Chronic lymphocytic leukemia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: CD19, CD20, CD21, CD23Haytham Allaham, M.D. [2]

Overview

Chronic lymphocytic leukemia arises from pre-follicular center B cells, that are normally involved in the process of human immunoglobulin production. Development of chronic lymphocytic leukemia is the result of multiple genetic mutations that promote both malignant leukemic proliferation and apoptotic resistance of mature B cells. Structural genetic mutations involved in the pathogenesis of chronic lymphocytic leukemia include chromosome 13q deletion, chromosome 17p deletion, and chromosome 11q deletion. On microscopic histopathological analysis, characteristic findings of chronic lymphocytic leukemia include small lymphoid cells, thin cytoplasmic border, lack of nucleolus, and the presence of smudge cells.

Pathogenesis

• Chronic lymphocytic leukemia is defined as clonal proliferation of incompetent B-cells.
• Chronic lymphocytic leukemia arises from pre-follicular center B cells that are normally involved in the process of human immunoglobulins production.
• Chronic lymphocytic leukemia cells are clonal B cells and their differentiation is halted between the pre-B cells and mature B cells.
• Pre-malignant B cell proliferative precedes chronic lymphocytic leukemia/small lymphocytic leukemia and is known as monoclonal B cell lymphocytosis (MBL).
• There are multiple factors leading to production of MBL, which invilves antigen stimulation, gene mutation, environment factors, immunologic and cytogenetic modifications.
• Repeated results from these factors leads to advancement of MBL to chronic lymphocytic leukemia.
• Most of the patients of chronic lymphocytic leukemia are asymptomatic, until the incomptent lymphocytes start to accumulate and infiltrate organ systems.
• Malignant lymphocytic cells infiltrate hematopoietic sites ,such as the bone marrow, where they interfere with the production of red blood cells and platelets.
• Chronic lymphocytic leukemia may also infiltrate the lymph nodes, spleen, and liver.
• Immune deficiency may occur in chronic lymphocytic leukemia as the majority of cases develop hypogammaglobulinemia.
• Warm autoimmune hemolytic anemia may develop due to the production of IgA and IgG autoantibodies among certain cases of chronic lymphocytic anemia.
• Autoimmune thrombocytopenia may develop due to the production of autoantibodies.
• Production of cytokines, angiogenic factors, and chemokines by the surrounding macrophages and T cells provide important stimuli for malignant B cells proliferation in chronic lymphocytic leukemia.
• Richter's transformation represents the conversion of chronic lymphocytic leukemia into a more aggressive and rapidly growing large B cell lymphoma.
• Richter's transformation may occur among 1-5% of chronic lymphocytic leukemia cases.

The pathogenesis of Chronic lymphocytic leukemia can be classified according to the following:

Immunology

• Chronic lymphocytic leukemia express B-cell surface antigens such as CD19, CD20, CD21, CD23

Genetics

• Development of chronic lymphocytic leukemia is the result of multiple genetic mutations that promote both malignant leukemic proliferation and apoptotic resistance of mature B cells.
• Structural genetic mutations involved in the pathogenesis of chronic lymphocytic leukemia include:

• Chromosome 11 long arm deletion
• Chromosome 13 long arm deletion (most common genetic mutation)
• Chromosome 17 short arm deletion
• Trisomy 12

• Somatic genetic mutations involved in the pathogenesis of chronic lymphocytic leukemia include:

• SF3B1 gene located on chromosome 2
• FBXW7 gene located on chromosome 4
• MYD88 gene located on chromosome 3
• TP53 gene located on chromosome 7
• NOTCH1 gene located on chromosome 9
• ATM gene located on chromosome 11
• CHD2 gene located on chromosome 15

• The type of the genetic mutation is considered one of the important factors that determine the optimal management protocol of chronic lymphocytic leukemia patients.

Microscopic Pathology

• On microscopic histopathological analysis, characteristic findings of chronic lymphocytic leukemia include:

• Small lymphoid cells
• Thin cytoplasmic border
• Dense nucleus
• Lack of nucleolus
• Clumped chromatin aggregates
• The presence of smudge cells
• The presence of gumprecht nuclear shadows

• On immunohistochemistry, characteristic findings of chronic lymphocytic leukemia include:

• CD5 +ve
• CD19 +ve
• CD20 +ve
• CD23 +ve/-ve
• CD38 +ve/-ve
• CD43 +ve
• Cyclin D1 -ve

• Illustrated below is a series of microscopic images observed in chronic lymphocytic leukemia:

• 
  Chronic lymphocytic leukemia illustrated on low magnification
• 
  Chronic lymphocytic leukemia illustrated on intermediate magnification
• 
  Chronic lymphocytic leukemia illustrated on high magnification
• 
  Chronic lymphocytic leukemia illustrated on very high magnification

References

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