MZBCL, while only lymphocytopenia was retained as a risk factor for non-MZBCL [21]. Between various studies there are inconsistencies regarding the frequency of the different subtypes of lymphomas. Baimpa et al. proposed a diversity of triggering stimuli of lymphomagenesis in different geographic areas as one reason [21]. Another might be that low-grade MALT lymphomas can be difficult to detect in some patients without active searches and may come to medical attention only at the time they transform into DLBCL [42].

33.5Pathogenetic Mechanisms

The underlying mechanisms for the inter-relationship of autoimmune disease and lymphoproliferative neoplasias are still insufficiently understood. Both situations occur in hosts with altered immune responses and surveillance mechanisms. The interplay of genetic, environmental, and infectious agents may be regarded as critical to the development of both autoimmunity and malignancy.

Certain risk factors for malignancy in pSS (e.g., hypergammaglobulinemia, chronic lymphocytic infiltration into salivary glands, germinal centre formation) are consistent with the hypothesis of chronic antigenic stimulation of B-cell subsets within the salivary glands. Other risk factors, e.g., lymphopenia and neutopenia, suggest the importance of decreased immune surveillance. Still others (monoclonal immunoglobulin) imply the survival of B cells with potential for malignancy supported by factors such as BAFF or APRIL. BAFF levels have not yet been directly associated with lymphoma development in pSS, but are known to play a role in the evolution of idiopathic NHLs and in hepatitis C-associated NHLs [43, 44]. Among the autoimmune diseases, BAFF levels are highest in pSS, both in the systemic circulation and in salivary glands; higher even than in SLE and RA. Increased B cell survival is favored further by upregulation of the anti-apoptotic mediator Bcl-2.

Although such predictors of lymphoma are present at the time of SS diagnosis and thus often many years before the clinical appearance of the lymphoma, additional triggers – possibly local aberrant genetic events within the GCs – must be necessary to inducethefinalmultisteptransitionresultinginlymphomagenesis[41,45].Understanding these additional triggers might permit more accurate predictions of the time when lymphoma will appear. The availability of therapeutic B-cell depletion makes precise prediction of when and in whom a lymphoma will develop particularly important.

In RA, disease activity and chronic inflammation have been identified as the major risk factors for lymphoma development. In pSS, measurement instruments for disease activity have been lacking until very recently, but are now available as the EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) instrument [46]. We have observed an association between higher ESSDAI scores in SS and germinal center-like structures in pSS lower lip salivary gland biopsies [38]. This may indicate that higher disease activity burden is also accompanied by increased lymphoma risk in pSS.

33.6Medication and Risk of Lymphoma in SS

The question of medication-induced lymphoma has been addressed in a number of publications in other rheumatic diseases, especially RA and SLE. Similar considerations are of interest in sSS associated with RA or SLE, but data on such questions are lacking. Immunosuppression is generally considered unnecessary or ineffective in pSS, at least with regard to traditional Disease Modifying Anti-Rheumatic Drugs (DMARDs) and TNF-alpha blocking agents, and is therefore avoided. A question important for pSS, however, is the potential efficacy of newer therapies directed against B cells and whether or not such interventions reduce the risk of lymphomagenesis. The short-term effects of B cell depletion in pSS, such as the reduction of the number of extraglandular manifestations [47] or the reduction in the number of germinal centers in the parotid gland [48], support such a strategy, but further studies are required. Long follow-up periods and use of surrogate biomarkers for lymphoma risk profile changes will be necessary before this question can be answered definitively.

33.7Associated Sjögren’s Syndrome and Lymphoma

Very little is known about the risk of lymphoproliferative disease in sSS or to what extent sSS enhances the risks of lymphoma known to exist for RA and SLE. A study by Kauppi et al. from Finland demonstrated a twofold increased risk of lymphoma for RA patients with sSS compared to RA alone [49]. The large InterLymph Consortium Study observed higher lymphoma risks for sSS than for pSS, with odds ratios of 9.57 and 4.75, respectively [20]. Löfström et al. documented that sicca symptoms constitute a risk factor for lymphoma development in SLE [50].

33.8Other Cancers in SS

Information about risk of other malignancies than lymphoproliferative disorders in pSS is scarce. In a Swedish cohort study including 286 pSS patients who fulfilled the AECC criteria, we found 33 malignancies compared to the expected number of 23, resulting in a SIR for all malignancies of 1.42 (95% CI 0.98–2.00). However, instead of the expected 0.71 cases of NHL, we detected 11. Thus, ten excess malignancies were attributable to an increased risk of NHL in pSS [10].

Lazarus confirmed in a British SS cohort a lack of increased cancer risk for other malignancies than hematological ones: SIR 1.5 (95% CI 0.9–2.6) [51]. In contrast, the recently published cohort study investigating cancer risk in young Chinese SS patients revealed a SIR for all tumors of 3.25 (95% CI 2.12–4.52), and for nonhematological tumors the SIR was 2.12 (95% CI 1.27–3.31) [17]. There is not much information about risk factors or predictors for development of other cancers than

lymphoma in pSS. In the Swedish cohort described above [10], a trend towards lower percentage of CD4+ T cells, but no other marker of lymphoma development seemed to predict other malignancy as well. Anticipating similarities between SLE and SS one might speculate that hormonal and reproductive factors would influence the risk of breast, cervix, uterus and ovarian cancer in a similar way as in the general population, as does smoking with regard to lung cancer [52]. Do several cancers appear in the same patient, or do other cancers increase the risk of lymphoma development? In the British cohort nine patients had two or more cancers [51], and in the Swedish cohort there seemed to be an increased risk of lymphoproliferative diseases in patients with concomitant skin cancer [10], in concordance with general findings of increased risks for other cancers in patients with skin cancers [53–55].

33.9Conclusion

Patients with pSS who have persistent salivary gland swelling, hypocomplementemia, cytopenia or germinal center-like structures within their salivary glands should be followed more closely than others. Recent research supports the opinion that increasing number or risk factors increase the lymphoma risk, but the ability to predict lymphomagenesis from these identified risk factors remains imperfect. The increased risk in patients with other cancers, especially skin cancers, and concomitant lymphoma associated autoimmune diseases, requires further prospective studies. Regular follow-up of high-risk groups with longitudinal assessments of all known risk factors, including increased disease activity as assessed by the ESSDAI instrument, will facilitate understanding of these questions. Research must now be directed towards understanding the mechanism of lymphomagenesis in SS and in designing intervention strategies to prevent such events.

Acknowledgments The authors are grateful to Prof. Otto Ljungberg and Dr. Malin V. Jonsson for providing photographs of B cell lymphomas and germinal center-like structures in the salivary glands and Prof. Küppers for allowing the reproduction of the cartoon on B cell development within the Germinal Centers.

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