Upregulated Expression of Activation-Induced Cytidine Deaminase in Ocular Adnexal Marginal Zone Lymphoma with IgG4-Positive Cells

Nishikori, Asami; Nishimura, Yoshito; Shibata, Rei; Ohshima, Kohichi; Gion, Yuka; Ikeda, Tomoka; Nishimura, M.; Yoshino, Tadashi; Sato, Yasuharu

doi:10.3390/ijms22084083

Cited by 5 publications

(8 citation statements)

References 38 publications

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“…It may correlate with MZL with surrounding polyclonal IgG4‐positive cells, and IgG4‐producing MZL (Figure 2). As previously reported, activation‐induced cytidine deaminase overexpression, a potential oncogenic driver also noted in double‐hit lymphoma, could be mediating the oncogenesis in patients with IgG4‐RD to IgG4‐positive MZLs 11 . In de novo IgG4‐positive MZLs, IgG4 itself secreted by clonal IgG4‐producing tumor cells could be a driver of tumorigenesis.…”

Section: Discussionmentioning

confidence: 56%

“…In particular, marginal zone lymphoma (MZL), a type of non‐Hodgkin lymphoma, has been reported to arise in the context of IgG4‐RD in various organs such as the ocular adnexa 10,11 . Although it is rare, pathological analyses of ocular MZLs showed clonal IgG4‐positive or IgG4‐producing lymphoma cells forming a unique disease entity 12,13 .…”

Section: Introductionmentioning

confidence: 99%

“…[3][4][5][6][7][8][9] In particular, marginal zone lymphoma (MZL), a type of non-Hodgkin lymphoma, has been reported to arise in the context of IgG4-RD in various organs such as the ocular adnexa. 10,11 Although it is rare, pathological analyses of ocular MZLs showed clonal IgG4-positive or IgG4-producing lymphoma cells forming a unique disease entity. 12,13 While it has been speculated that IgG4-positive MZLs might emerge in the setting of IgG4-RD due to upregulated expression of activation-induced cytidine deaminase, 11 it is still unclear if IgG4-positive MZLs can emerge without concurrent IgG4-RD or if IgG4-positive MZL has different clinical characteristics from IgG4-negative MZL.…”

Section: Introductionmentioning

confidence: 99%

“…10,11 Although it is rare, pathological analyses of ocular MZLs showed clonal IgG4-positive or IgG4-producing lymphoma cells forming a unique disease entity. 12,13 While it has been speculated that IgG4-positive MZLs might emerge in the setting of IgG4-RD due to upregulated expression of activation-induced cytidine deaminase, 11 it is still unclear if IgG4-positive MZLs can emerge without concurrent IgG4-RD or if IgG4-positive MZL has different clinical characteristics from IgG4-negative MZL. Also, although a previous study suggested that IgG4-positive MZL is associated with a favorable prognosis without expiration of patients within the median follow-up of 66 months, 14 clinical characteristics and prognosis of IgG4-positive MZLs is yet to be defined.…”

Section: Introductionmentioning

confidence: 99%

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Clinical characteristics and outcomes of IgG4‐positive marginal zone lymphoma: Systematic scoping review

Nishimura

Wien

Nishimura

et al. 2022

Pathology International

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Immunoglobulin G4 (IgG4)‐positive marginal zone lymphoma (MZL) is rare and undefined. It is unclear whether IgG4‐positive MZLs have as favorable an outcome as MZLs in general. Also, correlation with IgG4‐related disease (IgG4‐RD) and IgG4‐positive MZLs is unknown. Following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses extension for scoping reviews, we searched MEDLINE and EMBASE for all peer‐reviewed articles using keywords including“IgG4” and “marginal zone lymphoma” from their inception to February 20, 2022. Twenty‐two articles, including six observational studies and 24 cases from 16 case reports and case series, were included. Only one study had a comparative group, and the other five were exploratory observational studies. IgG4‐positive MZLs commonly occurred in males (83.3%). It primarily involved ocular adnexa (41.7%) and skin (29.2%). Only 29.2% had concurrent IgG4‐RD, and no expiration was noted. While most cases were treated with excision, resection, or clinical observation, 21.7% received rituximab‐cyclophosphamide, doxorubicin, vincristine, and prednisone as a first‐line treatment. This systematic review summarizes the current understanding of the characteristics of IgG4‐positive MZLs. While there seems to be IgG4‐RD‐related and de novo IgG4‐positive MZLs, future research needs to clearly define MZL with polyclonal IgG4‐positive cells and IgG4‐producing lymphoma. Further studies are critical to clarifying long‐term prognosis and optimal surveillance planning.

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinical characteristics and outcomes of IgG4‐positive marginal zone lymphoma: Systematic scoping review

Nishimura

Wien

Nishimura

et al. 2022

Pathology International

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“…Infraorbital nerve enlargement is a unique feature on MRI scans [ 31 ]. Upregulation of activation-induced cytidine deaminase (AID)—the master factor for somatic hypermutation and class-switch recombination of immunoglobulin genes—was observed in IgG4-related ophthalmic disease and OAMZL, whereas AID expression was lower in IgG4-negative OAMZL [ 36 ]. AID might be a driver for oncogenesis in the development of IgG4-related ophthalmic disease to IgG4-positive OAMZL.…”

Section: Etiology and Pathogenesismentioning

confidence: 99%

The Biology of Ocular Adnexal Marginal Zone Lymphomas

Johansson

Eckstein

Küppers

2022

Cancers

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This review focuses on the biology of ocular adnexal marginal zone B-cell lymphomas of the mucosa-associated lymphatic tissue (MALT) (OAMZL) subtype. The ocular adnexa includes all structures and tissues within the orbit except for the eye bulb. In the region of the ocular adnexa, MALT lymphomas represent the most common subtype of lymphoma, accounting for around 8% of all non-Hodgkin lymphomas. These lymphomas are often preceded by inflammatory precursor lesions. Either autoantigens or infectious antigens may lead to disease development by functioning as continuous antigenic triggers. This triggering leads to a constitutive activation of the NF-κB signaling pathway. The role of antigenic stimulation in the pathogenesis of OAMZL is supported by the detection of somatic mutations (partially with further intraclonal diversity) in their rearranged immunoglobulin V genes; hence, their derivation from germinal-center-experienced B cells, by a restricted IGHV gene usage, and the validation of autoreactivity of the antibodies in selected cases. In the established lymphomas, NF-κB activity is further enforced by mutations in various genes regulating NF-κB activity (e.g., TNFAIP3, MYD88), as well as recurrent chromosomal translocations affecting NF-κB pathway components in a subset of cases. Further pathogenetic mechanisms include mutations in genes of the NOTCH pathway, and of epigenetic regulators. While gene expression and sequencing studies are available, the role of differential methylation of lymphoma cells, the role of micro-RNAs, and the contribution of the microenvironment remain largely unexplored.

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