HAEM5:NK-large granular lymphocytic leukaemia: Difference between revisions

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{{DISPLAYTITLE:NK-large granular lymphocytic leukaemia}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
{{Under Construction}}
<blockquote class='blockedit'>{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Chronic Lymphoproliferative Disorder of NK Cells]].
}}</blockquote>
<br />
==Primary Author(s)*==
==Primary Author(s)*==


Line 15: Line 5:


Michelle Don, MD, UC San Diego
Michelle Don, MD, UC San Diego
__TOC__
==WHO Classification of Disease==
==WHO Classification of Disease==


Line 39: Line 26:
|NK-large granular lymphocytic leukaemia
|NK-large granular lymphocytic leukaemia
|}
|}
==Related Terminology==


==Definition / Description of Disease==
A neoplasm characterized by a persistent (>6 months) increase in peripheral NK cells (> 2 x 10^9/L) and a chronic indolent clinical course. Additional essential diagnostic criteria include flow cytometric evidence of peripheral blood or bone marrow involvement by a uniform population of sCD3(-), CD16(+) NK cells and demonstration of a restricted pattern of KIR expression.
The differential diagnosis includes other mature T-cell neoplasms with a leukemic presentation. T-cell large granular lymphocytic leukemia is a disorder with clinical and pathological overlap; NK-LGL cannot be distinguished from T-LGL by cytological features. If there is prominent lymphocytosis, an aggressive NK-cell leukemia can be considered and NK-LGL is distinguished by an indolent clinical presentation and lack of nuclear EBV positivity. <ref name=":0" />
==Synonyms / Terminology==
*Chronic lymphoproliferative disorder of NK cells
*Chronic NK-large granular lymphocyte lymphoproliferative disorder
*Chronic NK-cell lymphocytosis (historical)
*Indolent leukemia of NK cells (historical) <ref name=":0" />
==Epidemiology / Prevalence==
*Median age: 60 years
*Does not show sex, racial, geographical, or genetic predisposition <ref name=":0" />
==Clinical Features==
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|Acceptable
|Asymptomatic (incidental finding on complete blood counts)
|Chronic lymphoproliferative disorder of NK cells; chronic NK-large granular lymphocyte lymphoproliferative disorder
May occur in association with autoimmune disorders, solid tumors, hematological neoplasms, and neuropathy
 
Uncommon/atypical: splenomegaly, hepatomegaly, lymphadenopathy, skin involvement <ref name=":0" />
|-
|-
|'''Laboratory Findings'''
|Not Recommended
|Lymphocytosis, variable neutropenia and/or anemia <ref name=":0" />
|Chronic NK-cell lymphocytosis; indolent leukaemia of NK cells
|}
|}


==Sites of Involvement==
==Gene Rearrangements==
 
None
*Peripheral blood and bone marrow
 
*Uncommon: spleen <ref name=":0" />
 
==Morphologic Features==
 
*NK-cells are typically intermediate to large in size with small, round nuclei and moderate cytoplasm with fine or coarse azurophilic granules.
 
*Intrasinusoidal and sometimes interstitial infiltration of bone marrow and possibly spleen. <ref name=":0" />
 
==Immunophenotype <ref name=":0" />==
 
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
|-
!Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)
|Positive||CD16
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
|-
!Established Clinical Significance Per Guidelines - Yes or No (Source)
|Positive||cytoplasmic CD3-epsilon
!Clinical Relevance Details/Other Notes
|-
|Positive (frequent)||CD56
|-
|Positive||Cytotoxic markers
(TIA1, granzyme B & granzyme M)
|-
|Positive
|CD94
|-
|Decreased to negative
|CD2, CD7, CD57, CD161
|-
|-
|Negative
|N/A
|surface CD3
|N/A
|-
|N/A
|Restricted or lack of expression
|N/A
|KIR isoforms (CD158a, b, c)
|N/A
|-
|N/A
|Negative
|N/A
|EBV
|N/A
|}
|}
==WHO Essential and Desirable Genetic Diagnostic Criteria==
 
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
==Individual Region Genomic Gain/Loss/LOH==
{| class="wikitable"
None
|+
{| class="wikitable sortable"
|WHO Essential Criteria (Genetics)*
|
|-
|-
|WHO Desirable Criteria (Genetics)*
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
|
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
|Other Classification
|N/A
|
|N/A
|N/A
|N/A
|N/A
|N/A
|N/A
|}
|}
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
==Related Terminology==
<span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
{| class="wikitable"
|+
|Acceptable
|
|-
|Not Recommended
|
|}
==Gene Rearrangements==
None
==Individual Region Genomic Gain/Loss/LOH==


None
==Characteristic Chromosomal or Other Global Mutational Patterns==
==Characteristic Chromosomal or Other Global Mutational Patterns==
None
None
==Gene Mutations (SNV/INDEL)==
==Gene Mutations (SNV/INDEL)==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
!Chromosomal Pattern
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
!Molecular Pathogenesis
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
!Prevalence -  
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Clinical Relevance Details/Other Notes'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|N/A
|N/A
|N/A
|N/A
|N/A
|N/A
|}


<br />
==Gene Mutations (SNV/INDEL)==
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|<span class="blue-text">EXAMPLE:</span> T
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|<span class="blue-text">EXAMPLE:</span> P
|
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|
|-
|
|
|
|
|
|
|
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
!'''Diagnostic Significance (Yes, No or Unknown)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Prognostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Therapeutic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!Clinical Relevance Details/Other Notes
|-
|-
|STAT3; exons 12-21 encoding the Src homology 2 (SH2 domain on two hotspots: D661 and Y640), driver mutation <ref name=":1">{{Cite journal|last=Rajala|first=Hanna L. M.|last2=Eldfors|first2=Samuli|last3=Kuusanmäki|first3=Heikki|last4=van Adrichem|first4=Arjan J.|last5=Olson|first5=Thomas|last6=Lagström|first6=Sonja|last7=Andersson|first7=Emma I.|last8=Jerez|first8=Andres|last9=Clemente|first9=Michael J.|date=2013-05-30|title=Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/23596048|journal=Blood|volume=121|issue=22|pages=4541–4550|doi=10.1182/blood-2012-12-474577|issn=1528-0020|pmc=3668487|pmid=23596048}}</ref>
|''STAT3''
|
|Exons 12-21 encoding the Src homology 2 (SH2 domain on two hotspots: D661 and Y640), driver mutation <ref name=":1">{{Cite journal|last=Rajala|first=Hanna L. M.|last2=Eldfors|first2=Samuli|last3=Kuusanmäki|first3=Heikki|last4=van Adrichem|first4=Arjan J.|last5=Olson|first5=Thomas|last6=Lagström|first6=Sonja|last7=Andersson|first7=Emma I.|last8=Jerez|first8=Andres|last9=Clemente|first9=Michael J.|date=2013-05-30|title=Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia|url=https://pubmed.ncbi.nlm.nih.gov/23596048|journal=Blood|volume=121|issue=22|pages=4541–4550|doi=10.1182/blood-2012-12-474577|issn=1528-0020|pmc=3668487|pmid=23596048}}</ref>
|Variable: 9% <ref>{{Cite journal|last=Gasparini|first=Vanessa Rebecca|last2=Binatti|first2=Andrea|last3=Coppe|first3=Alessandro|last4=Teramo|first4=Antonella|last5=Vicenzetto|first5=Cristina|last6=Calabretto|first6=Giulia|last7=Barilà|first7=Gregorio|last8=Barizza|first8=Annica|last9=Giussani|first9=Edoardo|date=2020-04-22|title=A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells|url=https://pubmed.ncbi.nlm.nih.gov/32321919|journal=Blood Cancer Journal|volume=10|issue=4|pages=42|doi=10.1038/s41408-020-0309-2|issn=2044-5385|pmc=7176632|pmid=32321919}}</ref> to 30% <ref name=":2">{{Cite journal|last=Jerez|first=Andres|last2=Clemente|first2=Michael J.|last3=Makishima|first3=Hideki|last4=Koskela|first4=Hanna|last5=Leblanc|first5=Francis|last6=Peng Ng|first6=Kwok|last7=Olson|first7=Thomas|last8=Przychodzen|first8=Bartlomiej|last9=Afable|first9=Manuel|date=2012-10-11|title=STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia|url=https://pubmed.ncbi.nlm.nih.gov/22859607|journal=Blood|volume=120|issue=15|pages=3048–3057|doi=10.1182/blood-2012-06-435297|issn=1528-0020|pmc=3471515|pmid=22859607}}</ref>
|
|
|
|Yes
|Variable: 9% <ref name=":8">{{Cite journal|last=Gasparini|first=Vanessa Rebecca|last2=Binatti|first2=Andrea|last3=Coppe|first3=Alessandro|last4=Teramo|first4=Antonella|last5=Vicenzetto|first5=Cristina|last6=Calabretto|first6=Giulia|last7=Barilà|first7=Gregorio|last8=Barizza|first8=Annica|last9=Giussani|first9=Edoardo|date=2020-04-22|title=A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells|url=https://pubmed.ncbi.nlm.nih.gov/32321919|journal=Blood Cancer Journal|volume=10|issue=4|pages=42|doi=10.1038/s41408-020-0309-2|issn=2044-5385|pmc=7176632|pmid=32321919}}</ref> to 30% <ref name=":2">{{Cite journal|last=Jerez|first=Andres|last2=Clemente|first2=Michael J.|last3=Makishima|first3=Hideki|last4=Koskela|first4=Hanna|last5=Leblanc|first5=Francis|last6=Peng Ng|first6=Kwok|last7=Olson|first7=Thomas|last8=Przychodzen|first8=Bartlomiej|last9=Afable|first9=Manuel|date=2012-10-11|title=STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia|url=https://pubmed.ncbi.nlm.nih.gov/22859607|journal=Blood|volume=120|issue=15|pages=3048–3057|doi=10.1182/blood-2012-06-435297|issn=1528-0020|pmc=3471515|pmid=22859607}}</ref>
|Higher frequency of symptomatic disease; no difference in overall survival <ref name=":2" />
(NK-LGL)
|D,P
|Yes (NCCN)
|No current approved therapeutic targets <ref name=":1" />
|No current approved therapeutic targets <ref name=":1" />
| - Also seen in T-LGL <ref name=":2" />
Higher frequency of symptomatic disease; no difference in overall survival <ref name=":2" />
- Commonly associated  with CD16high/CD57low or cytotoxic memory NK-LGL's <ref name=":3">{{Cite journal|last=Drillet|first=Gaëlle|last2=Pastoret|first2=Cédric|last3=Moignet|first3=Aline|last4=Lamy|first4=Thierry|last5=Marchand|first5=Tony|date=2022|title=Toward a Better Classification System for NK-LGL Disorders|url=https://pubmed.ncbi.nlm.nih.gov/35178350|journal=Frontiers in Oncology|volume=12|pages=821382|doi=10.3389/fonc.2022.821382|issn=2234-943X|pmc=8843930|pmid=35178350}}</ref> <br />
Also seen in T-LGL <ref name=":2" />
Commonly associated  with CD16high/CD57low or cytotoxic memory NK-LGL's <ref name=":3">{{Cite journal|last=Drillet|first=Gaëlle|last2=Pastoret|first2=Cédric|last3=Moignet|first3=Aline|last4=Lamy|first4=Thierry|last5=Marchand|first5=Tony|date=2022|title=Toward a Better Classification System for NK-LGL Disorders|url=https://pubmed.ncbi.nlm.nih.gov/35178350|journal=Frontiers in Oncology|volume=12|pages=821382|doi=10.3389/fonc.2022.821382|issn=2234-943X|pmc=8843930|pmid=35178350}}</ref>
|-
|-
|TET2; loss of function <ref name=":4">{{Cite journal|last=Pastoret|first=Cédric|last2=Desmots|first2=Fabienne|last3=Drillet|first3=Gaëlle|last4=Le Gallou|first4=Simon|last5=Boulland|first5=Marie-Laure|last6=Thannberger|first6=Alexia|last7=Doncker|first7=Anne-Violaine|last8=Salaun|first8=Véronique|last9=Damaj|first9=Gandhi Laurent|date=2021-06-10|title=Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells|url=https://pubmed.ncbi.nlm.nih.gov/33512451|journal=Blood|volume=137|issue=23|pages=3237–3250|doi=10.1182/blood.2020006721|issn=1528-0020|pmc=8351897|pmid=33512451}}</ref>
|''TET2''
|Loss of function <ref name=":4">{{Cite journal|last=Pastoret|first=Cédric|last2=Desmots|first2=Fabienne|last3=Drillet|first3=Gaëlle|last4=Le Gallou|first4=Simon|last5=Boulland|first5=Marie-Laure|last6=Thannberger|first6=Alexia|last7=Doncker|first7=Anne-Violaine|last8=Salaun|first8=Véronique|last9=Damaj|first9=Gandhi Laurent|date=2021-06-10|title=Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells|url=https://pubmed.ncbi.nlm.nih.gov/33512451|journal=Blood|volume=137|issue=23|pages=3237–3250|doi=10.1182/blood.2020006721|issn=1528-0020|pmc=8351897|pmid=33512451}}</ref>
|Other: TET2 induces an oxidation of 5mC into 5hmc in active DNA demethylation <ref name=":4" />
|Other: TET2 induces an oxidation of 5mC into 5hmc in active DNA demethylation <ref name=":4" />
|28% <ref name=":5">{{Cite journal|last=Olson|first=Thomas L.|last2=Cheon|first2=HeeJin|last3=Xing|first3=Jeffrey C.|last4=Olson|first4=Kristine C.|last5=Paila|first5=Umadevi|last6=Hamele|first6=Cait E.|last7=Neelamraju|first7=Yaseswini|last8=Shemo|first8=Bryna C.|last9=Schmachtenberg|first9=Matt|date=2021-08-26|title=Frequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias|url=https://pubmed.ncbi.nlm.nih.gov/33786584|journal=Blood|volume=138|issue=8|pages=662–673|doi=10.1182/blood.2020005831|issn=1528-0020|pmc=8394905|pmid=33786584}}</ref> - 34% <ref name=":4" />
|Common: 28% <ref name=":5">{{Cite journal|last=Olson|first=Thomas L.|last2=Cheon|first2=HeeJin|last3=Xing|first3=Jeffrey C.|last4=Olson|first4=Kristine C.|last5=Paila|first5=Umadevi|last6=Hamele|first6=Cait E.|last7=Neelamraju|first7=Yaseswini|last8=Shemo|first8=Bryna C.|last9=Schmachtenberg|first9=Matt|date=2021-08-26|title=Frequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias|url=https://pubmed.ncbi.nlm.nih.gov/33786584|journal=Blood|volume=138|issue=8|pages=662–673|doi=10.1182/blood.2020005831|issn=1528-0020|pmc=8394905|pmid=33786584}}</ref> - 34% <ref name=":4" />
|STAT3 <ref name=":4" />
(NK-LGL)
|
|D
|Yes
|Yes (NCCN)
|Unknown
|Resistance to immunosuppressive agents have been observed; no current therapeutic target <ref name=":5" />
|Resistance to immunosuppressive agents have been observed; no current therapeutic target <ref name=":5" />
| - Also seen in T-LGL  
Also seen in T-LGL
- Commonly associated with CD16 low phenotype
Commonly associated with CD16 low phenotype
 
Associated with thrombocytopenia <ref name=":4" />
- Associated with thrombocytopenia <ref name=":4" />
|-
|-
|CCL22; gain of function <ref name=":6">{{Cite journal|last=Baer|first=Constance|last2=Kimura|first2=Shunsuke|last3=Rana|first3=Mitra S.|last4=Kleist|first4=Andrew B.|last5=Flerlage|first5=Tim|last6=Feith|first6=David J.|last7=Chockley|first7=Peter|last8=Walter|first8=Wencke|last9=Meggendorfer|first9=Manja|date=2022-05|title=CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk|url=https://pubmed.ncbi.nlm.nih.gov/35513723|journal=Nature Genetics|volume=54|issue=5|pages=637–648|doi=10.1038/s41588-022-01059-2|issn=1546-1718|pmc=9117519|pmid=35513723}}</ref>
|''CCL22''
|
|Gain of function <ref name=":6">{{Cite journal|last=Baer|first=Constance|last2=Kimura|first2=Shunsuke|last3=Rana|first3=Mitra S.|last4=Kleist|first4=Andrew B.|last5=Flerlage|first5=Tim|last6=Feith|first6=David J.|last7=Chockley|first7=Peter|last8=Walter|first8=Wencke|last9=Meggendorfer|first9=Manja|date=2022-05|title=CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk|url=https://pubmed.ncbi.nlm.nih.gov/35513723|journal=Nature Genetics|volume=54|issue=5|pages=637–648|doi=10.1038/s41588-022-01059-2|issn=1546-1718|pmc=9117519|pmid=35513723}}</ref>
|21.5% <ref name=":6" />
|
|
|Common: 21.5% <ref name=":6" />
(NK-LGL)
|
|
|No
|No
|No
|Specific to NK-LGL <ref name=":3" />
|No
| - Specific to NK-LGL <ref name=":3" />
|-
|-
|TNFAIP3; loss of function <ref name=":4" />
|''TNFAIP3''
|Loss of function <ref name=":4" />
|TSG
|TSG
|6% <ref>{{Cite journal|last=Kawakami|first=Toru|last2=Sekiguchi|first2=Nodoka|last3=Kobayashi|first3=Jun|last4=Yamane|first4=Taku|last5=Nishina|first5=Sayaka|last6=Sakai|first6=Hitoshi|last7=Hirabayashi|first7=Yukio|last8=Nakazawa|first8=Hideyuki|last9=Ishida|first9=Fumihiro|date=2019-05|title=STAT3 mutations in natural killer cells are associated with cytopenia in patients with chronic lymphoproliferative disorder of natural killer cells|url=https://pubmed.ncbi.nlm.nih.gov/30859397|journal=International Journal of Hematology|volume=109|issue=5|pages=563–571|doi=10.1007/s12185-019-02625-x|issn=1865-3774|pmid=30859397}}</ref> - 10% <ref name=":4" />
|Recurrent: 6% <ref name=":9">{{Cite journal|last=Kawakami|first=Toru|last2=Sekiguchi|first2=Nodoka|last3=Kobayashi|first3=Jun|last4=Yamane|first4=Taku|last5=Nishina|first5=Sayaka|last6=Sakai|first6=Hitoshi|last7=Hirabayashi|first7=Yukio|last8=Nakazawa|first8=Hideyuki|last9=Ishida|first9=Fumihiro|date=2019-05|title=STAT3 mutations in natural killer cells are associated with cytopenia in patients with chronic lymphoproliferative disorder of natural killer cells|url=https://pubmed.ncbi.nlm.nih.gov/30859397|journal=International Journal of Hematology|volume=109|issue=5|pages=563–571|doi=10.1007/s12185-019-02625-x|issn=1865-3774|pmid=30859397}}</ref> - 10% <ref name=":4" />
(NK-LGL)
|
|
|
|No
|No
|No
|No
|
|
|-
|-
|PI3K pathway genes; PIK3CD activating mutation, PIK3AP1 mutation not previously described <ref name=":5" />
|''PI3K'' pathway genes
|
|PIK3CD activating mutation, PIK3AP1 mutation not previously described <ref name=":5" />
|3 patients (5%) <ref name=":5" />
|
|
|Rare: 3 patients (5%) <ref name=":5" />
(NK-LGL)
|
|
|No
|No
|No
|No
|PIK3CD mutations are observed as de novo germline mutations causing activated PI3 kinase delta syndrome <ref name=":5" />
|PIK3CD mutations are observed as de novo germline mutations causing activated PI3 kinase delta syndrome <ref name=":5" />
|-
|-
|STAT5b; exon 16 missense N642H mutation in the SH2 domain, driver mutation <ref name=":1" />
|''STAT5b''
|Exon 16 missense N642H mutation in the SH2 domain, driver mutation <ref name=":1" />
|
|
|1 patient <ref name=":1" />
|Rare: 1 patient <ref name=":1" />
|
|
|
|No
|Unknown
|Progressed to aggressive disease and died due to disease <ref name=":1" />
|Unknown; progressed to aggressive disease and died due to disease <ref name=":1" />
|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
|No current approved therapeutic targets <ref name=":1" />
|
|}
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


==Epigenomic Alterations==
==Epigenomic Alterations==
 
TET2 shows increased methylated regions in clonal NK-LGLs compared to normal NK-cells <ref name=":5" />
*TET2 shows increased methylated regions in clonal NK-LGLs compared to normal NK-cells <ref name=":5" />


==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
{| class="wikitable sortable"
!Gene; Genetic Alteration
!Pathway
!Pathophysiologic Outcome
|-
|''STAT3;'' gain of function mutations
|JAK/STAT signaling
|Persistent STAT3 activation leads to increased transcription of anti-apoptotic/pro-proliferative genes, clonal NK cell expansion, and enhanced survival; contributes to cytopenias and disease severity <ref>{{Cite journal|last=Marchand|first=Tony|last2=Lamy|first2=Thierry|last3=Loughran|first3=Thomas P.|date=2024-10-31|title=A modern view of LGL leukemia|url=https://pubmed.ncbi.nlm.nih.gov/38848524|journal=Blood|volume=144|issue=18|pages=1910–1923|doi=10.1182/blood.2023021790|issn=1528-0020|pmid=38848524}}</ref>
|-
|''TET2''; loss of function mutations
|DNA methylation/epigenetic regulation
|DNA methylation alters NK cell gene expression<ref>{{Cite journal|last=Semenzato|first=Gianpietro|last2=Teramo|first2=Antonella|last3=Barilà|first3=Gregorio|last4=Calabretto|first4=Giulia|last5=Rampazzo|first5=Elisa|last6=Buson|first6=Elena|last7=Zambello|first7=Renato|date=2025-06|title=NK-type large granular lymphocyte leukemia comes of age|url=https://pubmed.ncbi.nlm.nih.gov/40568352|journal=HemaSphere|volume=9|issue=6|pages=e70161|doi=10.1002/hem3.70161|issn=2572-9241|pmc=12194722|pmid=40568352}}</ref>
|-
|''CCL22''; gain of function mutations
|Chemokine signaling and microenvironmental interaction
|Alters NK cell interaction with the microenvironment, contributing to clonal dominance and unique immunophenotype <ref name=":6" />
|-
|''TNFAIP3''; inactivating alterations
|NF-κB negative regulation
|Loss of negative regulation enhances NF-κB signaling, promoting cell survival and anti-apoptotic transcription<ref name=":4" />
|-
|''KRAS, NOTCH1'' ''PTEN; PIK3R1'', ''PIK3CD,''  PIK3AP1
|RAS/MAPK and Pi3K/AKT pathways
|Dysregulation of the balance between survival and apoptosis <ref name=":8" /><ref name=":3" />
|}


Pathways involved include anti-apoptotic signaling and cell survival pathways. This includes the JAK/STAT pathway with constitutive activation of STAT3 and an activating mutation in STAT3. Also involved are RAS/MAPK and Pi3K/AKT pathways, which are constitutionally activated. <ref name=":3" />
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


*Assessing for restricted expression of KIR isoforms, is often used as a surrogate for clonality <ref name=":7">{{Cite journal|last=Lamy|first=Thierry|last2=Moignet|first2=Aline|last3=Loughran|first3=Thomas P.|date=2017-03-02|title=LGL leukemia: from pathogenesis to treatment|url=https://pubmed.ncbi.nlm.nih.gov/28115367|journal=Blood|volume=129|issue=9|pages=1082–1094|doi=10.1182/blood-2016-08-692590|issn=1528-0020|pmid=28115367}}</ref>.
*Assessing for restricted expression of KIR isoforms, is often used as a surrogate for clonality <ref name=":7">{{Cite journal|last=Lamy|first=Thierry|last2=Moignet|first2=Aline|last3=Loughran|first3=Thomas P.|date=2017-03-02|title=LGL leukemia: from pathogenesis to treatment|url=https://pubmed.ncbi.nlm.nih.gov/28115367|journal=Blood|volume=129|issue=9|pages=1082–1094|doi=10.1182/blood-2016-08-692590|issn=1528-0020|pmid=28115367}}</ref>.


*Mutational screen for STAT3, STAT5b, TET2, TNFAIP3 and CCL22 mutations may be more helpful when compared to KIR analysis on diagnostic work-up <ref name=":3" />.
*Mutational screen for ''STAT3, STAT5b, TET2, TNFAIP3'' and ''CCL22'' mutations may be more helpful when compared to KIR analysis on diagnostic work-up <ref name=":3" />.


*Absence of T-cell receptor gene rearrangement studies <ref name=":7" />.
*Absence of T-cell receptor gene rearrangements by PCR<ref name=":7" />.


*Sanger Sequencing.
*Sanger Sequencing.
Line 295: Line 211:


==Additional Information==
==Additional Information==
NK-LGLL is characterized by a persistent (>6 months) increase in peripheral NK cells (> 2 x 10^9/L) and a chronic indolent clinical course. Additional essential diagnostic criteria include flow cytometric evidence of peripheral blood or bone marrow involvement by a uniform population of sCD3(-), CD16(+) NK cells and demonstration of a restricted pattern of KIR expression.
<u>Epidemiology/prevalence</u>: Median age: 60 years; does not show sex, racial, geographical, or genetic predisposition<ref name=":0">WHO Classification of Tumours Editorial Board, eds, WHO Classification of Tumours, Haematolymphoid Tumours Part A. 5th edition, IARC Press:Lyon, 2024.</ref>
<u>Clinical features</u>:
*Signs and symptoms - Asymptomatic (incidental finding on complete blood counts); May occur in association with autoimmune disorders, solid tumors, hematological neoplasms, and neuropathy; Uncommon/atypical: splenomegaly, hepatomegaly, lymphadenopathy, skin involvement<ref name=":0" />
*Laboratory findings - Lymphocytosis, variable neutropenia and/or anemia<ref name=":0" />
<u>Sites of involvement:</u> Peripheral blood and bone marrow; uncommonly spleen<ref name=":0" />
<u>Morphologic features</u>: NK-cells are typically intermediate to large in size with small, round nuclei and moderate cytoplasm with fine or coarse azurophilic granules. Intrasinusoidal and sometimes interstitial infiltration of bone marrow and possibly spleen.<ref name=":0" />


None
<u>Immunophenotype</u>:
 
* Positive - CD16, CD56 (frequent), cytoplasmic CD3-epsilon, cytotoxic markers (TIA1, granzyme B & granzyme M), CD94
 
* Decreased to negative - CD2, CD7, CD57, CD161; restricted or lack of expression - KIR isoforms (CD158a, b, c)
 
* Negative - surface CD3, EBV


==Links==
==Links==


<br />
N/A


==References==
==References==
<references />
<references />


<br />
==Notes==
<nowiki>*</nowiki>''Citation of this Page'': St. Louis H, Don M. “NK-large granular lymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:NK-large_granular_lymphocytic_leukaemia</nowiki>.
 


==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 [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.
<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 [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.


Prior Author(s):   
Prior Author(s):   
       
<nowiki>*</nowiki>''Citation of this Page'': “NK-large granular lymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:NK-large_granular_lymphocytic_leukaemia</nowiki>.
[[Category:HAEM5]]
[[Category:HAEM5]]
[[Category:DISEASE]]
[[Category:DISEASE]]
[[Category:Diseases N]]
[[Category:Diseases N]]

Latest revision as of 21:52, 6 January 2026

Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Hailee St. Louis, MD, UC San Diego

Michelle Don, MD, UC San Diego

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category T-cell and NK-cell lymphoid proliferations and lymphomas
Family Mature T-cell and NK-cell neoplasms
Type Mature T-cell and NK-cell leukaemias
Subtype(s) NK-large granular lymphocytic leukaemia

Related Terminology

Acceptable Chronic lymphoproliferative disorder of NK cells; chronic NK-large granular lymphocyte lymphoproliferative disorder
Not Recommended Chronic NK-cell lymphocytosis; indolent leukaemia of NK cells

Gene Rearrangements

None

Driver Gene Fusion(s) and Common Partner Genes Molecular Pathogenesis Typical Chromosomal Alteration(s) Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
N/A N/A N/A N/A N/A N/A N/A N/A

Individual Region Genomic Gain/Loss/LOH

None

Chr # Gain, Loss, Amp, LOH Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] Relevant Gene(s) Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
N/A N/A N/A N/A N/A N/A N/A

Characteristic Chromosomal or Other Global Mutational Patterns

None

Chromosomal Pattern Molecular Pathogenesis Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
N/A N/A N/A N/A N/A N/A

Gene Mutations (SNV/INDEL)

Gene Genetic Alteration Tumor Suppressor Gene, Oncogene, Other Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

Diagnostic, Prognostic, and Therapeutic Significance - D, P, T   Established Clinical Significance Per Guidelines - Yes or No (Source) Clinical Relevance Details/Other Notes
STAT3 Exons 12-21 encoding the Src homology 2 (SH2 domain on two hotspots: D661 and Y640), driver mutation [1] Variable: 9% [2] to 30% [3]

(NK-LGL)

D,P Yes (NCCN) No current approved therapeutic targets [1]

Higher frequency of symptomatic disease; no difference in overall survival [3] Also seen in T-LGL [3] Commonly associated  with CD16high/CD57low or cytotoxic memory NK-LGL's [4]

TET2 Loss of function [5] Other: TET2 induces an oxidation of 5mC into 5hmc in active DNA demethylation [5] Common: 28% [6] - 34% [5]

(NK-LGL)

D Yes (NCCN) Resistance to immunosuppressive agents have been observed; no current therapeutic target [6]

Also seen in T-LGL Commonly associated with CD16 low phenotype Associated with thrombocytopenia [5]

CCL22 Gain of function [7] Common: 21.5% [7]

(NK-LGL)

No Specific to NK-LGL [4]
TNFAIP3 Loss of function [5] TSG Recurrent: 6% [8] - 10% [5]

(NK-LGL)

No
PI3K pathway genes PIK3CD activating mutation, PIK3AP1 mutation not previously described [6] Rare: 3 patients (5%) [6]

(NK-LGL)

No PIK3CD mutations are observed as de novo germline mutations causing activated PI3 kinase delta syndrome [6]
STAT5b Exon 16 missense N642H mutation in the SH2 domain, driver mutation [1] Rare: 1 patient [1] No Progressed to aggressive disease and died due to disease [1]

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

TET2 shows increased methylated regions in clonal NK-LGLs compared to normal NK-cells [6]

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
STAT3; gain of function mutations JAK/STAT signaling Persistent STAT3 activation leads to increased transcription of anti-apoptotic/pro-proliferative genes, clonal NK cell expansion, and enhanced survival; contributes to cytopenias and disease severity [9]
TET2; loss of function mutations DNA methylation/epigenetic regulation DNA methylation alters NK cell gene expression[10]
CCL22; gain of function mutations Chemokine signaling and microenvironmental interaction Alters NK cell interaction with the microenvironment, contributing to clonal dominance and unique immunophenotype [7]
TNFAIP3; inactivating alterations NF-κB negative regulation Loss of negative regulation enhances NF-κB signaling, promoting cell survival and anti-apoptotic transcription[5]
KRAS, NOTCH1 PTEN; PIK3R1, PIK3CD, PIK3AP1 RAS/MAPK and Pi3K/AKT pathways Dysregulation of the balance between survival and apoptosis [2][4]

Genetic Diagnostic Testing Methods

  • Assessing for restricted expression of KIR isoforms, is often used as a surrogate for clonality [11].
  • Mutational screen for STAT3, STAT5b, TET2, TNFAIP3 and CCL22 mutations may be more helpful when compared to KIR analysis on diagnostic work-up [4].
  • Absence of T-cell receptor gene rearrangements by PCR[11].
  • Sanger Sequencing.
  • Whole Genome Sequencing.

Familial Forms

None

Additional Information

NK-LGLL is characterized by a persistent (>6 months) increase in peripheral NK cells (> 2 x 10^9/L) and a chronic indolent clinical course. Additional essential diagnostic criteria include flow cytometric evidence of peripheral blood or bone marrow involvement by a uniform population of sCD3(-), CD16(+) NK cells and demonstration of a restricted pattern of KIR expression.

Epidemiology/prevalence: Median age: 60 years; does not show sex, racial, geographical, or genetic predisposition[12]

Clinical features:

  • Signs and symptoms - Asymptomatic (incidental finding on complete blood counts); May occur in association with autoimmune disorders, solid tumors, hematological neoplasms, and neuropathy; Uncommon/atypical: splenomegaly, hepatomegaly, lymphadenopathy, skin involvement[12]
  • Laboratory findings - Lymphocytosis, variable neutropenia and/or anemia[12]

Sites of involvement: Peripheral blood and bone marrow; uncommonly spleen[12]

Morphologic features: NK-cells are typically intermediate to large in size with small, round nuclei and moderate cytoplasm with fine or coarse azurophilic granules. Intrasinusoidal and sometimes interstitial infiltration of bone marrow and possibly spleen.[12]

Immunophenotype:

  • Positive - CD16, CD56 (frequent), cytoplasmic CD3-epsilon, cytotoxic markers (TIA1, granzyme B & granzyme M), CD94
  • Decreased to negative - CD2, CD7, CD57, CD161; restricted or lack of expression - KIR isoforms (CD158a, b, c)
  • Negative - surface CD3, EBV

Links

N/A

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Rajala, Hanna L. M.; et al. (2013-05-30). "Discovery of somatic STAT5b mutations in large granular lymphocytic leukemia". Blood. 121 (22): 4541–4550. doi:10.1182/blood-2012-12-474577. ISSN 1528-0020. PMC 3668487. PMID 23596048.
  2. ↑ 2.0 2.1 Gasparini, Vanessa Rebecca; et al. (2020-04-22). "A high definition picture of somatic mutations in chronic lymphoproliferative disorder of natural killer cells". Blood Cancer Journal. 10 (4): 42. doi:10.1038/s41408-020-0309-2. ISSN 2044-5385. PMC 7176632 Check |pmc= value (help). PMID 32321919 Check |pmid= value (help).
  3. ↑ 3.0 3.1 3.2 Jerez, Andres; et al. (2012-10-11). "STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemia". Blood. 120 (15): 3048–3057. doi:10.1182/blood-2012-06-435297. ISSN 1528-0020. PMC 3471515. PMID 22859607.
  4. ↑ 4.0 4.1 4.2 4.3 Drillet, Gaëlle; et al. (2022). "Toward a Better Classification System for NK-LGL Disorders". Frontiers in Oncology. 12: 821382. doi:10.3389/fonc.2022.821382. ISSN 2234-943X. PMC 8843930 Check |pmc= value (help). PMID 35178350 Check |pmid= value (help).
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Pastoret, Cédric; et al. (2021-06-10). "Linking the KIR phenotype with STAT3 and TET2 mutations to identify chronic lymphoproliferative disorders of NK cells". Blood. 137 (23): 3237–3250. doi:10.1182/blood.2020006721. ISSN 1528-0020. PMC 8351897 Check |pmc= value (help). PMID 33512451 Check |pmid= value (help).
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 Olson, Thomas L.; et al. (2021-08-26). "Frequent somatic TET2 mutations in chronic NK-LGL leukemia with distinct patterns of cytopenias". Blood. 138 (8): 662–673. doi:10.1182/blood.2020005831. ISSN 1528-0020. PMC 8394905 Check |pmc= value (help). PMID 33786584 Check |pmid= value (help).
  7. ↑ 7.0 7.1 7.2 Baer, Constance; et al. (2022-05). "CCL22 mutations drive natural killer cell lymphoproliferative disease by deregulating microenvironmental crosstalk". Nature Genetics. 54 (5): 637–648. doi:10.1038/s41588-022-01059-2. ISSN 1546-1718. PMC 9117519 Check |pmc= value (help). PMID 35513723 Check |pmid= value (help). Check date values in: |date= (help)
  8. ↑ Kawakami, Toru; et al. (2019-05). "STAT3 mutations in natural killer cells are associated with cytopenia in patients with chronic lymphoproliferative disorder of natural killer cells". International Journal of Hematology. 109 (5): 563–571. doi:10.1007/s12185-019-02625-x. ISSN 1865-3774. PMID 30859397. Check date values in: |date= (help)
  9. ↑ Marchand, Tony; et al. (2024-10-31). "A modern view of LGL leukemia". Blood. 144 (18): 1910–1923. doi:10.1182/blood.2023021790. ISSN 1528-0020. PMID 38848524 Check |pmid= value (help).
  10. ↑ Semenzato, Gianpietro; et al. (2025-06). "NK-type large granular lymphocyte leukemia comes of age". HemaSphere. 9 (6): e70161. doi:10.1002/hem3.70161. ISSN 2572-9241. PMC 12194722 Check |pmc= value (help). PMID 40568352 Check |pmid= value (help). Check date values in: |date= (help)
  11. ↑ 11.0 11.1 Lamy, Thierry; et al. (2017-03-02). "LGL leukemia: from pathogenesis to treatment". Blood. 129 (9): 1082–1094. doi:10.1182/blood-2016-08-692590. ISSN 1528-0020. PMID 28115367.
  12. ↑ 12.0 12.1 12.2 12.3 12.4 WHO Classification of Tumours Editorial Board, eds, WHO Classification of Tumours, Haematolymphoid Tumours Part A. 5th edition, IARC Press:Lyon, 2024.

Notes

*Citation of this Page: St. Louis H, Don M. “NK-large granular lymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 01/6/2026, https://ccga.io/index.php/HAEM5:NK-large_granular_lymphocytic_leukaemia.


*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 Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):

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