A subset of ocular adnexal marginal zone lymphomas may arise in association with IgG4-related disease

Abstract

We previously suggested a relationship between ocular immunoglobulin (Ig)G4-related disease (IgG4-RD) and marginal zone lymphomas (MZLs). However, the cytokine background associated with these disorders and whether it differs between ocular adnexal MZLs with (IgG4-associated MZL) and without (IgG4-negative MZL) numerous IgG4(+) plasma cells are unknown. In this study, we identified the mRNA expression pattern of Th2 and regulatory T-cell (Treg) cytokines in IgG4-RD and in IgG4-associated MZL and IgG4-negative MZL using real-time polymerase chain reaction analysis. Ocular IgG4-RD and IgG4-associated MZL exhibited significantly higher expression ratios of interleukin (IL)-4/β-actin, IL-10/β-actin, IL-13/β-actin, transforming growth factor (TGF) β1/β-actin, and FOXP3/β-actin than did IgG4-negative MZL (p < 0.05). This finding further supports our prior observations that a significant subset of ocular MZLs arises in the setting of IgG4-RD. Furthermore, the presence of a different inflammatory background in IgG4-negative MZLs suggests that IgG4-associated MZLs may have a different pathogenesis.

Figure 1. IgG4-related disease (case 6).

Marked lymphoplasmacytic infiltration with dense fibrosis, scattered eosinophils, and interspersed reactive lymphoid follicles are shown (A,B) (hematoxylin & eosin). Numerous IgG⁺ (C) and IgG4⁺ (D) cells are present with an IgG4⁺/IgG⁺ cell ratio >40%.

Figure 2. IgG4-negative marginal zone lymphoma (case 16).

There is a diffuse proliferation of small- to medium-sized lymphoid cells (A,B) that are CD20⁺ (C) and CD3⁻ (D). Numerous Igκ⁺ plasma cells are present (E), but only very few Igλ⁺ plasma cells (F). Some IgG⁺ (G) and IgG4⁺ (H) cells are present but the IgG4⁺/IgG⁺ cell ratio is <40%.

Figure 3. IgG4-associated marginal zone lymphoma.

The diffusely proliferating small- to medium-sized lymphoid cells [(A,B) case 26] are CD20⁺ (C) and CD3⁻ (D). Infiltration of many IgG⁺ (E) and IgG4⁺ (F) cells are observed, but these cells are polytypic (G) (Igκ) and (H) (Igλ). The IgG4⁺/IgG⁺ cell ratio is >40%.

Figure 4. IgG4-associated marginal zone lymphoma (case 28).

Numerous plasmacytic cells are present (A,B) that are IgG⁺ (C). The lymphoma cells are κ light chain-restricted. (D) Igκ-in situ hybridization and (E) Igλ-in situ hybridization. Admixed IgG4⁺ plasma cells that appear to be polytypic are present (F).

Figure 5. Cytokine levels were measured by relative quantification of mRNA.

mRNA expression of Th2 cytokines (IL-4, IL-13) and regulatory cytokines (TGFβ1, IL-10) are significantly higher in the ocular adnexal regions from biopsies with IgG4-related disease and IgG4-associated marginal zone lymphoma than in the ocular adnexal regions from IgG4-negative marginal zone lymphomas. The expression levels of IL-5 are not significantly different. Data represent mean ± standard deviation (SD) values. Significant differences between groups were determined using the Mann-Whitney U test. (*p < 0.05). IgG4⁻ MZL, IgG4-negative marginal zone lymphoma; IgG4-RD, IgG4-related disease; IgG4⁺ MZL, IgG4-associated marginal zone lymphoma.

Figure 6. FOXP3 expression levels were measured by relative quantification of mRNA.

mRNA expressions of FOXP3 are significantly higher in the ocular adnexal regions from biopsies with IgG4-related disease and IgG4-associated marginal zone lymphoma than in the ocular adnexal resions from IgG4-negative marginal zone lymphomas. (*p < 0.05). IgG4⁻ MZL, IgG4-negative marginal zone lymphoma; IgG4-RD, IgG4-related disease; IgG4⁺ MZL, IgG4-associated marginal zone lymphoma.