Historical Perspective

The association between SS and lymphoma has been known since 1951, when Rothman et al. [6] described the first case of this association. Some years later, in 1964, Talal and Bunim [7] reported the first study on the incidence of lymphoma in a cohort of 58 patients with SS followed-up over 4 years and observed 3 cases of reticulosarcoma and 1 of IgM macroglobulinemia. In 1966, Hornbakeret al. [8] described the association of SS and nodular reticulum cell sarcoma in a patient dying due to a severe hemolytic crisis. One year later, Miller [9] studied the presence of autoimmune diseases in 264 patients with lymphoma and found 14 cases of autoimmune disorders, one was a patient who developed a reticulum cell sarcoma 4 years after the diagnosis of SS.

In the 1970s, several studies reported a broad spectrum of lymphoproliferative malignancies in patients with SS, and focused on the description of the clinical and immunological markers associated with the development of malignancy. In 1972, Anderson and Talal [10] reported the first compilation of patients who had SS and lymphoproliferative disorders, including 38 cases with several conditions such as pseudolymphoma, histiocytic lymphoma, nodular and diffuse lymphocytic lymphoma, thymoma or Waldenstrom macroglobulinemia. Hughes and Wha-ley [11] reviewed the association of SS with several lymphoproliferative disorders (reticulum cell sarcoma, lymphosarcoma, Waldenstrom's macroglobulinemia, pseudolymphoma) and stressed that benign lymphoproliferation, which occurs as a part of the spectrum of SS, may be difficult to distinguish from its malignant counterpart. Another similar review of this association was published by Pérez-Peña et al. in

1974 [12], In 1978, Faguet et al. [13] reported the first study of immunological cell markers in a patient in whom a malignant lymphoma was detected 22 months after the diagnosis of SS. These authors established the monoclonal origin of the lymphopro-liferation by the demonstration of IgM^: on more than 90% of the B cells obtained from fresh lymph node and biopsy specimens from a lymphoid lung nodule. The same year, Zulman et al. [14] demonstrated that 6 out of 9 lymphomas developed in patients with SS showed a proliferation of cells producing monoclonal immunoglobulins (MIgs), identifying these 6 cases as being of B-cell origin. Kassan et al. [15] published an epidemiological study, that attempted to estimate the risk of development of lymphoma in patients with SS and to study the clinical and immunological features associated with its development during the course of the disease. The authors studied 136 women with SS followed at the National Institutes of Health (NIH), and found that 7 patients developed non-Hodgkin lymphoma (NHL) from 6 months to 13 years after their first admission to the NIH. Analysis of the risk of development of lymphoma showed that the patients with SS had had 43.8 times the incidence expected from the rates of cancer prevailing among women of the same age range in the general population during this time, and the patients with a history of parotid enlargement, splenomegaly, and lymphadenopathy had an increased risk of lymphoma. The authors concluded that these clinical manifestations seem to identify a subset of patients with SS with marked lymphoid reactivity, who had a particularly high risk of subsequently developing lymphoma. This study remains during the following 20 years as the main reference point of the high risk of development of lymphoma in patients with SS.

In the 1980s, several studies have shown that patients with SS, in addition to the polyclonal B-cell activation, as illustrated by autoantibody production, express a mono/oligoclonal process. The latter was shown by the presence of serum MIgs as well as monoclonal type II cryoglobulins and excretion of monoclonal light chains in the urine. All these phenomena were evident in patients with systemic (extraglandular) disease and long before any overt clinical signs of lymphoid malignancy were present.

Finally, the most recent studies have focused on the pathogenesis of the B-cell lymphoproliferation, including the role of some infectious agents such as Epstein-Barr virus (EBV) or hepatitis C virus (HCV), as factors responsible for B-cell clonal expansion, as well as the potential role of molecular analysis for B-cell clonality as a first step for the diagnosis of malignancy.

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