Waldenstrom Macroglobulinemia

Waldenstrom macroglobulinemia is an uncommon, indolent B-cell malignancy defined by bone-marrow infiltration with lymphoplasmacytic lymphoma together with a monoclonal immunoglobulin M (IgM) protein in the blood. The large IgM molecule (the historical 'macroglobulin') accounts for several of the disorder's distinctive features. It sits at the interface of the indolent lymphomas and the plasma cell disorders.

Definition

Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma involving the bone marrow that is associated with a monoclonal immunoglobulin M protein, typically carrying the MYD88 L265P mutation, and distinguished from other indolent B-cell neoplasms by this combination of features.

Scope

This entry covers the defining combination of lymphoplasmacytic lymphoma and a monoclonal IgM protein, the recurrent molecular lesion that characterises most cases, the consequences of a high circulating IgM load, and the disorder's place within the World Health Organization classification. It is a reference description of the disease entity and not treatment guidance.

Core questions

• What combination of features defines Waldenstrom macroglobulinemia?
• How does the monoclonal IgM protein produce the disorder's manifestations?
• What recurrent molecular lesion characterises the disease?
• How is it distinguished from other indolent B-cell neoplasms and from IgM myeloma?

Key concepts

• Lymphoplasmacytic lymphoma
• Monoclonal immunoglobulin M (IgM)
• MYD88 L265P mutation
• Hyperviscosity
• Bone marrow infiltration
• Indolent B-cell neoplasm
• Differentiation from IgM multiple myeloma

Mechanisms

Waldenstrom macroglobulinemia arises from a clonal population of cells spanning the B-lymphocyte to plasma-cell spectrum (lymphoplasmacytic cells) that infiltrate the bone marrow and secrete a monoclonal IgM. The great majority of cases carry the MYD88 L265P mutation, which activates survival signalling and is a hallmark of the disease that helps distinguish it from related neoplasms. Because IgM is a large, pentameric molecule that remains largely in the circulation, a high IgM concentration can raise blood viscosity and underlie several of the disorder's distinctive features. Its position within the World Health Organization classification reflects this lymphoplasmacytic biology coupled with IgM secretion.

Clinical relevance

Waldenstrom macroglobulinemia is a reference example of an indolent lymphoma in which a secreted protein, rather than tumour bulk alone, shapes the disease, and of how a single recurrent mutation can define an entity. Understanding its defining features clarifies its place between lymphoma and plasma cell disease. This entry describes the disease conceptually and is not a basis for individual diagnosis or treatment.

Epidemiology

Waldenstrom macroglobulinemia is rare, occurring chiefly in older adults and somewhat more often in men. Like multiple myeloma it can be preceded by an IgM monoclonal gammopathy of undetermined significance, an asymptomatic precursor state that progresses to overt disease at a low rate.

History

The disorder was described by Jan Gosta Waldenstrom in the mid-twentieth century in patients with a high-molecular-weight serum protein, bleeding, and lymphoid infiltration. Its classification as a lymphoplasmacytic lymphoma was consolidated in the World Health Organization schemes, and the identification of the recurrent MYD88 L265P mutation in 2012 and after reframed understanding of its biology and diagnosis.

Debates

Boundary with IgM monoclonal gammopathy and other IgM-secreting neoplasms

Distinguishing Waldenstrom macroglobulinemia from IgM monoclonal gammopathy of undetermined significance and from rare IgM multiple myeloma rests on bone-marrow findings and molecular features, and the thresholds and criteria continue to be refined.

Key figures

• Steven P. Treon
• Jan Gosta Waldenstrom
• Steven H. Swerdlow

Seminal works

• treon-2013
• swerdlow-2016
• alaggio-2022

Frequently asked questions

What is the 'macroglobulin' in Waldenstrom macroglobulinemia?

It is a monoclonal immunoglobulin M (IgM), a large pentameric antibody produced by the malignant clone. Because IgM is big and stays mostly in the bloodstream, a high concentration can increase blood viscosity, which gives the disorder its historical name.

How is Waldenstrom macroglobulinemia different from multiple myeloma?

Waldenstrom macroglobulinemia is a lymphoplasmacytic lymphoma associated with a monoclonal IgM protein and typically the MYD88 L265P mutation, whereas multiple myeloma is a plasma cell neoplasm usually producing other immunoglobulin classes and characterised by distinct bone and organ effects.