SIR Standardized incidence ratio

more severe cases. This chapter therefore confines its conclusions to studies that have employed with case verification procedures based upon the AECC 2002 [4].

Another methodological concern is the possibility of reverse causality; that is, the chance that cancer or lymphoma might induce autoimmune phenomena and mimic the rheumatic disease in question. However, in the case of SS, disease onset is difficult to define and median delays of 8 years between first symptoms and diagnosis have been registered (personal communications and own unpublished experience). Short observation times may lead to underestimation of the risk of malignancy because in pSS, lymphoma frequently appears late instead of early [9, 10].

Lymphomas, the main type of malignancy associated with SS, have been classified according to various systems. Major advances in understanding of the biology of these diseases have led to the now universally accepted World Health Organization (WHO) classification [11]. The WHO classification separates the lymphomas into either B-cell or T/NK-cell neoplasms (previously “non-Hodgkin lymphoma” (NHL)) or Hodgkin lymphoma (HL), and each of these entities is then divided into a number of specific subtypes.

33.3Primary Sjögren’s Syndrome and Lymphoma

33.3.1Risk Levels

An increased risk for malignant lymphoma in patients with pSS has been observed in a number of studies (Table 33.1). Kassan et al. reported in their classic 1978 paper that 15 patients within their National Institute of Health (NIH) cohort of 142 patients with sicca syndrome had developed malignancies other than skin cancer, among whom seven patients had 7 NHL [12]. Although the incidence of the eight other types of cancer reported were within the expected range for the comparison population, the incidence of lymphomas was not. The Standardized Incidence Ratio (SIR) for NHL in the patients with pSS was calculated to be 44.4,

and for those with SS secondary to RA 42.9. The risk for patients with parotid enlargement was considerably higher (relative risk 66.7) than for those without (relative risk 12.5), and parotid radiation enhanced the risk (relative risk 300). This important first observation, though probably influenced by selection of patients with severe disease manifestations into the NIH cohort, stimulated research on SS and lymphoma.

More than 20 years after this study, registry-linkage studies gave more reliable estimations of the risk of malignancy in the pSS population [10, 13–15]. The magnitude of the association between lymphoma and SS shows wide variation among studies. Zintzaras et al. reported in a meta-analysis that the SIRs for NHL in SS cohorts varied between 8.7 and 44.4. The pooled analysis resulted in an SIR of 18.8 (95% CI 9.5–37.3) [16]. The results of our own cohort study, in which an SIR for NHL of 15.6 (95% CI 7.8–27.9) [10] was reported, were concordant with this meta-analysis.

A study by Zhang et al. that involved 1,320 Chinese pSS patients found an SIR for NHL of 48.1 (95% CI: 20.7–94.8) [17]. The mean age of these patients was only 39 years – very young for a pSS cohort. The high SIR in this study may pertain both to the lower mean age of the patients and also to selection bias of a patient cohort with more severe disease [17, 18]. The other investigations have revealed more modest risk increases. A recent study by Andersson et al. compared 44,350 patients with lymphoproliferative malignancies with 120,531 individuals without malignancies. All subjects in the study were older than 67 years. One hundred and forty-two patients in the malignancy group had SS, versus 255 subjects in the comparison group, for an odds ratio (OR) for having SS of 1.9 (95% CI: 1.5–2.3) [15].

The cumulative incidence of lymphoma in pSS was reported to be 18% after 20 years of observation in one study [19]. Most studies report a lifetime risk of lymphoma in pSS of approximately 5–10% [9].

33.3.2Lymphoma Subtypes

Various subtypes of lymphoma have been described in pSS. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (i.e., MALT lymphomas) were once considered to be the only lymphoma subtype associated with pSS. However, in recent years, appreciation has grown for the development of other subtypes, particularly diffuse large B-cell lymphomas (DLBCL) (Fig. 33.1). Smedby et al. presented risk ratios for the different subtypes and noted a 28-fold increased risk for marginal zone B-cell lymphoma (MZBCL) (including MALT lymphoma) and an 11-fold increase of DLBCL [13].

Taking into account that DLBCL is the most frequent lymphoma in the general population, the DLBCL is numerically more important in pSS than the MALT lymphoma [20]. Anderson et al. found in their nested case control study that patients with DLBCL had a twofold increase of SS compared to patients without

Fig. 33.1 Diffuse large B-cell lymphoma in a salivary gland. Hematoxylin and eosin staining

DLBCL (95% CI: 1.5–2.8) and patients with MZBCL had an odds ratio (OR) of 6.6 (95% CI: 4.6–9.5) for SS. Patients with other types of lymphomas, including Hodgkin lymphoma, did not have increased risks of SS [15]. However, in patients with salivary gland lymphomas and salivary gland MALT lymphomas, the ORs for SS were 22 (95% CI: 14–36) and OR 71 (95% CI: 40–120), respectively [15]. Among 40 pSS patients with lymphoma, Baimpa found 52.5% MALT lymphomas, 12.5% nodal MZBCLs, 17.5% DLBCLs, and 17.5% lymphomas of other subtypes (lymphoplasmocytic, follicular, polymorphic B cell, peripheral B cell, and Hodgkin disease) [21].

The features of MALT lymphomas in pSS are reviewed in detail recently [22]. MALT lymphomas may appear in salivary glands as the predominant site, but also in the stomach, nasopharynx, skin, kidney, and lungs. MALT lymphomas present at more than one extranodal site in 20% of patients, emphasizing the need for complete staging at diagnosis [22]. Bone marrow infiltration is rare (10%).

MALT lymphomas may transform into DLBCL in the course of the disease, but precisely what percentage of DLBCL arise from pre-existing MALT or follicular lymphomas is not known [22]. However, the histological transformation into a DLBCL is a poor prognostic sign, as survival in de novo or secondary DLBCL is poor [9, 10]. With the possible exception of vasculitis, lymphoma is the only cause of death conferring premature mortality to pSS patients, adding an excess death rate of 9.4 cases per 1,000 patient years at risk [3]. The median survival time for lowgrade lymphomas was 76 months, in contrast to that of only 31 months for highgrade lymphomas [10]. However, most of these cases were treated before rituximab was widely used in the treatment of lymphomas. In 2006, Friedman et al. proposed T-cell (CD3+) large granular lymphocyte (LGL) leukemia as an under-recognized association with pSS. Twelve of 48 patients with T-cell (CD3+) LGL leukemia met criteria for SS [23].