High IgG in Waldenström's Macroglobulinemia: An Atypical Finding Requiring Diagnostic Reassessment
The presence of elevated IgG (rather than IgM) in a patient with suspected Waldenström's macroglobulinemia is highly atypical and should prompt immediate reconsideration of the diagnosis, as WM is definitionally characterized by monoclonal IgM production, not IgG. 1
Understanding the Diagnostic Discrepancy
WM requires the presence of monoclonal IgM protein—not IgG—along with bone marrow infiltration by lymphoplasmacytic cells. 1 The diagnosis cannot be established without demonstrating IgM monoclonal protein by immunofixation. 1
Critical Differential Diagnosis
When IgG is elevated instead of IgM, consider these alternative diagnoses:
IgG Multiple Myeloma: The most likely diagnosis if you see IgG monoclonal protein with plasma cell infiltration rather than lymphoplasmacytic cells. 2 The MYD88 L265P mutation is present in ~90% of WM cases but is absent in IgM multiple myeloma, making this the definitive discriminator. 1, 2
IgG-secreting Lymphoplasmacytic Lymphoma: Approximately 5% of patients with lymphoplasmacytic lymphoma secrete non-IgM paraproteins (IgG, IgA, kappa, lambda) or are non-secretory—these should be managed like WM but technically don't meet WM diagnostic criteria. 1
Polyclonal IgG elevation: May occur in 15% of WM patients as a secondary phenomenon alongside the monoclonal IgM. 3 This represents reactive hypergammaglobulinemia, not the disease-defining monoclonal protein.
Immediate Diagnostic Steps Required
Order MYD88 L265P mutation testing by allele-specific PCR immediately, as this mutation is found in >90% of WM but is absent in multiple myeloma. 1, 2
Verify the immunoglobulin type with serum protein electrophoresis and immunofixation to definitively identify whether the monoclonal protein is IgM (WM) or IgG (likely myeloma). 1, 2, 4
Review bone marrow histopathology to distinguish lymphoplasmacytic cells (WM) from plasma cells (myeloma). 1, 2 Immunophenotyping should show CD19, CD20, CD22, and CD79a expression in WM. 1
Clinical Implications of Misdiagnosis
The distinction between WM and IgG myeloma is critical because treatment approaches differ significantly:
WM treatment centers on rituximab-based chemoimmunotherapy (bendamustine plus rituximab or cyclophosphamide-based regimens) or BTK inhibitors like ibrutinib/zanubrutinib. 1, 5, 6
Multiple myeloma treatment uses proteasome inhibitors, immunomodulatory drugs, and different chemotherapy backbones. 2
Common Pitfall to Avoid
Do not assume a diagnosis of WM based solely on bone marrow lymphoplasmacytic infiltration without confirming monoclonal IgM. 1 The presence of any other immunoglobulin type (IgG, IgA) with similar bone marrow findings suggests a different diagnosis entirely, even if the morphology appears consistent with lymphoplasmacytic lymphoma. 1
If you're seeing "high IgG" reported in a WM patient, verify whether this represents:
- A polyclonal elevation (common, clinically insignificant) 3
- A monoclonal IgG (wrong diagnosis—likely myeloma) 2
- A laboratory or documentation error
The level of monoclonal protein alone—whether IgM or IgG—is not an indication to start treatment. 1 Treatment decisions should be based on symptoms (cytopenias, hyperviscosity, B symptoms, neuropathy, organomegaly), not protein levels. 1