A diagnosis of WM can involve several stages and a range of investigative procedures. Here, we will explore these stages in more detail.
WM risk factors in accordance with the International Prognostic Scoring System for Waldenstrom macroglobulinemia (IPSSWM)*[^1]:
WM patients can be categorised into three stages:
Hb=haemoglobin; IgM=immunoglobulin M; OS=overall survival.
*The IPSSWM is a collaboration between 7 international cooperative groups, sharing collective data to create a prognostically meaningful international scoring system for patients with WM requiring therapy because of a symptomatic disease, according to the Athens workshop recommendations.
At diagnosis, 30-50% of patients with WM are asymptomatic and do not require therapy. The risk of progression to symptomatic disease is 59% at 5 years.
DLBCL=diffuse large B-cell lymphoma; IgH=immunoglobulin heavy locus; IgM=immunoglobulin M; LPL, lymphoplasmacytic lymphoma; MGUS=monoclonal gammopathy of undetermined significance; WM=Waldenström’s macroglobulinemia.
*The table lists some important differential features of IgM monoclonal gammopathies. IgM paraprotein can be present in virtually all B-cell lymphoproliferative disorders.† b Mayo clinical criteria require at least 10% bone marrow involvement by LPL, while the Second International Workshop on WM (IWWM-2) eliminated the requirement for a minimal amount of spinal cord involvement.ǂ Constitutional symptoms: hepatosplenomegaly, lymphadenopathy, anaemia, hyperviscosity, solid organ involvement and rarely lytic lesions.
Table adapted from Paludo, et al. 2016.
Implication of other organs
Production of excessive monoclonal IgM
A diagnosis of WM requires histopathological confirmation of bone marrow (BM) infiltration by monoclonal lymphoplasmacytic cells and the presence of any amount of monoclonal IgM protein, confirmed by immunofixation.
The presence of monoclonal IgM without bone marrow infiltration does not fulfil the diagnostic criteria for WM, as this could also correspond to monoclonal gammopathy of undetermined significance (MGUS). Differential diagnosis is crucial, as raised IgM is also a feature of marginal zone lymphoma and IgM multiple myeloma, which constitutes approximately 1% of all multiple myeloma cases. Please refer to “Immunophenotypic evaluation.”
Bone marrow infiltration by clonal lymphoplasmacytic cells can be confirmed by immunophenotypic studies, showing expression of CD19, CD20, CD22 and CD79a.
About 90% of patients with WM harbour the myeloid differentiation primary response MYD88(L265P) gene mutation in their lymphoplasmacytic cells, which may support a differential diagnosis from other morphologically similar conditions.
However, MYD88(L265P) is also found in 50–80% of patients with IgM MGUS and may also be found in other lymphomas, such as marginal zone lymphoma. In addition, patients may fulfil the immunophenotypic and clinical criteria for WM but have other MYD88 mutations or wild-type MYD88.
Approximately 30% of patients with WM have activating CXCR4 mutations. Clinical testing for CXCR4 mutations is not routinely recommended beyond the scope of clinical trials.
Sensitive assay methods such as allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) are recommended for immunophenotypic assessment.
Bing-Neel syndrome (BNS) is a rare complication of WM that occurs in intracranial tissues, mainly causing neurological and ocular involvement.
Bing-Neel syndrome (BNS) occurs when lymphoplasmacytic cells infiltrate different areas of the central nervous system, such as the brain parenchyma, leptomeninges, dura, or cerebrospinal fluid.
Normally, the nervous symptoms derived from WM are due to hyperviscosity or to IgM-mediated demyelinating neuropathies.
BNS affects the central nervous system and can include neurological symptoms such as:
Balance and gait disorders
(visual and hearing loss)
The following methods are used to diagnose BNS:
MRI of the brain and spinal cord
Lumbar puncture for analysis of CSF
CSF is analysed by flow cytometry and cytology to determine the presence of lymphoplasmacytic cells and their morphology, and the presence of markers such as IgM[^11]:
Additionally, PCR of the CSF could be used to determine if the patient has the MYD88(L265P) mutation, and rearrangement in the IGH gene.
BM=bone marrow; BMB=bone marrow biopsy; CBC: BNS=Bing-Neel syndrome; CBC=complete blood count; Add: CSF=cerebrospinal fluid; CXCR4=C-X-C chemokine receptor type 4; DLBCL=diffuse large B-cell lymphoma; IgH=heavy chain immunoglobulin (immunoglobulin heavy locus); IgM=immunoglobulin M; LPL: IPSSWM=International Prognostic Scoring System for Waldenström’s macroglobulinaemia; LPL=lymphoplasmacytic lymphoma; MGUS=monoclonal gammopathy of undetermined significance; MRI=magnetic resonance imaging; PCP=primary care physician; PCP: PCR=polymerase chain reaction; WM=Waldenström’s macroglobulinemia.
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