Prognosis

8.1. Predictive Factors for Lymphoma Development

8.1.1. Clinical features

Lymphoma is an extraglandular complication whose early diagnosis in patients with SS has high priority. Knowing that patients with SS are at higher risk of developing lymphoma, several investigators have attempted to establish predictive factors for this progression (Table 7). In 1978, Kassan et al. [15] were the first to show prospectively that lymphadenopathy, splenomegaly, parotid gland enlargement and previous exposure to cytotoxic agents are more often observed in patients with SS that developed lymphoma. Recent data of Valesini et al. [17] confirm that lymphadenopathy and splenomegaly are, as observed by Kassan et al. [15], risk factors of developing NHL, but retrospective studies [25] failed to support these findings.

Other risk factors or associated disease phenomena of significance for the development of lymphoma are the presence of multiorgan involvement [15], Zufferey et al. [25] described that the presence of extraglandular manifestations at the time of SS diagnosis was seen in all the patients who develop lymphoma. Purpura of the lower limbs is an extraglandular manifestation that has often been reported in SS patients with lymphoma [26, 125] and was seen in 3 out of the 5 lymphoma patients many years before the development of lymphoma [25 ]. On the contrary, Valesini et al. [17] found that patients who developed lymphoma showed a lower prevalence of ocular symptoms, arthralgia and anti-Ro/SSA antibodies. Recently, we have found that patients with a younger onset of SS (before the age of 35) have a higher prevalence of lymphadenopathy, RF and MIgs, as well as a higher incidence of development of lym-phoproliferative disease, thus conferring to the age at onset of symptoms an important prognostic value [19].

8.1.2. Immunological markers

In 1971, Cummings et al. [213] suggested that a sharp reduction in hypergammaglobulinemia was frequent just before the development of lymphoma. Other authors described decreases in previously elevated serum IgM and IgM-RF levels [214], but this finding has not been confirmed in some subsequent studies. Some authors also described elevated serum levels of P2-microglobulin [215] and soluble IL-2 receptor [216] as laboratory markers of lymphoma development in SS.

In 1986, Walters et al. [97] described that urinary monoclonal free light chains in primary SS may be an aid to the diagnosis of malignant lymphoma, and studies on RF from patients with SS have shown that the presence of CRI 17-109 and G6 are associated with NHL [217]. In a recent study, Tzioufas [218] prospectively investigated whether the presence of mixed monoclonal cryoglobulinemia and the monoclonal RF CRI may serve as predictive factors for lymphoma development in primary SS. In a series of 103 consecutive patients with SS followed for a period of 5 years, 7 patients developed lymphoma. Six of these 7 patients (86%) had cryoglobulinemia before the appearance of lymphoma, as compared to 12/96 (12%) of the remainder. The CRI 17-109 and G6 were also correlated with the development of lymphoma. A step-wise multiple comparison analysis revealed that both of these CRI were linked to the presence of monoclonal mixed cryoglobulinemia. These recent data clearly demonstrate that the determination of cryoglobulins, a simple and easily performed test, can be used as a predictive factor for lymphoma development in SS, and that the CRIs 17-109 and G6 may also be used to predict lymphoma development, especially when the monoclonal component is absent.

Finally, the finding of light-chain restriction in lip minor salivary gland biopsy samples is a strong evidence of a monoclonal population of B cells and early evidence of dysregulation of the B-cell system, and seems to predispose to the development of malignant lymphoproliferation. In patients with SS who develop lymphomas, dissemination of malignant cells may result in detectable disease in the minor salivary glands and other tissues and determination of k : X ratios in labial minor salivary glands may thus provide important prognostic information [189],

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