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

Figures & data

Table 1 Classification of Immunoproliferative Disorders with Monoclonal IgM

	Symtoms^a Attributtable to Tissue Infiltration	Symtoms^b Attributable to IgM	Bone Marrow Infiltration^c	Ig Monoclonal Protein^b
Symptomatic WM	(+)	(+)	(+)	IgM
Asymptomatic WM	(–)	(–)	(+)	IgM
IgM-related disorders^d	(–)	(+)^c	(–)^b	IgM
IgM MGUS	(–)	(–)	(–)^b	IgM
Lymphoplasmacytic lymphoma^e	(+/–)	(+/–)	(+/–)	IgM > IgG > IgA or absent

Notes: ^aSymptoms attributable to tumor infiltration will include any of the following manifestations: B symptoms, cytopenia(s), or symptomatic organ infiltration (ie central nervous system: Bing-Neel syndrome). ^bThere is no definition of an IgM concentration threshold to differentiate between MGUS and WM. ^cPatients with demonstrated bone marrow infiltration by lymphoplasmacytic lymphoma have a WM, while patients without evidence of infiltration have an MGUS. Detection of clonal B-cells by flow cytometry or MYD88 L265P mutation by polymerase chain reaction will help in this definition, but in the absence of morphological evidence of bone marrow infiltration these patients should still be classified as having an MGUS. ^dThere are patients who have symptoms attributable to the IgM monoclonal protein but no overt evidence of tissue infiltration by LPL. These patients may show peripheral neuropathy, Schnitzler Syndrome, symptomatic cryoglobulinemia, amyloidosis, or cold agglutinin disease. ^eAnatomo-clinical entity present in patients in whom, having a lesion with histological diagnosis of LPL, there are no criteria of WM (they lack on IgM M-component and/or bone marrow infiltration). As other indolent lymphomas they can have or not of symptoms related to the infiltration or M-component.

Table 2 Inside the Bone Marrow: Histology, Immunophenotype and Molecular Features

Bone Marrow	Relevant Findings
Morphological evaluation	Pleomorphic B lineage cells at different stages of maturation: B lymphocyte cells with lymphoplasmacytic differentiation with small population of clonal plasma cells. The presence of prominent mast cells is frequent.
Flow cytometry	1) B-cell monoclonal population: sIgM +,CD19+,CD20+,CD22 +,CD79 +, CD25+, CD27+, FMC7+, BCL-2+, Up to 10–20% of WM cases may be CD5+, CD10+, or CD23+. 2) Plasma cell population: CD138+ CD38++, CD19+, CD45+, CD56-, CD117-
Molecular aspects	MYD88 L265P mutation: > 90%. The presence of MYD88 L265P mutation supports the diagnosis of WM CXCR4 mutation: 30–40%
Cytogenetics	6q21 deletion, is the most common cytogenetic abnormality reported in 30–60% of WM patients (can be seen by fluorescence in situ hybridization, FISH)
Histology	Diffuse, interstitial and /or nodular infiltration of small B lymphocytes, lymphoplasmacytoid and plasma cells, with the predominately intertrabecular pattern associated with the restriction of light chains.

Table 3 Outside the Bone Marrow: IgM Related Symptoms

Clinical Features	IgM Related Disease
New onset headaches, blurred vision, mucosal bleeding, hearing loss, tinnitus, neurologic disorders, retinopathy and retinal hemorrhage	Hyperviscosity
Distal, symmetric, progressive, sensorio-motor peripheral neuropathies with predominantly demyelinating features in the nerve conduction studies. (50% of cases anti-MAG +) IgM antibodies against other neural targets: gangliosides GM1, GD1a, GD1b, GT1b, GM2 and GM3 and the paragloboside, sulphate-3-glucuronyl para-globoside (SGPG).	Peripheral neuropathies related to IgM
Raynaud like symptoms, acrocyanosis, ulcerations on extremities, purpura, cold urticaria	Cryoglobulinemia I
Arthralgias, sensorimotor neuropathies, purpura, renal failure.	Cryoglobulinemia II
Extra vascular Hemolytic anemia (cold exposure), Raynaud phenomenon, acrocyanosis.	Cold agglutinins
Recurrent thrombotic events	Antiphospholipid syndrome
Peripheral sensory neuropathies with axonal pattern associated with autonomic nerve dysfunction. Other organ involvements: kidneys, heart, lung, liver and Gastointestinal tracts.	Amyloidosis AL
Chronic urticarial eruptions, recurrent fever, arthralgia ± lymphadenopathy	Schnitzler’s Syndrome, (Auto-inflammatory disease)
Renal Failure ± Proteinuria (Moncolnal- IgM +/_ Light chain deposition)	Proliferative glomerulonephritis, Amyloidosis AL Cryoglobulinaemia II

Table 4 Essential Evaluation of Patients with Waldenström Macroglobulinemia (WM)

Evaluation  ● Clinical history and physical examination  ● Familial history for WM and other B-cell lymphoproliferative disorders  ● Funduscopic examination: fotographic documentation  ● Review of systems	If clinically indicated  ● Cryoglobulins  ● Cold agglutinin titre  ● Serum viscosity  ● Screening for von Willebrand disease  ● 24-h urine protein quantification
	Bone marrow aspiration and biopsy  ● Immunohistochemistry  ● Flow cytometry  ● Testing for MYD88 L265P gene mutation  ● FISH analysis of del(6q21) and del(17p)
Laboratory studies  ● Complete blood count  ● Complete metabolic panel  ● Serum immunoglobulin levels (IgA, IgG, IgM)  ● Serum and urine electrophoresis with immunofixation  ● Serum free light assessment  ● Serum beta-2-microglobulin level
	Total body CT-scan with IV contrast  ● In patients being considered for therapy  ● PET-CT if transformation is suspected

Notes: Modified from reference 37: Castillo JJ, Garcia-Sanz R, Hatjiharissi E, Kyle RA, Leleu X, McMaster M, Merlini G, Minnema MC, Morra E, Owen RG, Poulain S, Stone MJ, Tam C, Varettoni M, Dimopoulos MA, Treon SP, Kastritis E. Recommendations for the diagnosis and initial evaluation of patients with WaldenströmMacroglobulinaemia: A Task Force from the 8th International Workshop on WaldenströmMacroglobulinaemia. Br J Haematol. 2016 Oct;175(1):77–86. doi: 10.1111/bjh.14196. Epub 2016 Jul 5. PMID: 27378193; PMCID: PMC5154335.