Defining Waldenstrom's macroglobulinemia

Abstract

NEARLY 60 YEARS have passed since Jan Gosta Waldenstrom (Fig 1) first described two patients with oronasal bleeding, lymphadenopathy, anemia and thrombocytopenia, elevated erythrocyte sedimentation rate, high serum viscosity level, normal bone radiographs, and bone marrow demonstrating predominately lymphoid cells.1 These seminal observations provided the foundation for the widely recognized, though uncommon, clinical diagnosis of Waldenstrom’s macroglobulinemia (WM). Likely hampered by its uncommon presentation, estimated at 1.7 (for females) and 3.4 (for males) per million person-years at risk,2 WM remained a loosely defined clinical diagnosis that encompassed patients with an elevated serum IgM level and a monoclonal IgM gammopathy. Many interpretations of what was considered WM existed, which differed largely on the basis of arbitrarily established serum IgM level cutoffs, while no underlying histopathological diagnosis existed to provide a firm pathological basis for the disease. With improvements in the diagnosis of lymphoid malignancies introduced by successive pathological classification systems, a pathological accounting for patients with WM was attempted. The most recent of these classification schemes, the World Health Organization and (WHO) and Revised European and American Lymphoma (REAL) classifications, attempted to define “real” disease entities among the lymphoid neoplasms by reconciling morphological, immunophenotypic, genetic, and clinical features.3,4 Within the WHO and REAL classifications, WM was recognized as a clinical syndrome that largely corresponded to the “real” disease entity of “lymphoplasmatic lymphoma.” Although the WHO and REAL classification systems provided a pathological basis to diagnose many patients with WM, they left open the possibility that patients with WM could have any of the recognized IgM-secreting lymphoid neoplasms as their underlying diagnosis, thereby hampering the conduct or interpretation of clini-