Bailey.Glen: Created page with "==Primary Author(s)== Snehal Patel, MD, PhD TOC ==Cancer Category/Type== *Mature B-Cell Neoplasm ==Cancer Sub-Classification / Subtype==..."

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Created page with "==Primary Author(s)*== *Snehal Patel, MD, PhD __TOC__ ==Cancer Category/Type== *Mature B-Cell Neoplasm ==Cancer Sub-Classification / Subtype==..."

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==Primary Author(s)*==

*Snehal Patel, MD, PhD
__TOC__

==Cancer Category/Type==

*[[Mature B-Cell Neoplasms|Mature B-Cell Neoplasm]]

==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<ref name=":1" /><ref>{{Cite journal|last=Lr|first=Teras|last2=Ce|first2=DeSantis|last3=Jr|first3=Cerhan|last4=Lm|first4=Morton|last5=A|first5=Jemal|last6=Cr|first6=Flowers|date=2016|title=2016 US Lymphoid Malignancy Statistics by World Health Organization Subtypes|url=https://pubmed.ncbi.nlm.nih.gov/27618563/|language=en|pmid=27618563}}</ref>==

*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<ref name=":1" /><ref name=":2">{{Cite journal|last=Grever|first=Michael R.|last2=Abdel-Wahab|first2=Omar|last3=Andritsos|first3=Leslie A.|last4=Banerji|first4=Versha|last5=Barrientos|first5=Jacqueline|last6=Blachly|first6=James S.|last7=Call|first7=Timothy G.|last8=Catovsky|first8=Daniel|last9=Dearden|first9=Claire|date=2017|title=Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia|url=https://ashpublications.org/blood/article/129/5/553/36153/Consensus-guidelines-for-the-diagnosis-and|journal=Blood|language=en|volume=129|issue=5|pages=553–560|doi=10.1182/blood-2016-01-689422|issn=0006-4971|pmc=PMC5290982|pmid=27903528}}</ref>==

'''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<ref name=":1" /><ref name=":2" />==

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

==Morphologic Features<ref name=":1" /><ref name=":2" />==

*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<ref name=":1" /><ref name=":2" />==

{| class="wikitable"
|-
!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<ref name=":3">{{Cite journal|last=Thompson|first=Ella R.|last2=Lim|first2=Kenneth J. C.|last3=Kuzich|first3=James A.|last4=McBean|first4=Michelle|last5=Westerman|first5=David|last6=Tam|first6=Constantine S.|last7=Blombery|first7=Piers|date=2020|title=Detection of an IGH-BRAF fusion in a patient with BRAF Val600Glu negative hairy cell leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/32319330|journal=Leukemia & Lymphoma|pages=1–3|doi=10.1080/10428194.2020.1753045|issn=1029-2403|pmid=32319330}}</ref>
*Single case report of IGH-CCND1 fusion positive, BRAF p.Val600Glu mutation positive HCL<ref name=":4">{{Cite journal|last=Rahman|first=Zaid Abdel|last2=Muwalla|first2=Firas|last3=Jiang|first3=Liuyan|last4=Foran|first4=James|date=2020|title=Hairy cell leukemia with CCND1/IGH fusion gene and BRAF V600E mutation|url=https://www.ncbi.nlm.nih.gov/pubmed/32257795|journal=Leukemia Research Reports|volume=13|pages=100197|doi=10.1016/j.lrr.2020.100197|issn=2213-0489|pmc=7096740|pmid=32257795}}</ref>

==Characteristic Chromosomal Aberrations / Patterns==

*IGHV4-34 (Immunoglobulin heavy chain variable segment) utilization is seen only in 10%<ref name=":0" /> of HCL but has predictive and prognostic implications<ref>{{Cite journal|last=Arons|first=Evgeny|last2=Kreitman|first2=Robert J.|date=2011|title=Molecular variant of hairy cell leukemia with poor prognosis|url=https://www.ncbi.nlm.nih.gov/pubmed/21599610|journal=Leukemia & Lymphoma|volume=52 Suppl 2|pages=99–102|doi=10.3109/10428194.2011.565841|issn=1029-2403|pmid=21599610}}</ref>.

==Genomic Gain/Loss/LOH==

*Recurrent gains and losses were found to be absent in HCLs from Chinese patients<ref>{{Cite journal|last=Zhang|first=Rui|last2=Wu|first2=Yongli|last3=Wang|first3=Xianfu|last4=Lu|first4=Xianglan|last5=Li|first5=Yan|last6=Li|first6=Shibo|last7=Yan|first7=Xiaojing|date=2020|title=Difference of genomic copy numbers alterations between hairy cell leukemia-variant and classical hairy cell leukemia: a pilot retrospective study in Chinese|url=https://www.ncbi.nlm.nih.gov/pubmed/32132867|journal=International Journal of Medical Sciences|volume=17|issue=3|pages=325–331|doi=10.7150/ijms.39307|issn=1449-1907|pmc=7053350|pmid=32132867}}</ref>

{| class="wikitable"
!chromosome<ref>{{Cite journal|last=Durham|first=Benjamin H.|last2=Getta|first2=Bartlomiej|last3=Dietrich|first3=Sascha|last4=Taylor|first4=Justin|last5=Won|first5=Helen|last6=Bogenberger|first6=James M.|last7=Scott|first7=Sasinya|last8=Kim|first8=Eunhee|last9=Chung|first9=Young Rock|date=2017|title=Genomic analysis of hairy cell leukemia identifies novel recurrent genetic alterations|url=https://www.ncbi.nlm.nih.gov/pubmed/28801450|journal=Blood|volume=130|issue=14|pages=1644–1648|doi=10.1182/blood-2017-01-765107|issn=1528-0020|pmc=5630011|pmid=28801450}}</ref><ref>{{Cite journal|last=A|first=Nordgren|last2=M|first2=Corcoran|last3=A|first3=Sääf|last4=A|first4=Bremer|last5=Hc|first5=Kluin-Nelemans|last6=J|first6=Schoumans|last7=D|first7=Grandér|date=2010|title=Characterisation of Hairy Cell Leukaemia by Tiling Resolution Array-Based Comparative Genome Hybridisation: A Series of 13 Cases and Review of the Literature|url=https://pubmed.ncbi.nlm.nih.gov/19682064/|language=en|pmid=19682064}}</ref>
!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)==
{| class="wikitable"
|-
!Gene<sup>‡</sup>!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism
(LOF/GOF/Other)
!Prevalence<ref name=":1">{{Cite journal|last=Maitre|first=Elsa|last2=Cornet|first2=Edouard|last3=Troussard|first3=Xavier|date=2019|title=Hairy cell leukemia: 2020 update on diagnosis, risk stratification, and treatment|url=https://www.ncbi.nlm.nih.gov/pubmed/31591741|journal=American Journal of Hematology|volume=94|issue=12|pages=1413–1422|doi=10.1002/ajh.25653|issn=1096-8652|pmid=31591741}}</ref>
|-
|[[BRAF]]||Oncogene||GOF||70-100%*
|-
|[[MAP2K1]]
|Oncogene
|GOF
|0-22%*
|-
|[[TP53]]
|Tumor Suppressor
|LOF
|2-28%
|-
|KLF2
|Oncogene/Tumor Suppressor
|context dependent<ref>{{Cite journal|last=Wang|first=Chunmei|last2=Li|first2=Liang|last3=Duan|first3=Qiuhui|last4=Wang|first4=Qingqing|last5=Chen|first5=Jinlian|date=2017|title=Krüppel-like factor 2 suppresses human gastric tumorigenesis through inhibiting PTEN/AKT signaling|url=https://www.ncbi.nlm.nih.gov/pubmed/29245984|journal=Oncotarget|volume=8|issue=59|pages=100358–100370|doi=10.18632/oncotarget.22229|issn=1949-2553|pmc=5725026|pmid=29245984}}</ref>
|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%
|}
<sup>‡</sup>Specific mutations in these genes can be found in [https://www.cbioportal.org/ cBioPortal] and [https://cancer.sanger.ac.uk/cosmic 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 [[Hairy Cell Leukemia Variant|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<ref>{{Cite journal|last=Tschernitz|first=Sebastian|last2=Flossbach|first2=Lucia|last3=Bonengel|first3=Margrit|last4=Roth|first4=Sabine|last5=Rosenwald|first5=Andreas|last6=Geissinger|first6=Eva|date=2014|title=Alternative BRAF mutations in BRAF V600E-negative hairy cell leukaemias|url=https://www.ncbi.nlm.nih.gov/pubmed/24433452|journal=British Journal of Haematology|volume=165|issue=4|pages=529–533|doi=10.1111/bjh.12735|issn=1365-2141|pmid=24433452}}</ref>
*HCLs that utilize the IGVH4-34 segment lack BRAF p.Val600Glu mutations<ref>{{Cite journal|last=Xi|first=Liqiang|last2=Arons|first2=Evgeny|last3=Navarro|first3=Winnifred|last4=Calvo|first4=Katherine R.|last5=Stetler-Stevenson|first5=Maryalice|last6=Raffeld|first6=Mark|last7=Kreitman|first7=Robert J.|date=2012|title=Both variant and IGHV4-34-expressing hairy cell leukemia lack the BRAF V600E mutation|url=https://www.ncbi.nlm.nih.gov/pubmed/22210875|journal=Blood|volume=119|issue=14|pages=3330–3332|doi=10.1182/blood-2011-09-379339|issn=1528-0020|pmc=3321859|pmid=22210875}}</ref> and instead harbor MAP2K1 mutations in most cases<ref>{{Cite journal|last=Waterfall|first=Joshua J.|last2=Arons|first2=Evgeny|last3=Walker|first3=Robert L.|last4=Pineda|first4=Marbin|last5=Roth|first5=Laura|last6=Killian|first6=J. Keith|last7=Abaan|first7=Ogan D.|last8=Davis|first8=Sean R.|last9=Kreitman|first9=Robert J.|date=2014|title=High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias|url=https://www.ncbi.nlm.nih.gov/pubmed/24241536|journal=Nature Genetics|volume=46|issue=1|pages=8–10|doi=10.1038/ng.2828|issn=1546-1718|pmc=3905739|pmid=24241536}}</ref>

==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==
{| class="wikitable"
!Molecular feature
!Pathway
!Pathophysiologic outcome
|-
|BRAF & MAP2K1 activating mutations
(IGH-BRAF fusion, 1 report<ref name=":3" />)
|MAPK signaling
|Increased cell growth and proliferation
|-
|CDKN1B inactivating mutations
(IGH-CCND1 fusion, 1 report<ref name=":4" />)
|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<ref>{{Cite journal|last=Ritterhouse|first=Lauren L.|last2=Barletta|first2=Justine A.|date=2015|title=BRAF V600E mutation-specific antibody: A review|url=https://www.ncbi.nlm.nih.gov/pubmed/25744437|journal=Seminars in Diagnostic Pathology|volume=32|issue=5|pages=400–408|doi=10.1053/j.semdp.2015.02.010|issn=0740-2570|pmid=25744437}}</ref><ref>{{Cite journal|last=Loo|first=Eric|last2=Khalili|first2=Parisa|last3=Beuhler|first3=Karen|last4=Siddiqi|first4=Imran|last5=Vasef|first5=Mohammad A.|date=2018|title=BRAF V600E Mutation Across Multiple Tumor Types: Correlation Between DNA-based Sequencing and Mutation-specific Immunohistochemistry|url=https://www.ncbi.nlm.nih.gov/pubmed/29271794|journal=Applied immunohistochemistry & molecular morphology: AIMM|volume=26|issue=10|pages=709–713|doi=10.1097/PAI.0000000000000516|issn=1533-4058|pmid=29271794}}</ref> 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<ref name=":1" />
*IGHV4-34 utilization can be detected by NGS

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
{| class="wikitable"
!Alteration
!Clinical Significance
!Note
|-
|BRAF p.Val600Glu
|Predictive*
|vemurafenib for 2nd line; vemurafenib ± rituximab for 3rd line (NCCN, v 1.2020, pg. HCL-A)<ref>{{Cite journal|displayauthors=1|last=National Comprehensive Cancer Network|first=|date=January 2020|title=NCCN Clinical Practice Guidelines in Oncology: Hairy Cell Leukemia|url=https://www.nccn.org/professionals/physician_gls/pdf/hairy_cell.pdf|journal=|volume=|pages=|via=}}</ref>
|-
|BRAF p.Val600Glu
|Diagnostic
|May be useful when immunophenotype is equivocal; Excludes [[Hairy Cell Leukemia Variant|HCLv]]
|-
|MAP2K1
|Predictive
|Certain mutations may confer sensitivity to ERK inhibitors
|-
|IGHV4-34 utilization
|Predictive
|Reduced response to purine analogs<ref name=":0">{{Cite journal|last=Arons|first=Evgeny|last2=Suntum|first2=Tara|last3=Stetler-Stevenson|first3=Maryalice|last4=Kreitman|first4=Robert J.|date=2009|title=VH4-34+ hairy cell leukemia, a new variant with poor prognosis despite standard therapy|url=https://www.ncbi.nlm.nih.gov/pubmed/19745070|journal=Blood|volume=114|issue=21|pages=4687–4695|doi=10.1182/blood-2009-01-201731|issn=1528-0020|pmc=2780305|pmid=19745070}}</ref>
|-
|IGHV4-34 utilization
|Prognostic
|Less favorable prognosis<ref name=":0" />
|}
<nowiki>*</nowiki>Not all BRAF mutations confer sensitivity to BRAF inhibitors, even if they are activating mutations<ref>{{Cite journal|last=Bracht|first=Jillian Wilhelmina Paulina|last2=Karachaliou|first2=Niki|last3=Bivona|first3=Trever|last4=Lanman|first4=Richard B.|last5=Faull|first5=Iris|last6=Nagy|first6=Rebecca J.|last7=Drozdowskyj|first7=Ana|last8=Berenguer|first8=Jordi|last9=Fernandez-Bruno|first9=Manuel|date=2019|title=BRAF Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale|url=https://www.ncbi.nlm.nih.gov/pubmed/31533235|journal=Cancers|volume=11|issue=9|doi=10.3390/cancers11091381|issn=2072-6694|pmc=6770188|pmid=31533235}}</ref>.

==Familial Forms==

*Familial association has been reported in several case reports
*Some linked to various HLA type<ref>{{Cite journal|last=Villemagne|first=Bruno|last2=Bay|first2=Jacques-Olivier|last3=Tournilhac|first3=Olivier|last4=Chaleteix|first4=Carine|last5=Travade|first5=Philippe|date=2005|title=Two new cases of familial hairy cell leukemia associated with HLA haplotypes A2, B7, Bw4, Bw6|url=https://www.ncbi.nlm.nih.gov/pubmed/15621808|journal=Leukemia & Lymphoma|volume=46|issue=2|pages=243–245|doi=10.1080/10428190400013589|issn=1042-8194|pmid=15621808}}</ref>
*Others to familial occupation<ref>{{Cite journal|last=Casado|first=L. F.|last2=Mouleon|first2=P.|last3=Villarrubia|first3=B.|last4=Toledo|first4=M. C.|last5=Martinez-Frejo|first5=M. C.|date=1998|title=Familial hairy cell leukemia: a HLA-linked disease or farmers-linked disease?|url=https://www.ncbi.nlm.nih.gov/pubmed/9793263|journal=Haematologica|volume=83|issue=8|pages=751–752|issn=0390-6078|pmid=9793263}}</ref>

==Other Information==

*N/A

==Links==

*[[Hairy Cell Leukemia Variant]]
*[[Splenic Diffuse Red Pulp Small B-cell Lymphoma]]

==References==
<references />

===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==
<nowiki>*</nowiki>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.

HAEM4Backup:Hairy Cell Leukemia - Revision history

Bailey.Glen: Created page with "==Primary Author(s)*== *Snehal Patel, MD, PhD __TOC__ ==Cancer Category/Type== *Mature B-Cell Neoplasm ==Cancer Sub-Classification / Subtype==..."

Bailey.Glen: Created page with "==Primary Author(s)== Snehal Patel, MD, PhD TOC ==Cancer Category/Type== *Mature B-Cell Neoplasm ==Cancer Sub-Classification / Subtype==..."