Waldenström's macroglobulinemia pathophysiology

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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], Roukoz A. Karam, M.D.[3], Mirdula Sharma, MBBS [4]; Grammar Reviewer: Natalie Harpenau, B.S.[5]

Overview

Waldenstrom's macroglobulinemia is an uncontrolled clonal proliferation of terminally differentiated B lymphocytes, which are normally involved in humoral immunity. Two main factors mediating this disease include IgM paraprotein secretion and tissue infiltration with neoplastic lymphoplasmacytic cells. Genes involved in the pathogenesis of WM include MYD88-L265P, and CXCR4 alongwith various other cytogenetic and epigenetic abnormalities. In patients of Waldenstrom's macroglobulinemia, there is an increased incidence of diffuse large B-cell lymphoma, myelodysplastic syndrome (acute myeloid leukemia), brain tumor, and renal MALT lymphoma. Two histologic subtypes include lymphoplasmacytoid and lymphoplasmacytic which invade the lymphoid organs such as spleen, lymph nodesand bone marrow. Bone marrow is infiltrated by small lymphocytes, well-formed plasma cells, and plasmacytoid lymphocytes in diffuse, interstitial, nodular, paratrabecular, nodular-interstitial and mixed paratrabacular-nodular patterns. Lymph nodes infiltration shows Dutcher and Russell bodies, mast cells, and hemosiderin-laden macrophages. Peripheral smear shows circulating malignant cells with a plasmacytoid appearance, having basophilic cytoplasm, perinuclearhalo, and nucleus with "clock-face" chromatin without nucleoli. Immunohistochemistry shows pan B-cell surface antigens such as Ig+CD19+, CD20+, CD22+, CD79A+ and variable expression of some other antigens.

Pathophysiology

• Waldenstrom's macroglobulinemia arises from terminally differentiated B lymphocytes. which are normally involved in humoral immunity

B lymphocytes

Development

• B cells develop from hematopoietic stem cells (HSCs) in bone marrow
• Then undergo 2 types of selection in bone marrow:
  • Positive selection by antigen-independent signaling involving both the pre-BCR and the BCR
  • Negative selection leads to a state of central tolerance, by binding of self-antigen with the BCR which if binds strongly to self-antigen, leads to four fates of B-cell:
    • Clonal deletion
    • Receptor editing
    • Anergy
    • Ignorance (B cell ignores signal and continues development)
• Immature B cells then migrate from bone marrow to secondary lymphoid organs (SLOs) such as spleen and lymph nodes
• B cell activation begins when the B cell binds to an antigen via its BCR in SLOs

Function

B cells are:

• Lymphocyte subtype of white blood cells
• Function as a part of humoral immunity which is a component of adaptive immune system
• Secrete antibodies
• Secrete cytokines
• Classified as professional antigen-presenting cells (APCs)

Factors mediating Waldenstrom's macroglobulinemia

• It is understood that WM is mediated by 2 major factors:
  1. The secretion of IgM paraprotein:
     • Causes symptoms of hyperviscosity syndrome
  2. The infiltration of tissues with neoplastic lymphoplasmacytic cells:
     • Mainly the bone marrow, spleen,and lymph nodes
     • Sometimes the liver, gastrointestinal tract, lungs, kidneys, skin, eyes, and central nervous system

Genetics

• The exact pathogenesis of Waldenstrom's macroglobulinemia is not completely understood; however, its familial pattern of involvement supports the role played by genetic factors in the pathogenesis of this disease
• Development of WM is the result of multiple genetic mutations
• Somatic hypermutations of immunoglobulin heavy chain gene, without any intraclonal variation, suggests that the cell of origin is a post-germinal center B cell that has undergone affinity maturation as well as chromosomal abnormalities play a part in the pathogenesis of this disease:
  • A mutation of the MYD88 gene (L265P) has been found in more than 90% of patients with Waldenstrom's macroglobulinemia, while it has rarely presented in patients with other types of mature B-cell tumors
    • MYD88: The activating point mutation of MYD88 augments signaling by Toll-like receptor and Bruton tyrosine kinase (BTK), which leads to activation of transcription factors of the NF-kB family which are involved in growth and survival of both normal and neoplastic B cells by preventing apoptosis. Point mutation of MYD88 leads to leucine to proline substitution in codon 265 (L265P) of MYD88 and produces constantly overactive protein causing proliferation of malignant cells that should normally undergo apoptosis.
    • Monoclonal gammopathy of undetermined significance patients found to have MYD88 L265P mutation have significantly higher risk of progression to Waldenström macroglobulinemia or to other lymphoproliferative disorders
  • Less commonly (30-35%), nonsense or frameshift mutations in the C-X-C chemokine receptor type 4 (CXCR4) 5338X gene have also been reported in patients with Waldenstrom's macroglobulinemia. Mutations in CXCR4 are similar to those seen in patients with the warts, hypogammaglobulinemia, infection, and myelokathexis (WHIM) syndrome:
    • Patients with Waldenstrom's macroglobulinemia with co-existing mutation of MYD88 & CXCR4 are more likely to have hyper-viscosity syndrome and bone marrow involvement
    • Somatic hypermutation in IGHV/IG gene rearrangement
    • ARIDA mutations (17%)

Cytogenetics

• Many cytogenetic abnormalities were reported in Waldenstrom's macroglobulinemia's patients including:
  • Deletion of the long arm of chromosome 6q21-22.1 (most common, 50%)
  • t(9;14) (p13;q32) (50% of patients)
  • Trisomy 4 (20%)
  • Deletion of long arm of chromosome 10, 12 or 20
  • Trisomy 3
  • Trisomy 5
  • Monosomy 8
  • Deletions of regions of 13q14 that include MIRN15A and MIRN16-1
  • t(11;18) (q21;q21) involving API-malt1
  • t(8;14)
  • t(14;18)

Epigenetics:

• Three most common epigenetic causes are:
  • DNA methylation, histone acetylation, and non-coding RNAs such as miRNAs
• Upregulation of miRNAs 155, 184, 206, 363, 494, and 542-3p occurs in Waldenström macroglobulinemia; among which miRNA-155 has a crucial role in tumor cell growth and proliferation in Waldenström macroglobulinemia
• Gene transcription through histone acetylation occurs following increased expression of miRNA-206 and reduced expression of miRNA-9

Associated Conditions

Several studies showed an increased incidence of following second cancers in patients with Waldenstrom's macroglobulinemia:

• Diffuse large B-cell lymphoma
• Myelodysplastic syndrome/Acute myeloid leukemia
• Brain tumor
• Renal MALT lymphoma

Microscopic Pathology

• Following lymphoid organs are involved in WM:
  • Bone marrow
  • Lymph nodes (nodal involvement is characterized by paracortical and hilar infiltration with frequent sparing of the subscapular and marginal sinuses)
  • Spleen
• After a detailed clinicopathological assessment and review of the published literature, the following diagnostic criteria was proposed for WM:
• IgM monoclonal gammopathy of any concentration
• Bone marrow infiltration by:
  • Small lymphocytes with clumped chromatin, inconspicuous nucleoli, and sparse cytoplasm
  • Well-formed plasma cells
  • Plasmacytoid lymphocytes (have cytologic features intermediate between above 2 extremes), in following patterns:
    • Diffuse
    • Interstitial
    • Nodular
    • Paratrabecular
    • Nodular-interstitial
    • Mixed paratrabacular-nodular
• WM has two histologic subtypes:
  • Lymphoplasmacytoid (73%)
  • Lymphoplasmacytic (27%)
• The cytologic composition and the degree of plasmacytic differentiation varies from case to case
• The bone marrow contains variable numbers of pleomorphic lymphoid cells
• Russell bodies (cytoplasmic) or Dutcher bodies (pseudonuclear) which are positive for periodic acid Schiff, can be seen due to accumulation of cytoplasmic IgM in some bone marrow cells
• Mast cell hyperplasia is common and may stimulate tumor cell proliferation and monoclonal IgM secretion
• Gene expression profiling has indicated that lymphoid cells of WM more closely resemble those of chronic lymphocytic leukemia than those of myeloma
• Lymph nodes involvement has following characteristics:
  • Dutcher and Russell bodies, mast cells, and hemosiderin-laden macrophages comprise the typical characteristic lymph node involvement
  • Numerous non-caseating granulomas are rarely observed
  • Lymph node architecture is frequently preserved
  • Diffuse and interstitial infiltration pattern is observed containing small lymphocytes, plasma cells, and plasmacytoid cells
  • Sometimes, large, immunoblast-like cells may be present
  • Often, sinuses remain open, and may contain histiocytes reacting to secreted periodic acid Schiff (PAS) positive immunoglobulin
  • Proliferation centers, which are the hallmark of chronic lymphocytic leukemia/small lymphocytic leukemia, are absent, as is paler-appearing marginal zone differentiation, which is seen in marginal zone lymphoma
• Spleen involvement comprises of:
  • Both red and white pulp
  • Infiltration in a diffuse pattern
  • No distinct marginal zone or nodularity in the red pulp
• Peripheral blood contains:
  • Circulating malignant cells with a plasmacytoid appearance (i.e, resembling a plasma cell)
  • These cells are typically oval-shaped with abundant basophilic cytoplasm
  • Round and eccentrically located nucleus with a perinuclear halo, or cytoplasmic clearing
  • Nucleus has "clock-face" or "spoke wheel" chromatin without nucleoli

High-power field of peripheral blood smear revealing a large, atypical B cell with mild cytoplasmic expansion, coarse chromatin, multiple distinct nucleoli and peripheral vacuolation.Source: Charakidis M. et al, Department of Haematology-Oncology, Royal Hobart Hospital, Tasmania, 7000, Australia.

Low-power magnification of the splenic tissue. This slide displays significant distortion and diffuse infiltration of the splenic parenchyma by lymphoid cells. Of particular note is the expansion of the white pulp by this infiltrate. Source: Charakidis M. et al, Department of Haematology-Oncology, Royal Hobart Hospital, Tasmania, 7000, Australia.

Medium-power field of bone marrow aspirate demonstrating a population of small atypical lymphocytes admixed with normal cells of erythroid, myeloid and lymphoid lineage.Source: Charakidis M. et al, Department of Haematology-Oncology, Royal Hobart Hospital, Tasmania, 7000, Australia.

(A) Rouleaux formation, plasmacytoid cells, and lymphoid cells in the PBF (Leishman, ×1000). (B) Uni-binucleated plasmacytoid cells in the PBF (Leishman, ×1000).Source: Sethi B. et al, Department of Pathology, Hamdard Institute of Medical Sciences and Research, New Delhi, India.

Photomicrograph showing hypercellular marrow with diffuse infiltration by lymphoid cells, plasmacytoid lymphocytes, a few plasma cells, and mast cells (hematoxylin and eosin stain, ×1,000); inset photomicrograph showing strong cytoplasmic positivity for CD20 in the majority of the lymphoid cells (immunohistochemical stain for CD20, ×400).Source: Pujani M. et al, Department of Pathology, Hamdard Institute of Medical Sciences and Research, New Delhi, India.

High-power magnification of splenic lymphoid infiltrate. This slide demonstrates that the infiltrate consists of small- and medium-sized atypical lymphocytes, which display dense chromatin clumping and prominent nucleoli.Source: Charakidis M. et al, Department of Haematology-Oncology, Royal Hobart Hospital, Tasmania, 7000, Australia.

Photomicrograph showing hypercellular bone marrow smears with the presence of mostly bare nuclei, few lymphoid cells, and plasmacytic cells (Wright's stain, ×1,000).Source: Pujani M. et al, Department of Pathology, Hamdard Institute of Medical Sciences and Research, New Delhi, India.

(A) Plasmacytoid cells in the bone marrow aspirates (Leishman, ×1000). (B) Tetranucleated plasmacytoid/plasma cell and lymphoid cell in the bone marrow aspirates (Leishman, ×1000). Source: Sethi B. et al, Department of Pathology, VCSGGMS & RI Srinagar, Pauri Garhwal, Uttarakhand, India.

Electron Microscopy. There is marked thickening of the glomerular basement membrane due to the presence of numerous electron dense deposits located at different levels. The deposits vary in size, tend to be spherical in shape and blend together. Under higher magnifications, they did not exhibit a fibrillary or micro-tubular substructure. Notice a thin subendothelial layer of duplicated basement membrane, also containing electron dense deposits, with cellular interposition. The capillary lumen appears significantly reduced in diameter. Also notice electron dense deposits present in the basement membrane of Bowman's capsule on the right upper corner (Uranyl acetate & lead citrate × 35,000).Source: Castro H. et al, Department of Medicine, Division of General Internal Medicine, University of Miami/Jackson Memorial Medical Center, Miami, Florida, USA.

Electron Microscopy. This field illustrates a large subendothelial and several, much smaller, subepithelial electron dense deposits. This pattern is similar to that originally described in MPGN type III and also often seen in proliferative lupus GN. Notice the duplication of the glomerular basement membrane with cellular interposition. The duplicated segment also contains electron dense deposits. Occasionally giant, subendothelial, globular electron dense deposits reduced the capillary loop to a pin-point lumen. Probably they correspond to the globules seen by light and fluorescence microscopy (Uranyl acetate and lead citrate × 40,000).Source: Castro H. et al, Department of Medicine, Division of General Internal Medicine, University of Miami/Jackson Memorial Medical Center, Miami, Florida, USA.

Light Microscopy. There is marked, global, homogeneous, eosinophilic thickening of the glomerular basement membrane with segmental accentuation. Homogeneous, eosinophilic globules are seen in the lumen of occasional capillary loops. The capillary lumina appear reduced in diameter but no inflammatory or proliferative changes are observed. The periglomerular interstitial space shows lymphocytic infiltration. Focal interstitial deposition of homogeneous eosinophilic material is present in the right upper corner of the picture (H&E × 400). Source: Castro H. et al, Department of Medicine, Division of General Internal Medicine, University of Miami/Jackson Memorial Medical Center, Miami, Florida, USA.

Immunofluorescence. Global granular and homogeneous deposition of IgG along the glomerular basement membrane. Notice the presence of IgG containing globules in rare capillary loops. They seem to correspond to the eosinophilic globules seen by light microscopy and large electron dense deposits detected by electron microscopy (FITC labeled anti-IgG × 400).Source: Castro H. et al, Department of Medicine, Division of General Internal Medicine, University of Miami/Jackson Memorial Medical Center, Miami, Florida, USA.

Renal biopsy. (A) Immunofluorescent microscopic study showed 2+ reaction for IgM. (B) On the electron microscopic (EM) findings (× 20,000), there are subendothelial (arrow) and mesangial electron dense deposits revealing microtubular structures (25 nm in average diameter).Source: Kim YL. et al, Department of Internal Medicine, Eulji University College of Medicine, Seoul, Korea

Immunohistochemistry

Malignant cells in Waldenstrom's macroglobulinemia have following immunophenotypic characteristics:

• Express pan B-cell surface antigens with following immunophenotype:
  • Ig+CD19+
  • CD20+
  • CD22+
  • CD79A+
• Variable expression of:
  • CD11c+
  • CD43+
  • CD38+
  • CD45+
  • CD138+
  • CD25+
  • CD27+
  • FMC7+
  • PAX5+
  • CD38+
  • Bcl2+
• Following aren't expressed:
  • CD5-
  • CD10-
  • CD23-
  • CD103-
  • Bcl6-
  • CD75-
• IgM positive (mostly)
• IgG positive (few)
• IgA (rare)
• IgD negative (lack)