Malignancies in Immunoglobulin G4-Related Ophthalmic Disease

doi:10.21203/rs.3.rs-924731/v1

Download PDF

Research Article

Malignancies in Immunoglobulin G4-Related Ophthalmic Disease

https://doi.org/10.21203/rs.3.rs-924731/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Purpose: Clinical phenotypes in Immunoglobulin G4-related disease (IgG4-RD) according to the affected organs affected have different risks of malignancies. We attempt to determine the association of malignances with IgG4-related ophthalmic disease (IgG4-ROD).

Design: Retrospective cohort study.

Methods: Review of medical records, orbital images and histopathology reports in a territory-wide cohort of patients fulfilling the “probable” or “definite” comprehensive diagnostic criteria of IgG4-RD from 2005-2019.

Findings: Among 122 patients who had biopsies taken from adnexal lesions including lacrimal glands (n=108), orbital mass (n=30), infiltrated orbital fat (n=10), conjunctiva (n=2) or extraocular muscles (n=3), 16 (13%) developed malignancies over 73±48months’ follow-up. There were 9 cases of ocular adnexal lymphoma (OAL) and 7 extra-orbital malignancies. Compared with the general population, the incidence of OAL was significantly higher (standardized incidence ratios, SIRs=10.0, 95%CI=4.5-17.6) while that of extraorbital malignancy was similar. The SIR was highest within the first year (SIR=46.7, 95%CI=18.5-87.6) when 7 OAL were concomitantly diagnosed. Patients who developed OAL or extra-orbital malignancies were older than other patients when diagnosed of IgG4-ROD (64.9±7.1, 68.3±8.5 versus 55.2±15.0 years, p<0.05). Asymmetric lacrimal gland enlargement (78% versus 13%), lack of frontal (0% versus 12%) or infraorbital nerve enlargement (0% versus 36%)were associated with OAL (all p<0.05). Pre-treatment serum IgG4 level or pattern of extraorbital involvement was similar among patients with or without malignancies.

Conclusion: In this biopsy-proven IgG4-ROD cohort, 7% developed OAL which was 10 times higher than the general population. Patients with asymmetric lacrimal gland enlargement or without trigeminal nerves involvement radiologically were associated with OAL.

Ophthalmology

Immunoglobulin G4 related disease ophthalmic disease

Immunoglobulin G4 related ophthalmic disease

Ocular Adnexal Lymphoma

Standardized incidence ratios

Malignancies

IgG4-related disease (IgG4-RD) is an immune-mediated fibroinflammatory disease characterized by tumefactive lesions with noticeable IgG4 + plasma cells infiltrating¹ into different organs including the hepatobiliary tree, pancreas, exocrine glands, kidneys, lungs, lymph nodes, meninges, aortas and prostate.^2,3,4,5 IgG4-RD was first recognized as a single disease entity, but some recent studies suggested several clinical phenotypes according to the affected organs. ^6,7,8 While Lanzillotta et al⁶ reported an increased prevalence of allergic manifestations in head and neck limited phenotype, Niwamoto et al⁷ reported association between malignancies and specific phenotypes in IgG4-RD, especially IgG4-related autoimmune pancreatitis. But the incidence of solid or hematological cancers did not differ among different phenotypes of IgG4-RD. ⁶

In IgG4-related ophthalmic disease (IgG4-ROD), infiltration, fibrosis and dysfunction of the lacrimal glands, extraocular muscles, periorbital and optic nerves, the eyelid and orbital soft tissues have been reported.⁹ Cheuk et al ¹⁰ first reported 6 patients with ocular adnexal lymphoma (OAL) associated with IgG4-ROD. The Japanese study group of IgG4-ROD showed that 9.8% of mucosa associated lymphoid tissue (MALT) orbital lymphoma in their multi-center cohort were IgG4-positive.¹¹ IgG4-ROD appeared to have a strong association with lymphoma, compared to other organ-specific phenotype of IgG4-RD.¹² In this study, we compare the incidence of malignancies in a well-characterized and biopsy-proven IgG4-ROD cohort with the local population, and we compare the clinical, serological and radiological features of patients who developed cancer at the time of or after the diagnosis of IgG4-ROD to those who did not.

We conducted a retrospective study of all consecutive patients of biopsy-proven IgG4-ROD diagnosed from 2005 to 2019 in Hong Kong. They were managed by all 7 Hospital Authority clusters covering the territory-wide, publicly funded ophthalmology service in Hong Kong as previously reported.²¹ Some patients were managed by the Hong Kong Sanatorium & Hospital over the same period. Medical records including orbital images and histological slides were reviewed. This study followed the Declaration of Helsinki and ethical approval was obtained from the Institutional Review Board (IRD) of each participating hospital. Orbital adnexal specimens including the lacrimal glands (n = 108), discrete masses (n = 30), infiltrated fat (n = 10), conjunctiva (n = 2) and extraocular muscles (n = 3) were obtained by open surgical biopsies. Diagnosis of IgG4-ROD required histological evidences of lymphoplasmacytic infiltrates of > 50 IgG4 + cells per high power field (PHF) x400 and an IgG4+/IgG + ratio of > 40% of the biopsied orbital tissue²². Histological specimens reported before 2005 were retrospectively reviewed and stained, and the diagnosis of IgG4-ROD was confirmed if they fulfilled the diagnostic criteria. An independent consultant histopathologist with over 30 years’ experience reviewed slides of all available malignant lesions to evaluate the presence and degree of IgG4-plasma cell infiltrations. An independent nuclear medicine physician reviewed the positron emission tomography (PET) scan of a patient with radiologically diagnosed lung cancer.

Numerical results were presented as mean ± standard deviation (SD) and range unless otherwise stated. The incidence rate of malignancies was compared to the general population using the standardized incidence ratios (SIRs) and 95% confidence interval²³. The incidence of malignancies in the general population of Hong Kong was obtained from the Hong Kong Cancer Registry²⁴, which included patients of all types of malignancies diagnosed in both public and private healthcare sectors. Information was also obtained from the Deaths Registry, Pediatric Hematology and Oncology study group, and voluntary notifications in Hong Kong up to 2017. The SIRs were further adjusted according to age as stratified by the Hong Kong Cancer Registry based on gender and the types of malignancies. Clinical, serological, and radiological risk factors were compared using the Fisher’s exact test and chi-square test taking p < 0.05 as significant. All statistical analyses were performed using SPSS statistical software package (Window version 24.0; IBM Corp., Armonk, NY).

Records of 122 patients over a follow-up period of 73±48 (12 to 260) months were reviewed. Three patients were diagnosed with cancer 85±27 (60 to 123) months before the diagnosis of IgG4-ROD: one with breast cancer, one with prostate adenocarcinoma, and one with diffuse large B cell lymphoma (DLBCL) of the ipsilateral cervical lymph node. The patient with breast cancer was subsequently diagnosed with endometrial adenocarcinoma at the time of IgG4-ROD diagnosis. Malignancies in 16 (13%) patients, including 12 males, were diagnosed at the time of or after the diagnosis of IgG4-ROD over 38±25 (7 to 84) months. Ocular adnexal lymphoma (OAL) was found in 9 patients (Table 1) and extra-orbital systemic malignancies (Table 2) in 7. Comparing these 16 patients diagnosed with malignancies at the time of or after the diagnosis of IgG4-ROD with the rest of the cohort without any history of cancer (104 patients), the age at IgG4-ROD diagnosis was significantly higher (66.3±7.9 years versus 55.2±15.0 years, p<0.05), while the male to female ratio was higher but not reaching statistical significance (12:4 versus 53:51 p=0.13). Nine (56%) of the 16 cancer patients had extra-orbital involvement of IgG4-RD, as compared to 53% in the rest of the cohort (p= 0.80). Also, 13 of the 15 tested (87%) among the 16 patients developed malignancies had elevated pre-treatment serum IgG4 compared to 90 of the 100 tested (90%) patients from the rest of the cohort (p=0.74), mean level was 2.5±1.7(1.3-5.7) times compared to 11±2.7 (1.1-22.8) times of normal in the rest of the cohort (p>0.05). Smoking status was similar (25% versus 24%, p=0.47). Totally 98 (74%) patients of the whole cohort were presented first with periocular symptoms, 14 (11%) patients with salivary gland and 6 (5%) patients with neck swelling (cervical lymphadenopathy). Type 1 autoimmune pancreatitis (AIP) were diagnosed in 4 (3%) patients with before presenting to us.

IgG4-related ocular adnexal lymphoma (OAL)

Nine (7.4%) patients, including 6 males, among all the 122 IgG4-ROD patients developed OAL at the time of or after the diagnosis of IgG4-ROD (Table 1). Seven were diagnosed concomitantly and 2 were diagnosed 24 and 48 months following the diagnosis of IgG4-ROD. One patient was a chronic smoker. Six patients had extranodal marginal zone B Cell lymphoma of MALT type (EMZL), affecting the lacrimal glands (n=3), the eyelids (n=2) and the orbital soft tissue (n=1). Two patients had follicular lymphoma affecting the lacrimal glands and 1 patient had orbital DLBCL. Comparing these 9 OAL patients with the rest of the cohort that had no history of cancer (104 patients), the male to female ratio was higher (6:3 versus 56:50, p>0.5), and the mean age of IgG4-ROD diagnosis older (64.9+/-7.1 vs 55.2+/-15.0, p<0.05). The commonest presentation was upper lid swelling (62% versus 71%, p=0.78), followed by proptosis (25% versus 20%, p=0.15) and palpable mass (22% versus 20%, p=0.37). Seven of the 8 tested (88%) among the 9 patients with OAL had elevated pre-treatment serum IgG4 compared to 90 of the 100 tested (90%) patients from the rest of the cohort (p>0.05). Radiologically, 7 patients had asymmetric enlargement of the lacrimal gland (78% versus 13%, p<0.05) (Figure1), and 5 patients showed retrobulbar extension. There was no frontal or infraorbital nerve enlargement, as defined by the nerve diameter equal to or larger than that of the ipsilateral optic nerve on coronal imaging, in all 9 OAL patients (0% versus 12%, 0% versus 36%, p<0.05). Four patients had extra-orbital involvement of the parotid glands (n=4), kidneys (n=4), lungs (n=2), liver (n=1), aorta (n=1) and mediastinal lymph node (n=1) (44% versus 65%, p>0.05) by IgG4-RD. Six patients had paranasal sinus involvement (75% versus 65%, p=0.20).

Extra-orbital systemic malignancies

Six of these 7 patients were diagnosed with extra-orbital systemic malignancies in 38±25 (range: 7-84) months after the IgG4-ROD, while 1 patient with history of breast cancer was found to have endometrial adenocarcinoma at the time of IgG4-ROD diagnosis (Table 2). One patient was diagnosed radiologically with primary lung cancer with metastasis as evident by a grossly elevated serum carcinoembryonic antigen (CEA) level of 2753ug/L (normal range <=5) and PET scan showing multiple hypermetabolic lesions in both lungs, liver and extensive lytic osseous lesions over different long bones. The average latency from IgG4-ROD diagnosis to the diagnosis of extra-orbital malignancies was 34±30 (0-84) months. Five of these 6 malignant lesions underwent additional IgG4 immunostaining. There were increased IgG4+ plasma cell infiltration (IgG4/IgG ratio= 49-62%) of the nearby cervix but not the endometrial adenocarcinoma. The other malignant lesions did not show any IgG4+ plasma cell infiltration. Comparing the 7 patients with extra-orbital malignancies to those without any history of cancer (104 patients), the male to female ratio was higher (6:1 versus 28:25, p=0.11), and the average age of diagnosis of IgG4-ROD was 13 years older (68.3±8.5 versus 55.2±15.0, p<0.05). Otherwise the initial clinical presentation, the mean level of and the percentage of patients with raised pre-treatment serum IgG4, radiological changes and pattern of extraorbital IgG4RD involvement were not statistically different between the 2 groups. Before the development of extra-orbital malignancies, 4 patients (57% versus 70%, p>0.05) received oral steroids (3 prednisolone and 1 dexamethasone) and one (14% versus 29%, p>0.05) patient received both steroid and steroid-sparing immunosuppressant (azathioprine). The percentage of patients receiving immunosuppressive therapy was similar between the 2 groups, 5 out of 7 (71%) vs 87 out of 106 (82%) in those without malignancies, p>0.05. The mean cumulative dosage of oral prednisolone (n=3) was 5745±3145 mg compared to 6006±4942 mg in patients who did not develop any malignancy (n=71) (p>0.05). Two (29% versus 19%, p>0.05) of these 7 patients opted not to receive any treatment in view of their stable IgG4-ROD.

Incidence of malignancies in the study cohort of IgG4-ROD (Table 3)

The overall incidence of OAL was higher (SIRs=10.0, 95%CI=4.5-17.6), especially within the first year of IgG4-ROD diagnosis (SIRs=46.7, 95%CI=18.5-87.6). The overall, age- and gender-adjusted incidence rates and SIRs of OAL were increased. On the contrary, the overall incidence of extra-orbital malignancies was comparable (SIRs=0.54, 95% CI=0.2-1.0) to the general population. The incidence was similar within the first 2 years of IgG4-ROD diagnosis (SIRs=1.2, 95% CI=0.4-2.5). The overall, age- and gender-adjusted incidence rate and SIRs of systemic malignancies were similar.

The overall incidence of malignancies (all types) diagnosed concomitantly with or subsequently after IgG4-ROD was comparable to the general population (SIR=1.03, 95% CI=0.6-1.6). The incidence of malignancies (all types) was higher within the first 2 years of IgG4-ROD diagnosis (first year: SIRs=3.5, 95% CI=1.6-6.1, first 2 years: SIRs=2.6, 95% CI=1.4-4.1) and similar to the level of the general population by the end of the third year (SIR=1.7, 95% CI=0.9-2.7).

In this multi-centered, territory-wide, and biopsy-proven IgG4-ROD cohort of 122 patients, 16 (13%) developed cancer at the time of or after IgG4-ROD diagnosis over a follow-up period of 73 ± 48 (12 to 260) months. Nine patients were diagnosed with OAL and 7 patients extra-orbital cancer including one case of DLBCL of seminal vesicles. Compared to the general population, the overall SIRs of OAL was 10 times higher while that of extra-orbital malignancy was similar. Increased risk of malignancies has been reported in various inflammatory disorders such as Systemic lupus erythematous²⁵, Sjogren’s syndrome²⁶ and IgG4-RD¹³. Long-term immunosuppressive therapies and chronic immune dysregulation are likely associated with tumorigenesis. Wallace et al ⁹ proposed that both IgG4-RD and malignancies shared similar risk factors, and the increased risk of IgG4-RD might be resulted from the treatment of malignancies such as chemotherapy which negatively affected the immune system.

Some studies reported an association between IgG4-RD and malignancies.^13,14,15 Among epithelial malignancies, colorectal^15,18 and gastric¹⁷ cancer showed stronger associations with IgG4-RD. The overall risk of malignancies (all types) was the highest in patients during the first year of the diagnosis of IgG4-related AIP^16,17,18. Higher incidences of malignancies (including both pancreatic and extra pancreatic cancer) in patients with IgG4-related AIP were reported in 2 studies with comparable SIRs = 2.08 (95%CI:1.32–2.85)²⁷ and SIRs = 2.7(95%CI:1.4–3.9)¹⁷. IgG4-related AIP may develop as paraneoplastic syndrome, since non-pancreatic cancerous tissues of 6 patients in one study showed abundant IgG4-positive plasma cells infiltration.¹⁷ In our study, all available tumor specimens from patients with extraorbital malignancies showed no IgG4-positive plasma cell infiltration, except one patient with endometrial adenocarcinoma, where the IgG4-positive plasma cells infiltrated the nearby cervix but not the endometrial tumor itself.

Yamamoto et al¹³ reported an increased incidence of malignancies after the diagnosis of IgG4-RD over an average follow-up period of 3.1 years. Two of their patients with chronic sclerosing sialadenitis and dacryoadenitis were diagnosed with lung cancer. However, our study was the first to systematically report the risk of OAL and extraorbital malignancies before and after the histological diagnosis of IgG4-ROD. In contrast to the reported increase in both pancreatic and extra-pancreatic malignancies (lymphoma and carcinoma) in IgG4-related AIP patients,^17,18,27 our data showed an increase only in OAL but not extra-orbital malignancies in IgG4-ROD patients. Three patients were diagnosed with breast cancer, DLBCL of an ipsilateral cervical lymph node and prostate adenocarcinoma respectively at an average of 73+/-40 (range 24–123) months before the diagnosis of IgG4-ROD in our cohort. Meanwhile they had no self-reported or recorded feature of IgG4-RD before malignancies.

Lymphoma was the commonest malignancy associated with IgG4-RD in a report by Ahn et al.²⁰ Among 46 published cases of IgG4-ROD associated with OAL, 2 cases previously reported by Cheuk et al¹⁰ were included in the current study. The mean age of diagnosis of IgG4-ROD was 62 (30–90) years (Table 4), while our mean age of diagnosis was 64 (range 54–74) years. Notably, 25 (63%) of the 46 published cases presented as unilateral or asymmetric enlargement of lacrimal glands, comparable to our finding that asymmetric enlargement of the lacrimal gland was associated with OAL. We also found, for the first time, “atypical” presentations of IgG4ROD including asymmetric lacrimal gland enlargement and lack of frontal or infraorbital nerve enlargement, were associated with OAL.

Sato et al¹² reported 7 cases of ocular extranodal marginal zone lymphoma (EMZL) associated with IgG4-ROD. The Japanese prevalence study group of orbital lymphoproliferative disease¹¹ reported 9.8% (n = 44) of MALT lymphoma cases being IgG4 positive, and the mean age of patients with IgG4-positive MALT lymphoma was significantly higher than those with IgG4-ROD alone. One of our patients was diagnosed with IgG4-ROD 4 years before orbital extranodal marginal zone lymphoma (EMZL) showing positive light chain restriction among the IgG4 + plasma cells, indicating the malignant transformation of lesions in IgG4-ROD over time. On the other hand, a Japanese patient developed IgG4-ROD 10 years after receiving external beam radiotherapy for orbital MALT lymphoma.²⁸ Meanwhile one of our patients was diagnosed with EMZL affecting the left lacrimal gland 2 months prior to the right lacrimal gland and becoming clinically enlarged. It was affected by IgG4-ROD alone as confirmed by histology. While IgG4 positive MALT lymphoma may evolve secondary to the lymphomatous transformation of longstanding IG4-ROD¹² and thus the older age on presentation, it may also be originated from de novo development of IgG4-producing MALT lymphoma in older patients.

One of our patients developed diffuse orbital DLBCL, which is extremely rare in IgG4-ROD. The contralateral lacrimal gland showed atypical Hodgkin-like cells. Subsequent negative PET-CT scan and kappa light chain restriction of plasma cells excluded bilateral IgG4-related OAL. We found other reported case of DLBCL in IgG4-ROD involving the lacrimal sac.²⁹ One of our male patients developed DLBCL of the seminal vesicles 5 years after IgG4-ROD diagnosis and also suffered from infiltrative IgG4-related optic neuropathy as previously reported.²¹

Hiwatashi et al³⁰ proposed the use of non-echo planar (NEP) diffusion-weighted imaging (DWI) to obtain the apparent diffusion coefficient (ADC) of any region of interest to differentiate OAL from IgG4-ROD. Since diagnosis of OAL requires histological confirmation, we recommend sampling the region of lowest ADC if DWI is available and repeating biopsy in previously stable IgG4-ROD patients with noticeable unusual worsening of periocular swelling or proptosis. Three of our OAL patients had prior biopsies showing lymphoid hyperplasia (n = 2) or chronic dacryocystitis (n = 1). Whether the use of MRI or NEP-DWI guided biopsy reduces sampling errors in IgG4-related OAL warrants further investigation.

Our data suggested that patients with “typical” presentations of IgG4-ROD including bilateral symmetrical lacrimal gland, frontal or infraorbital nerve involvement had a lower risk of OAL. We therefore recommend clinical surveillance every quarterly in IgG4-ROD patients presented with asymmetric lacrimal gland involvement during the first 2 years from diagnosis. If clinically suspicious, radiological workup, e.g. MRI and DWI for ADC or PET-CT, should be arranged to look for radiological evidence of OAL and to arrange image-guided biopsy as appropriate.

Our study was based on a retrospective cohort with limitations of selection and recall bias, incomplete documentation and inconsistent screening protocol for asymptomatic systemic involvment. The risk of malignancy in IgG4ROD may vary among different study populations. Our results thus require verification by other cohorts. As newly diagnosed patients often undergo systemic workup, we acknowledge possible incidental occult malignancies which were developed years before and attributed to an increase in malignancy especially during the first few years after IgG4-ROD diagnosis. Large and prospective cohorts are needed to compare the long-term association of malignancies in different organ-presenting phenotypes of IgG4-RD to the general population.

In this cohort of 122 biopsy-proven IgG4-ROD patients, the incidence of OAL was 10 times higher while the incidence of extra-orbital malignancies was similar to that of the general population. IgG4-ROD patients presenting with asymmetric lacrimal gland enlargement, lack of frontal or infraorbital nerves involvement radiologically were associated with OAL.

Acknowledgment:

We thank the Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Department of Pathology, United Christian Hospital

Department of Pathology, Pamela Youde Nethersole Eastern Hospital

Department of Pathology, Queen Elizabeth Hospital for their support in terms of data retrieval.

Ethics approval: This study followed the Declaration of Helsinki and ethical approval was obtained from the Institutional Review Board (IRD) of each participating hospital as following:

Joint Chinese University of Hong Kong- New Territories East Cluster Ethics Committee: 2020.478
New Territories West Cluster Ethics Committee: NTWC/CREC/17097
Kowloon Central Kowloon East Clusters Ethics Committee: KC/KE-17-164/ER-2
Kowloon West Cluster Ethics Committee: KW/EX-17-149(117-16)
Hong Kong East Cluster Ethics Committee: HKECREC-2017-75
Hong Kong West Cluster Ethics Committee: UW18-120
Hong Kong Sanatorium & hospital Ethics Committee: RC-2017-16

The need for consent is deemed unnecessary according to the institutional regulations.

Authors Contributions: KL, JY, KW and KC analyzed and interpreted the data. CW performed the histological review of specimens. KL and KC were the major contributors in writing the manuscript. All authors read and approved the final manuscript.

Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Financial support: None

Conflict of interest disclosure: No conflicting relationship exists for any author.

Stone, J.H., Y. Zen, and V. Deshpande. IgG4-related disease. N Engl J Med. 2012; 366(6): p. 539–51.
Carruthers, M.N., et al. Development of an IgG4-RD Responder Index. Int J Rheumatol. 2012; 2012: p. 259408.
Mulay K, Honavar SG. Orbital Immunoglobulin G4-Related Disease: A Systematic Review. Asia Pac J Ophthalmol (Phila). 2014 Sep-Oct;3(5):322–5.
Campochiaro C, Ramirez GA, Bozzolo EP, et al. IgG4-related disease in Italy: clinical features and outcomes of a large cohort of patients. Scand J Rheumatol. 2016;45(2):135–45.
Lin W, Lu S, Chen H, et al. Clinical characteristics of immunoglobulin G4-related disease: a prospective study of 118 Chinese patients. Rheumatology (Oxford). 2015 Nov;54(11):1982–90.
Lanzillotta M, Campochiaro C, Mancuso G, Ramirez GA, Capurso G, Falconi M, et al. Clinical phenotypes of IgG4-related disease reflect different prognostic outcomes. Rheumatology (Oxford). 2020 Sep 1;59(9):2435–2442.
Niwamoto T, Handa T, Matsui S, Yamamoto H, Yoshifuji H, Abe H, et al. Phenotyping of IgG4-related diseases based on affected organ pattern: A multicenter cohort study using cluster analysis. Mod Rheumatol. 2020 Jan 4:1–6.
Wallace ZS, Zhang Y, Perugino CA, Naden R, Choi HK, Stone JH; ACR/EULAR IgG4-RD Classification Criteria Committee. Clinical phenotypes of IgG4-related disease: an analysis of two international cross-sectional cohorts. Ann Rheum Dis. 2019 Mar;78(3):406–412.
Wallace ZS, Deshpande V, Stone JH. Ophthalmic manifestations of IgG4-related disease: single-center experience and literature review. Semin Arthritis Rheum. 2014 Jun;43(6):806–17.
Cheuk W, Yuen HK, Chan AC, et al. Ocular adnexal lymphoma associated with IgG4 + chronic sclerosing dacryoadenitis: a previously undescribed complication of IgG4-related sclerosing disease. Am J Surg Pathol. 2008;32(8):1159–1167.
Japanese study group of IgG4ROD. A prevalence study of IgG4-related ophthalmic disease in Japan. Jpn J Ophthalmol. 2013; 57(6): p. 573–9.
Sato Y, Notohara K, Kojima M, Takata K, Masaki Y, Yoshino T. IgG4-related disease: historical overview and pathology of hematological disorders. Pathol Int. 2010;60(4):247–258.
Yamamoto M, Takahashi H, Tabeya T, et al. Risk of malignancies in IgG4-related disease. Mod Rheumatol. 2012 Jun;22(3):414–8.
Wallace ZS, Wallace CJ, Lu N, Choi HK, Stone JH. Association of IgG4-Related Disease with History of Malignancy. Arthritis Rheumatol. 2016 Sep;68(9):2283–9.
Tang H, Yang H, Zhang P, et al. Malignancy and IgG4-related disease: the incidence, related factors and prognosis from a prospective cohort study in China. Sci Rep. 2020;10(1):4910.
Schneider A, Hirth M, Münch M, et al. Risk of Cancer in Patients with Autoimmune Pancreatitis: A Single-Center Experience from Germany. Digestion. 2017;95(2):172–180.
Shiokawa M, Kodama Y, Yoshimura K, et al. Risk of cancer in patients with autoimmune pancreatitis. Am J Gastroenterol. 2013 Apr;108(4):610–7.
Huggett MT, Culver EL, Kumar M et al. Type 1 autoimmune pancreatitis and IgG4-related sclerosing cholangitis is associated with extrapancreatic organ failure, malignancy, and mortality in a prospective UK cohort. Am J Gastroenterol. 2014 Oct;109(10):1675–1683.
Inoue D, Yoshida K, Yoneda N, et al. IgG4-related disease: dataset of 235 consecutive patients. Medicine (Baltimore). 2015 Apr;94(15):e680.
Ahn SS, Song JJ, Park YB, Lee SW. Malignancies in Korean patients with immunoglobulin G4-related disease. Int J Rheum Dis. 2017 Aug;20(8):1028–1035.
Lai KKH, Chan RYC, Chin JKY, et al. Upper Cranial Nerve Involvement and Immunoglobulin G4-Related Optic Neuropathy. Ophthalmology. 2019;S0161-6420(19)32296–1.
Umehara, H., et al. Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011. Mod Rheumatol. 2012; 22(1): p. 21–30.
Becher H, Winkler V. Estimating the standardized incidence ratio (SIR) with incomplete follow-up data. BMC Med Res Methodol. 2017;17(1):55. Published 2017 Apr 12.
Website of Hong Kong Cancer Registry, Hospital Authority: www3.ha.org.hk/cancereg/dataNstat.asp. Accessed: December 2020.
Cao L, Tong H, Xu G, et al. Systemic lupus erythematous and malignancy risk: a meta-analysis. PLoS One. 2015 Apr 17;10(4):e0122964.
Alunno A, Leone MC, Giacomelli R, Gerli R, Carubbi F. Lymphoma and Lymphomagenesis in Primary Sjögren's Syndrome. Front Med (Lausanne). 2018 Apr 13;5:102.
Asano J, Watanabe T, Oguchi T, et al. Association Between Immunoglobulin G4-related Disease and Malignancy within 12 Years after Diagnosis: An Analysis after Longterm Followup. J Rheumatol. 2015;42(11):2135–2142.
Matsuo T, Ichimura K, Yoshino T. Local recurrence as immunoglobulin G4 (IgG4)-related disease 10 years after radiotherapy to ocular adnexal extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue. J Clin Exp Hematop. 2011;51(2):125–133.
Marunaka H, Orita Y, Tachibana T, et al. Diffuse large B-cell lymphoma of the lacrimal sac arising from a patient with IgG4-related disease. Mod Rheumatol. 2018 May;28(3):559–563.
Hiwatashi A, Yoshiura T, Togao O, et al. Diffusivity of intraorbital lymphoma versus. IgG4-related DISEASE: 3D turbo field echo with diffusion-sensitised driven-equilibrium preparation technique. Eur Radiol. 2014 Mar;24(3):581–6.
Sato Y, Ohshima K, Ichimura K, et al. Ocular adnexal IgG4-related disease has uniform clinicopathology. Pathol Int. 2008;58(8):465–470.
Kubota T, Moritani S, Yoshino T, Nagai H, Terasaki H. Ocular adnexal marginal zone B cell lymphoma infiltrated by IgG4-positive plasma cells. J Clin Pathol. 2010 Dec;63(12):1059–65.
Kase S, Noda M, Ishijima K, Yamamoto T, Hatanaka K, Ishida S. IgG4-related inflammation of the orbit simulating malignant lymphoma. Anticancer Res. 2013 Jun;33(6):2779–83.
Nakayama R, Matsumoto Y, Horiike S, et al. Close pathogenetic relationship between ocular immunoglobulin G4-related disease (IgG4-RD) and ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma. Leuk Lymphoma. 2014 May;55(5):1198–202.
Ohno K, Sato Y, Ohshima K, et al. A subset of ocular adnexal marginal zone lymphomas may arise in association with IgG4-related disease. Sci Rep. 2015 Aug 27;5:13539.
Wu YH, Wang LC, Yen SH, et al. Change of Serum IgG4 in Patients with Ocular Adnexal Marginal Zone B Cell Lymphoma Associated with IgG4-Related Ophthalmic Disease After Treatment. J Ocul Pharmacol Ther. 2017;33(7):543–548.
Sohn EJ, Ahn HB, Roh MS, Jung WJ, Ryu WY, Kwon YH. Immunoglobulin G4 (IgG4)-Positive Ocular Adnexal Mucosa-Associated Lymphoid Tissue Lymphoma and Idiopathic Orbital Inflammation. Ophthalmic Plast Reconstr Surg. 2018;34(4):313–319.
Nishida K, Sogabe Y, Makihara A, et al. Ocular adnexal marginal zone lymphoma arising in a patient with IgG4-related ophthalmic disease. Mod Rheumatol. 2019;29(2):383–387.
Lorenzano D, Rose GE. The "Wedge Sign": An Imaging Sign for Aggressive Lacrimal Gland Disease. Ophthalmology. 2017 Jul;124(7):1081–1083.

Table3: Incidence of malignancies in the study cohort:

All types of cancer found with or after the IgG4-ROD diagnosis (n=16)
	Incidence rate	Person-Time (years)	Observed no.	Expected no.	SIRs	95% CI
Overall	0.020933	744	16	15.6	1.03	0.6-1.6
1 years	0.020933	122	9	2.6	3.5	1.6-6.1
2 years	0.020933	244	13	5.1	2.6	1.4-4.1
3 years	0.020933	366	13	7.7	1.7	0.9-2.7
4 years	0.020933	488	15	10.2	1.5	0.8-2.3
5 years	0.020933	610	15	12.77	1.2	0.7-1.8
Male (68)	0.024217	469	12	11.36	1.1	0.5-1.7
Female (54)	0.018013	274	4	4.9	0.8	0.2-1.8
Age >=65(37)	0.014312	339	7	4.8	1.4	0.6-2.7
Age <65(85)	0.006621	401	9	2.7	3.4	1.5-6.0
Ocular adnexal lymphoma found with or after the IgG4-ROD diagnosis (n=9)
Overall	0.001231	744	9	0.9	10.0	4.5-17.6
1 year	0.001231	122	7	0.2	46.7	18.5-87.6
2 years	0.001231	244	8	0.3	26.7	11.4-48.3
3 years	0.001231	366	8	0.5	17.8	7.6-32.2
4 years	0.001231	488	9	0.6	15.0	6.8-26.4
5 years	0.001231	610	9	0.8	12.0	5.4-22.1
Male (68)	0.001523	469	6	0.7	8.4	3.0-16.5
Female (54)	0.000975	274	3	0.3	11.2	2.1-27.5
Age>=65(37)	0.000774	339	4	0.3	15.2	4.0-33.8
Age<65(85)	0.000457	401	5	0.2	27.3	8.6-56.4
Extra orbital systemic malignancies found with or after the IgG4-ROD diagnosis:
Overall	0.017286	744	7	12.9	0.54	0.2-1.0
1 year	0.017286	122	2	2.1	0.9	0.09-2.7
2 years	0.017286	244	5	4.2	1.2	0.4-2.5
3 years	0.017286	366	5	7.7	0.7	0.2-1.4
4 years	0.017286	488	5	8.4	0.6	0.19-1.2
5 years	0.017286	610	5	10.5	0.5	0.1-1.0
Male (68)	0.023787	469	6	11.2	0.5	0.2-1.1
Female (54)	0.013094	274	1	3.6	0.3	0.0-1.1
Age >=65(37)	0.01213	339	4	4.0	1.0	0.3-2.2
Age <65(85)	0.005156	401	3	2.07	1.5	0.3-3.6

Legends: 95% CI=95% Confidence interval. IgG4-ROD= Immunoglobulin G4-related ophthalmic disease. no=number(s). SIRs=Standardized incidence ratios.

Table 4- Published cases of IgG4 related ocular adnexal lymphoma (OAL)

No.	Ref	Year	Country	Age	Sex	Laterality	IgG4/ IgG ratio	IgG4 count per HPF	Duration	OAL type
1	#31	2008	Japan	64	M	L	>=30	46.7	Concurrent	EMZL
2	#31	2008	Japan	57	F	B	>=30	77.8	Concurrent	EMZL
3	#10	2008	China(HK)	69	F	B*	68	\	3 years	FL
4	#10	2008	China(HK)	69	M	B	94	\	1 year	EMZL
5	#10	2008	China(HK)	60	M	R	91	\	1 year	EMZL @
6	#10	2008	China(HK)	69	M	B *	53	\	Concurrent	EMZL
7	#10	2008	China(HK)	72	M	R	83	\	Concurrent	EMZL
8	#10	2008	China(HK)	55	F	R	209	\	Concurrent	EMZL
9	#32	2010	Japan	66	M	B	100 to 43	N/A	N/A	EMZL
10	#32	2010	Japan	66	M	L		N/A	N/A	EMZL
11	#32	2010	Japan	67	F	L		N/A	N/A	EMZL
12	#32	2010	Japan	75	M	L		N/A	N/A	EMZL
13	#32	2010	Japan	64	F	L		N/A	N/A	EMZL
14	#32	2010	Japan	70	M	R		N/A	N/A	EMZL
15	#32	2010	Japan	61	M	L		N/A	N/A	EMZL
16	#32	2010	Japan	90	M	L		N/A	N/A	EMZL
17	#32	2010	Japan	65	M	R		N/A	N/A	EMZL
18	#32	2010	Japan	64	M	R		N/A	N/A	EMZL
19	#13	2012	Japan	55	M	R	63	N/A	concurrent	EMZL
20	#33	2013	Japan	72	F	B	N/A	Several	Concurrent	EMZL
21	#34	2014	Japan	61	F	R	80	\	Concurrent	EMZL
22	#34	2014	Japan	47	F	L	90	\	Concurrent	EMZL
23	#35	2015	Japan	57	F	NA	69.9	128	Concurrent	EMZL
24	#35	2015	Japan	72	M	NA	83.8	128	Concurrent	EMZL
25	#35	2015	Japan	65	F	NA	47.5	143	Concurrent	EMZL
26	#35	2015	Japan	56	M	NA	86.3	189	Concurrent	EMZL
27	#35	2015	Japan	42	F	NA	80.7	123	Concurrent	EMZL
28	#35	2015	Japan	71	F	NA	/	147	Concurrent	EMZL
29	#29	2016	Japan	78	F	B	>80	>50	Concurrent	DLBCL
30	#36	2017	China (TW)	78	F	R	>40	\	Concurrent	EMZL
31	#36	2017	China (TW)	67	M	L	>50			EMZL
32	#36	2017	China (TW)	67	F	R	90	\	Concurrent	EMZL
33	#37	2018	S. Korea	30	M	U	42	12	concurrent	EMZL
34	#37	2018	S. Korea	63	F	B	65	38	Concurrent	EMZL
35	#37	2018	S. Korea	63	F	B	58	13	Concurrent	EMZL
36	#37	2018	S. Korea	55	F	B	41	12	Concurrent	EMZL
37	#37	2018	S. Korea	57	F	B	65	14	Concurrent	EMZL
38	#37	2018	S. Korea	44	F	B	47	30	Concurrent	EMZL
39	#37	2018	S. Korea	76	F	B	55	13	Concurrent	EMZL
40	#37	2018	S. Korea	73	F	U	57	12	Concurrent	EMZL
41	#37	2018	S. Korea	35	M	B	72	16	Concurrent	EMZL
42	#37	2018	S. Korea	65	M	U	73	15	Concurrent	EMZL
43	#37	2018	S. Korea	48	M	U	69	21	Concurrent	EMZL
44	#37	2018	S. Korea	45	F	U	70	56	Concurrent	EMZL
45	#37	2018	S. Korea	68	M	B	58	23	Concurrent	EMZL
46	#38	2016	Japan	41	M	B	>70	>400	5 years	EMZL

Legends:

Age: Age of IgG4-ROS onset. B=Bilateral, B*=Bilateral (asymmetrical),

DLBCL= Diffuse large B cell lymphoma.

EMZL= Extranodal marginal zone lymphoma of MALT type. F=Female. IgG4ROD=Immunoglobulin G4 related ophthalmic disease. HK=Hong Kong Special Administrative Region. HPF=high power field. L=Left. M=Male. NA=Information not available. No.=Number. OAL= Ocular adnexal lymphoma. R=Right, Ref=Reference. S. Korea=South Korea. TW=Taiwan. U=unilateral. Year=Year of publication. @= with large cell transformation

Due to technical limitations, Tables 1 and 2 are only available as a download in the Supplemental Files section.

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Malignancies in Immunoglobulin G4-Related Ophthalmic Disease

Status:

Version 1

Abstract

Figures

Introduction

Methods

Results

Discussion

Conclusion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1