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Key Features

Essentials of Diagnosis

  • Monoclonal immunoglobulin M (IgM) paraprotein

  • Infiltration of bone marrow by plasmacytic lymphocytes

  • Absence of lytic bone disease

General Considerations

  • Syndrome of IgM hypergammaglobulinemia

  • Occurs in the setting of a low-grade non-Hodgkin lymphoma characterized by B-cells that are morphologically a hybrid of lymphocytes and plasma cells

  • Cells characteristically secrete IgM paraprotein, and this macroglobulin causes many clinical manifestations

Demographics

  • Occurs mainly in patients aged 60–79

Clinical Findings

Symptoms and Signs

  • Insidious fatigue related to anemia

  • Mucosal or gastrointestinal bleeding is related to engorged blood vessels and platelet dysfunction with hyperviscosity syndrome (usually when viscosity > 4 times that of water)

  • Nausea, vertigo, or visual disturbances

  • Alterations in consciousness from mild lethargy to stupor and coma with hyperviscosity syndrome

  • Symptoms of cold agglutinin disease or chronic demyelinating peripheral neuropathy from IgM paraprotein

  • Hepatosplenomegaly or lymphadenopathy may be present

  • Retinal vein engorgement

  • Purpura may be present

  • Bone tenderness absent

Differential Diagnosis

  • Monoclonal gammopathy of unknown significance

  • Plasma cell myeloma

  • Chronic lymphocytic leukemia

  • Lymphoma

Diagnosis

Laboratory Tests

  • Anemia is nearly universal, and rouleaux formation common

  • White blood cell and platelet count are usually normal

  • Peripheral blood smear: abnormal plasmacytic lymphocytes may be present in small numbers

  • Serum protein electrophoresis (SPEP) demonstrates monoclonal IgM spike in β-globulin region

  • Serum viscosity is usually increased above normal (> 1.4–1.8 times viscosity of water)

  • No direct correlation between paraprotein concentration and serum viscosity

  • Antiglobulin (Coombs), cold agglutinin, or cryoglobulin tests may be positive because of IgM paraprotein

  • If macroglobulinemia is suspected but the SPEP shows only hypogammaglobulinemia, repeat the SPEP while maintaining blood at 37°C, because the paraprotein may precipitate at room temperature

  • No evidence of kidney failure

Imaging Studies

  • Bone radiographs are normal

Diagnostic Procedures

  • Bone marrow aspiration and biopsy: characteristic infiltration by the plasmacytic lymphocytes

Treatment

Medications

  • Chemotherapy with fludarabine

  • Rituximab (375 mg/m2 intravenously weekly for 4–8 weeks)

  • Ibrutinib, 420 mg orally daily, has shown significant activity

  • Bortezomib

  • Lenalidomide

  • Bendamustine

  • Combination therapy for advanced disease

  • See Table 39–3

Table 39–3.Common chemotherapeutic agents.1

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