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The following websites contain valuable information regarding the research and treatment of Waldenstrom's Macroglobulinemia:

Please visit our main program website: Bing Center for Waldenstrom's Research. This site contains information on the latest treatment recommendations, abstracts, news and events, current and pending clinical trials and participating institutions, basic research, and publications, as well as photos and brief bios of the Bing Center staff.


Also feel free to visit our WM Workshop Website where you will find information about our most recent conference in August, 2014 in London, UK.

WALDENSTROM’S MACROGLOBULINEMIA/LYMPHOPLASMACYTIC LYMPHOMA (Page 4)

Cold agglutinin hemolytic anemia

Monoclonal IgM may present with cold agglutinin activity, i.e. it can recognize specific red cell antigens at temperatures below physiological, producing chronic hemolytic anemia. This disorder occurs in <10% of WM patients65 and is associated with cold agglutinin titers >1:1000 in most cases. The monoclonal component is usually an IgMk and reacts most commonly with I/i antigens, with complement fixation and activation.66,67 Mild chronic hemolytic anemia can be exacerbated after cold exposure but rarely does hemoglobin drop below 70 g/L. The hemolysis is usually extravascular (removal of C3b opsonized cells by the reticuloendotelial system, primarily in the liver) and rarely intravascular from complement destruction of red blood cell (RBC) membrane. The agglutination of RBCs in the cooler peripheral circulation also causes Raynaud’s syndrome, acrocyanosis, and livedo reticularis. Macroglobulins with the properties of both cryoglobulins and cold agglutinins with anti-Pr specificity have been reported. These properties may have as a common basis the immune binding of the sialic acid-containing carbohydrate present on red blood cell glycophorins and on Ig molecules. Several other macroglobulins with various antibody activity toward autologous antigens (i.e. phospholipids, tissue and plasma proteins, etc.) and foreign ligands have also been reported.

Tissue deposition

The monoclonal protein can deposit in several tissues as amorphous aggregates. Linear deposition of monoclonal IgM along the skin basement membrane is associated with bullous skin disease.68 Amorphous IgM deposits in the dermis determine the so-called IgM storage papules on the extensor surface of the extremities – macroglobulinemia cutis.69 Deposition of monoclonal IgM in the lamina propria and/or submucosa of the intestine may be associated with diarrhea, malabsorption, and gastrointestinal bleeding.70,71 It is well known that kidney involvement is less common and less severe in WM than in multiple myeloma, probably because the amount of light chain excreted in the urine is generally lower in WM than in myeloma and because of the absence of contributing factors, such as hypercalcemia, although cast nephropathy has also been described in WM.72 On the other hand, the IgM macromolecule is more susceptible to being trapped in the glomerular loops where ultrafiltration presumably contributes to its precipitation, forming subendothelial deposits of aggregated IgM proteins that occlude the glomerular capillaries.73 Mild and reversible proteinuria may result and most patients are asymptomatic. The deposition of monoclonal light chain as fibrillar amyloid deposits (AL amyloidosis) is uncommon in patients with WM.74 Clinical expression and prognosis are similar to those of other AL patients with involvement of heart (44%), kidneys (32%), liver (14%), lungs (10%), peripheral/autonomic nerves (38%), and soft tissues (18%). However, the incidence of cardiac and pulmonary involvement is higher in patients with monoclonal IgM than with other immunoglobulin isotypes. The association of WM with reactive amyloidosis (AA) has been documented rarely.75,76 Simultaneous occurrence of fibrillary glomerulopathy, characterized by glomerular deposits of wide non-congophilic fibrils and amyloid deposits, has been reported in WM.77

Manifestations related to tissue infiltration by neoplastic cells

Tissue infiltration by neoplastic cells is rare and can involve various organs and tissues, from the bone marrow (described later) to the liver, spleen, lymph nodes, and possibly the lungs, gastrointestinal tract, kidneys, skin, eyes, and central nervous system. Pulmonary involvement in the form of masses, nodules, diffuse infiltrate, or pleural effusions is relatively rare, since the overall incidence of pulmonary and pleural findings reported for WM is only 3–5%.78-80 Cough is the most common presenting symptom, followed by dyspnea and chest pain. Chest radiographic findings include parenchymal infiltrates, confluent masses, and effusions. Malabsorption, diarrhea, bleeding, or obstruction may indicate involvement of the gastrointestinal tract at the level of the stomach, duodenum, or small intestine.81-84 In contrast to multiple myeloma, infiltration of the kidney interstitium with lymphoplasmacytoid cell has been reported in WM,85 while renal or perirenal masses are not uncommon.86 The skin can be the site of dense lymphoplasmacytic infiltrates, similar to that seen in the liver, spleen, and lymph nodes, forming cutaneous plaques and, rarely, nodules.87 Chronic urticaria and IgM gammopathy are the two cardinal features of the Schnitzler syndrome, which is not usually associated initially with clinical features of WM,88 although evolution to WM is not uncommon. Thus, close follow-up of these patients is warranted. Invasion of articular and periarticular structures by WM malignant cells is rarely reported.89 The neoplastic cells can infiltrate the periorbital structures, lacrimal gland, and retro-orbital lymphoid tissues, resulting in ocular nerve palsies.90,91 Direct infiltration of the central nervous system by monoclonal lymphoplasmacytic cells as infiltrates or as tumors constitutes the rarely observed Bing–Neel syndrome, characterized clinically by confusion, memory loss, disorientation, and motor dysfunction (reviewed in Civit et al.92).

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