On diagnostic grounds, clonal lymphoid proliferation in HCV-positive patients can be divided into two main groups, monotypic lymphoproliferative disorders of undetermined significance (MLDUS) and overt lymphomas (27,28,32,65). The former cannot be recognized without clinical data, as their histopathologic picture is basically indistinguishable from that of some lymphoid tumors, which are indolent but nevertheless invariably fatal. In this section, we use the concepts and terminology of the Revised European-American-Lymphoma (REAL) Classification (66), which recently has been validated in a study sponsored by the National Cancer institute (NCI) of the United States (67) and has been adopted as operational guidelines by the World Health Organization (68). MLDUS occur in HCV-positive patients, who often show the clinical and laboratory pattern of type II MC (21,22,27,65,69). Histologically (Fig. 1), they have lymphoid infiltrates in the bone marrow and liver that resemble peripheral B-cell lymphomas of the small cell/B-chronic lymphocytic leukemia (CLL) type or, more rarely, immunocytoma/lymphoplasmacytic lymphoma (lc). The main morphologic, pheno-typic, and genotypic findings are summarized in Table 2.
Some groups have reported that MLDUS show immunocytic morphology (35,36,46,51,70,72,73). This does not correspond to our experience, perhaps owing to differences in terminology between the Updated Kiel Classification (UKC) (73) and
Leukocytoclastic vasculitis is the histologic hallmark of cutaneous manifestations of MC (14-17). Cryoglobulinemic vasculitis is secondary to the deposition of circulating immune complexes, mainly the cryoglobulins as well as complement, in the small blood vessels and, less frequently, in medium-sized arteries. Moreover, various organ involvement with diffuse or nodular lymphoid aggregates in the liver, bone marrow, and spleen is the expression of an underlying lymphoproliferative disorder (14,15). Mono- or polyclonal B-lymphocyte expansion (19) is related to the production of immune complexes responsible for systemic vasculitis.
With chronic hepatitis in more than two-thirds of MC patients (15-18), a possible role of hepatotropic viruses in the etiopathogenesis of the disease has long been suggested. Hepatitis B virus infection appears to be the etiologic factor of MC in only a few (<5%) patients (15). On the contrary, HCV infection has been demonstrated in the large majority of cases (20-24; Table 1). Support for an etiopathogenetic role of HCV in this disease came from virologic studies demonstrating that HCV infects peripheral blood mononuclear cells, as well as lymphoid tissues in MC patients (12,25,26). Chronic HCV infection is responsible for both the chronic hepatitis and the B-cell expansion that characterize the cryoglobulinemic syndrome (3,12,19,25,26).
Circulating immune complexes and various autoantibodies, often associated with autoimmune manifestations, have been observed in many patients with B-cell neo-plasias, including monoclonal gammopathies, chronic lymphocytic leukemia, and low-grade NHL (14). In these lymphoproliferative disorders, serum monoclonal (IgMk) RFs also have been detected. Like natural autoantibodies, monoclonal RFs share a major complementary determining region named Wa, and they invariably express a Vk light chain derived from a single germinal gene, the human Kv 325 (14,22). A large body of clinicopathologic investigations indicate that autoimmune and B-cell lympho-proliferative disorders often are closely related (14,15). MC, characterized by a large amount of circulating immune complexes, also can be regarded as a "benign" B-cell neoplasm. The presence in the serum of Wa RF (14,22), and the clonal expansion of IgMk-bearing B-cells (19), together with lymphocyte and plasmacytoid cell infiltrates in the bone marrow, suggest that low-grade or in situ NHL is the underlying disorder of MC (27). More interestingly, this lymphoproliferation can switch to frank, malignant B-cell NHL (28,29), generally after a long follow-up period. These clinicoserologic and pathologic observations indicate that there is a continuum among some autoimmune disorders, MC, and B-cell neoplasias (13-15). In this scenario, MC represents an interesting example of coexistence of autoimmune and lymphoproliferative disorders, for which HCV infection can be a common triggering factor.
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