Primary Author(s)* 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] [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] [6]
KMT2C
Tumor Suppressor
LOF
25%[6]
KDM6A
Tumor Suppressor
LOF
13%[6] [8]
ARID1A
Tumor Suppressor
LOF
13%[6] [8]
CREBBP
Tumor Suppressor
LOF
13%[6] [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]
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 Other Information Links References
↑ 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 . ↑ 2.0 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 . ↑ 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 ) ↑ 4.0 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 ) ↑ 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 . ↑ 6.0 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 . ↑ 7.0 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 . ↑ 8.0 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 . ↑ 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 . ↑ 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 . ↑ 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 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 *Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.