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Macroglobulinemia

(Primary Macroglobulinemia; Waldenström Macroglobulinemia)

by James R. Berenson, MD

Macroglobulinemia is a malignant plasma cell disorder in which B cells produce excessive amounts of IgM M-proteins. Manifestations may include hyperviscosity, bleeding, recurring infections, and generalized adenopathy. Diagnosis requires bone marrow examination and demonstration of M-protein. Treatment includes plasma exchange as needed for hyperviscosity, and systemic therapy with alkylating drugs, corticosteroids, nucleoside analogs, or monoclonal antibodies.

Macroglobulinemia, an uncommon B-cell cancer, is clinically more similar to a lymphomatous disease than to myeloma and other plasma cell disorders. Cause is unknown. Men are affected more often than women; median age is 65.

After myeloma, macroglobulinemia is the 2nd most common malignant disorder associated with a monoclonal gammopathy. Excessive amounts of IgM M-proteins can also accumulate in other disorders, causing manifestations similar to macroglobulinemia. Small monoclonal IgM components are present in the sera of about 5% of patients with B-cell non-Hodgkin lymphoma; this circumstance is termed macroglobulinemic lymphoma. Additionally, IgM M-proteins are occasionally present in patients with chronic lymphocytic leukemia or other lymphoproliferative disorders.

Clinical manifestations of macroglobulinemia may be due to the large amount of high molecular weight monoclonal IgM proteins circulating in plasma, but most patients do not develop problems related to high IgM levels. Some of these proteins are antibodies directed toward autologous IgG (rheumatoid factors) or I antigens (cold agglutinins). About 10% are cryoglobulins. Secondary amyloidosis occurs in 5% of patients.

Symptoms and Signs

Most patients are asymptomatic, but many present with anemia or manifestations of hyperviscosity syndrome: fatigue, weakness, skin and mucosal bleeding, visual disturbances, headache, symptoms of peripheral neuropathy, and other changing neurologic manifestations. An increased plasma volume can precipitate heart failure. Cold sensitivity, Raynaud syndrome, or recurring bacterial infections may occur.

Examination may disclose lymphadenopathy, hepatosplenomegaly, and purpura (which rarely can be the first manifestation). Marked engorgement and localized narrowing of retinal veins, which resemble sausage links, suggests hyperviscosity syndrome. Retinal hemorrhages, exudates, microaneurysms, and papilledema occur in late stages.

Pearls & Pitfalls

  • Marked engorgement and localized narrowing of retinal veins, which resemble sausage links, suggests hyperviscosity syndrome.

Diagnosis

  • CBC with platelets, RBC indices, and peripheral blood smear

  • Serum protein electrophoresis followed by serum and urine immunofixation and quantitative immunoglobulin levels

  • Serum viscosity assay

  • Bone marrow examination

  • Sometimes lymph node biopsy

Macroglobulinemia is suspected in patients with symptoms of hyperviscosity or other typical symptoms, particularly if anemia is present. However, it is often diagnosed incidentally when protein electrophoresis reveals an M-protein that proves to be IgM by immunofixation. Laboratory evaluation includes tests used to evaluate plasma cell disorders (see Multiple Myeloma) as well as measurement of cryoglobulins, rheumatoid factor, and cold agglutinins; coagulation studies; and direct Coombs test.

Moderate normocytic, normochromic anemia, marked rouleau formation, and a very high ESR are typical. Leukopenia, relative lymphocytosis, and thrombocytopenia occasionally occur. Cryoglobulins, rheumatoid factor, or cold agglutinins may be present. If cold agglutinins are present, the direct Coombs test usually is positive. Various coagulation and platelet function abnormalities may occur. Results of routine blood studies may be spurious if cryoglobulinemia or marked hyperviscosity is present. Normal immunoglobulins are decreased in half of patients.

Immunofixation electrophoresis of concentrated urine frequently shows a monoclonal light chain (usually κ), but gross Bence Jones proteinuria is unusual. Bone marrow studies show a variable increase in plasma cells, lymphocytes, plasmacytoid lymphocytes, and mast cells. Periodic acid-Schiff–positive material may be present in lymphoid cells. Lymph node biopsy, done if bone marrow examination is normal, is frequently interpreted as diffuse well-differentiated or plasmacytic lymphocytic lymphoma. Serum viscosity is measured to confirm suspected hyperviscosity and when present is usually > 4.0 (normal, 1.4 to 1.8).

Treatment

  • Plasma exchange (when hyperviscosity is present)

  • Corticosteroids, alkylating drugs, nucleoside analogs, monoclonal antibodies (rituximab), or a combination

  • Possibly bortezomib, thalidomide, or lenalidomide

The course is variable, with a median survival of 7 to 10 yr. Age > 60 yr, anemia, and cryoglobulinemia predict shorter survival.

Often, patients require no treatment for many years. If hyperviscosity is present, initial treatment is plasma exchange, which rapidly reverses bleeding as well as neurologic abnormalities. Plasma exchange often needs to be repeated.

Corticosteroids may be effective in reducing tumor load. Treatment with oral alkylating drugs may be indicated for palliation, but bone marrow toxicity can occur. Nucleoside analogs (fludarabine and 2-chlorodeoxyadenosine) produce responses in large numbers of newly diagnosed patients but have been associated with a high risk of myelodysplasia and myeloid leukemia. Rituximab can reduce tumor burden without suppressing normal hematopoiesis. However, during the first several months, IgM levels may increase, requiring plasma exchange. The proteasome inhibitor bortezomib and the immunomodulating agents thalidomide and lenalidomide are also effective in this cancer.

Key Points

  • Macroglobulinemia is a malignant plasma cell disorder in which B cells produce excessive amounts of IgM M-proteins.

  • Most patients are initially asymptomatic, but many present with anemia or hyperviscosity syndrome (fatigue, weakness, skin and mucosal bleeding, visual disturbances, headache, peripheral neuropathy and other neurologic manifestations).

  • Do serum protein electrophoresis followed by serum and urine immunofixation, and quantitative immunoglobulin levels.

  • Treat hyperviscosity using plasma exchange, which rapidly reverses bleeding as well as neurologic abnormalities.

  • Corticosteroids, fludarabine, rituximab, bortezomib, and thalidomide or lenalidomide may be helpful; alkylating drugs can be used for palliation.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • THALOMID
  • VELCADE
  • REVLIMID
  • No US brand name
  • RITUXAN

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