed the infiltration of foamy histiocytes, Touton giant cells and lymphocytes;\u003c/p\u003e\n\u003cp\u003eD. External photograph after receiving combined methylprednisolone and surgery therapy displayed the satisfactory outcome with remarkable correction of ptosis and improved eyelid fullness.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6225843/v1/69e84ab0db95d1e0ca9308ce.png"},{"id":82309840,"identity":"09a30273-6409-4d67-a646-7d7c470a8564","added_by":"auto","created_at":"2025-05-09 01:49:42","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":533054,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSerum and tissue IgG4 expression\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA. Immunohistochemical staining for IgG4 positive plasma cells and IgG4 positive plasma cells in AOXGD tissues;\u003c/p\u003e\n\u003cp\u003eB. Serum IgG4 level in AOXGD patients;\u003c/p\u003e\n\u003cp\u003eC. Ratio of IgG4/IgG positive plasma cells in AOXGD tissues.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6225843/v1/b8daa2a61a01dc037bd6ae00.png"},{"id":82309157,"identity":"e7df7f43-4549-4b11-8abc-f31986231d71","added_by":"auto","created_at":"2025-05-09 01:41:42","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":336288,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTIMP-1 expression in AOXGD and normal tissues\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA. The protein level of TIMP-1 in normal tissues;\u003c/p\u003e\n\u003cp\u003eB. TIMP-1 expression in normal tissues in DAPI fluorescence;\u003c/p\u003e\n\u003cp\u003eC. The protein level of TIMP-1 in normal tissues;\u003c/p\u003e\n\u003cp\u003eD. TIMP- 1 expression in AOXGD tissues in DAPI fluorescence.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6225843/v1/a734be7295930be2d70e2e57.png"},{"id":109032247,"identity":"8245416a-68a4-4f8b-9ebb-6c003eea831d","added_by":"auto","created_at":"2026-05-12 01:10:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2776911,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6225843/v1/595eee0b-ee90-410a-878f-ff072a96c977.pdf"},{"id":82309838,"identity":"611f77e7-291c-4ac5-b06e-f2a3b1d8cace","added_by":"auto","created_at":"2025-05-09 01:49:42","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23397,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-6225843/v1/88c2cefd86c98ca687975a94.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Adult Orbital Xanthogranulomatous Disease: a retrospective analysis on clinical characteristics, serological examination and immunohistochemical findings of different subtypes","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eAdult orbital xanthogranulomatous disease (AOXGD) is a rare non-Langerhans cell histiocytosis comprising four syndromes: adult-onset xanthogranuloma (AOX), adult-onset asthma and periocular xanthogranuloma (AAPOX)[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], necrobiotic xanthogranuloma (NBX)[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and Erdheim-Chester disease (ECD)[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. AOX is an isolated xanthogranuloma located subcutaneously around the eyelid without systemic involvement. AAPOX is a syndrome showing yellow, swelling and indurated xanthomatous eyelids and/or periorbital masses[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. It always combined with asthma, extraocular muscle and lacrimal gland involvement. NBX is characterized by subcutaneous lesions tending to ulcerated and fibrose[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. ECD is the severest type of AOXGD together with progressive lymphohistiocytic infiltration in the orbit and internal organs including mediastinum, pericardium and pleural, perinephric and other tissues[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The histopathologic features ofAOXGD are mononucleated foamy histiocytes accompanied by lymphocytes, plasma cells and Touton giant cells[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The diagnosis of each type of AOXGD is difficult to subclassify on the basis of histopathology alone and usually requires the correlation of systemic involvement. There were some evidences suggesting a strong link between IgG4 related disease (IgG4-RD) and AOXGD[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. IgG4-RD is an immune-mediated tumor-like swelling of involved organs, fibrosis and the lymphocytic infiltration dominant for IgG4-positive plasma cells[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. However, because of the low incidence, these findings were mainly from case reports and lack of substantial evidences. This study collected 20 AOXGD patients to summarize the clinical features, to expound the association between characteristics and IgG4, additionally to propose the appropriate therapeutic regimen.\u003c/p\u003e"},{"header":"2 Methods","content":"\u003cp\u003e 20 patients of definite AOXGD diagnosis who presented to Department of Ophthalmology, Shanghai Ninth People\u0026rsquo;s Hospital, Shanghai Jiao Tong University School of Medicine were reviewed from January 2015 to January 2019. Basic information included age, gender, disease duration, medication, previous surgical procedure and local recurrence. The evaluative clinic features included nodularity, yellow discoloration, laterality of involvement, margin reflex distance 1(MRD1), relative eyelid thickness (RET), orbital involvement, systemic diseases, serum immunoglobulin level (IgG, IgA, IgM, IgE, IgG4). The degree of mechanical ptosis and eyelid swelling was assessed by MRD1 and RET respectively. RET was determined in the lateral view and defined as the most swelling eyelid site to the cornea compared with the lateral corneal height which was set as 1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The orbital involvement was measured through CT or MRI images including periorbital masses, enlargement of lacrimal gland and extraocular muscle ( Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA ). Thoracoabdominal CT, X-ray or ultrasound examinations were collected to estimate systemic diseases. All patients underwent surgeries to remove most lesions and obtain definite pathological diagnosis. Then following methylprednisolone and methotrexate administration. Methylprednisolone was taken orally according to weight (0.5mg/kg) and tapered regularly (5mg reduction per month). Methotrexate was administrated concomitantly with dose of 10mg/d and tapered in 9 months (2.5mg reduction every 3 months). The IgG4 and IgG positive plasma cells in AOXGD tissues were examined in immumohistochemical staining assay. The evaluations and operative procedures were performed by the same surgical team. A minimum follow-up of 6 month was required. SPSS (IBM Statistics Software Version 22) was used for Statistical analysis. The gender distribution and orbital involvement between groups was analyzed using the X2 test. Other characteristics between groups was analysed using one-way ANOVA. Correlation of IgG4, IgE and clinical characteristics was analyzed by Spearman rank correlation test. Evaluation values of pre-operation and post-operation was analyzed by independent-samples T test. The average was present as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. A P value less than 0.05 was considered significant. Informed consent for treatment, clinical and radiographic photographs was obtained for all patients. This study was approved by Shanghai Ninth People\u0026rsquo;s Hospital Ethical Committee.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Clinical characteristics of AOXGD\u003c/h2\u003e \u003cp\u003eThe clinical characteristics of 22 AOXGD patients were summarized in Table\u0026nbsp;1 (as shown in Supplemental Table\u0026nbsp;1). Based on the biopsy (distinctive Touton giant cells, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC), imaging features and medical history, all AOXGD patients were classified into three subtypes: 10 AAPOX patients, 7 NBX patients and 3 AOX patients. There was no ECD in these patients. 7 of 20 patients were male (35%) and the other 13 were female (65%). The average age was 48.74\u0026thinsp;\u0026plusmn;\u0026thinsp;7.65 years old (range from 27 to 64 years old). The average duration ofAOXGD before presentation was 6.77\u0026thinsp;\u0026plusmn;\u0026thinsp;4.07 years and no patient had self-limited tendency. There was no previous medical or surgical procedure before presentation in all patients. All cases were bilateral involved (40 eyes) with typical symptoms of nodularity, yellow discoloration and eyelid swelling (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). RET, the index of evaluating eyelid swelling, was from 1.08 to 2.1 (average RET was 1.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35). Because of eyelid swelling, the patients displayed various degrees of ptosis. MRD1, index of evaluating ptosis, ranged from 0.5 to 3.5mm (average MRD1was 2.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.75mm). The orbital involvement was present in 12 cases (60%) through CT or MRI, including lacrimal gland enlargement in 8 patients, lacrimal gland prolapse in 2 patients, extraocular muscle enlargement in 4 patients. Five AAPOX patients had the adult-onset asthma history, nine AAPOX patients had diffuse enlargement of bilateral salivary glands, one NBX patient had leukoderma history and no systemic diseases were found in the other 16 patients. The mean serum IgG4 level was 2.97\u0026thinsp;\u0026plusmn;\u0026thinsp;2.29g/L (range from 0.17 to 7.31g/L, normal: 0.03g/L\u0026thinsp;~\u0026thinsp;1.35g/L). The mean serum IgE level was 94.86\u0026thinsp;\u0026plusmn;\u0026thinsp;53.85IU/ml (range from 18 to 267IU/ml, normal: 0\u0026thinsp;~\u0026thinsp;100IU/ml).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Clinical characteristics of AOXGD subtypes\u003c/h2\u003e \u003cp\u003eTo investigate the features of three types of AAPOX in our study, the difference analysis of variance was performed in Table\u0026nbsp;1 (as shown in Supplemental Table\u0026nbsp;1). There was no difference of age, gender, duration and serum IgE level among three groups. However, serum IgG4 level, MRD1, RET and orbital involvement displayed significant difference in three groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). 55 percent of patients showed high serum IgG4 including 8 AAPOX, 2 NBX and 1 AOX. Elevated serum IgG4 was significantly distributed in AAPOX group with average of 4.63\u0026thinsp;\u0026plusmn;\u0026thinsp;2.21g/L (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) compared with average of 1.78\u0026thinsp;\u0026plusmn;\u0026thinsp;1.27g/L and 1.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9g/L in NBX and AOX respectively. AAPOX subtype was also prone to have decreased MRD1 and increased RET with average of 1.65\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58mm and 1.86\u0026thinsp;\u0026plusmn;\u0026thinsp;0.21 respectively (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Because of the definition ofAAPOX, the orbital involvement was mainly present in all AAPOX patients and 2 out of 7 (28.6%) in NBX.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e3.3 High Serum IgG4 is the feature of AOXGD\u003c/h2\u003e \u003cp\u003eAs mentioned above, 55% AOXGD had the elevated serum IgG4 especially in AAPOX subtype (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). To further explore the association of IgG4 and AOXGD, tissues IgG4 examination was performed through immumohistochemical staining assay. The results showed that AOXGD tissues had various degrees of IgG4 staining (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). The ratio of IgG4/IgG positive plasma cells in tissues was from 2.9\u0026ndash;33.4%, with average of 15.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7%. According to 2012 comprehensive clinical diagnostic criteria for IgG4-RD: (1) single or multiple swelling organs, (2) high serum IgG4 level and (3) a ratio of IgG4/IgG positive plasma cells\u0026thinsp;\u0026gt;\u0026thinsp;40%[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], the definite diagnosis for IgG4-RD should meet three items of criteria. Both (1) and (3) was the more probable histological diagnosis for IgG4-RD. Both (1) and (3) was the possible diagnosis for IgG4-RD. All AOXGD patients presented swelling organs of eyelid masses or enlarged lacrimal gland. However, none of the patients fulfill the histological diagnostic criteria for IgG4-RD. Base on the diagnostic criteria, these 20 AOXGD patients failed to confirm to definite IgG4-RD diagnosis. These results suggested that AOXGD was not considered to be definite IgG4-RD. AOXGD, especially AAPOX, was a special disease characterized by high serum IgG4 alone.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Association of serum IgG4 and AOXGD characteristics\u003c/h2\u003e \u003cp\u003eElevated serum IgG4 was common in AOXGD, herein correlation analysis was performed to explore the association between clinical characteristics and serum IgG4 (as shown in Supplemental Table\u0026nbsp;2). The serum IgG4 level was significant associated with RET and orbital involvement (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), but shared no correlation with age, gender, duration and MRD1. Although the MRD1 and RET displayed negative correlation (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05), the serum IgG4 did not share correlation with MRD1 directly. It was indicated that AOXGD patients with elevated serum IgG4 was prone to have symptoms of severe swelling eyelid, together with orbital involvement. Additionally, serum IgE was also examined, which was reported abnormal in some previous study. 8 patients (40%) showed increased serum IgE. However, no correlation was observed between serum IgE level and all clinical characteristics.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Treatment of surgery combined with methylprednisolone and methotrexate\u003c/h2\u003e \u003cp\u003eAll patients received the resection of palpebral masses and most of orbital lesions. Methylprednisolone and methotrexate was concomitantly administrated the day after the operation. The average follow-up was 11.32\u0026thinsp;\u0026plusmn;\u0026thinsp;4.69 mouths. After the treatment ptosis was corrected obviously with significantly increased MRD1 (as shown in Supplemental Table\u0026nbsp;3). Postoperative mean MRD1 was 3.45\u0026thinsp;\u0026plusmn;\u0026thinsp;0.65mm (range from 3.5 to 4 mm, P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Compared with pre-operation, the eyelid swelling was improved remarkably with significantly decreased RET value (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eD). Postoperative mean RET was 0.88\u0026thinsp;\u0026plusmn;\u0026thinsp;0. 17 (range from 0.66 to 1.41, P\u0026thinsp;\u0026lt;\u0026thinsp;0.01). Until the last follow-up, no local recurrence was observed in all cases.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Immunohistochemistry analysis of AOXGD tissues\u003c/h2\u003e \u003cp\u003eAdditional paraffin-embedded samples were collected, and silanized slides containing 3-\u0026micro;m-thick tissue sections were divided for immunohistochemistry analysis. Immunohistochemistry was performed using antibodies against TIMP- 1. The immunohistochemistry results showed that the TIMP- 1 protein level was higher in AOXGD tissues (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eAdult orbital xanthogranulomatous disease (AOXGD) is a rare non-Langerhans cell histiocytosis comprised of four subtypes: AOX, AAPOX[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], NBX[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and ECD[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. AOX is an isolated xanthogranuloma located subcutaneously around the eyelid without orbital and systemic involvement. AAPOX is a syndrome with yellow, swelling and indurated\u003c/p\u003e \u003cp\u003exanthomatous eyelids and periorbital masses[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. It always combined with adult-onset asthma, extraocular muscle and lacrimal gland involvement. NBX is characterized by subcutaneous lesions tending to ulcerated and fibrose[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. ECD is the severest type of AOXGD together with progressive lymphohistiocytic infiltration in the orbit and internal organs including mediastinum, pericardium and pleural, perinephric and other tissues[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The histopathologic features ofAOXGD are mononucleated foamy histiocytes accompanied by lymphocytes, plasma cells and specific Touton giant cells (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC)[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. The diagnosis of each type of AOXGD is difficult to subclassify on the basis of histopathology alone and usually requires the correlation of systemic involvement. Because of the rarity, majority of previous researches were case reports or overviews of reference literature and few studies were carried in patients. In present study, 20 patients of definite AOXGD diagnosis were reviewed and classified into three categories: 10 AAPOX patients, 7 NBX patients and 3 AOX patients. Among four subtypes of AOXGD, AOX was considered to be the least common and NBX was considered to be the most common[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, our results showed the proportion of 210 50% AAPOX and 35%NBX. No ECD patient was in our study, because ECD patients were always combined with severe systemic involvement which made them not to preferentially visit to Ophthalmology.\u003c/p\u003e \u003cp\u003eIn reviews there was no sex preference in AOX and NBX[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], but male preferential in AAPOX and ECD (male to female ratio, 2:1)[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Our gender distribution was different from the that of literature. There was female preferential in NBX (male to female ratio, 1:6), but no difference was observed between three groups. Although the sample number here was far bigger than that of previous studies, it still belonged to small sample leading to bias.\u003c/p\u003e \u003cp\u003eThe clinical manifestations of AOXGD were palpebral nodularity, yellow discoloration, eyelid swelling and mechanical ptosis. The degree of AOXGD severity was always declarative alone in most study[\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] and there was lack of appropriate and quantitative outcome measures to evaluate the effects of treatment. Here we used MRD1 and RET as the before-and-after treatment outcome measures to assess the degree of mechanical ptosis and eyelid swelling respectively. RET was determined in the lateral view and defined as the most swelling eyelid site to the cornea compared with the lateral corneal height which was set as 1 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). These two important indexes helped us to better analyze in this study.\u003c/p\u003e \u003cp\u003eThere is a viewpoint that AOXGD, AAPOX or NBX, is associated with IgG4-related disease (IgG4-RD)[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. IgG4-RD is a systemic inflammatory fibrosing disorder frequently with elevated serum IgG4 level, which may involve almost every organ[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Ophthalmic manifestations include: dacryoadenitis, orbital pseudotumor, orbital myositis, scleritis, and nasolacrimal duct obstruction. The main histopathological characteristics are an association of lymphoplasmacytic infiltrate with increased number of IgG4-positive plasma cells, storiform-type fibrosis, and obliterative phlebitis. IgG4-RD is diagnosed by 2012 comprehensive clinical diagnostic criteria: (1) single or multiple swelling organs, (2) high serum IgG4 level and (3) a ratio of IgG4/IgG positive plasma cells\u0026thinsp;\u0026gt;\u0026thinsp;40%[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The definite diagnosis for IgG4-RD should meet three items of criteria. Both (1) and (3) is the more probable histological diagnosis for IgG4-RD. Both (1) and (3) is the possible diagnosis for IgG4-RD. It was reported that significant infiltration of IgG4-positive plasma cells and elevated IgG4 serology were observed in part of AOXGD cases. In our results 55 percent of patients (11 of 20) had high serum IgG4 including 8 AAPOX, 2 NBX and 1 AOX. The ratio of IgG4/IgG positive plasma cells in tissues was from 2.9\u0026ndash;33.4%. None of the patients fulfill the histological diagnostic criteria for IgG4-RD. Base on the diagnostic criteria, these AOXGD patients were not considered to be definite IgG4-RD.\u003c/p\u003e \u003cp\u003eElevated serum IgG4 was significantly distributed in AAPOX group with average of 4.63\u0026thinsp;\u0026plusmn;\u0026thinsp;2.21g/L, but not in NBX and AOX. AAPOX subtype was also prone to have decreased MRD1 and increased RET. To further investigate the association between IgG4 and AOXGD, we performed the correlation analysis between serum IgG4 level and clinical characteristics. Orbital involvement and eyelid swelling were significantly associated with the increased serum lgG4 level. It is reminded in the future that examination of serum IgG4 level is indispensable in AOXGD patients present with the swelling appearance. It is suggested that AOXGD, especially AAPOX, was a special disease characterized by high serum IgG4 alone.\u003c/p\u003e \u003cp\u003eTissue inhibitors of metalloproteinases (TIMPs) have been described to be related with a wide range of inflammatory and pathological processes. Of 4 paralogous genes in human genome encoding TIMPs, TIMP-1 is the most important in the regulation of the extracellular matrix which is proved to exist in various pathological processes such as inflammation and tumor invasion. According to the immunohistochemistry result that TIMP-1 protein level in AOXGD tissues was higher than that in normal tissues, inflammatory processes participated in the development of AOXGD and thus AOXGD may be a kind of inflammatory disease.\u003c/p\u003e \u003cp\u003eA myriad of therapies has been attempted including administration of corticosteroid[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] (topical, intralesional, and systemic), alkylating agents[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], antimetabolites and interferon[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], radiotherapy, plasmapheresis and surgical debulking[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The effect of each therapy is still controversial and amphibolous. Some study claimed only observation for AOX patients because of self-limited tendency. However, we failed to observe this tendency in our 3 AOX patients and it was suggested that treatment should be required on the early phase because of possible scarring or necrosis[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. By now there is no uniform standard for AOXGD treatment. In our study, surgery was the first step of sequential treatment. The aim of surgery is not only to remove most of lesions, but also to obtain definite pathological diagnosis. Based on pathological features and the abnormal serum IgG4, methylprednisolone and methotrexate was administrated in our study after the operation. The methylprednisolone was available for relieve edema, inflammation and enlargement of orbital involvement in addition to debulking. Methotrexate is a folate antagonist that affects T cells and macrophage recruitment and function. It has anti-inflammatory properties and is the most frequently reported in the treatment of IgG4-ROD. Methotrexate can be initiated as a steroid-sparing agent. This sequential therapy achieved satisfactory outcomes with remarkable correction of ptosis, improved eyelid fullness and satisfactory contour. Until the last follow-up, no local recurrence was observed in all cases. The prognosis in AOXGD is also different from that of IgG4-RD, which always has a high recurrence rate. It is demonstrated that surgery combined with methylprednisolone and methotrexate is effective.\u003c/p\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eIn our cases AOXGD is a rare and special disease characterized by elevated serum IgG4 alone, especially in AAPOX subtype. Degree of eyelid swelling and orbital involvement in AOXGD is significantly associated with serum IgG4 level. Surgery assisted with methylprednisolone and methotrexate is an effective therapy for AOXGD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This work was supported by the National Natural Science Foundation of China (grants 81870688, 81970834 and\u0026nbsp;82371067), the Science and Technology Commission of Shanghai Municipality (grants 19441900800) and\u0026nbsp;the Clinical Research Program of 9th People\u0026apos;s Hospital, Shanghai Jiao Tong University School of Medicine (JYLJ202418). The funders had no role in study design, data collection and analysis, decision to publish,or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u003c/strong\u003e This study has no commercial or propriety interest. The authors report no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u0026nbsp;\u003c/strong\u003eThe datasets used or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCode availability:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eEthical approval was given by Shanghai Ninth People\u0026rsquo;s Hospital Ethical Committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to participate:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ePatient consent was obtained to publish the clinical photographs. All figures in the manuscript were drawn and composed by ourselves.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eWritten informed consent for publication was obtained from all participants.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eJakobiec FA, MD Mills, AA Hidayat, and etc. Periocular xanthogranulomas associated with severe adult-onset asthma. Trans Am Ophthalmol Soc, 1993. 91: p. 99-125; discussion 125-9.\u003c/li\u003e\n \u003cli\u003eRobertson, D.M. and R.K. Winkelmann. Ophthalmicfeatures of necrobiotic xanthogranuloma with paraproteinemia. Am J Ophthalmol, 1984. 97(2): p. 173-83.\u003c/li\u003e\n \u003cli\u003eAlper, M.G., L.E. Zimmerman, and F.G. Piana. Orbital manifestations of Erdheim-Chesterdisease. Trans Am Ophthalmol Soc, 1983. 81: p. 64-85.\u003c/li\u003e\n \u003cli\u003eSivak-Callcott, J.A., J. Rootman, S.L. Rasmussen, and etc. Adult xanthogranulomatous disease of the orbit and ocular adnexa: new immunohistochemical findings and clinical review. Br J Ophthalmol, 2006. 90(5): p. 602-8.\u003c/li\u003e\n \u003cli\u003eHammond, M.D., E.W. Niemi, T.P. Ward, and A.S. Eiseman. Adult orbital xanthogranuloma with associated adult-onset asthma. Ophthal Plast Reconstr Surg, 2004. 20(4): p. 329-32.\u003c/li\u003e\n \u003cli\u003eRayner SA, AS Duncombe, M Keefe, and etc. Necrobiotic xanthogranuloma occurring in an eyelid scar. Orbit, 2008.27(3): p. 191-4.\u003c/li\u003e\n \u003cli\u003eLau, W.W., E. Chan, and C.W. Chan. Orbital involvement in Erdheim-Chesterdisease. Hong Kong Med J, 2007. 13(3): p. 238-40.\u003c/li\u003e\n \u003cli\u003ePeric, P., B. Antic, S. Knezevic-Usaj, and etc. Successful treatment with cladribine of Erdheim-Chester disease with orbital and central nervous system involvement developing after treatment of Langerhans cell histiocytosis. Vojnosanit Pregl, 2016.73(1): p. 83-7.\u003c/li\u003e\n \u003cli\u003eHonda, Y., S. Nakamizo, T. Dainichi, and etc.Adult-onset asthma and periocular xanthogranuloma associated with IgG4-related disease with infiltration of regulatory T cells. J Eur Acad Dermatol Venereol,2017.31(2): p. e124-e125.\u003c/li\u003e\n \u003cli\u003eBurris CK, ME Rodriguez, ML Raven, and etc.Adult-Onset Asthma and Periocular Xanthogranulomas Associated with Systemic IgG4-Related Disease. Am J Ophthalmol Case Rep, 2016. 1: p.34-37.\u003c/li\u003e\n \u003cli\u003eStone, J.H., Y. Zen, and V. Deshpande. IgG4-relateddisease. N Engl J Med, 2012. 366(6): p. 539-51.\u003c/li\u003e\n \u003cli\u003eUmehara H, K Okazaki, Y Masaki, and etc. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol, 2012.22(1): p. 21-30.\u003c/li\u003e\n \u003cli\u003eGuo J and J Wang. Adult orbital xanthogranulomatous disease: review of the literature. Arch Pathol Lab Med, 2009. 133(12): p. 1994-7.\u003c/li\u003e\n \u003cli\u003eDavies MJ, K Whitehead, G Quagliotto, and etc. Adult Orbital and Adnexal Xanthogranulomatous Disease.Asia Pac J Ophthalmol (Phila), 2017. 6(5): p. 435-443.\u003c/li\u003e\n \u003cli\u003eMcKelvie P, AA McNab, T Hardy, and etc. Comparative Study of Clinical, Pathological, Radiological, and Genetic Featuresof Patients With Adult Ocular Adnexal Xanthogranulomatous Disease, Erdheim-Chester Disease, and IgG4-Related Disease of the Orbit/Ocular Adnexa. Ophthal Plast Reconstr Surg, 2017. 33(2): p. 112-119.\u003c/li\u003e\n \u003cli\u003eMukherjee B and N Shrirao. Adult-onset asthma and periocular xanthogranulomawithorbital involvement: A rare entity. Ann Allergy Asthma Immunol, 2016. 116(5): p. 466-7.\u003c/li\u003e\n \u003cli\u003eSatchi K, AA McNab, T Godfrey, and etc. Adult orbital xanthogranuloma successfully treated with rituximab. Ophthalmology,2014. 121(8): p. 1664-5 e1-3.\u003c/li\u003e\n \u003cli\u003eRubinstein TJ, MP Mehta, L Schoenfield, and etc.Orbital xanthogranuloma in an adult patient with xanthelasma palpebrarum and hypercholesterolemia. Ophthal Plast Reconstr Surg, 2014. 30(1): p. e6-8.\u003c/li\u003e\n \u003cli\u003eLondon J, A Martin, M Soussan, and etc. Adult Onset Asthma and Periocular Xanthogranuloma (AAPOX), a Rare Entity With a Strong Linkto IgG4-Related Disease: An Observational Case Report Study. Medicine (Baltimore), 2015. 94(43): p. e1916.\u003c/li\u003e\n \u003cli\u003eVerdijk RM, P Heidari, R Verschoote, and etc. Raised numbers of IgG4-positive plasmacells are a common histopathological finding in orbital xanthogranulomatous disease. Orbit, 2014. 33(1): p. 17-22.\u003c/li\u003e\n \u003cli\u003eSingh K, KD Rajan, and C Eberhart. Orbital necrobiotic xanthogranuloma associated with systemic IgG4 disease. Ocul Immunol Inflamm, 2010. 18(5): p. 373-8.\u003c/li\u003e\n \u003cli\u003eHeymann WR. Conceptual Confluence: The Marriage of IgG4-Related Disease and Adult-Onset Asthma With Periocular Xanthogranulomas. Skinmed, 2016. 14(6): p. 449-451.\u003c/li\u003e\n \u003cli\u003eWallace ZS, V Deshpande, and JH Stone. Ophthalmic manifestations of IgG4-related disease: single-center experience and literature review. Semin Arthritis Rheum, 2014. 43(6): p. 806-17.\u003c/li\u003e\n \u003cli\u003eElner VM, R Mintz, H Demirci, and etc. Local corticosteroid treatment of eyelid and orbital xanthogranuloma. Ophthal Plast Reconstr Surg, 2006. 22(1): p. 36-40.\u003c/li\u003e\n \u003cli\u003eTorabian SZ, N Fazel, and R Knuttle. Necrobiotic xanthogranuloma treated with chlorambucil. Dermatol Online J, 2006. 12(5): p. 11.\u003c/li\u003e\n \u003cli\u003eLiszewski W, JD Wisniewski, H Safah, and etc. Treatment of refractory necrobiotic xanthogranulomas with extracorporeal photopheresis and intravenous immunoglobulin. Dermatol Ther, 2014.27(5): p. 268-71.\u003c/li\u003e\n \u003cli\u003eMiguel D, J Lukacs, T Illing, and etc. Treatment of necrobiotic xanthogranuloma - a systematic review. J Eur Acad Dermatol Venereol,2017. 31(2): p. 221-235.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Adult orbital xanthogranulomatous disease (AOXGD), IgG4, Therapy","lastPublishedDoi":"10.21203/rs.3.rs-6225843/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6225843/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eAdult orbital xanthogranulomatous disease (AOXGD) is a rare non-Langerhans cell histiocytosis comprising four syndromes, which were only reported in some case reviews. Here we summarized characteristics of 20 AOXGD patients to explore the ethnic features of these disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003ePatients of definite AOXGD diagnosis undergoing treatment were reviewed. Clinical characteristics were collected and analyzed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003e20 AOXGD patients were composed of 10 adult-onset asthma and periocular xanthogranuloma (AAPOX), 7 necrobiotic xanthogranuloma (NBX), 3 adult-onset xanthogranuloma (AOX). All cases were bilateral involved with symptoms of nodularity, yellow discoloration, eyelid swelling and mechanical ptosis. 10 patients (45%) had elevated serum IgG4 with average of 2.97±2.29g/L, which was significantly associated with relative eyelid thickness (RET) and orbital involvement (dominant in AAPOX subtype, P\u0026lt;0.05). The ratio of IgG4/IgG positive plasma cells in tissues was from 2.9% to 33.4%. Based on the IgG4 related disease (IgG4-RD) diagnostic criteria, no AOXGD patients met the definitive diagnostic criteria of IgG4-RD. All patients underwent surgeries to remove most lesions and obtain definite pathological diagnosis, then following methylprednisolone and methotrexate administration. After the treatment, ptosis and swelling were significantly corrected without local recurrence. The immunohistochemistry results showed that the TIMP- 1 protein level was higher in AOXGD tissues than in normal tissues.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eIn our cases AOXGD is a rare and special disease characterized by elevated serum IgG4 alone, especially in AAPOX subtype. Degree of eyelid swelling and orbital involvement in AOXGD is significantly associated with serum IgG4 level, which serves as a potent indicator to choose the therapeutic regimen and operation opportunity. Surgery assisted with methylprednisolone and methotrexate administration is an effective therapy for AOXGD. Inflammatory processes participated in the development of AOXGD and thus AOXGD may be a kind of inflammatory disease.\u003c/p\u003e","manuscriptTitle":"Adult Orbital Xanthogranulomatous Disease: a retrospective analysis on clinical characteristics, serological examination and immunohistochemical findings of different subtypes","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 01:41:37","doi":"10.21203/rs.3.rs-6225843/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"899d8bf0-af44-4b99-a457-24ec16addd11","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[{"type":"decision","content":"Withdrawn","date":"2026-05-12T01:06:59+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-12T01:10:27+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-09 01:41:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6225843","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6225843","identity":"rs-6225843","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}