Is There a Narrow Connection Between the Two Subsets of Cutaneous MALT Lymphomas and the Dynamics of the Follicle?

To the Editors: In the past few years, it has been discovered that there are probably 2 subsets of cutaneous marginal zone (MZ)-associated lymphoid tissue (MALT) lymphomas.1 One type seems to be made of non–switched immunoglobulin tumoral cells. Such cases mainly express IgM, and they are commonly positive for CXCR3. Moreover, this subset of MALT lymphoma develops most frequently in a predominant B cell–reactive environment1 and has been associated with the infection caused by Borrelia burgdorferi.2–4 The second subset of cutaneous MALT lymphomas consists of switched immunoglobulin tumoral B cells, expressing γ-, α-, or [Latin Small Letter Open E]-Ig heavy chain.1 These cases do not generally express CXCR3, and they develop in a predominantly reactive T cell environment.1 Unlike the first subset, this variant has not been associated with the infection caused by B. burgdorferi. The clinical relevance of distinguishing between these 2 subsets is considerable. Although class-switched cases commonly stay confined to the skin, the IgM+ cases show extracutaneous involvement in up to 50% of the cases.1 Moreover, there is growing evidence to suggest that switched cases could be considered a nonmalignant reactive condition rather than a lymphoma.1 In this letter, we would like to draw further attention to the parallelism between these 2 subtypes of lymphomas and the physiological immune response in the lymphoid tissue. Briefly, 2 types of responses can be distinguished: a non–germinal center (non-GC) response and a germinal center response. The non-GC response is mainly led by either B1 cells or MZ cells.5 Although B1 cells are antigen insensitive,6 MZ cells are antigen-sensitive B2 cells of the MZ.7,8 The non-GC response is mainly oriented to produce a rapid immune low-affinity response, with short-living plasma cells against (mainly) T cell–independent antigens but also against T cell–dependent antigens.9 In the non-GC response, there is very little (if any) isotype-immunoglobulin-class switching and no (or little) somatic hypermutations.10 This is why such a response consists mainly of IgM antibodies. The blasts that result from this response can, alternatively, enter the GC and start the second pathway: the GC one. The GC pathway leads to a highly effective humoral immune response of long-living memory cells or plasma cells. One way that such a high-affinity response is achieved is through the mechanisms of somatic hypermutations and isotype-immunoglobulin-class switching.11 Non-GC and GC responses are also commonly known as early and late immune responses, respectively. Although it is still not entirely clear what factors determine whether one specific B cell differentiates in one direction or another, it is known that MZ cells are frequently recruited in the non-GC pathway, whereas recirculating B cells are mainly recruited in the GC pathway.9,12 However, some authors believe that it is the type of antigen that determines whether a B cell follows one path or another.13 In summary, MZ cells dominate both the T cell–independent responses and the early stages of the T cell–dependent responses (non-GC pathway), whereas GC cells dominate the late stages of the T cell–dependent immunologic response (GC pathway).14 Our study considers the possibility that the 2 subsets of cutaneous MALT lymphomas might be related to these two pathways. Consequently, we could hypothesize that MZ cells might be the cells of origin for non-switched cases. This would explain why these cells are actually “non-switched.” It would also explain why the environment for such cases includes mainly B cells because the extra GC response is primarily T cell independent. If this hypothesis is correct, non-switched cases would actually be “real” MALT lymphomas that occur in the skin in the same way that they do in several other organs. This would also make sense in light of the similarities found between non-switched–type cutaneous MALT lymphoma cases and the MALT lymphoma cases that form in other organs. With respect to the association between non-switched cases and infections caused by B. burgdorferi, it is curious that the response against bacterial capsular polysaccharide mainly elicits a T cell–independent non-GC response.15,16 Based on our hypothesis, switched cases that are not related to the MZ would be made from B2 cells. These cells mainly trigger a T cell–dependent immune response, which would be in agreement with the finding of a T cell predominant environment in such variants of cutaneous MALT lymphomas. Such a response would not be related to bacterial capsule polysaccharides, and, curiously, switched cases of cutaneous MALT lymphoma are not related to B. burgdorferi infection. We also wonder if switched cases might be better considered as an “exaggerated” GC response to certain T cell–dependent stimuli rather than a lymphoma per se. This would explain their good behavior and that they do not tend to show extracutaneous spread.