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

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{{DISPLAYTITLE:NK-large granular lymphocytic leukaemia}}
 
{{DISPLAYTITLE:NK-large granular lymphocytic leukaemia}}
−
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]
+
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
  
 
{{Under Construction}}
 
{{Under Construction}}
  
−
<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-11-03. The original page can be found at [[HAEM4:Chronic Lymphoproliferative Disorder of NK Cells]].
+
<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>
 
}}</blockquote>
−
==Primary Author(s)*==
 
  
−
Michelle Don, MD
+
<br />
  
−
__TOC__
+
==Primary Author(s)*==
−
 
 
−
==Cancer Category/Type==
 
−
 
 
−
Lymphoproliferative disorder (provisional entity)<ref name=":0">Villamor N, et al., (2017). Chronic lymphoproliferative disorder of NK cells, 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, p 3351-352</ref>
 
−
 
 
−
==Cancer Sub-Classification / Subtype==
 
−
 
 
−
Put your text here
 
−
 
 
−
==Definition / Description of Disease==
 
−
 
 
−
 
 
−
*Persistent (>6 months) increase in peripheral blood NK-cell count without a clearly identifiable cause
 
−
*NK-cell count usually >2x10<sup>9</sup>/L
 
−
*Indolent
 
−
 
 
−
 
 
−
<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref name=":0" /></blockquote>
 
−
==Synonyms / Terminology==
 
−
 
 
−
 
 
−
*Chronic NK-lymphocytosis
 
−
*Chronic NK large granular lymphocyte lymphoproliferative disorder
 
−
*Indolent large granular NK-cell lymphoproliferative disorder
 
−
 
 
−
 
 
−
<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref name=":0" /></blockquote>
 
−
==Epidemiology / Prevalence==
 
  
 +
Hailee St. Louis, MD, UC San Diego
  
−
*Adults (median age 60 years old)
+
Michelle Don, MD, UC San Diego
−
*No known racial or genetic predisposition
+
==WHO Classification of Disease==
  
−
 
−
<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref name=":0" /></blockquote>
 
−
==Clinical Features==
 
−
 
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table'') </span>
 
 
{| class="wikitable"
 
{| class="wikitable"
−
|'''Signs and Symptoms'''
+
!Structure
−
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
+
!Disease
−
 
 
−
EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
−
 
 
−
EXAMPLE Fatigue
 
−
 
 
−
EXAMPLE Lymphadenopathy (uncommon)
 
 
|-
 
|-
−
|'''Laboratory Findings'''
+
|Book
−
|EXAMPLE Cytopenias
+
|Haematolymphoid Tumours (5th ed.)
−
 
 
−
EXAMPLE Lymphocytosis (low level)
 
−
|}
 
−
 
 
−
==Sites of Involvement==
 
−
 
 
−
 
 
−
*Peripheral blood
 
−
*Bone marrow
 
−
 
 
−
 
 
−
<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref name=":0" /></blockquote>
 
−
==Morphologic Features==
 
−
 
 
−
 
 
−
*NK-cells are typically intermediate in size
 
−
*Monotonous cells with round nuclei and moderate cytoplasm with fine or coarse azurophilic granules
 
−
*Intrasinusoidal and interstitial infiltration of bone marrow
 
−
 
 
−
 
 
−
<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref name=":0" /></blockquote>
 
−
==Immunophenotype==
 
−
 
 
−
 
 
−
<br />
 
−
 
 
−
{| class="wikitable sortable"
 
 
|-
 
|-
−
!Finding!!Marker
+
|Category
 +
|T-cell and NK-cell lymphoid proliferations and lymphomas
 
|-
 
|-
−
|Positive||CD16
+
|Family
 +
|Mature T-cell and NK-cell neoplasms
 
|-
 
|-
−
|Positive||cytoplasmic CD3-epsilon
+
|Type
 +
|Mature T-cell and NK-cell leukaemias
 
|-
 
|-
−
|Positive (frequent)||weak CD56
+
|Subtype(s)
 +
|NK-large granular lymphocytic leukaemia
 +
|}
 +
==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>
 +
{| class="wikitable"
 +
|+
 +
|WHO Essential Criteria (Genetics)*
 +
|
 
|-
 
|-
−
|Positive||Cytotoxic markers
+
|WHO Desirable Criteria (Genetics)*
−
(TIA1, granzyme B & granzyme M)
+
|
 
|-
 
|-
−
|Positive
+
|Other Classification
−
|CD94
+
|
 +
|}
 +
<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
 +
|
 
|-
 
|-
−
|Decreased to negative
+
|Not Recommended
−
|CD2, CD7, CD57, CD161
+
|
−
|-
+
|}
−
|Negative
 
−
|surface CD3
 
−
|-
 
−
|Restricted or lack of expression
 
−
|KIR isoforms (CD158a, b, c)
 
−
|-
 
−
|Negative
 
−
|EBV
 
−
|}<br />
 
−
 
 
−
<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}<ref name=":0" /></blockquote>
 
−
==Chromosomal Rearrangements (Gene Fusions)==
 
−
 
 
−
Put your text here and fill in the table
 
  
 +
==Gene Rearrangements==
 +
None
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
−
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
+
!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)
−
!Diagnostic Significance (Yes, No or Unknown)
+
!Prevalence -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
 
|-
 
|-
−
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
+
|
−
EXAMPLE 30% (add reference)
+
|
−
|Yes
+
|
−
|No
+
|
−
|Yes
+
|
−
|EXAMPLE
+
|
−
 
+
|
−
The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
+
|
−
|}
+
|}
−
 
−
 
 
−
 
 
−
<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
 
−
* Chromosomal Rearrangements (Gene Fusions)
 
−
* Individual Region Genomic Gain/Loss/LOH
 
−
* Characteristic Chromosomal Patterns
 
−
* Gene Mutations (SNV/INDEL)}}
 
−
 
 
−
* Presence of STAT mutations could imply therapeutic targets
 
  
−
</blockquote>
 
 
==Individual Region Genomic Gain/Loss/LOH==
 
==Individual Region Genomic Gain/Loss/LOH==
−
 
+
None
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable.'') </span>
 
−
 
 
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
−
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
+
!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
−
!Diagnostic Significance (Yes, No or Unknown)
+
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
−
!Prognostic Significance (Yes, No or Unknown)
+
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
−
!Therapeutic Significance (Yes, No or Unknown)
+
!'''Clinical Relevance Details/Other Notes'''
−
!Notes
 
−
|-
 
−
|EXAMPLE
 
−
 
 
−
7
 
−
|EXAMPLE Loss
 
−
|EXAMPLE
 
−
 
 
−
chr7:1- 159,335,973 [hg38]
 
−
|EXAMPLE
 
−
 
 
−
chr7
 
−
|Yes
 
−
|Yes
 
−
|No
 
−
|EXAMPLE
 
−
 
 
−
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
 
 
|-
 
|-
−
|EXAMPLE
+
|
−
 
+
|
−
8
+
|
−
|EXAMPLE Gain
+
|
−
|EXAMPLE
+
|
−
 
+
|
−
chr8:1-145,138,636 [hg38]
+
|
−
|EXAMPLE
 
−
 
 
−
chr8
 
−
|No
 
−
|No
 
−
|No
 
−
|EXAMPLE
 
−
 
 
−
Common recurrent secondary finding for t(8;21) (add reference).
 
 
|}
 
|}
−
==Characteristic Chromosomal Patterns==
 
−
 
−
Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis'')</span>
 
  
 +
==Characteristic Chromosomal or Other Global Mutational Patterns==
 +
None
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
 
!Chromosomal Pattern
 
!Chromosomal Pattern
−
!Diagnostic Significance (Yes, No or Unknown)
+
!Molecular Pathogenesis
−
!Prognostic Significance (Yes, No or Unknown)
+
!'''Prevalence -'''
−
!Therapeutic Significance (Yes, No or Unknown)
+
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
−
!Notes
+
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
 +
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
 +
!'''Clinical Relevance Details/Other Notes'''
 
|-
 
|-
−
|EXAMPLE
+
|
−
 
+
|
−
Co-deletion of 1p and 18q
+
|
−
|Yes
+
|
−
|No
+
|
−
|No
+
|
−
|EXAMPLE:
+
|}
  
−
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
 
−
|}
 
 
==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"
 +
|-
 +
!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'''
 +
|-
 +
|<span class="blue-text">EXAMPLE:</span>''EGFR''
  
−
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 and common as well either disease defining and/or clinically significant. Can include references 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.'') </span>
+
<br />
 +
|<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"
Line 230: Line 172:
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE: TP53; Variable LOF mutations
+
|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>
−
 
+
|
−
EXAMPLE:
+
|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>
−
 
 
−
EGFR; Exon 20 mutations
 
−
 
 
−
EXAMPLE: BRAF; Activating mutations
 
−
|EXAMPLE: TSG
 
−
|EXAMPLE: 20% (COSMIC)
 
−
 
 
−
EXAMPLE: 30% (add Reference)
 
−
|EXAMPLE: IDH1 R123H
 
−
|EXAMPLE: EGFR amplification
 
 
|
 
|
 
|
 
|
 +
|Yes
 +
|Higher frequency of symptomatic disease; no difference in overall survival <ref name=":2" />
 +
|No current approved therapeutic targets <ref name=":1" />
 +
| - 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> <br />
 +
|-
 +
|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" />
 +
|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" />
 
|
 
|
−
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
+
|Yes
−
<br />
+
|Unknown
−
|}
+
|Resistance to immunosuppressive agents have been observed; no current therapeutic target <ref name=":5" />
−
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.
+
| - Also seen in T-LGL
−
 
+
- Commonly associated with CD16 low phenotype
−
 
 
−
<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}
 
−
 
 
−
Put your text here and/or fill in the tables
 
  
−
{| class="wikitable sortable"
+
- Associated with thrombocytopenia <ref name=":4" />
 
|-
 
|-
−
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence
+
|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>
−
!Additional information
+
|
 +
|21.5% <ref name=":6" />
 +
|
 +
|
 +
|No
 +
|No
 +
|No
 +
| - Specific to NK-LGL <ref name=":3" />
 
|-
 
|-
−
|STAT3||
+
|TNFAIP3; loss of function <ref name=":4" />
−
* exons 12-21
+
|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" />
−
* encoding the Src homology 2 (SH2) domain
+
|
−
|EXAMPLE Tumor Suppressor||Driver mutation<ref name=":1" />||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=04 22, 2020|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>{{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>
+
|
 +
|No
 +
|No
 +
|No
 
|
 
|
 
|-
 
|-
−
|STAT5b<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>
+
|PI3K pathway genes; PIK3CD activating mutation, PIK3AP1 mutation not previously described <ref name=":5" />
 
|
 
|
−
* Exon 16
+
|3 patients (5%) <ref name=":5" />
−
 
 
−
* Missense N642H mutation in the SH2 domain<ref name=":1" />
 
 
|
 
|
−
|Driver mutation<ref name=":1" />
 
−
|1 patient<ref name=":1" />
 
 
|
 
|
−
*Progressed to aggressive disease<ref name=":1" />
+
|No
−
|}
+
|No
−
+
|No
−
===Other Mutations===
+
|PIK3CD mutations are observed as de novo germline mutations causing activated PI3 kinase delta syndrome <ref name=":5" />
−
{| class="wikitable sortable"
 
 
|-
 
|-
−
!Type!!Gene/Region/Other
+
|STAT5b; exon 16 missense N642H mutation in the SH2 domain, driver mutation <ref name=":1" />
−
|-
+
|
−
|Concomitant Mutations||EXAMPLE IDH1 R123H
+
|1 patient <ref name=":1" />
−
|-
+
|
−
|Secondary Mutations||EXAMPLE Trisomy 7
+
|
−
|-
+
|Unknown
−
|Mutually Exclusive||EXAMPLE EGFR Amplification
+
|Unknown; progressed to aggressive disease and died due to disease <ref name=":1" />
 +
|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.
  
−
</blockquote>
 
 
==Epigenomic Alterations==
 
==Epigenomic Alterations==
  
−
Put your text here
+
*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==
  
−
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
+
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" />
−
{| class="wikitable sortable"
+
==Genetic Diagnostic Testing Methods==
−
|-
+
 
−
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
+
*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>.
−
|-
 
−
|EXAMPLE: BRAF and MAP2K1; Activating mutations
 
−
|EXAMPLE: MAPK signaling
 
−
|EXAMPLE: Increased cell growth and proliferation
 
−
|-
 
−
|EXAMPLE: CDKN2A; Inactivating mutations
 
−
|EXAMPLE: Cell cycle regulation
 
−
|EXAMPLE: Unregulated cell division
 
−
|-
 
−
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
 
−
|EXAMPLE:  Histone modification, chromatin remodeling
 
−
|EXAMPLE:  Abnormal gene expression program
 
−
|}
 
  
−
<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}
+
*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" />.
  
−
* Most patients carry heavy mutational burden
+
*Absence of T-cell receptor gene rearrangement studies <ref name=":7" />.
−
*
 
  
−
</blockquote>
+
*Sanger Sequencing.
−
==Genetic Diagnostic Testing Methods==
 
  
−
Put your text here
+
*Whole Genome Sequencing.
  
 
==Familial Forms==
 
==Familial Forms==
  
−
Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
+
None
  
 
==Additional Information==
 
==Additional Information==
  
−
Put your text here
+
This disease is <u>defined/characterized</u> as detailed below:
 +
 
 +
*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">WHO Classification of Tumours Editorial Board, eds, WHO Classification of Tumours, Haematolymphoid Tumours Part A. 5th edition, IARC Press:Lyon, 2024.</ref>
 +
 
 +
The <u>epidemiology/prevalence</u> of this disease is detailed below:
 +
 
 +
*Median age: 60 years
 +
 
 +
*Does not show sex, racial, geographical, or genetic predisposition<ref name=":0" />
 +
 
 +
The <u>clinical features</u> of this disease are detailed below:
 +
 
 +
*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" />
 +
 
 +
The <u>sites of involvement</u> of this disease are detailed below:
 +
 
 +
*Peripheral blood and bone marrow
 +
 
 +
*Uncommon: spleen<ref name=":0" />
 +
 
 +
The <u>morphologic features</u> of this disease are detailed below:
 +
 
 +
*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" />
 +
 
 +
The <u>immunophenotype</u> of this disease is detailed below:
 +
 
 +
Positive - CD16, cytoplasmic CD3-epsilon, Cytotoxic markers (TIA1, granzyme B & granzyme M), CD94
 +
 
 +
Positive (frequent) - CD56
 +
 
 +
Decreased to negative - CD2, CD7, CD57, CD161
 +
 
 +
Restricted or lack of expression - KIR isoforms (CD158a, b, c)
 +
 
 +
Negative - surface CD3, EBV
  
 
==Links==
 
==Links==
  
−
Put your text placeholder here (or anywhere appropriate on the page) and use the "Link" icon at the top of the page <span style="color:#0070C0">(''Instructions: Once you have a text placeholder entered to which you want to add a link, highlight that text, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address including the "<nowiki>http://www</nowiki>." portion.'')</span>
+
N/A<br />
  
 
==References==
 
==References==
−
(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
+
<references />
  
−
'''
+
<br />
  
 
==Notes==
 
==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.
+
<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): 
 +
 
 +
       
 
<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>.
 
<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:DISEASE]][[Category:Diseases N]]
+
[[Category:HAEM5]]
 +
[[Category:DISEASE]]
 +
[[Category:Diseases N]]

Latest revision as of 12:42, 24 March 2025

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent 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.


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

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

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

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

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

Gene Mutations (SNV/INDEL)

Put your text here and fill in the table (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.)

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
EXAMPLE:EGFR


EXAMPLE: Exon 18-21 activating mutations EXAMPLE: Oncogene EXAMPLE: Common (lung cancer) EXAMPLE: T EXAMPLE: Yes (NCCN) EXAMPLE: 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).
EXAMPLE: TP53; Variable LOF mutations


EXAMPLE: Variable LOF mutations EXAMPLE: Tumor Supressor Gene EXAMPLE: Common (breast cancer) EXAMPLE: P EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations EXAMPLE: Activating mutations EXAMPLE: Oncogene EXAMPLE: Common (melanoma) EXAMPLE: T

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.

Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) 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] Yes Higher frequency of symptomatic disease; no difference in overall survival [3] No current approved therapeutic targets [1] - 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] 28% [6] - 34% [5] STAT3 [5] Yes Unknown 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] 21.5% [7] No No No - Specific to NK-LGL [4]
TNFAIP3; loss of function [5] TSG 6% [8] - 10% [5] No No No
PI3K pathway genes; PIK3CD activating mutation, PIK3AP1 mutation not previously described [6] 3 patients (5%) [6] No No 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] 1 patient [1] Unknown Unknown; progressed to aggressive disease and died due to disease [1] No current approved therapeutic targets [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

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

Genes and Main Pathways Involved

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. [4]

Genetic Diagnostic Testing Methods

  • Assessing for restricted expression of KIR isoforms, is often used as a surrogate for clonality [9].
  • 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 rearrangement studies [9].
  • Sanger Sequencing.
  • Whole Genome Sequencing.

Familial Forms

None

Additional Information

This disease is defined/characterized as detailed below:

  • 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.[10]

The epidemiology/prevalence of this disease is detailed below:

  • Median age: 60 years
  • Does not show sex, racial, geographical, or genetic predisposition[10]

The clinical features of this disease are detailed below:

  • 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[10]
  • Laboratory findings - Lymphocytosis, variable neutropenia and/or anemia[10]

The sites of involvement of this disease are detailed below:

  • Peripheral blood and bone marrow
  • Uncommon: spleen[10]

The morphologic features of this disease are detailed below:

  • 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.[10]

The immunophenotype of this disease is detailed below:

Positive - CD16, cytoplasmic CD3-epsilon, Cytotoxic markers (TIA1, granzyme B & granzyme M), CD94

Positive (frequent) - CD56

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. ↑ Jump up to: 1.0 1.1 1.2 1.3 1.4 1.5 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. ↑ 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. ↑ Jump up to: 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. ↑ Jump up to: 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. ↑ Jump up to: 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. ↑ Jump up to: 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. ↑ Jump up to: 7.0 7.1 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. ↑ Jump up to: 9.0 9.1 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.
  10. ↑ Jump up to: 10.0 10.1 10.2 10.3 10.4 10.5 WHO Classification of Tumours Editorial Board, eds, WHO Classification of Tumours, Haematolymphoid Tumours Part A. 5th edition, IARC Press:Lyon, 2024.


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 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):


*Citation of this Page: “NK-large granular lymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/24/2025, https://ccga.io/index.php/HAEM5:NK-large_granular_lymphocytic_leukaemia.

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