Waldenström's macroglobulinemia diagnostic study of choice

Waldenström's macroglobulinemia Microchapters
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sara Mohsin, M.D.[2], Shyam Patel [3], Roukoz A. Karam, M.D.[4]; Grammar Reviewer: Natalie Harpenau, B.S.[5]

Overview

The diagnosis of Waldenstrom's macroglobulinemia is based on bone marrow aspiration and biopsy and serum protein analysis studies such as immunohistochemistry, flow cytometry and cytogenetics to distinguish WM from other types of B-cell lymphomas. CSF flow cytometry, protein electrophoresis and immunofixation is done for the diagnosis of Bing-Neel syndrome (a late, but severe, rare complication).

Diagnostic Study of Choice

• There is no single diagnostic study of choice for the diagnosis of Waldenstrom's macroglobulinemia (WM), but bone marrow aspiration and biopsy is considered to be mandatory for the assessment of patients with WM and further supported by monoclonal protein/immunophenotypic studies such as immunohistochemistry, flow cytometry and cytogenetics to distinguish WM from other types of B-cell lymphomas.
• Not all the diagnostic tests mentioned are performed in a patient with Waldenstrom's macroglobulinemia. A doctor takes into account the following factors before choosing diagnostic tests in a particular patient:
  • Suspected type of cancer
  • Signs and symptoms
  • Age
  • Medical condition of the patient
  • Results of earlier medical tests

Diagnostic Criteria:

Diagnostic criteria presented in second International Workshop, Greece, 2002

In September 26-30, 2002, in Athens, Greece,the Second International Workshop was held in which a diagnostic criteria for Waldenstrom's Macroglobulinemia was proposed. According to this criteria, the following findings on performing bone marrow biopsy and serum protein analysis are confirmatory of Waldenström macroglobulinemia and exclude other small B cell lymphoid neoplasms with plasmacytic differentiation:

Diagnostic criteria presented in second International Workshop, Greece, 2002
1:Presence of IgM monoclonal gammopathy of any concentration on serum protein analysis		Necessary criteria
2:A bone marrow biopsy demonstrating more than 10% infiltration by small lymphocytes, plasmacytoid lymphocytes, and plasma cells, (with variable numbers of admixed immunoblasts), with an intertrabecular pattern consistent with lymphoplasmacytic lymphoma	Proliferation centers (pathognomonic of CLL/SLL) and paler-appearing marginal zone type differentiation (seen in marginal zone lymphoma) are absent	Necessary criteria
	IgM concentration widely varies in WM, and it is not possible to define a concentration that reliably distinguishes WM from other lymphoproliferative disorders. Hence, a diagnosis of WM can be made irrespective of IgM concentration if there is an evidence of bone marrow infiltration by lymphoplasmacytoid lymphoma as defined by the Revised European-American Lymphoma classification and WHO criteria. This is a tumor of small lymphocytes showing evidence of plasmacytoid or plasma cell differentiation.
	A recent study found that, in 39% of patients, the bone marrow aspirate contained a spectrum of small lymphocytes, plasmacytoid lymphocytes, and plasma cells; in 39% of patients, there was a predominance of small lymphocytes with fewer plasmacytoid lymphocytes or plasma cells, and 22% of the patients contained a mixture of small lymphocytes and plasma cells, with rare plasmacytoid cells. Mast cells were increased in 26% of patients.
3:Intertrabecular pattern of bone marrow infiltration		Supportive criteria
4:Immunophenotype of the lymphoplasmacytic infiltrate consistent with Waldenstrom's macroglobulinemia. This includes: IgM+, CD5-, CD10-, CD11c-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103- and CD138+		Supportive criteria

mSMART guidelines for diagnosis of Waldenstrom macroglobulinemia and associated disorders

Mayo Stratification of Macroglobulinemia and Risk-Adapted Therapy (mSMART) Guidelines 2016 for diagnosis of Waldenstrom macroglobulinemia and associated disorders are as follows:

mSMART guidelines 2016 for diagnosis of Waldenstrom macroglobulinemia and associated disorders
Waldenström macroglobulinemia	IgM monoclonal gammopathy (regardless of the size of the M protein) with >10% bone marrow lymphoplasmacytic infiltration (usually intertrabecular) by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation and a typical immunophenotype (surface IgM+, CD5–, CD10–, CD19+, CD20+, CD23–) that satisfactorily excludes other lymphoproliferative disorders, including chronic lymphocytic leukemia and mantle cell lymphoma
IgM MGUS	Serum IgM monoclonal protein level <3 g/dL, bone marrow lymphoplasmacytic infiltration <10%, and no evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly
Smoldering Waldenström macroglobulinemia (indolent /asymptomatic Waldenström macroglobulinemia)	Serum IgM monoclonal protein level ≥3 g/dL and/or bone marrow lymphoplasmacytic infiltration ≥10% and no evidence of end-organ damage, such as anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, or hepatosplenomegaly, that can be attributed to a lymphoplasmacytic proliferative disorder

Definitive Diagnostic Tests

• Genetic Testing:
  • ARIDA
  • IG gene rearrangement
  • CXCR4 5338X
  • MYD88 L265P
• Immunophenotyping
• Serum paraprotein

Bone Marrow Aspirate:

• A bone marrow aspirate is essential in the diagnosis of Waldenstrom's macroglobulinemia
• Findings suggestive of Waldenstrom's macroglobulinemia include:
  • Hypercellular bone marrow aspirate
  • Lymphoplasmacytic infiltrate with characteristic immunophenotype

Bone marrow aspirate. Lymphocytes with lymphoplasmacytoid appearance (arrows).Source: D'Angelo G. et al, Laboratorio di Chimica-Clinica, Ematologia e Microbiologia (Ematologia/Coagulazione), Azienda Ospedaliera "S. Antonio Abate" di Gallarate, Varese, Italy.

Bone Marrow Biopsy:

• A bone marrow biopsy may be helpful in the diagnosis of Waldenstrom's macroglobulinemia
• Findings on the biopsy suggestive of Waldenstrom's macroglobulinemia include:
  • Hypercellular and infiltrated with lymphoid and plasmacytoid cells
  • Dutcher bodies (PAS positive intra-nuclear vacuoles containing IgM monoclonal protein)
    • Characteristic feature of Waldenstrom's macroglobulinemia
• Three patterns of marrow involvement are described, as follows:
  • Lymphoplasmacytoid cells (lymphoplasmacytic and small lymphocytes) in a nodular pattern
  • Lymphoplasmacytic cells (small lymphocytes, mature plasma cells, mast cells) in an interstitial/nodular pattern
  • A polymorphous infiltrate (small lymphocytes, plasma cells, plasmacytoid cells, immunoblasts with mitotic figures)

Electrophoresis and Immunofixation

• Serum protein electrophoresis is important for the diagnosis of Waldenstrom's macroglobulinemia
• Findings on an electrophoresis diagnostic of Waldenstrom's macroglobulinemia include:
  • Sharp, narrow spike of monoclonal IgM protein
  • Dense band of monoclonal IgM protein
  • The paraprotein can be of any size
• Serum immunofixation is important for the diagnosis of Waldenstrom's macroglobulinemia. It helps in confirming the presence of a monoclonal protein, in addition to determining its type

Serum immunofixation electrophoresis. (A) There is a slightly dense band with IgM, kappa antisera, suggestive of monoclonal gammopathy (B) After the treatment, a dense band with IgM was disappeared.Source: Kim YL. et al, Department of Internal Medicine, Eulji University College of Medicine, Seoul, Korea.

CSF flow cytometry, protein electrophoresis and immunofixation for diagnosis of Bing-Neel syndrome:

• For diagnosing Bing-Neel syndrome, after lumbar puncture, CSF flow cytometry is done which shows a lambda light chain-restricted population of B-cells consistent with a CD5+ CD10+ B-cell lymphoma
• Furthermore, protein electrophoresis and immunofixation should be done for the detection and classification of a monoclonal protein as well as molecular diagnostic testing for immunoglobulin gene rearrangement and mutated MYD88

Stereostactic brain biopsy showing diffuse infiltration of atypical plasmacytoid lymphocytes into the dural fibrous tissue (A) Hematoxylin & eosin (original magnification ×200); (B) Positive immunohistochemical staining for CD20 (original magnification ×40). Source: Kim HD. et al, Department of Internal Medicine, Yeoungnam University College of Medicine, Daegu, Korea.

Plasmacytoid cells found on cytospin of the cerebrospinal fluid confirming cellular infiltration of the central nervous system.Source: Halperin D. et al, Whipps Cross Hospital, London E11 1NR, UK.