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Created page with "==Primary Author(s)*== *Snehal Patel, MD, PhD __TOC__ ==Cancer Category/Type== *Splenic B-cell Lymphoma/Leukemia, Unclassifiable ==Cancer Sub-Classification / Subtype=..."

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==Primary Author(s)*==

*Snehal Patel, MD, PhD
__TOC__

==Cancer Category/Type==

*[[Splenic B-cell Lymphoma/Leukemia, Unclassifiable]]

==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|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<ref name=":0" /><ref name=":5" />==
'''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<ref name=":0" /><ref name=":5" />==

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

==Morphologic Features<ref name=":0" /><ref name=":5" />==

*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<ref name=":0" /><ref name=":5" />==

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (B-cell lineage markers)||CD19, CD20 (bright), CD22, CD79b, PAX5, FMC7, sIg (bright, monotypic)
|-
|Positive||CD11c, CD72, CD103
|-
|Negative ([[Hairy Cell Leukemia|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%<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://ashpublications.org/blood/article/119/14/3330/29588/Both-variant-and-IGHV434expressing-hairy-cell|journal=Blood|language=en|volume=119|issue=14|pages=3330–3332|doi=10.1182/blood-2011-09-379339|issn=0006-4971|pmc=PMC3321859|pmid=22210875}}</ref> and has clinical implications<ref name=":4">{{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://ashpublications.org/blood/article/114/21/4687/26430/VH434-hairy-cell-leukemia-a-new-variant-with-poor|journal=Blood|language=en|volume=114|issue=21|pages=4687–4695|doi=10.1182/blood-2009-01-201731|issn=0006-4971|pmc=PMC2780305|pmid=19745070}}</ref>

==Genomic Gain/Loss/LOH==

{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Consequence
!Prevalence
|-
|17p13||Loss||TP53 deletion
|42%<ref name=":0">{{Cite journal|last=Angelova|first=Evgeniya A.|last2=Medeiros|first2=L. Jeffrey|last3=Wang|first3=Wei|last4=Muzzafar|first4=Tariq|last5=Lu|first5=Xinyan|last6=Khoury|first6=Joseph D.|last7=Ravandi|first7=Farhad|last8=Patel|first8=Keyur P.|last9=Hu|first9=Zhihong|date=2018|title=Clinicopathologic and molecular features in hairy cell leukemia-variant: single institutional experience|url=https://www.ncbi.nlm.nih.gov/pubmed/29955146|journal=Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc|volume=31|issue=11|pages=1717–1732|doi=10.1038/s41379-018-0093-8|issn=1530-0285|pmid=29955146}}</ref>
|-
|11q22||Loss||ATM deletion
|22%<ref name=":0" />
|}
==Gene Mutations (SNV/INDEL)==

{| class="wikitable sortable"
|-
!Gene*!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other)!!Prevalence
|-
|MAP2K1||Oncogene||GOF||7-50%<ref name=":0" /><ref>{{Cite journal|last=Mason|first=Emily F.|last2=Brown|first2=Ronald D.|last3=Szeto|first3=David P.|last4=Gibson|first4=Christopher J.|last5=Jia|first5=Yonghui|last6=Garcia|first6=Elizabeth P.|last7=Jacobson|first7=Caron A.|last8=Dal Cin|first8=Paola|last9=Kuo|first9=Frank C.|date=2017|title=Detection of activating MAP2K1 mutations in atypical hairy cell leukemia and hairy cell leukemia variant|url=https://www.ncbi.nlm.nih.gov/pubmed/27241017|journal=Leukemia & Lymphoma|volume=58|issue=1|pages=233–236|doi=10.1080/10428194.2016.1185786|issn=1029-2403|pmid=27241017}}</ref><ref name=":2" /><ref name=":1">{{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><ref name=":3">{{Cite journal|last=Maitre|first=Elsa|last2=Bertrand|first2=Philippe|last3=Maingonnat|first3=Catherine|last4=Viailly|first4=Pierre-Julien|last5=Wiber|first5=Margaux|last6=Naguib|first6=Dina|last7=Salaün|first7=Véronique|last8=Cornet|first8=Edouard|last9=Damaj|first9=Gandhi|date=2018|title=New generation sequencing of targeted genes in the classical and the variant form of hairy cell leukemia highlights mutations in epigenetic regulation genes|url=https://www.ncbi.nlm.nih.gov/pubmed/29989027|journal=Oncotarget|volume=9|issue=48|pages=28866–28876|doi=10.18632/oncotarget.25601|issn=1949-2553|pmc=6034755|pmid=29989027}}</ref>
|-
|TP53
|Tumor Suppressor
|LOF
|29%<ref name=":1" /> - 38%<ref name=":2">{{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>
|-
|KMT2C
|Tumor Suppressor
|LOF
|25%<ref name=":2" />
|-
|KDM6A
|Tumor Suppressor
|LOF
|13%<ref name=":2" /> - 50%<ref name=":3" />
|-
|ARID1A
|Tumor Suppressor
|LOF
|13%<ref name=":2" /> - 25%<ref name=":3" />
|-
|CREBBP
|Tumor Suppressor
|LOF
|13%<ref name=":2" /> - 25%<ref name=":3" />
|-
|CCND3
|Oncogene
|change of function
|13%<ref name=":2" />
|-
|U2AF
|Oncogene
|change of function
|13%<ref name=":2" />
|}
<sup>‡</sup>Specific mutations in these genes can be found in [https://www.cbioportal.org/ cBioPortal] and [https://cancer.sanger.ac.uk/cosmic 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==
{| class="wikitable"
!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<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://linkinghub.elsevier.com/retrieve/pii/S0740257015000118|journal=Seminars in Diagnostic Pathology|language=en|volume=32|issue=5|pages=400–408|doi=10.1053/j.semdp.2015.02.010}}</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=2017|title=BRAF V600E Mutation Across Multiple Tumor Types: Correlation Between DNA-based Sequencing and Mutation-specific Immunohistochemistry|url=http://journals.lww.com/00129039-900000000-98873|journal=Applied Immunohistochemistry & Molecular Morphology|language=en|pages=1|doi=10.1097/PAI.0000000000000516|issn=1541-2016}}</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=":5">{{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://onlinelibrary.wiley.com/doi/abs/10.1002/ajh.25653|journal=American Journal of Hematology|language=en|volume=94|issue=12|pages=1413–1422|doi=10.1002/ajh.25653|issn=0361-8609}}</ref>
*IGHV4-34 utilization can be detected by NGS and Sanger sequencing of IgH mRNA

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
{| class="wikitable"
!Alteration
!Clinical Significance
!Note
|-
|BRAF activating mutations
|Diagnostic
|Excludes HCL
|-
|MAP2K1 activating mutations
|Prediction
|May be targetable with MEK inhibitors<ref>{{Cite journal|last=Andritsos|first=Leslie A.|last2=Grieselhuber|first2=Nicole R.|last3=Anghelina|first3=Mirela|last4=Rogers|first4=Kerry A.|last5=Roychowdhury|first5=Sameek|last6=Reeser|first6=Julie W.|last7=Timmers|first7=Cynthia D.|last8=Freud|first8=Aharon G.|last9=Blachly|first9=James S.|date=2018|title=Trametinib for the treatment of IGHV4-34, MAP2K1-mutant variant hairy cell leukemia|url=https://www.tandfonline.com/doi/full/10.1080/10428194.2017.1365853|journal=Leukemia & Lymphoma|language=en|volume=59|issue=4|pages=1008–1011|doi=10.1080/10428194.2017.1365853|issn=1042-8194}}</ref>
|-
|IGHV4-34
|Prediction
|Reduced response to purine analogs<ref name=":4" />
|-
|IGHV4-34
|Prognostic
|Less favorable prognosis<ref name=":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==

*[[Hairy Cell Leukemia]]
*[[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 Variant - Revision history

Bailey.Glen: Created page with "==Primary Author(s)*== *Snehal Patel, MD, PhD __TOC__ ==Cancer Category/Type== *Splenic B-cell Lymphoma/Leukemia, Unclassifiable ==Cancer Sub-Classification / Subtype=..."

Bailey.Glen: Created page with "==Primary Author(s)== Snehal Patel, MD, PhD TOC ==Cancer Category/Type== *Splenic B-cell Lymphoma/Leukemia, Unclassifiable ==Cancer Sub-Classification / Subtype=..."