HAEM4:Hairy Cell Leukemia Variant

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Primary Author(s)*

  • Snehal Patel, MD, PhD

Cancer Category/Type

Cancer Sub-Classification / Subtype

  • Hairy Cell Leukemia Variant (HCLv)

Definition / Description of Disease

  • HCLv is a rare chronic neoplasm of B-cell origin seen mostly in adults
  • Name derives from clinicopathologic similarity to hairy cell leukemia (HCL) but with important differences
  • Marked splenomegaly and marrow infiltration result in left flank discomfort, fatigue, and susceptibility to infections
  • Most respond poorly to monotherapy with a purine analog or interferon alpha (used for HCL)
  • Lack BRAF p.Val600Glu (V600E) mutations but some have mutations in MAP2K1

Synonyms / Terminology

  • Prolymphocytic variant of hairy cell leukemia

Epidemiology / Prevalence

  • ~0.2% of lymphoid leukemias
  • Median age: 70 years
  • Males:Females: 2:1

Clinical Features[1][2]

Signs & Symptoms

  • Often asymptomatic
  • Splenic enlargement and/or discomfort
  • B-symptoms (weight loss, fever, night sweats)
  • Fatigue
  • Bruising
  • Lymphadenopathy (uncommon)

Laboratory findings

  • Cytopenias
  • Lymphocytosis
  • No monocytopenia

Sites of Involvement[1][2]

  • Spleen (red pulp)
  • Bone marrow
  • Blood
  • Liver
  • Lymph node (uncommon)

Morphologic Features[1][2]

  • Intermediate-sized lymphoid cells
  • Abundant pale blue-grey lacey cytoplasm
  • prolymphocytoid or blastoid nuclear features
  • Cytoplasmic projections either villous or hair-like
  • "Fried egg" appearance of cells (tissue sections)
  • Interstitial pattern of marrow involvement
  • No/minimal reticulin fibrosis

Immunophenotype[1][2]

Finding Marker
Positive (B-cell lineage markers) CD19, CD20 (bright), CD22, CD79b, PAX5, FMC7, sIg (bright, monotypic)
Positive CD11c, CD72, CD103
Negative (HCL markers) CD25, CD123, annexin A1, TRAP, BRAF V600E
Negative CD5, CD10, CD23, CD38, CD43, BCL1

Chromosomal Rearrangements (Gene Fusions)

  • No consistent gene fusions

Characteristic Chromosomal Aberrations / Patterns

  • Preferential utilization of IGHV4-34 (Immunoglobulin heavy chain variable segment) in 40%[3] and has clinical implications[4]

Genomic Gain/Loss/LOH

Chromosome Number Gain/Loss/Amp/LOH Consequence Prevalence
17p13 Loss TP53 deletion 42%[1]
11q22 Loss ATM deletion 22%[1]

Gene Mutations (SNV/INDEL)

Gene* Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other) Prevalence
MAP2K1 Oncogene GOF 7-50%[1][5][6][7][8]
TP53 Tumor Suppressor LOF 29%[7] - 38%[6]
KMT2C Tumor Suppressor LOF 25%[6]
KDM6A Tumor Suppressor LOF 13%[6] - 50%[8]
ARID1A Tumor Suppressor LOF 13%[6] - 25%[8]
CREBBP Tumor Suppressor LOF 13%[6] - 25%[8]
CCND3 Oncogene change of function 13%[6]
U2AF Oncogene change of function 13%[6]

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

  • There is wide variation in the reported prevalence of MAP2K1 mutations across studies for unclear reasons

Epigenomics (Methylation)

  • Epigenetic dysregulation is expected in a subset of HCLv due to mutations in epigenetic regulators:
    • KMT2C is a histone methyltransferase
    • KDM6A is a histone demethylase
    • CREBBP is a histone acetyltransferase
    • ARID1A is a SWI/SNF family member

Genes and Main Pathways Involved

Molecular feature Pathway Physiologic outcome
MAP2K1 activating mutations MAPK signaling Unregulated cell growth and proliferation
KMT2C, KDM6A, CREBBP, and ARID1A LOF mutations Histone modification, chromatin remodeling Abnormal gene expression program
TP53 LOF mutations DNA damage, apoptosis Cell survival and genomic instability

Diagnostic Testing Methods

  • HCLv is a provisional entity and definitive diagnostic criteria have not been determined
  • BRAF p.Val600Glu testing may be useful diagnostically in limited situations to exclude HCL
  • BRAF p.Val600Glu may be detected by IHC using a mutant-specific antibody[9][10] 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[2]
  • IGHV4-34 utilization can be detected by NGS and Sanger sequencing of IgH mRNA

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Alteration Clinical Significance Note
BRAF activating mutations Diagnostic Excludes HCL
MAP2K1 activating mutations Prediction May be targetable with MEK inhibitors[11]
IGHV4-34 Prediction Reduced response to purine analogs[4]
IGHV4-34 Prognostic Less favorable prognosis[4]
  • The 2017 WHO notes that whether cases that are classified as classical HCL but lack BRAF mutations and harbor MAP2K1 mutations are more like HCLv remains to be established

Familial Forms

  • Not described

Other Information

  • N/A

Links

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Angelova, Evgeniya A.; et al. (2018). "Clinicopathologic and molecular features in hairy cell leukemia-variant: single institutional experience". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 31 (11): 1717–1732. doi:10.1038/s41379-018-0093-8. ISSN 1530-0285. PMID 29955146.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 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 0361-8609.
  3. ↑ 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 0006-4971. PMC 3321859. PMID 22210875.CS1 maint: PMC format (link)
  4. ↑ 4.0 4.1 4.2 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 0006-4971. PMC 2780305. PMID 19745070.CS1 maint: PMC format (link)
  5. ↑ Mason, Emily F.; et al. (2017). "Detection of activating MAP2K1 mutations in atypical hairy cell leukemia and hairy cell leukemia variant". Leukemia & Lymphoma. 58 (1): 233–236. doi:10.1080/10428194.2016.1185786. ISSN 1029-2403. PMID 27241017.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 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.
  7. ↑ 7.0 7.1 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.
  8. ↑ 8.0 8.1 8.2 8.3 Maitre, Elsa; et al. (2018). "New generation sequencing of targeted genes in the classical and the variant form of hairy cell leukemia highlights mutations in epigenetic regulation genes". Oncotarget. 9 (48): 28866–28876. doi:10.18632/oncotarget.25601. ISSN 1949-2553. PMC 6034755. PMID 29989027.
  9. ↑ 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.
  10. ↑ Loo, Eric; et al. (2017). "BRAF V600E Mutation Across Multiple Tumor Types: Correlation Between DNA-based Sequencing and Mutation-specific Immunohistochemistry". Applied Immunohistochemistry & Molecular Morphology: 1. doi:10.1097/PAI.0000000000000516. ISSN 1541-2016.
  11. ↑ Andritsos, Leslie A.; et al. (2018). "Trametinib for the treatment of IGHV4-34, MAP2K1-mutant variant hairy cell leukemia". Leukemia & Lymphoma. 59 (4): 1008–1011. doi:10.1080/10428194.2017.1365853. ISSN 1042-8194.

EXAMPLE Book

  1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.

Notes

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