Hairy cell leukaemia

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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
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Primary Author(s)*

  • 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

Definition / Description of Disease

  • 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

Synonyms / Terminology

  • Leukemic reticuloendotheliosis

Epidemiology / Prevalence

  • 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


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[1][2]

Clinical Features

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)


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Signs & Symptoms

  • Asymptomatic (incidental finding on complete blood counts)
  • B-symptoms (weight loss, fever, night sweats)
  • Fatigue
  • LUQ pain (splenomegaly)
  • Lymphadenopathy (uncommon)

Laboratory findings

  • Cytopenias
  • Monocytopenia
  • Lymphocytosis (low level)
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[1][3]

Sites of Involvement

  • Spleen (red pulp)
  • Bone marrow
  • Liver
  • Blood (small number)
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[1][3]

Morphologic Features

  • 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


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[1][3]

Immunophenotype

Finding Marker
Positive (B-cell lineage markersl) 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


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Finding Marker
Positive (B-cell lineage markers) 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


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[1][3]

Chromosomal Rearrangements (Gene Fusions)

  • No consistent gene fusions
  • Single case report of IGH-BRAF fusion positive, BRAF p.Val600Glu mutation negative HCL[4]
  • Single case report of IGH-CCND1 fusion positive, BRAF p.Val600Glu mutation positive HCL[5]
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[4]
  • Single case report of IGH-CCND1 fusion positive, BRAF p.Val600Glu mutation positive HCL[5]


editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).
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  • 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)[6]
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[7]
IGHV4-34 utilization Prognostic Less favorable prognosis[7]

*Not all BRAF mutations confer sensitivity to BRAF inhibitors, even if they are activating mutations[8].

Individual Region Genomic Gain / Loss / LOH

chromosome[9][10] 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[11]
chromosome[9][10] 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%

Characteristic Chromosomal Patterns

IGHV4-34 (Immunoglobulin heavy chain variable segment) utilization is seen only in 10%[7] of HCL but has predictive and prognostic implications[12].

editv4:Characteristic Chromosomal Aberrations / Patterns
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  • IGHV4-34 (Immunoglobulin heavy chain variable segment) utilization is seen only in 10%[7] of HCL but has predictive and prognostic implications[12].

Gene Mutations (SNV / INDEL)

Gene‡ Oncogene/Tumor Suppressor/Other Presumed Mechanism

(LOF/GOF/Other)

Prevalence[1]
BRAF Oncogene GOF 70-100%*
MAP2K1 Oncogene GOF 0-22%*
TP53 Tumor Suppressor LOF 2-28%
KLF2 Oncogene/Tumor Suppressor context dependent[13] 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[14]
  • HCLs that utilize the IGVH4-34 segment lack BRAF p.Val600Glu mutations[15] and instead harbor MAP2K1 mutations in most cases[16]


editv4:Gene Mutations (SNV/INDEL)
The content below was from the old template. Please incorporate above.
Gene‡ Oncogene/Tumor Suppressor/Other Presumed Mechanism

(LOF/GOF/Other)

Prevalence[1]
BRAF Oncogene GOF 70-100%*
MAP2K1 Oncogene GOF 0-22%*
TP53 Tumor Suppressor LOF 2-28%
KLF2 Oncogene/Tumor Suppressor context dependent[13] 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[14]
  • HCLs that utilize the IGVH4-34 segment lack BRAF p.Val600Glu mutations[15] and instead harbor MAP2K1 mutations in most cases[16]

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[4])

MAPK signaling Increased cell growth and proliferation
CDKN1B inactivating mutations

(IGH-CCND1 fusion, 1 report[5])

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[4])

MAPK signaling Increased cell growth and proliferation
CDKN1B inactivating mutations

(IGH-CCND1 fusion, 1 report[5])

Cell cycle regulation Unregulated cell division
KMT2C & ARID1A inactivating mutaitons Histone modification, chromatin remodeling Abnormal gene expression program

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[17][18] 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[1]
  • 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[19]
  • Others to familial occupation[20]

Additional Information

  • N/A

Links

References

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  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Maitre, Elsa; et al. (2019). "Hairy cell leukemia: 2020 update on diagnosis, risk stratification, and treatment". American Journal of Hematology. 94 (12): 1413–1422. doi:10.1002/ajh.25653. ISSN 1096-8652. PMID 31591741.
  2. ↑ Lr, Teras; et al. (2016). "2016 US Lymphoid Malignancy Statistics by World Health Organization Subtypes". PMID 27618563.
  3. ↑ 3.0 3.1 3.2 3.3 Grever, Michael R.; et al. (2017). "Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia". Blood. 129 (5): 553–560. doi:10.1182/blood-2016-01-689422. ISSN 0006-4971. PMC 5290982. PMID 27903528.CS1 maint: PMC format (link)
  4. ↑ 4.0 4.1 4.2 4.3 Thompson, Ella R.; et al. (2020). "Detection of an IGH-BRAF fusion in a patient with BRAF Val600Glu negative hairy cell leukemia". Leukemia & Lymphoma: 1–3. doi:10.1080/10428194.2020.1753045. ISSN 1029-2403. PMID 32319330 Check |pmid= value (help).
  5. ↑ 5.0 5.1 5.2 5.3 Rahman, Zaid Abdel; et al. (2020). "Hairy cell leukemia with CCND1/IGH fusion gene and BRAF V600E mutation". Leukemia Research Reports. 13: 100197. doi:10.1016/j.lrr.2020.100197. ISSN 2213-0489. PMC 7096740 Check |pmc= value (help). PMID 32257795 Check |pmid= value (help).
  6. ↑ National Comprehensive Cancer Network (January 2020). "NCCN Clinical Practice Guidelines in Oncology: Hairy Cell Leukemia" (PDF).CS1 maint: display-authors (link)
  7. ↑ 7.0 7.1 7.2 7.3 Arons, Evgeny; et al. (2009). "VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy". Blood. 114 (21): 4687–4695. doi:10.1182/blood-2009-01-201731. ISSN 1528-0020. PMC 2780305. PMID 19745070.
  8. ↑ Bracht, Jillian Wilhelmina Paulina; et al. (2019). "BRAF Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale". Cancers. 11 (9). doi:10.3390/cancers11091381. ISSN 2072-6694. PMC 6770188. PMID 31533235.
  9. ↑ 9.0 9.1 Durham, Benjamin H.; et al. (2017). "Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations". Blood. 130 (14): 1644–1648. doi:10.1182/blood-2017-01-765107. ISSN 1528-0020. PMC 5630011. PMID 28801450.
  10. ↑ 10.0 10.1 A, Nordgren; et al. (2010). "Characterisation of Hairy Cell Leukaemia by Tiling Resolution Array-Based Comparative Genome Hybridisation: A Series of 13 Cases and Review of the Literature". PMID 19682064.
  11. ↑ Zhang, Rui; et al. (2020). "Difference of genomic copy numbers alterations between hairy cell leukemia-variant and classical hairy cell leukemia: a pilot retrospective study in Chinese". International Journal of Medical Sciences. 17 (3): 325–331. doi:10.7150/ijms.39307. ISSN 1449-1907. PMC 7053350 Check |pmc= value (help). PMID 32132867 Check |pmid= value (help).
  12. ↑ 12.0 12.1 Arons, Evgeny; et al. (2011). "Molecular variant of hairy cell leukemia with poor prognosis". Leukemia & Lymphoma. 52 Suppl 2: 99–102. doi:10.3109/10428194.2011.565841. ISSN 1029-2403. PMID 21599610.
  13. ↑ 13.0 13.1 Wang, Chunmei; et al. (2017). "Krüppel-like factor 2 suppresses human gastric tumorigenesis through inhibiting PTEN/AKT signaling". Oncotarget. 8 (59): 100358–100370. doi:10.18632/oncotarget.22229. ISSN 1949-2553. PMC 5725026. PMID 29245984.
  14. ↑ 14.0 14.1 Tschernitz, Sebastian; et al. (2014). "Alternative BRAF mutations in BRAF V600E-negative hairy cell leukaemias". British Journal of Haematology. 165 (4): 529–533. doi:10.1111/bjh.12735. ISSN 1365-2141. PMID 24433452.
  15. ↑ 15.0 15.1 Xi, Liqiang; et al. (2012). "Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation". Blood. 119 (14): 3330–3332. doi:10.1182/blood-2011-09-379339. ISSN 1528-0020. PMC 3321859. PMID 22210875.
  16. ↑ 16.0 16.1 Waterfall, Joshua J.; et al. (2014). "High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias". Nature Genetics. 46 (1): 8–10. doi:10.1038/ng.2828. ISSN 1546-1718. PMC 3905739. PMID 24241536.
  17. ↑ Ritterhouse, Lauren L.; et al. (2015). "BRAF V600E mutation-specific antibody: A review". Seminars in Diagnostic Pathology. 32 (5): 400–408. doi:10.1053/j.semdp.2015.02.010. ISSN 0740-2570. PMID 25744437.
  18. ↑ Loo, Eric; et al. (2018). "BRAF V600E Mutation Across Multiple Tumor Types: Correlation Between DNA-based Sequencing and Mutation-specific Immunohistochemistry". Applied immunohistochemistry & molecular morphology: AIMM. 26 (10): 709–713. doi:10.1097/PAI.0000000000000516. ISSN 1533-4058. PMID 29271794.
  19. ↑ Villemagne, Bruno; et al. (2005). "Two new cases of familial hairy cell leukemia associated with HLA haplotypes A2, B7, Bw4, Bw6". Leukemia & Lymphoma. 46 (2): 243–245. doi:10.1080/10428190400013589. ISSN 1042-8194. PMID 15621808.
  20. ↑ Casado, L. F.; et al. (1998). "Familial hairy cell leukemia: a HLA-linked disease or farmers-linked disease?". Haematologica. 83 (8): 751–752. ISSN 0390-6078. PMID 9793263.


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