Alteration of Cell Surface Markers CD38 and CD138 in Lymphoproliferative Disorders in the Ocular Adnexa

Discussion

IgG4-ROD is a chronic inflammatory condition characterized by enlargement of orbital tissues such as lacrimal glands, extraocular muscles and infraorbital nerves. Histologically, IgG4-ROD demonstrates tissue infiltration by T and B lymphocytes, as well as IgG4-secreting plasma cells with fibrosis (1). It has been hypothesized that IgG4-ROD is triggered by autoimmunity and infectious agents (10). Th2-dominant helper T cells and regulatory T cells release various cytokines, which subsequently activate various inflammatory cells such as B lymphocytes, fibroblasts and eosinophils (10). Activated B lymphocytes turn into plasma cells, secreting IgG4. Activated fibroblasts play a critical role in fibrosis formation in IgG4-ROD tissues (10).

In contrast, EMZL is a low-grade B-cell lymphoma, derived from memory B cells in the marginal zone of lymphoid organs. Histological findings in EMZL tissues revealed infiltration of centrocyte-like and monocytoid tumor cells in the marginal zone surrounding reactive follicles. The fact that tumor cells often manifest plasmacytic differentiation is of morphological importance. Coupland et al. have reported that 57 (42%) of the 136 EMZL tissues of the ocular adnexa showed a plasmacytic differentiation (13).

This is the first study investigating the difference in CD38 and CD138-positive rates between IgG4-ROD and EMZL tissues. We found that although the rates of CD138-positive cells were low in both IgG4-ROD and EMZL, the number of both CD38- and CD138-positive cells were greater in IgG4-ROD than in EMZL. CD38 is detectable throughout the cells of the immune system: activated T cells, activated B cells (plasma cells) and NK cells (7). In addition, both CD38 and CD138 are present on pre-B-cells and plasma cells but they are absent in circulating and peripheral B lymphocytes (8, 9). In this study, among the IgG4-ROD cases, there was no positive correlation between the rates of CD38 and CD138 (Figure 1A). Double-staining FCM demonstrated that several CD38-positive cells were positive for CD5, a T-cell marker, in two available IgG4-ROD cases (Figure 2). Therefore, the higher rate of CD38 in IgG4-ROD may possibly reflect the infiltration of activated T cells in the tissue.

As described above, CD38 is expressed not only in plasma cells and activated T cells but also in NK cells. In this study, the population of CD56-positive cells, a common marker for NK cells, was significantly higher in IgG4-ROD than in EMZL, although the number of NK cells was considered low compared to CD38-positive cells. Therefore, the CD38 population detected in IgG4-ROD tissues may be partially correlated with NK cells; however, there is no evidence that NK cells play a role in the pathogenesis of IgG4-ROD. Further studies are needed to clarify the role of NK cells in IgG4-ROD.

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Figure 2.

Double-staining FCM analysis for CD38, a marker for activated T cells, plasma cells and NK cells, and CD5, a representative T cell marker, in 2 cases with IgG4-ROD. In one case, the rate of CD38 and CD5 double positive cells was 45% (A). In the other case, it was 20% (B).

Concerning EMZL, a previous study has demonstrated that almost half of ocular adnexal EMZL tissues showed histologically a plasmacytic differentiation, in which most of plasmacytoid cells were positive for CD38 (89%) and CD138 (91%) (13). In this study, among the EMZL cases, there was a positive correlation between CD38 and CD138 (Figure 1B), suggesting that CD38-positive cells detected by FCM may be associated with the plasmacytic differentiation.

There are limitations in this study. First, there is relatively a small number of patients examined in this study. Next, although plasma cell infiltration is one of the characteristic pathological findings in IgG4-ROD, the rates of CD138-positive cells were low in both IgG4-ROD and EMZL (2.5±1.5% and 1.3±1.3%, respectively). These results might not reflect the true population of CD138-positive cells in the tissues of each disease owing to the decreased sensitivity of the antibody used or unknown problems during the process of FCM procedure. Further studies are required to clarify the correlation between the percentages of FCM-based and histological CD138-positive cells. Third, we applied double staining for CD38 and CD5 with FCM in only 2 cases that were available. Further examinations are needed to clarify the origin of high CD38 population in IgG4-ROD. Finally, this study did not examine orbital tissues from patients with plasmacytoma and IgG4-producing EMZL, in which populations of CD38 and CD138 might also be altered. Therefore, further enrollment of patients that can provide such tissue and FCM analysis would provide additional insights.

In conclusion, FCM-based analysis of the difference in the rates of CD38- and CD138-potitive cells between IgG4-ROD and EMZL, due to different lymphocyte populations, may lead to better understanding of the pathogenesis of the two diseases often hardly distinguishable from each other.