Waldenstrom Macroglobulinemia Workup

Updated: Feb 03, 2022
  • Author: Karen Seiter, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Approach Considerations

The manifestations of Waldenström macroglobulinemia are protean. Considering the diagnosis of Waldenström macroglobulinemia in patients who present with unexplained fatigue and weakness, neurologic symptoms, unexplained bleeding, visual blurring, and neuropathies is important, especially because hyperviscosity symptoms can be life threatening. Performing protein electrophoresis, immunoglobulin quantitation, and hyperviscosity measurements is critical.

The laboratory diagnosis of Waldenström macroglobulinemia is contingent on demonstrating a significant monoclonal IgM spike and identifying malignant cells consistent with Waldenström macroglobulinemia; thus, diagnosis requires monoclonal protein studies and bone marrow biopsy (with or without lymph node/involved tissue biopsy).

General studies include the following:

  • Complete blood count (CBC)
  • Red cell indices
  • Platelet count
  • Peripheral smear

Normocytic normochromic anemia, leukopenia, and thrombocytopenia may be observed. Anemia is the most common finding, being present in 80% of patients with symptomatic Waldenström macroglobulinemia.

Other workup includes the following:

  • Imaging studies are used for assessment of lymphadenopathy, extramedullary disease, or organomegaly.
  • Fundoscopic examination is recommended in all patients with visual disturbance, hyperviscosity symptoms, and/or an IgM level ≥3000 mg/dL. [4]  
  • Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin-associated glycoprotein serology. [24]

See also Waldenstrom Macroglobulinemia Staging.


Laboratory Studies

A peripheral smear may reveal plasmacytoid lymphocytes, normocytic normochromic red cells, and rouleaux formation. Neutropenia can be found in some patients. Thrombocytopenia is found in approximately 50% of patients with bleeding diathesis.

Chemistry tests include the following [25] :

  • Lactate dehydrogenase (LDH) levels - May be elevated, indicating the extent of Waldenström macroglobulinemia–related tissue involvement
  • Uric acid levels - May be elevated
  • Erythrocyte sedimentation rate (ESR) - May be elevated
  • Renal and hepatic function
  • Total protein levels
  • Albumin-to-globulin ratio
  • Creatinine - Occasionally elevated
  • Electrolytes - Occasionally abnormal; hypercalcemia is noted in approximately 4% of patients; hyponatremia may be present
  • Rheumatoid factor, cryoglobulins, direct antiglobulin test, and cold agglutinin titer results - May be positive

Beta-2-microglobulin and C-reactive protein test results are not specific for Waldenström macroglobulinemia. Beta-2-microglobulin is elevated in proportion to tumor mass and is important in determining prognosis.

Coagulation abnormalities may be present. Prothrombin time, activated partial thromboplastin time, thrombin time, and fibrinogen tests should be performed. Platelet aggregation studies are optional.

Results from characterization studies of urinary immunoglobulins indicate that light chains (Bence Jones protein), usually of the kappa type, can be found in the urine. Urine collections should be concentrated. Bence Jones proteinuria is observed in approximately 40% of patients and exceeds 1g/day in approximately 3% of patients.

Electrophoresis and immunofixation

Serum protein electrophoresis results indicate evidence of a monoclonal spike but cannot establish the spike as IgM. An M component with beta-to-gamma mobility is highly suggestive of Waldenström macroglobulinemia.

Immunoelectrophoresis and immunofixation studies help to identify the type of immunoglobulin, the clonality of the light chain, and the monoclonality and quantitation of the paraprotein. High-resolution electrophoresis and serum and urine immunofixation are recommended to help identify and characterize the monoclonal IgM paraprotein. The light chain of the monoclonal protein is usually the kappa light chain. At times, patients with Waldenström macroglobulinemia may exhibit more than 1 M protein.


Imaging Studies

Imaging studies used in the evaluation of Waldenström macroglobulinemia include the following [26] :

  • Chest radiographs - These should be obtained to evaluate for pulmonary infiltrates, nodules or effusion, and congestive heart failure

  • Computed tomography (CT) scans - Images of the chest, abdomen, and pelvis may show evidence of adenopathy, hepatosplenomegaly, or both

  • Magnetic resonance imaging (MRI) - This is usually not needed for clinical management; however, MRI of the spine shows findings of bone marrow involvement in 90% of patients


Bone Marrow Aspiration and Biopsy


Bone marrow aspiration and biopsy are required to establish the diagnosis of Waldenström macroglobulinemia. Bone marrow examination findings show infiltration by small lymphocytes showing plasmacytic differentiation. The pattern of infiltration is diffuse or interstitial in most cases. A paratrabecular pattern should raise the possibility of follicular lymphoma.

Periodic acid-Schiff (PAS) staining results are often positive because of the high polysaccharide content in the cells.

Three patterns of marrow involvement are described, as follows:

  • Lymphoplasmacytoid cells (ie, predominantly lymphoplasmacytic and small lymphocytes) in a nodular pattern
  • Lymphoplasmacytic cells (ie, small lymphocytes, mature plasma cells, mast cells) in an interstitial/nodular pattern
  • A polymorphous infiltrate (ie, small lymphocytes, plasma cells, plasmacytoid cells, immunoblasts with mitotic figures).

The abnormal cells may have PAS-positive intranuclear inclusions called Dutcher bodies (deposits of IgM around the nucleus).

Primary amyloidosis is a rare complication of IgM gammopathies. If this is suspected (because of neuropathy, nephrotic syndrome, or cardiac failure), then abdominal fat-pad needle aspiration, along with bone marrow biopsy, may help to demonstrate amyloid deposits on Congo red staining (ie, apple-green birefringence under polarized light).

Flow cytometry

Flow cytometry results show B-cell features with surface expression of IgM and B-cell differentiation markers. Waldenström macroglobulinemia is characterized in most cases by a surface IgM+ sIgD+/- CD5- CD10- CD19+ CD20+ CD22+ CD23- CD25+ CD27+ CD75- CD79+ CD103- CD138- FMC7+ BCL- 2+ BCL- 6- PAX- 5+ immunophenotype. In practice, a sIgM+ CD5- CD10- CD19+ CD20+ CD23- immunophenotype in association with a nonparatrabecular pattern of infiltration is diagnostic of Waldenström macroglobulinemia.

Genetic studies

Various chromosomal abnormalities are common in patients with Waldenström macroglobulinemia.The L265P mutation in MYD88 can be found in more than 90% of patients and has clinical and prognostic significance. [5] Whole genome sequencing in 30 patients with Waldenström macroglobulinemia also found the WHIM (warts, hypogammaglobulinemia, infection, myelokathexis syndrome) mutation in CXCR4 (27%) and mutations in ARID1A (17%). [27]

Although no evidence to date links Waldenström macroglobulinemia with consistent chromosomal or genetic changes, and prognostic implications are uncertain, a French study suggested that a polymorphism may be a prognostic factor following initiation of treatment for this disease. Poulain et al evaluated the distribution and clinical influence of the CXCL12 (-801GA) polymorphism in 114 patients with Waldenström macroglobulinemia and found that the CXCL12 (-801AA) genotype occurred more commonly in affected patients than in control subjects. [28]

In addition, patients in the study with CXCL12 (-801GG) had a shorter median survival time following administration of first-line therapy than did the remaining patients. The investigators suggested the CXCL12 (-801GA) polymorphism may be associated with a higher incidence of Waldenström macroglobulinemia or may influence clinical outcome.