Why Waldenström Macroglobulinemia is not Just Another Indolent Lymphoma

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Waldenstrom macroglobulinemia (WM) is an uncommon B-cell malignancy arising from B cells that are arrested after somatic hypermutation in the germinal center and before terminal differentiation to plasma cells [1]. It is characterized by IgM monoclonal gammopathy and bone marrow involvement by a lymphoplasmacytic lymphoma clone. WM accounts for approximately 5% of non-Hodgkin’s lymphomas, although recent data suggest its incidence is declining [2,3]. WM, considered an incurable disease in most cases, is an indolent lymphoma with a median age at diagnosis of 65 years and median survival of 5–10 years [4]. While once thought to closely resemble multiple myeloma, genomic studies of WM have found that this condition genetically clusters with other indolent lymphomas [5]. Morphologically, bone marrow in WM reveals plasmacytoid lymphocytes, small lymphocytes and plasma cells [6]. Characteristic features include the presence of Dutcher bodies (intranuclear pseudo-inclusions of IgM) and Russell bodies (prominent cytoplasmic globules). Cells stain positive for pan-B-cell markers, including CD19, CD20, CD25 and, in most cases, CD79a. Unlike chronic lymphocytic leukemia and follicular lymphoma, cells are usually negative for CD5, CD10 and CD23. One of the unique features of WM is its genetics. Recent studies revealed that deletion of 6q21 occurs in 42–63% of WM cases and over 70% demonstrate MYD88 mutations, which may convey a more aggressive phenotype [7]. In addition, the mutation of CXCR4 is present in 29% of cases and appears to play a critical role in WM biology [8]. WM is associated with a spectrum of disease severity. The presence of IgM monoclonal gammopathy of unknown significance (serum M spike <3 g/dl and <10% clonal marrow involvement) commonly precedes development of WM. Cytopenias, adenopathy, organomegaly or hyperviscosity syndrome is often absent at diagnosis and approximately a third of patients with WM remain asymptomatic. Patients with asymptomatic disease are considered to have smoldering disease and a watch-and-wait approach is appropriate.