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Macroglobulinemia
Last reviewed: 07.07.2025
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Macroglobulinemia (primary macroglobulinemia; Waldenstrom's macroglobulinemia) is a malignant plasma cell disorder in which B cells produce large amounts of monoclonal IgM. Manifestations include hyperviscosity, bleeding, recurrent infections, and generalized adenopathy. Diagnosis requires bone marrow examination and measurement of M-protein. Treatment includes plasmapheresis for hyperviscosity and systemic therapy with alkylating agents, glucocorticoids, nucleoside analogues, or rituximab.
Macroglobulinemia is clinically more similar to lymphoproliferative disease than to myeloma and other plasma cell diseases. The cause of the disease is unknown. Men are affected more often than women. The median age is 65 years.
Macroglobulinemia develops in 12% of patients with monoclonal gammopathy. Large amounts of monoclonal IgM may be produced in other diseases, causing manifestations similar to macroglobulinemia. Small amounts of monoclonal IgM are present in the serum of 5% of patients with B-cell non-Hodgkin lymphoma, in which case it is called macroglobupinemic lymphoma. In addition, monoclonal IgM is sometimes detected in patients with chronic lymphocytic leukemia or other lymphoproliferative disorders.
Many clinical manifestations of macroglobulinemia are due to large amounts of high-molecular-weight monoclonal IgM circulating in plasma. Some of these proteins are antibodies to autologous IgG (rheumatoid factor) or I antigens (cold agglutinins), and about 10% are cryoglobulins. Secondary amyloidosis occurs in 5% of patients.
[ Symptoms of Macroglobulinemia
Most patients are asymptomatic, but many have manifestations of hyperviscosity syndrome: weakness, fatigue, bleeding of the mucous membranes and skin, visual impairment, headache, symptoms of peripheral neuropathy and other neurological disorders. Increased plasma volume may contribute to the development of heart failure. Cold sensitivity, Raynaud's phenomenon and recurrent bacterial infections occur. Generalized lymphadenopathy, hepatosplenomegaly and purpura may be detected on examination. Congestive, narrowed retinal veins are characteristic of hyperviscosity syndrome. In the late stages, hemorrhages, exudate, microaneurysms and edema of the optic nerve papilla are detected in the retina.
Diagnosis of macroglobulinemia
Macroglobulinemia may be suspected in patients with symptoms of hyperviscosity or other typical manifestations, especially in the presence of anemia. However, the disease is often diagnosed by chance when M-protein is detected during protein electrophoresis and its belonging to IgM is proven by immunofixation. Laboratory examination includes a set of tests for the detection of plasma cell diseases, as well as the determination of cryoglobulins, rheumatoid factor, cold agglutinins, coagulation tests and the direct Coombs test.
Typical manifestations are mild normocytic, normochromic anemia, marked agglutination, and a very high ESR. Leukopenia, relative lymphocytosis, and thrombocytopenia are sometimes present. Cryoglobulins, rheumatoid factor, or cold agglutinins may be present. In the presence of cold agglutination, the direct Coombs test is usually positive. A variety of coagulation and platelet functional disorders may be present. Routine blood tests may be falsely false in the presence of cryoglobulinemia or marked hyperviscosity. Normal immunoglobulin levels are reduced in half of patients.
Immunofixation electrophoresis of urine concentrate often shows monoclonal light chains (usually κ), but marked Bence Jones proteinuria is not usually present. Bone marrow examination reveals varying elevations of plasma cells, lymphocytes, plasmacytoid lymphocytes, and mast cells. PAS-positive material is occasionally found in lymphoid cells. Lymph node biopsy is performed when bone marrow is normal and often shows diffuse, well-differentiated, or lymphoplasmacytic lymphoma. Serum viscosity is determined to confirm hyperviscosity, which is usually greater than 4.0 (normal 1.4-1.8).
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Treatment of macroglobulinemia
Macroglobulinemia often does not require treatment for many years. If hyperviscosity is present, treatment begins with plasmapheresis, which quickly corrects coagulation disorders and neurological disorders. Plasmapheresis courses often need to be repeated.
Long-term therapy with oral alkylating agents is indicated to reduce symptoms but may be associated with myelotoxicity. Nucleoside analogues (fludarabine and 2-chlorodeoxyadenosine) induce a response in most newly diagnosed patients. Rituximab may reduce tumor burden without suppressing normal hematopoiesis.
Prognosis for macroglobulinemia
The course of the disease is variable with a median survival of 7 to 10 years. Age over 60 years, anemia, and cryoglobulinemia worsen the prognosis for survival.