Aetiology

The cause of Waldenström's macroglobulinaemia (WM) is unknown. Genetic factors may play a role, as family clusters have been described, but, in the vast majority of cases, WM is a sporadic disorder.[11] A history of immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS) and/or a family history of a first-degree relative with B-cell lymphoproliferative disorder are the only risk factors strongly supported by epidemiological studies.[12][13][14][15] Genetic linkage analysis suggests the possibility of chromosome 1q and 4q abnormalities.[16]

In over 90% of patients with WM, the tumour has acquired a MYD88 L265P somatic mutation on chromosome 3p.[17] This mutation (in concert with Bruton's tyrosine kinase [BTK]) acts as a driver for B-cell tumour growth.[18] An MYD88-independent Sp1 transcription factor has emerged as another important regulator of cell survival and growth in WM.[19]

Another mutation associated with WM is the C1013G/C-X-C chemokine receptor type 4 (CXCR4)-WHIM mutation in approximately 28% of patients with WM (versus 7% in other low-grade lymphomas).[20] The CXCR4 mutation is an activating mutation in WM and is found in patients who have a MYD88 mutation.[21] These mutations are critical to the pathogenesis of the disease and may be important for the development of targeted treatments.[22][23]​ The minority of patients who lack a MYD88 mutation have a worse prognosis and are less responsive to targeted treatment with ibrutinib.[17][24]​ Patients with a MYD88 mutation who lack the CXCR4 mutation may have the best response to BTK inhibitors including ibrutinib and zanubrutinib.[17]

Pathophysiology

Origin of Waldenström's macroglobulinaemia (WM) malignant clone

  • Pluripotent haematopoietic stem cells give origin to B lymphocyte-committed stem cells that proceed to immature antigen-naive B cells. These cells then mature and express immunoglobulin M (IgM) or IgD surface immunoglobulin after completion of V(D)J recombination and may move to lymph nodes and engage an antigen using their surface antibody. This triggers the process of antigen-dependent B-cell maturation, during which B cells divide in germinal lymphoid centres, undergoing genetic mutations (somatic hypermutation) to select the antibodies with the highest binding affinity for the antigen. In addition, antibody class switching occurs to produce new classes of IgG, IgA, and IgE antibodies. Somatic hypermutation has a high risk of errors and malignant transformation. It has been hypothesised that the WM tumour cell originates from a B cell that has passed the stage of hypermutation but has not yet gone through isotope class switching.[25]

The two main pathophysiological processes characteristic of WM are:

  • Infiltration and uncontrolled proliferation of malignant lymphoplasmacytic cells in the bone marrow and visceral organs, leading to bone marrow failure, lymphadenopathy, and splenomegaly.

  • Production of abnormal high molecular weight monoclonal IgM leading to symptoms related to hyperviscosity, and direct damage of nerves (neuropathy) and other targets (e.g., red cells, clotting factors). Hyperviscosity requires urgent treatment.

Classification

The 2022 revision of the World Health Organization (WHO) classification of lymphoid neoplasms[1]​​

The WHO classifies WM as a type of lymphoplasmacytic lymphoma (LPL) under the group mature B-cell neoplasms.

The WHO classification recognises two sub-types of LPL:

  • IgM LPL/WM type (defined as LPL in the bone marrow with monoclonal IgM in the blood)

  • Non-WM type LPL (includes: LPL in the bone marrow with IgG or IgA monoclonal protein; or non-secretory LPL; or IgM LPL without bone marrow involvement)

The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee[2]

The International Consensus Classification also defines Waldenström's macroglobulinaemia as an LPL under the group mature B-cell neoplasms, although it does not distinguish any sub-types.

Clinical classification[3]

There are two clinical sub-groups of WM:

  • Symptomatic WM that requires treatment

  • Smouldering WM (SWM). This is defined as asymptomatic WM without clinical indications for treatment for a minimum of 12 months following diagnosis.

Use of this content is subject to our disclaimer