Mutiple Choice and Discussion Questions

Waldenström’s macroglobulinemia (WM) is defined by the World Health Organization as a lymphoplasmacytic lymphoma (LPL) associated with a monoclonal immunoglobulin M (IgM) protein. The classic characteristic pentad of WM is (i) M-protein on serum protein electrophoresis confirmed to be (ii) IgM by immunofixation, with (iii) bone marrow evidence of lymphoplasmacytic lymphoma and, in some patients, evidence of (iv) hyperviscosity syndrome with (v) normocytic anemia. Using the Surveillance, Epidemiology, and End Results (SEER) data, WM represented 1.9% of all non-Hodgkin lymphoma. The median age at diagnosis was 73 years, with a predilection for men (5.4/million/year) as opposed to women (2.7/million), and a racial skewing toward Caucasians (4.1/million) rather than African Americans (1.8/million). First-degree relatives of patients with LPL–WM have a 20-fold increased risk of LPL–WM.

Other IgM-related conditions include IgM monoclonal gammopathy of undetermined significance (IgM <3 g/dl; no evidence of marrow infiltration >10%; and without symptoms of tumor mass or infiltrations, e.g., adenopathy, organomegaly, anemia, or IgM-mediated symptoms), smoldering WM (IgM >3 g/dl; marrow infiltration > 10%; and with no symptoms of tumor mass or infiltration or IgM-mediated symptoms), IgM-related cold agglutinin hemolytic anemia, type II cryoglobulin, neuropathy, and amyloidosis.

1. t(11;18)
   
2. BRAF V600E
   
3. MYD88 L265P
   
4. NOTCH2

Using whole-genome sequencing, over 90% of patients with WM or non-IgM LPL have been found to have a common mutation, MYD88 L265P. This mutation also appears to be useful in differentiating LPL from other B cell lymphoproliferative disorders such as splenic marginal zone lymphoma. Furthermore, on metaphase cytogenetics, a deletion in the long arm of chromosome 6 (6q−) may be seen in 40–50% patients. Epigenetic dysregulation; aberrations in the phosphatidylinositol-3 kinase–mammalian target of rapamycin (PI3K–mTOR), nuclear factor kappa B, and Janus kinase–signal transducer and activator of transcription (JAK–STAT) signaling pathways; as well as bone marrow microenvironmental interactions may be other key factors that are involved in the pathogenesis of WM.