B-cell lymphoma pathophysiology

It is understood that there are different factors that have important roles in the pathogenesis of B-cell lymphomas including reciprocal translocations that occur between one of the immunoglobulin loci and proto-oncogene, the selection for expression of a B-cell receptor (BCR) that promotes survival, increased survival and proliferation of B-cells mediated by antigen binding, and malignant interaction between B-cells and other cells in the tumor microenvironment. Chromosomal translocations involving the immunoglobulin heavy locus (IGH@) is a classic cytogenetic abnormality for many B-cell lymphomas, including follicular lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, MALT lymphoma, lymphoplasmacytoid lymphoma, multiple myeloma, and Burkitt’s lymphoma.

The normal physiology of B-cells can be understood as follows:

• Development of mature B-cells include:
  • B-cells develop from hematopoietic stem cells originating from bone marrow. B-cell development occurs in the bone marrow through several steps including the ordered rearrangement of [[IGH@|Ig H] and L chain loci (i.e., VDJ recombination), positive selection, and negative selection.^[1]
  • B-cell surface consists of membrane-bound Ig, complement component receptors, Fc receptors, and B cell-specific cell surface molecules representing by CDs (i.e., CD19, CD20, CD21, etc.).
  • Immature (transitional) B-cells migrate from the bone marrow to secondary lymphoid organs (i.e., lymph nodes, spleen) for activation. Activation begins with either T-cell dependent or T-cell independent. T-cell-dependent B-cell activation begins with the binding of the B-cell receptor (BCR) to the T-cell-dependent antigen. T-cell independent B-cell activation begins with BCR crosslinking through polysaccharides or via BCR and toll-like receptor (TLR) costimulation. Following the activation, further maturation steps including germinal center reaction (i.e., clonal expansion, class switch recombination, somatic hypermutation, affinity maturation) occur.^[2][1]
  • B-cells can be divided into 3 main types include: B1 B-lymphoctes (originates from fetal liver), marginal zone (MZ) B2 B-lymphocyes, and follicular (FO) B2 B-lymphocytes.^[3]
  • B-cells complete their maturation by differention into memory B cells or antibody-secreting plasma cells.
• Functions of B-cells include:^[1]
  • Antibody production
  • Production of cytokines (i.e. IFN-γ, IL-6, IL-10)
  • Lymphoid tissue organogenesis
  • Wound healing
  • Tumor immunity
  • Transplant rejection
  • Dentritic cell regulation
  • TH1/TH2 cytokine balance
  • Antigen presentation
  • Co-stimulation

It is understood that there are different factors that have important roles in the pathogenesis of B-cell lymphomas including:^[4]

• Reciprocal translocations that occur between one of the immunoglobulin loci and proto-oncogene
• The selection for expression of a B-cell receptor (BCR) that promotes survival
• Increased survival and proliferation of B-cells mediated by antigen binding
• Malignant interaction between B-cells and other cells in the tumor microenvironment

Chromosomal translocations involving the immunoglobulin heavy locus (IGH@) is a classic cytogenetic abnormality for many B-cell lymphomas, including follicular lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, MALT lymphoma, lymphoplasmacytoid lymphoma, multiple myeloma, and Burkitt’s lymphoma. In these cases, the immunoglobulin heavy locus forms a fusion protein with another protein that has pro-proliferative or anti-apoptotic abilities. The enhancer element of the immunoglobulin heavy locus, which normally functions to make B cells produce massive production of antibodies, now induces massive transcription of the fusion protein, resulting in excessive pro-proliferative or anti-apoptotic effects on the B cells containing the fusion protein. Chromosomal translocations and mutations of tumor suppressor genes that are associated with B-cell lymphomas include:^[4]

• Burkitt’s lymphoma is characterized by the chromosomal translocations between MYC and either IGH@ or IGL@. Mutations of tumor suppressor genes causing Burkitt lymphoma include TP53 and retinoblastoma-like protein 2.
• Mantle-cell lymphoma is characterized by the chromosomal translocation between cyclin D1 and IGH@. Mutations of tumor suppressor gene ATM, is also associated with mantle-cell lymphoma.
• Follicular lymphoma is characterized by the chromosomal translocation between Bcl-2 and IGH@.
• Diffuse large B cell lymphoma is characterized by the chromosomal translocations of Bcl-2–IGH@, MYC–IGH@, MYC–IGL@, or the chromosomal translocations involving BCL6. Mutations of tumor suppressor genes causing diffuse large B cell lymphoma include CD95, ATM, and TP53.
• The mutation of tumor suppressor gene SOCS1 is associated with primary mediastinal B-cell lymphoma.
• Classical Hodgkin’s lymphoma is associated with mutations of tumor suppressor genes including IκBα, IκBe, and CD95.
• Lymphocyte-predominant Hodgkin’s lymphoma is characterized by the chromosomal translocations involving BCL6.
• MALT lymphoma is characterized by the chromosomal translocations of API2–MALT1, BCL10–IGH@, MALT1–IGH@, or FOXP1–IGH@. The mutation of tumor suppressor gene CD95 is associated with MALT lymphoma.
• Lymphoplasmacytoid lymphoma is characterized by the chromosomal translocation between PAX5 and IGH@.
• Multiple myeloma is characterized by the chromosomal translocations of cyclin D1–IGH@, FGFR3–IGH@, or MAF–IGH@. The mutation of tumor suppressor gene CD95 is associated with multiple myeloma.

Conditions associated with B-cell lymphoma include:^[4]

• Viral infections:
  • Epstein Barr virus (EBV)
  • HHV8
  • Hepatitis C virus
• Bacterial infections:
  • Helicobacter pylori
• Autoimmune diseases:
  • Sjögren’s syndrome
  • Rheumatoid arthritis

There is no gross pathologic finding characteristic of B-cell lymphoma.

Below is a microscopic image of a lymph node fine needle aspiration (FNA) specimen (Field’s stain) of a patient with Hodgkin’s lymphoma, a type of B cell lymphoma. The micrograph shows a mixture of cells commonly seen in Hodgkin’s lymphoma:

• Eosinophils
• Reed-Sternberg cells (hallmark tumor cells of Hodgkin’s lymphoma)
• Plasma cells
• Histiocytes

Shown below is a video of diffuse large B cell lymphoma {{#ev:youtube|9gEo7si6jtc}}

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