Hairy cell leukemia pathophysiology

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

Overview

Hairy cell leukemia arises from B cells, that are normally involved in the process of human immunoglobulins production. However, the exact B cell maturation stage involved in the development of hairy cell leukemia is still unclear. The most common gene involved in the pathogenesis of hairy cell leukemia is BRAF V600E mutation. On microscopic histopathological analysis, characteristic findings of hairy cell leukemia include small cells with "fried egg"-like appearance, well-demarcated thread-like cytoplasmic extensions, and a clear cytoplasm.

Pathogenesis

• Hairy cell leukemia arises from B cells, that are normally involved in the process of human immunoglobulins production.
• However, the exact B cell maturation stage involved in the development of hairy cell leukemia is still unclear.
• Bone marrow failure may develop among hairy cell leukemia patients due to:

• Malignant cells infiltration of the bone marrow, resulting in bone marrow failure or pancytopenia.
• Reticulin fibrosis of the bone marrow
• Dysregulated cytokine production

• The development of bone marrow failure interferes with the normal production of red blood cells and platelets among hairy cell leukemia patients.
• Leukemic cells may also infiltrate both the spleen and liver and leads to organomegaly.
• Extravascular hemolysis may develop due to splenic sequestration of the circulating red blood cells.
• In very rare occasions leukemic cells may infiltrate the peripheral lymph nodes.
• Production of cytokines, such as TNF alpha and IL-2R, provide important stimuli for malignant B cells proliferation in hairy cell leukemia.
• Leukemic cells demonstrate prolonged survival due to the up-regulation of apoptosis-inhibitors such as IAP1 and IAP2 by TNF alpha.
• In approximately 40% of hairy cell leukemia cases, malignant cells co-express multiple clonally related IgG, IgA, and IgM isotypes.

Genetics

• The most common gene involved in the pathogenesis of hairy cell leukemia is BRAF V600E mutation.
• The BRAF V600E mutations is present among most of the patients with hairy cell leukemia (classic).
• The BRAF V600E mutations is absent among patients with hairy cell leukemia (variant).
• Molecular pathways involved in the pathogensis of hairy cell leukemia include:

• The p38-MAPK-JNK cascade is inhibited which will suppress the apoptotic signaling pathways.
• The MEK-ERK cascade is activated which will amplify the cytoprotective survival pathways.
• The Phosphatidylinositol 3 kinase (PI3K)-AKT cascade is activated thus suppressing the apoptotic signaling pathways.

Associated Conditions

• Hairy cell leukemia has been found to be associated with trisomy 5 in a number of reported cases.

Microscopic Pathology

• On microscopic histopathological analysis, characteristic findings of hairy cell leukemia include:

• Small cells with "fried egg"-like appearance
• Well-demarcated thread-like cytoplasmic extensions
• Clear cytoplasm
• Central round nucleus
• Peri-nuclear clearing ("water-clear rim" appearance)

• A positive tartrate-resistant acid phosphatase (TRAP) stain is a key diagnostic feature for hairy cell leukemia.
• On immunohistochemistry, characteristic findings of hairy cell leukemia include:

• Annexin A1 +ve
• CD20 +ve
• CD25 +ve
• CD103 +ve

• On flow cytometry, characteristic findings of hairy cell leukemia include:

• CD19 +ve
• CD11c +ve
• FMC7 +ve

• Illustrated below is a series of microscopic images observed in hairy cell leukemia:

• 

  Hairy cell leukemia illustrated on a blood film

• 

  Hairy cell leukemia illustrated on high magnification

• 

  Hairy cell leukemia illustrated on very high magnification

References

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