We have performed an analysis of the risk of malignancy, in general, and lymphoproliferative neoplasms, in particular, in our prospectively followed cohort of patients with pSS. The focus of this study was on patients fulfilling the AECC for pSS.1
There are two main new messages:
- The often cited risk estimate for NHL of a 44‐fold increase compared with the background population is probably valid only for highly selected patient populations with severe disease, while a lower risk estimate as found in this study (16‐fold increase) is probably more representative for an average pSS population. No other malignancies were overrepresented with statistical significance, although the power to detect such deviations was low.
- Our results show a substantially increased risk for developing lymphoproliferative malignancy in patients with a decreased CD4+/CD8+ T lymphocyte ratio. No previous longitudinal cohort study has evaluated the significance of T cell disturbances with respect to outcome in pSS, even though the presence of CD4+ T lymphocytopenia was described years ago and suggested to be associated with cases of NHL.17 Earlier proposed risk factors such as hypocomplementaemia and skin vasculitis are confirmed.
Additional interesting observations include the presence of further predisposing factors, such as autoimmune thyroiditis, coeliac disease, H pylori
infection, skin cancers or psoriasis, which may deserve increased awareness and intensified search for lymphoma when combined with suspicious clinical or laboratory signs. The significance of these coincidences requires confirmation. However, the high prevalence of earlier non‐melanoma skin cancers in our lymphoma patients is in concordance with several recent reports on increased lymphoma risks in patients with skin cancer.39,40
Surprisingly, the NHLs in our pSS cohort are high grade, diffuse large B cell (DLBC) lymphomas in 58% of cases.
In concordance with our previous study on mortality, the present investigation also underlines the importance of strict and universally accepted classification criteria, as patients not fulfilling the AECC criteria do not show any increased lymphoma risk, in contrast with those who do fulfil the criteria.
The strengths of the present study are the strict prospective design of the data collection from one centre, in combination with the highly reliable Swedish general health registers.25
In addition, the follow up time of up to 19 years (median 8 years) is relatively long. This seems to be a prerequisite to allow evaluation of long term severe outcomes such as death or cancer development. When Kirtava et al
in 1995 described six patients with CD4+ T lymphocytopenia from our department (follow up for up to 7 years), only one had developed lymphoma17
. In the present study we found that another two of these patients had developed a lymphoma. The mean time between diagnosing pSS and the appearance of the lymphoma was in the present study 8 years (1–13 years). The risk of lymphoma increases with time, exemplified by the highest SIR of >20 being observed in those followed up for more than 10 years.
CD4+ T lymphocytopenia has been described in association with, and pre‐existing before, NHLs.41,42,43,44
In our study all the risk calculations were performed using the first available CD4+ T cell analysis, most often performed at or shortly after the time of diagnosing pSS, and always before the lymphoma detection (table 3), which excludes the possibility of a lymphoma‐induced CD4+ T lymphocytopenia. We have to acknowledge the lack of systematic cryoglobulin analysis in our cohort as an important drawback. The assumption that cryoglobulinaemia is rare in Swedish patients with pSS34
needs to be revised in the light of the new classification criteria.
Our study differs from previous studies in several important aspects. The lymphoma incidence was lower than in Kassan's original description, which, however, as the authors themselves point out, may not be generalised to other populations less prone to selection bias.7
Furthermore, their study had slightly less precision, being based on only seven (four pSS lymphoma) cases. The described histiocytic diffuse and Lennert's lymphomas in six of seven cases would correspond to high grade DLBC and T cell lymphomas in the present WHO classification. This is in accordance with our cases with predominantly high grade DLBC lymphoma. In contrast, two other case series have documented a predominance of low grade lymphomas, quite often in salivary glands and of MALT type,10,45
while another study did not find any MALT lymphomas among four patients with SS and associated NHLs.8
Only one of our cases could possibly be classified as MALT lymphoma. Our approach with linkage to the validated national cancer register excludes any major detection bias, which may operate when cases are identified in routine clinical settings. Transformation from earlier MALT lymphoma into DLBC lymphoma can, however, not be excluded. Survival after lymphoma was comparable with previous reports when groups of high and low grade lymphomas were compared separately.10
The lymphoma types found in our study are similar to those found in Swedish RA cohorts.46
Also in systemic lupus erythematosus, the associated lymphomas are predominantly of the DLBC type.47
The reported increase in risk with disease duration is similar to studies in rheumatoid arthritis (RA), but in contrast to studies in systemic lupus erythematosus, where the highest risk is observed within the first 5 years after diagnosis.47
In RA high disease activity is the most important predictive factor for lymphoma.48
Disease activity is difficult to assess in pSS. Correlation between extraglandular disease and CD4+ T lymphocytopenia due to apoptosis was described in pSS.19
It seems conceivable that a longstanding deficiency in immune surveillance finally allows malignant transformation in antigen stimulated proliferating B cells.
The causes of CD4+ T lymphocyte depletion or disturbed balance between CD4+ and CD8+ T cells are unknown. Anti‐CD4+ antibodies have been documented in patients with pSS without correlation to the level of CD4+ T cells.49
Virus infections are typical causes of lymphopenia, and HIV infection is the prototype of virus‐induced CD4+ T lymphocytopenia, associated with lymphoma development.50
and Epstein‐Barr virus52
are viruses associated with lymphoma development and autoimmunity. Coxsackie B virus was recently proposed as an aetiological factor in pSS,53,54
but its potential to induce cytopenia has not been studied. CD4+ T cells and subsets of the CD4+ T lymphocytes are important in tumour immunity.55
To what extent the different predictors for lymphoma development, such as cryoglobulinaemia, hypocomplementaemia, B cell activation, and CD4+ T cell depletion have a shared aetiology or represent different aspects of risk needs to be elucidated.
In summary, our results suggest that CD4+ T lymphocytopenia is a useful clinical predictor, which possibly is of crucial importance in the sequence of events leading to lymphoma development in patients with pSS. Previously proposed risk factors, such as hypocomplementaemia and skin vasculitis could be confirmed, while aggressive types of lymphomas were common in our cohort. The overall lymphoma risk was lower than proposed earlier, but increased with disease duration.