WALDENSTROM MACROGLOBULINEMIA (WM) (Waldenstrom Jan. Incipient myelomatosis with central hyperglobulinemia with fibrinogenopenia. A new syndrome ? Acta Med.Scand. 117:216 (1944)) is a distinct clinicopathological entity resulting from the proliferation of lymph node medullary cords B lymphocytes that show maturation to plasma cells, constituting a pathognomonic bone marrow lymphoplasmacytic infiltrate, and that synthesize monoclonal IgMref. This condition is considered to correspond to the lymphoplasmacytic, lymphoplasmacytoid or plasmacytoid lymphoma / immunocytoma / macroglobulinemic purpura as defined by the Revised European American Lymphoma (REAL) and World Health Organization classification systems.

Table of contents :

  • Epidemiology
  • Aetiology
  • Pathogenesis
  • Symptoms & signs
  • Laboratory examinations
  • Differential diagnosis
  • Therapy
  • Prognosis
  • Web resources

  • Epidemiology : 2% of all hematologic malignancies. The incidence rate for WM is higher among Caucasians, with African descendants representing only 5% of all patients. WM is a disease of the elderly, with a median age of 63 years (range 25–92), with a slight predominance of males over femalesref.
    Aetiology :

    Pathogenesis : the WM bone marrow B cell clone shows intraclonal differentiation from small lymphocytes with large focal deposits of surface immunoglobulins, to lymphoplasmacytic cells, to mature plasma cells that contain intracytoplasmic immunoglobulins. Clonal B cells are sometimes detectable among blood B lymphocytes, and their number increases in patients who fail to respond to therapy or who progressref. These clonal blood cells present the peculiar capacity to differentiate spontaneously, in in vitro culture, to plasma cells. This is through an IL-6–dependent process in IgM monoclonal gammopathy of undetermined significance (MGUS) and mostly an IL-6–independent process in WM patients. All these cells express the monoclonal IgM present in the blood, and a variable % of them also express surface IgD. Increased numbers of mast cells are found in the bone marrow of WM patients, wherein they are usually admixed with tumor aggregatesref. Mast cells induce WM cell proliferation and/or tumor colony formation—through, in part, constitutive expression of CD40L : furthermore, WM cells may in part support mast cell expansion through elaboration of IL-3, a cytokine found at significantly elevated levels in the sera of WM patients (Tournilhac O, Ditzel Santos D, Branagan AR, et al. Excess bone marrow mast cells constititvely express CD154 (CD40 ligand) in Waldenstrom’s macroglobulinemia and may support tumor cell growth through CD154/CD40 pathway [abstract]. J Clin Oncol. 22:571s). The morbidity associated with WM is caused by the concurrence of 2 main components: tissue infiltration by neoplastic cells and, more importantly, the physicochemical and immunological properties of the monoclonal IgM.
    Symptoms & signs : usually vague and non-specific, the most common being weakness, anorexia, and weight loss. Presenting features and physical findings at diagnosis in 215 patients with WM : The monoclonal IgM can produce clinical manifestations through several different mechanisms related to its physicochemical properties, nonspecific interactions with other proteins, antibody activity, and tendency to deposit in tissues. Clinical manifestations caused by monoclonal IgM :
    properties of the monoclonal IgM
    resulting condition
    clinical manifestations
    physicochemical intrinsic viscosity hyperviscosity syndrome fatigue, headache, blurred vision, easy mucosal bleeding, impaired mentation up to coma
    precipitation on cooling cryoglobulinemia type I Raynaud’s phenomenon, acrocyanosis, 
    necrosis, ulcers, purpura, cold urticaria
    protein-protein interaction hemostatic abnormalities bleeding diathesis: bruising, purpura, mucosal 
    bleeding; rarely, brain hemorrhages
    antibody activity versus: nerve constituents polyneuropathies
  • anti-myelin-associated glycoprotein (MAG)-related: symmetric, distal, progressive, sensorimotor neuropathy, ataxic gait, bilateral foot drop 
  • IgM with other specificities:
    • symmetric, distal, progressive painful sensory neuropathy
    • prominent motor neuropathy
    IgG cryoglobulinemia type II weakness, purpura, arthralgias, proteinuria, 
    renal failure, progressive, symmetric distal 
    sensorimotor neuropathy combined with 
    mononeuropathies (e.g., foot or wrist drop)
    RBC antigens cold agglutinin hemolytic 
    mild, chronic hemolytic anemia exacerbated 
    after cold exposure; Raynaud’s phenomenon, 
    acrocyanosis and livedo reticularis
    tendency to deposit into tissues as amorphous aggregates 
    in skin, GI tract, kidney
    specific organ dysfunction
  • skin: bullous skin disease, papules on extremities 
  • GI: diarrhea, malabsorption, bleeding 
  • kidney: mild, reversible proteinuria, mostly 

  • asymptomatic
    as amyloid fibrils (light chains) AL amyloidosis fatigue, weight loss, periorbital purpura, edema, 
    hepatomegaly, macroglossia 
    Dysfunction of organs involved: kidneys, heart, 
    liver, peripheral sensory and autonomic 
    Laboratory examinationsref : The phenotype of lymphoplasmacytic cells in WM suggests that the clone is a post-germinal center B cell. This indication is further strengthened by the results of the analysis of the nature (silent or amino-acid replacing) and distribution (in framework or CDRs) of somatic mutations in Ig H- and L-chain variable regions performed in patients with WMref1, ref2. This analysis showed a high rate of replacement mutations, compared with the closest germline genes, clustering in the CDR and without intraclonal variation. Subsequent studies showed a strong preferential usage of VH3/JH4 gene familiesref, no intraclonal variation, and no evidence for any isotype-switched transcriptsref. These data indicate that WM may originate from an IgM+ and/or IgM+ IgD+ memory B cell. Normal IgM+ memory B cells localize in bone marrow, where they mature to IgM-secreting cells.
    Differential diagnosis :
    laboratory features
    clinical features
    WM lymphoplasmacytic infiltrate in marrow 
    specific immunophenotype (sIg+CD19+CD20+CD22+CD79+
    serum monoclonal IgM
    may be symptomatic or asymptomatic
    IgM-related disorder no marrow infiltration symptomatic, e.g., peripheral neuropathy, cryoglobulins, cold agglutinin disease, AL amyloidosis
    IgM MGUS no marrow infiltrate asymptomatic
    other B cell 
    disorders (B-CLL, DLBCL, extranodal MZL, FL, MCL)
    differentiate by immunophenotype and 
    morphological characteristics
    µ-HCD heavy-chain fragment with no associated 
    light chain
    IgM myeloma IgM-producing plasma cells (cytoplasmic 
    IgM+, CD20+ CD138+, t(11;14))
    possibly associated with lytic skeletal lesions and 
    Therapy : initiation of therapy should not be based on the IgM level per se, since this may not correlate with the clinical manifestations of WM. The consensus panel, however, agreed that initiation of therapy was appropriate for patients with constitutional symptoms, such as recurrent fever, night sweats, fatigue due to anemia, or weight loss. The presence of progressive symptomatic lymphadenopathy or splenomegaly provides additional reasons to begin therapy. The presence of anemia with a hemoglobin value <10 g/dL or a platelet count < 100,000/ml owing to marrow infiltration also justifies treatment. Certain complications, such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia, may also be indications for therapyref. Response criteria : assessment of response to treatment of WM has been widely heterogeneous. As a consequence studies using the same regimen have reported significantly different response rates. During the 2nd International Workshop on WM a consensus panel proposed guidelines for standardized response criteria that were subsequently discussed and modified and are summarized belowref. Prognosis : WM presents with a chronic, indolent course and a highly variable prognosis. The median survival reported in large series ranges from 5 to 7 years, although an observed survival of 9 years and a 10-year projected overall survival of 55% have been reported (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004). Because WM is a rare disease, relatively few studies on prognosis have been conducted on large patient populations. Advanced age, anemia, and thrombocytopenia were correlated by univariate analysis with a poorer outcome in virtually all studies. Neutropenia and male sex, weight loss and cryoglobulinemia, albumin level and blood cell counts, serum ß2-microglobulin level and IgM level < 40 g/L, and hyperviscosity and ß2-microglobulin level were also significantly correlated with survival (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004). A few scoring systems have been proposed based on these analyses: An update of the study by Merlini et alref, which included 215 patients, indicated that serum ß2-microglobulin, hemoglobin, albumin, and age defined prognosis of patients with WM thoroughly. In agreement with other studies, serum ß2-microglobulin and hemoglobin level appeared to be the most consistent prognostic determinants. It is possible that with validation from future studies, both prognostic stratification and decision to start treatment may result from serum ß2-microglobulin level and hemoglobin. Asymptomatic patients with low serum ß2-microglobulin levels and preserved hemoglobin can be observed over long periods without therapy. Since WM is a disease of the elderly, up to 32% of patients die of unrelated causesref and the association with malignancy, both before therapy and during follow-up, is common (39% of patients in a seriesref). The most common causes of death in these patients are progression of the lymphoproliferative process (in about 50%), infections, and cardiac failureref. Few patients die of cerebrovascular accidents, renal failure, or gastrointestinal bleeding. In the pre-terminal stage of the disease, the development of aggressive large-cell lymphomas, usually of the immunoblastic type (Richter’s syndrome) have been reported in 6% of patients treated for WMref. This transformation is characterized by unexplained fever, weight loss, rapidly enlarging lymph nodes, extranodal extension, and reduction of the level of monoclonal IgM. Rarely, WM may be complicated by acute or chronic myeloid leukemia, in most cases after treatment with alkylating agents, although patients who had not been previously treated have also been reported.
    Concurrent diagnoses : acute myeloid leukemia in a patient with untreated WM (Natale A et al, SIES 2008, P127)

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