Etiology

The etiology is unknown. Case-control studies have suggested possible association with the following:[9][5][11][12][15][16][17][18]

  • Exposure to organic solvents and agricultural chemicals

  • Exposure to radiation

  • Woodworking

  • Epstein-Barr virus

  • History of infectious mononucleosis.

Familial cases of HCL have been described, suggesting a genetic predisposition.[19][20][21]

Pathophysiology

HCL is an indolent mature B-cell neoplasm.[22]

Leukemic (hairy) cells typically infiltrate the bone marrow, peripheral blood, spleen, and other hematopoietic organs.[22]

Accumulation of hairy cells in the bone marrow, combined with dysregulated cytokine production and reticulin fibrosis, can lead to bone marrow failure and subsequent pancytopenia.[23][24]

Hairy cells infiltrating the spleen can lead to splenomegaly and subsequent sequestration, marginalization, and destruction of healthy blood cells, which contributes to pancytopenia.

Genetic factors

The BRAF V600E mutation is a somatic mutation present in almost all patients with classic HCL.[25]​​[26][27]​​ The BRAF V600E mutation is an early disease-defining genetic event in classic HCL, and is thought to play a key role in its pathogenesis via activation of the MEK-ERK signaling pathway.[25][26][28] Constitutive activity of this pathway is thought to lead to increased cell proliferation, survival, and ultimately malignancy.[25][26][29]

The BRAF V600E mutation is absent in HCL variant (HCL-V), a separate disease entity (also known as splenic B-cell lymphoma/leukemia with prominent nucleoli [SBLPN]) that is more aggressive than HCL.[1]

Other chromosomal and genetic abnormalities reported in HCL include trisomy 5, trisomy 12, chromosome 5q13 deletion, and p53 mutation.[30][31][32]

Classification

5th edition of the World Health Organization (WHO) classification of hematolymphoid tumors: lymphoid neoplasms[1]

The WHO classifies HCL under the term "mature B-cell neoplasms", within the sub-classification "splenic B-cell lymphomas and leukemias".

The term "splenic B-cell lymphoma/leukemia with prominent nucleoli (SBLPN)" replaces the previous term "HCL variant (HCL-V)".

International Consensus Classification (ICC) of mature lymphoid and histiocytic/dendritic cell neoplasms[2]​​

The ICC classifies HCL and HCL variant (HCL-V) as separate diseases under the term "mature B-cell neoplasms". However, HCL-V is listed within the sub-classification "splenic B-cell lymphoma/leukemia (unclassified)".

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