HAEM5:Hairy cell leukaemia

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Hairy Cell Leukemia.

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

Snehal Patel, MD, PhD, Michael Lack, DO, Shivani Golem, PhD FACMG

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	B-cell lymphoid proliferations and lymphomas
Family	Mature B-cell neoplasms
Type	Splenic B-cell lymphomas and leukaemias
Subtype(s)	Hairy cell leukaemia

Related Terminology

Acceptable	N/A
Not Recommended	N/A

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: ABL1	EXAMPLE: BCR::ABL1	EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.	EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: Common (CML)	EXAMPLE: D, P, T	EXAMPLE: Yes (WHO, NCCN)	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
EXAMPLE: CIC	EXAMPLE: CIC::DUX4	EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5.	EXAMPLE: t(4;19)(q25;q13)	EXAMPLE: Common (CIC-rearranged sarcoma)	EXAMPLE: D		EXAMPLE: DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
EXAMPLE: ALK	EXAMPLE: ELM4::ALK Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1	EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18.	EXAMPLE: N/A	EXAMPLE: Rare (Lung adenocarcinoma)	EXAMPLE: T		EXAMPLE: Both balanced and unbalanced forms are observed by FISH (add references).
EXAMPLE: ABL1	EXAMPLE: N/A	EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.	EXAMPLE: N/A	EXAMPLE: Recurrent (IDH-wildtype Glioblastoma)	EXAMPLE: D, P, T

• No consistent gene fusions
• Single case report of IGH-BRAF fusion positive, BRAF p.Val600Glu mutation negative HCL
• Single case report of IGH-CCND1 fusion positive, BRAF p.Val600Glu mutation positive HCL

editv4:Chromosomal Rearrangements (Gene Fusions)

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• No consistent gene fusions
• Single case report of IGH-BRAF fusion positive, BRAF p.Val600Glu mutation negative HCL
• Single case report of IGH-CCND1 fusion positive, BRAF p.Val600Glu mutation positive HCL

End of V4 Section

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editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

Please incorporate this section into the relevant tables found in:

• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

Alteration	Clinical Significance	Note
BRAF p.Val600Glu	Predictive*	vemurafenib for 2nd line; vemurafenib ± rituximab for 3rd line (NCCN, v 1.2020, pg. HCL-A)
BRAF p.Val600Glu	Diagnostic	May be useful when immunophenotype is equivocal; Excludes HCLv
MAP2K1	Predictive	Certain mutations may confer sensitivity to ERK inhibitors
IGHV4-34 utilization	Predictive	Reduced response to purine analogs
IGHV4-34 utilization	Prognostic	Less favorable prognosis

*Not all BRAF mutations confer sensitivity to BRAF inhibitors, even if they are activating mutations.

End of V4 Section

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Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7	EXAMPLE: Unknown	EXAMPLE: D, P	EXAMPLE: No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8	EXAMPLE: Unknown	EXAMPLE: D, P		EXAMPLE: Common recurrent secondary finding for t(8;21) (add references).
EXAMPLE: 17	EXAMPLE: Amp	EXAMPLE: 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]	EXAMPLE: ERBB2	EXAMPLE: D, P, T		EXAMPLE: Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

chromosome	Alteration	Consequence	Prevalence
14q22-32	Heterozygous deletion	Uncertain	33%
7q	Heterozygous deletion	LOH of BRAF p.Val600Glu	9-21%
13q	Deletion	Loss of RB1, miR-15a, and miR-16-1	6%
5	Gain	Uncertain	9-15%

editv4:Genomic Gain/Loss/LOH

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• Recurrent gains and losses were found to be absent in HCLs from Chinese patients

chromosome	Alteration	Consequence	Prevalence
14q22-32	Heterozygous deletion	Uncertain	33%
7q	Heterozygous deletion	LOH of BRAF p.Val600Glu	9-21%
13q	Deletion	Loss of RB1, miR-15a, and miR-16-1	6%
5	Gain	Uncertain	9-15%

End of V4 Section

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Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

IGHV4-34 (Immunoglobulin heavy chain variable segment) utilization is seen only in 10% of HCL but has predictive and prognostic implications.

editv4:Characteristic Chromosomal Aberrations / Patterns

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• IGHV4-34 (Immunoglobulin heavy chain variable segment) utilization is seen only in 10% of HCL but has predictive and prognostic implications.

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Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Gene	Genetic Alteration	Tumor Suppressor Gene, Oncogene, Other	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE:EGFR	EXAMPLE: Exon 18-21 activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (lung cancer)	EXAMPLE: T	EXAMPLE: Yes (NCCN)	EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations	EXAMPLE: Variable LOF mutations	EXAMPLE: Tumor Supressor Gene	EXAMPLE: Common (breast cancer)	EXAMPLE: P		EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations	EXAMPLE: Activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (melanoma)	EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Gene‡	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other)	Prevalence
BRAF	Oncogene	GOF	70-100%*
MAP2K1	Oncogene	GOF	0-22%*
TP53	Tumor Suppressor	LOF	2-28%
KLF2	Oncogene/Tumor Suppressor	context dependent	13-16%
CDKN1B	Tumor Suppressor	LOF	10-16%
ARID1A	Tumor Suppressor	LOF	4-5%
KMT2C	Tumor Suppressor	LOF	15%
CREBBP	Tumor Suppressor	LOF	5-6%

^‡Specific mutations in these genes can be found in cBioPortal and COSMIC.

*The WHO states that BRAF p.Val600Glu is detected in virtually all cases and notes that the classification of B-cell leukemias that are immunophenotypically and morphologically classified as HCL but lack BRAF activating mutations (but instead have MAP2K1 activating mutations and use the IGHV4-34 gene segment) is uncertain. These seem to be more similar molecularly and clinically to HCLv.

• BRAF and MAP2K1 activating mutations are mutually exclusive
• BRAF p.Val600Glu and MAP2K1 account for the primary oncogene drivers in the majority of HCL (~95%)
• BRAF p.Val600Glu (p.V600E) accounts for the majority of BRAF mutations, but other have been reported
• HCLs that utilize the IGVH4-34 segment lack BRAF p.Val600Glu mutations and instead harbor MAP2K1 mutations in most cases

editv4:Gene Mutations (SNV/INDEL)

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Gene‡	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other)	Prevalence
BRAF	Oncogene	GOF	70-100%*
MAP2K1	Oncogene	GOF	0-22%*
TP53	Tumor Suppressor	LOF	2-28%
KLF2	Oncogene/Tumor Suppressor	context dependent	13-16%
CDKN1B	Tumor Suppressor	LOF	10-16%
ARID1A	Tumor Suppressor	LOF	4-5%
KMT2C	Tumor Suppressor	LOF	15%
CREBBP	Tumor Suppressor	LOF	5-6%

^‡Specific mutations in these genes can be found in cBioPortal and COSMIC.

*The WHO states that BRAF p.Val600Glu is detected in virtually all cases and notes that the classification of B-cell leukemias that are immunophenotypically and morphologically classified as HCL but lack BRAF activating mutations (but instead have MAP2K1 activating mutations and use the IGHV4-34 gene segment) is uncertain. These seem to be more similar molecularly and clinically to HCLv.

• BRAF and MAP2K1 activating mutations are mutually exclusive
• BRAF p.Val600Glu and MAP2K1 account for the primary oncogene drivers in the majority of HCL (~95%)
• BRAF p.Val600Glu (p.V600E) accounts for the majority of BRAF mutations, but other have been reported
• HCLs that utilize the IGVH4-34 segment lack BRAF p.Val600Glu mutations and instead harbor MAP2K1 mutations in most cases

End of V4 Section

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Epigenomic Alterations

• Altered epigenetic regulation is expected due to alterations in KMT2C and ARID1A in a subset of HCLs
  • KMT2C is a histone methyltransferase
  • ARID1A is a SWI/SNF family member

Genes and Main Pathways Involved

Molecular feature	Pathway	Pathophysiologic outcome
BRAF & MAP2K1 activating mutations (IGH-BRAF fusion, 1 report)	MAPK signaling	Increased cell growth and proliferation
CDKN1B inactivating mutations (IGH-CCND1 fusion, 1 report)	Cell cycle regulation	Unregulated cell division
KMT2C & ARID1A inactivating mutaitons	Histone modification, chromatin remodeling	Abnormal gene expression program

editv4:Genes and Main Pathways Involved

The content below was from the old template. Please incorporate above.

Molecular feature	Pathway	Pathophysiologic outcome
BRAF & MAP2K1 activating mutations (IGH-BRAF fusion, 1 report)	MAPK signaling	Increased cell growth and proliferation
CDKN1B inactivating mutations (IGH-CCND1 fusion, 1 report)	Cell cycle regulation	Unregulated cell division
KMT2C & ARID1A inactivating mutaitons	Histone modification, chromatin remodeling	Abnormal gene expression program

End of V4 Section

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Genetic Diagnostic Testing Methods

• Morphology and immunophenotyping (IHC or flow cytometry) are adequate for diagnosis in nearly all cases
• BRAF p.Val600Glu testing may be useful diagnostically in rare situations where clinicopathologic findings are equivocal
• BRAF p.Val600Glu may be detected by IHC using a mutant-specific antibody or various molecular methods (NGS, real-time PCR, massARRAY, etc.)
• The mutant-specific antibody does not detect other BRAF mutations
• BRAF p.Val600Glu and Non-p.Val600Glu mutations and MAP2K1 mutations can be interrogated with NGS in a single assay
• IGHV4-34 utilization can be detected by NGS

Familial Forms

• Familial association has been reported in several case reports
• Some linked to various HLA type
• Others to familial occupation

Additional Information

This disease is defined/characterized as detailed below:

• Hairy cell leukemia (HCL) is a rare indolent neoplasm of B-cell origin seen mostly in adults
• Name derives from the the hair-like projections of the cytoplasm that surround the cells
• Hairy cells most closely resemble mature lymphoid cells
• Marked splenomegaly and marrow infiltration result in left flank discomfort, fatigue, and susceptibility to infections
• Most respond well to monotherapy with a purine analog or interferon alpha

The epidemiology/prevalence of this disease is detailed below:

• Incidence (age adjusted) ~ 0.3/100,000
• 2% of lymphoid leukemias
• Median age: 58 years, rarely in patients in their 20s
• Males:Females: 4:1
• Whites >> Blacks
• 78% to 92% 5yr survival

The clinical features of this disease are detailed below:

• Signs and symptoms - Asymptomatic (incidental finding on complete blood counts); B-symptoms (weight loss, fever, night sweats); Fatigue; Splenic enlargement and discomfort; Recurrent infections; Lymphadenopathy (rare)
• Laboratory findings - Pancytopenia (monocytopenia is characteristic); Lymphocytosis (low level)

The sites of involvement of this disease are detailed below:

• Spleen (red pulp); Bone marrow; Liver; Blood (small number)

The morphologic features of this disease are detailed below:

• Small lymphoid cells; Abundant pale blue-grey lacey cytoplasm; Ovoid nuclei ± indentation or folding; Inconspicuous nucleoli; Circumferential hairy projections (smear preparations); "Fried egg" appearance of cells (tissue sections); Marrow (reticulin) fibrosis

The immunophenotype of this disease is detailed below:

Positive ((B-cell lineage markers) -

Positive - CD19, CD20 (bright), CD22, PAX5, FMC7, sIg (bright, monoclonal)

Positive - CD200 (bright), CD11c, CD103, CD123, CD25, CD72, annexin‐A1, BRAF V600E, phospho-ERK

Negative - CD5, CD10 (10-20% may be positive), CD23, CD27

Links

• HAEM5:Splenic B-cell lymphoma/leukaemia with prominent nucleoli
• HAEM5:Splenic diffuse red pulp small B-cell lymphoma

References

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Notes

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Prior Author(s):

*Citation of this Page: “Hairy cell leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 07/3/2025, https://ccga.io/index.php/HAEM5:Hairy_cell_leukaemia.