Waldenström’s Macroglobulinemia: An Exploration into the Pathology and Diagnosis of a Complex B-Cell Malignancy

Abstract

After 77 years since the initial description, Waldenström macroglobulinemia (WM) remains as a bone marrow neoplastic disorder with lymphoplasmacytic differentiation oversecreting a monoclonal immunoglobulin M (IgM). However, many biological and genetic aspects of this entity have been unraveled and it is now easy to correctly diagnose patients with this illness. The diagnosis requires the presence of a monoclonal IgM component and bone marrow lymphoid infiltration must be demonstrated. In addition, other small B-cell lymphoid neoplasms with plasma cell differentiation must be discarded. Although the clinical picture is highly heterogeneous, the diagnosis is much easier today compared to the past, since now we can demonstrate the presence of somatic mutations, especially the L265P mutation in the MYD88 gene, highly characteristic of WM (>90% of the patients), followed by the WHIM-like mutations in the CXCR4 gene (~35%). The identification of these mutations is very important, because they can modulate the response to new treatments with Bruton's tyrosine kinase (BTK) inhibitors. Thus, the conventional prognostic factors that predict the outcome of these patients (anemia, thrombopenia, high M component, high B2M, and advanced age), must be complemented with the genetic evaluation of the patient, that can help us in the prediction of the risk of transformation from asymptomatic to symptomatic forms (Del6q) and/or from indolent forms of the disease to aggressive lymphomas (CD79b mutations).

Nucleic Acid Biomarkers in Waldenström Macroglobulinemia and IgM-MGUS: Current Insights and Clinical Relevance

“…Other less frequent cytogenetics abnormalities include del13q (15%), trisomy 18 (10%), trisomy 4 and del17p (8%) (Figure 2B) [26,105,106]. Chromosome 6q deletion, mostly from q14 to q27, contains negative regulators of the MYD88/NFκB pathway (BLIMP1, TNFAIP3, HIVEP2, TRAF3IP2, IRAK1BP1), BTK inhibitors (IBTK) as well as controllers of apoptosis and differentiation (FOXO3, BCLAF1, PERP) [21,83,[107][108][109].…”

“…Immunophenotype: immunophenotype consistent with WM: CD19+, CD20+, CD22+, CD79+, CD5-, CD10-, CD23-. Of note, 5-10% of WM cases could express CD5 [20,21]. Symptoms: attributable to tumor infiltration (in BM or extramedullary) and/or to the monoclonal protein (related to immunological or chemical properties) [7,8,21].…”

“…Of note, 5-10% of WM cases could express CD5 [20,21]. Symptoms: attributable to tumor infiltration (in BM or extramedullary) and/or to the monoclonal protein (related to immunological or chemical properties) [7,8,21]. IgM-related disorders: patients who have clinical features attributable to the IgM monoclonal protein but without overt evidence of LPL in the BM.…”

Invasive Cutaneous Candidiasis, Autoimmune Hemolytic Anemia and Pancytopenia: A Challenging Scenario for Waldenström Macroglobulinemia in an Elderly Patient

“…As a result, manifestations may vary depending on the involved tissue, including BM or extramedullary infiltration, or those related to the monoclonal component [ 6 ]. Therefore, IgM paraprotein can cause specific complications due to its physical–chemical properties, autoantibody activity, tissue deposition and non-specific interactions with other proteins, such as cryoglobulins, cold agglutinin syndrome (CAS) and amyloidosis [ 7 ].…”

Case report: A rare case of coexisting Waldenstrom Macroglobulinemia and B-cell acute lymphoblastic leukemia with KMT2D and MECOM mutations

“…Under repeated stimulation by antigens, B-lymphocytes undergo proliferation and differentiation and are transformed into plasma cells. WM is a rare disease of plasma cell origin, characterized by the accumulation of malignant lymphoplasmacytes in the bone marrow and other organs, and the secretion of monoclonal IgM ( 1 , 2 ). WM is mostly seen in the elderly and is an indolent tumor with family heritability.…”