Waldenström's macroglobulinemia pathophysiology

Pathogenesis

Waldenström Macroglobulinemia is uncontrolled clonal proliferation of terminally differentiated B lymphocytes, which are normally involved in humoral immunity. In Waldenström Macroglobulinemia, peripheral B lymphocyte are stimulated to undergo somatic hypermutation of the immunoglobulin heavy chain gene in the germinal center, without class switching.

Genetics

• Development of Waldenström Macroglobulinemia is the result of multiple gene mutations.
• Genes involved in pathogenesis of Waldenström Macroglobulinemia are:

• MYD88 L265P in chromosome 3p22.2
• CXCR4

• MYD88: has a role in toll-like receptor and interleukin-1 receptor signaling causing activation of transcription factors of the NF-kB family. Thus, activating point mutation of MYD88 augments growth and survival of both normal and neoplastic B cells by preventing apoptosis. MYD88 also has role in BTK signaling which also helps in B cell growth and survival. Point mutation of MYD88 leads to leucine (L) to proline (P) substitution in codon 265 (L265P) of MYD88 and produces constantly overactive protein causing proliferation of malignant cells that should normally undergo apoptosis.
• Patients with Waldenström Macroglobulinemia with co-existing mutation of MYD88 & CXCR4 are more likely to have hyperviscosity syndrome and bone marrow involvement.

• 40-60 percent of patients with Waldenström Macroglobulinemia are associated with deletions of 6q21.

Pathology

Immunohistochemistry

Malignant cells in Waldenström Macroglobulinemia express IgM surface immunoglobulin and lack IgD.

Lymphocytic component: expresses pan B cell antigens

Plasma cell component: expresses CD138

Majority of malignant cells express:

• Adhesion molecules including:

• L-selectin
• ICAM-1
• CD44
• CD11c

• Lymphocyte function associated antigen 1 (LFA-1)

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