Splenic Marginal Zone Lymphoma

DISEASE FEATURES Pathology

The disease is characterized by a lymphoid infiltrate in the splenic white pulp that grows in a nodular patter replacing preexisting follicles.482 A variable degree of red pulp infiltration is also often present. Small lymphocytes are predominant in central areas, while medium-size cells resembling splenic marginal zone lymphocytes are present in the periphery. Plasmacytic differentiation as well as, rarely, clusters of plasma cells can be present.

The neoplastic cells show typical positivity for surface (and sometimes cytoplasmic) immunoglobulins and pan-B antigens (CD19, CD20, and CD22); they usually coexpress CD11c, and lack CD5, CD10, and CD23 expression.

Up to two-thirds of the patients with splenic MZL present the characteristic circulating villous lymphocytes, with short cytoplasmic projections. When these are more than 20% of the lymphocyte count, the term "splenic lymphoma with villous lymphocytes" is commonly used.83

Bone marrow is usually involved, even in cases with no circulating neoplastic cells. The pattern of infiltration is typically nonparatrabecular, intrasinusoidal only. However, this pattern of bone marrow involvement can be found also in other small-cell lym-phomas.84-86

When biopsied, the liver is usually involved with a nodular infiltration of portal tracts, and hilar splenic lymph node involvement is common. According to the WHO classification, the peripheral lymph node involvement is typically absent.87 Transformation to a diffuse large B-cell lymphoma occurs in about 15% of the cases.88

Genetic abnormalities

Sequence analysis of the immunoglobulin genes expressed by the splenic marginal zone B cells shows that approximately half of the cases bear unmutated and half have mutated immunoglobulin heavy-chain genes,89 90 suggesting the possibility that this lymphoma subtype derives from different B-cell subsets than those normally present in the marginal zone. Cases with unmutated IgH genes may have a poorer prognosis and are more commonly associated with the presence of chromosome 7q loss,89 but it has to be underscored that the 7q deletions are relatively common in hematologic malignancies and not specific for splenic MZL. Gain of chromosome 3 appears to be another common abnormality.9192 The t(9;14)(p13;q32) translocation which juxtaposes the IgH locus to the PAX5 gene93'94 has also been reported; however, its frequency is controversial.95 Using cDNA microarray, Thieblemont et al. have compared the gene expression profile of splenic MZL, mantle cell lymphoma, and small lymphocytic lymphoma.96 The gene coding for the serine threonine kinase AKT1 was the most representative among the gene clusters specific for splenic MZL; its possible role in the pathogenesis of splenic MZL needs to be further clarified.

Association with infectious agents Despite relevant geographic variations, hepatitis C virus (HCV) seems to be involved in splenic MZL and nodal MZL

lymphomagenesis.97-101 Of great interest, some patients with splenic lymphoma with villous lym-phocyes and HCV infection achieved a lymphoma remission after treatment with interferon alfa with or without concomitant ribavirin.101102 This suggests a strict relationship between HCV and splenic MZL, indicating the necessity to search for HCV infection in patients affected by this lymphoma subtype. Analogous to the H. Pylori infection in the gastric MZL, it appears that HCV may be responsible for an antigen-driven stimulation of the lymphoma clone. Prospective studies are warranted to confirm this interesting finding.

An association with malaria and with Epstein-Barr virus infection, both acting as strong polyclonal B-cell activators, has been shown in tropical Africa.103-105 Tropical splenic lymphoma appears as a form of splenic MZL, characterized by a high percentage of circulating villous lymphocytes, unmutated immunoglobulin genes, and a predilection for middle-age women.

Clinical features

Most patients are over 50 with a similar incidence in males and females.87 The disease usually presents with massive splenogamy, which produces abdominal discomfort and pain. Diagnosis is often made at splenectomy performed to establish the cause of unexplained spleen enlargement. B symptoms are present in 25-60% of cases; anemia, thrombocytopenia, or leukocytosis are reported in approximately 25% of cases. Autoimmune hemolytic anemia is not uncommon, being found in up to 15% of patients. Splenic hilar lymph nodes appear to be involved in about 25% of cases, but peripheral lymph node involvement is typically absent. Approximately 30% of cases have liver involvement.106-110 Nearly all patients have bone marrow involvement, often accompanied by involvement of peripheral blood (defined as the presence of absolute lymphocytosis of more than 5%).109 Because of the high frequency of bone marrow or liver involvement, about 95% of cases are classified as Ann Arbor stage IV. Serum paraproteinemia is observed in about 10-25% of cases,107-109 most frequently of IgM type posing the problem of the differential diagnosis with lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia.82111

In advanced stages of either splenic, nodal, or extra-nodal MZL, a precise diagnosis can be very difficult in cases presenting with concomitant splenic, extran-odal, and nodal involvement.108112

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