function such as the use of saliva substitutes, sugarless chewing gum, or systemic pilocarpine may be useful at addressing the underlying xerostomia [18].

11.3.4Panniculitis

Various forms of panniculitis are reported in association with SjS including erythema nodosum [19], lobular plasma cell panniculitis [20], necrotizing lymphocytic panniculitis [21], and granulomatous panniculitis [21].

Yamamoto et al. reported four cases of erythema nodosum associated with SjS [19]. All four patients were women (age 27, 43, 65, and 77) and all had lower extremity involvement. One patient had erythema nodosum on the forearms, as well. The patients responded to nonsteroidal anti-inflammatory drug therapy in all cases [19]. However, the precise relationship between SjS and erythema nodosum – direct association or chance co-occurrence – is uncertain.

Granulomatous panniculitis is perhaps the most distinctive form of SjS-associated panniculitis. Five cases, all tending to affect the forearms and lower legs of women, have been reported [21, 22]. The histopathologic findings in these cases were mixed lobular and septal granulomatous inflammation in the subcuticular adipose tissue and prominent multinucleated giant cells [21].

Plasma cell panniculitis has been rarely associated with SjS. This pattern of panniculitis is also reported to occur in association with both lupus erythematosus (lupus profundus) [23] and scleroderma (morphea profundus)[24].

11.3.5Primary Nodular Cutaneous Amyloidosis

Amyloidosis is characterized by the extracellular deposition of amyloid fibrils comprised of misfolded host proteins [25]. Primary cutaneous nodular amyloidosis (PCNA) is a rare condition characterized by cutaneous deposition of immunoglobin light chains produced by a clonal plasma cell population that infiltrates the skin (Fig. 11.3). The amyloid fibrils are of the same class (AL) as those found in primary systemic amyloidosis, but relate to a skin-limited plasma cell dyscrasia. At least 20 cases of PNCA – approximately a quarter of all reported patients with PNCA – have been reported in patients with SjS [25–30].

The typical clinical presentation of PCNA consists of waxy, red-to-yellow nodules located preferentially on the lower extremities, face, scalp, and genitals [27].

Histopathologic examination shows an amorphous eosinophilic material within the dermis that demonstrates apple-green birefringence upon Congo-red staining and visualization under polarized microscopy. Immunoblot analysis demonstrates immunoglobulin light chains. Monoclonal immunoglobulin is the more common pattern, though cases characterized by polyclonal immunoglobulin deposition have rarely been reported. Of 14 cases of SjS-associated PCNA for which positive

Fig. 11.3 Primary nodular cutaneous amyloidosis of the leg (Clinical images were kindly provided by Dr. Scott Florell, Department of Dermatology, University of Utah, USA)

immunoblotting was reported, 11 cases showed single class immunoglobulin staining and three cases showed staining with both anti-lambda- and anti-kappa-light-chain antibodies along with polyclonal gammaglobulinemia [25, 26, 28, 30–32]. Polyclonal immunoglobulin may be unique to PCNA associated with SjS, perhaps relating to development of polyclonal B cell proliferation in some SjS cases [26].

PCNA in SjS thus appears to result from a benign clonal proliferation of plasma cells that home to the skin, perhaps as part of the spectrum of SjS-related lymphoproliferative diseases [25]. The presence of PCNA warrants screening for lymphoproliferative disorders or systemic amyloidosis [27]. Systemic amyloidosis can also cause sicca syndrome through the deposition of amyloid fibrils within salivary glands [33].

11.3.6B Cell Lymphoma

Patients with SjS have a 6.5–40-fold increased risk of lymphoma, most often extranodal B cell lymphomas of the non-Hodgkin’s variety [34, 35]. The risk of nonHodgkin’s lymphoma may be somewhat higher in patients with secondary compared to primary SjS, though both have increased risk compared to the general population [35]. Indeed, a meta-analysis found the risk of non-Hodgkin’s lymphoma to be higher among patients with SjS compared to patients with SLE [36]. A long-term study of 723 patients with primary SjS (mean follow-up 6 years) found that one in five deaths was attributable to lymphoma [37].

Fig. 11.4 Cutaneous large B cell lymphoma of the leg (Clinical images were kindly provided by Dr. Glen Bowen, Department of Dermatology, University of Utah, USA)

Approximately 4–7.5% of SjS patients develop lymphoma over time [38–40]. In a multicenter European study of 768 SjS patients, 33 (4.6%) developed non-Hodgkin’s lymphoma [39]. Patients with severe parotid involvement by scintigraphy are more likely to develop lymphoma [41]. Other predictive factors for the development of lymphoma are splenomegaly, cryoglobulinemia, low C4 levels, neutropenia, and lymphadenopathy [40, 42]. Low serum C4 levels, presence of parotid enlargement, and presence of palpable purpura were independent predictors of eventual development of lymphoma [37]. Another study found the presence of vasculitis, low-grade fever, anemia, and peripheral nerve involvement to occur more frequently in SjS patients with lymphoma compared to SjS patients without lymphoma [39].

Marginal zone MALT-type (mucosa-associated lymphoid tissue) lymphoma is the most common type of non-Hodgkin’s lymphoma seen in SjS. Many cases involve the major salivary glands, frequently the parotid glands. In a multicenter European study of 765 SS patients, 33 (4.3%) developed non-Hodgkin’s lymphoma. The median age at lymphoma diagnosis was 58 years (range 33–82 years), and the median time from SjS diagnosis to lymphoma diagnosis was 7.5 years [39].

The skin, lungs, and stomach may also be sites of lymphoma involvement [43]. Bcl-2t(14;18) translocations may be present [1]. Markers for viruses associated with lymphoma (including Epstein-Barr virus, human T-leukotrophic virus, or human herpesvirus 8) are generally not present in biopsies of lymphomas from SjS patients [43].

Most cases of lymphoma in SjS patients are indolent and do not require aggressive chemotherapeutic regimens [39]. A small number of cases transform to highgrade lymphomas. Rituximab, a chimeric monoclonal antibody directed against the CD20 surface marker present on pre-B cells, is commonly employed as a therapy in this setting [44].

Other reported types of lymphoma in SS patients include follicle center lymphoma, lymphoplasmacytoid lymphoma, and diffuse, large B cell lymphomas [39] (Fig. 11.4). A large population-based from Sweden found the risk of lymphoplasmacytic lymphoma/Waldenström’s macroglobulinemia to be increased in patients with SjS (odds ratio 12.1) [45]. A case of subcutaneous panniculitis-like T-cell lymphoma associated with SjS has been described [46]. At times, subcutaneous