HAEM4:Hairy Cell Leukemia

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Primary Author(s)*

  • Snehal Patel, MD, PhD

Cancer Category/Type

Cancer Sub-Classification / Subtype

  • Hairy Cell Leukemia

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[1][2]

  • Incidence (age adjusted) ~ 0.3/100,000
  • 2% of lymphoid leukemias
  • Median age: ~60 years
  • Males:Females: 4:1 to 5:1
  • Whites >> Blacks
  • 78% to 92% 5yr survival

Clinical Features[1][3]

Signs & Symptoms

  • Asymptomatic (incidental finding on complete blood counts)
  • B-symptoms (weight loss, fever, night sweats)
  • Fatigue
  • Splenic enlargement and discomfort
  • Recurrent infections
  • Lymphadenopathy (uncommon)

Laboratory findings

  • Cytopenias
  • Monocytopenia
  • Lymphocytosis (low level)

Sites of Involvement[1][3]

  • Spleen (red pulp)
  • Bone marrow
  • liver
  • Blood

Morphologic Features[1][3]

  • 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

Immunophenotype[1][3]

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

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]

Characteristic Chromosomal Aberrations / Patterns

  • IGHV4-34 (Immunoglobulin heavy chain variable segment) utilization is seen only in 10%[6] of HCL but has predictive and prognostic implications[7].

Genomic Gain/Loss/LOH

  • Recurrent gains and losses were found to be absent in HCLs from Chinese patients[8]
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%

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[11] 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[12]
  • HCLs that utilize the IGVH4-34 segment lack BRAF p.Val600Glu mutations[13] and instead harbor MAP2K1 mutations in most cases[14]

Epigenomics (Methylation)

  • 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

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[15][16] 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

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Alteration Clinical Significance Note
BRAF p.Val600Glu Predictive* vemurafenib for 2nd line; vemurafenib ± rituximab for 3rd line (NCCN, v 1.2020, pg. HCL-A)[17]
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[6]
IGHV4-34 utilization Prognostic Less favorable prognosis[6]

*Not all BRAF mutations confer sensitivity to BRAF inhibitors, even if they are activating mutations[18].

Familial Forms

  • Familial association has been reported in several case reports
  • Some linked to various HLA type[19]
  • Others to familial occupation[20]

Other Information

  • N/A

Links

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 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 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 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. ↑ 6.0 6.1 6.2 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 1528-0020. PMC 2780305. PMID 19745070.
  7. ↑ 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.
  8. ↑ 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).
  9. ↑ 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. ↑ 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. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ National Comprehensive Cancer Network (January 2020). "NCCN Clinical Practice Guidelines in Oncology: Hairy Cell Leukemia" (PDF).CS1 maint: display-authors (link)
  18. ↑ 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.
  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.

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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