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 2023-12-04. 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>
 +
 +
<br />
 +
 
==Primary Author(s)*==
 
==Primary Author(s)*==
  
−
Michelle Don, MD
+
Hailee St. Louis, MD, UC San Diego
 +
 
 +
Michelle Don, MD, UC San Diego
  
 
__TOC__
 
__TOC__
  
−
==Cancer Category / Type==
+
==WHO Classification of Disease==
  
−
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>
+
{| class="wikitable"
−
 
+
!Structure
−
==Cancer Sub-Classification / Subtype==
+
!Disease
−
 
+
|-
−
Put your text here
+
|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
 +
|}
  
 
==Definition / Description of Disease==
 
==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.
  
  
−
*Persistent (>6 months) increase in peripheral blood NK-cell count without a clearly identifiable cause
+
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" />
−
*NK-cell count usually >2x10<sup>9</sup>/L
 
−
*Indolent
 
  
 +
==Synonyms / Terminology==
  
−
<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>
+
*Chronic lymphoproliferative disorder of NK cells
−
==Synonyms / Terminology==
 
  
 +
*Chronic NK-large granular lymphocyte lymphoproliferative disorder
  
−
*Chronic NK-lymphocytosis
+
*Chronic NK-cell lymphocytosis (historical)
−
*Chronic NK large granular lymphocyte lymphoproliferative disorder
 
−
*Indolent large granular NK-cell lymphoproliferative disorder
 
  
 +
*Indolent leukemia of NK cells (historical) <ref name=":0" />
  
−
<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==
 
==Epidemiology / Prevalence==
  
 +
*Median age: 60 years
  
−
*Adults (median age 60 years old)
+
*Does not show sex, racial, geographical, or genetic predisposition <ref name=":0" />
−
*No known racial or genetic predisposition
 
−
 
 
  
−
<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==
 
==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'''
 
|'''Signs and Symptoms'''
−
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
+
|Asymptomatic (incidental finding on complete blood counts)
−
 
+
May occur in association with autoimmune disorders, solid tumors, hematological neoplasms, and neuropathy
−
EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
−
 
 
−
EXAMPLE Fatigue
 
  
−
EXAMPLE Lymphadenopathy (uncommon)
+
Uncommon/atypical: splenomegaly, hepatomegaly, lymphadenopathy, skin involvement <ref name=":0" />
 
|-
 
|-
 
|'''Laboratory Findings'''
 
|'''Laboratory Findings'''
−
|EXAMPLE Cytopenias
+
|Lymphocytosis, variable neutropenia and/or anemia <ref name=":0" />
−
 
 
−
EXAMPLE Lymphocytosis (low level)
 
 
|}
 
|}
  
 
==Sites of Involvement==
 
==Sites of Involvement==
  
 +
*Peripheral blood and bone marrow
  
−
*Peripheral blood
+
*Uncommon: spleen <ref name=":0" />
−
*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==
 
==Morphologic Features==
  
 +
*NK-cells are typically intermediate to large in size with small, round nuclei and moderate cytoplasm with fine or coarse azurophilic granules.
  
−
*NK-cells are typically intermediate in size
+
*Intrasinusoidal and sometimes interstitial infiltration of bone marrow and possibly spleen. <ref name=":0" />
−
*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 />
+
==Immunophenotype <ref name=":0" />==
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 95: Line 96:
 
|Positive||cytoplasmic CD3-epsilon
 
|Positive||cytoplasmic CD3-epsilon
 
|-
 
|-
−
|Positive (frequent)||weak CD56
+
|Positive (frequent)||CD56
 
|-
 
|-
 
|Positive||Cytotoxic markers  
 
|Positive||Cytotoxic markers  
Line 114: Line 115:
 
|Negative
 
|Negative
 
|EBV
 
|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)==
 
==Chromosomal Rearrangements (Gene Fusions)==
 +
None
  
−
Put your text here and fill in the table
+
==Individual Region Genomic Gain / Loss / LOH==
  
−
{| class="wikitable sortable"
+
None
−
|-
+
==Characteristic Chromosomal Patterns==
−
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
 
−
!Diagnostic Significance (Yes, No or Unknown)
 
−
!Prognostic Significance (Yes, No or Unknown)
 
−
!Therapeutic Significance (Yes, No or Unknown)
 
−
!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).
+
None
−
|}
+
==Gene Mutations (SNV / INDEL)==
−
 
−
 
 
−
 
 
−
<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==
 
−
 
 
−
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
+
!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)
+
!'''Diagnostic Significance (Yes, No or Unknown)'''
 
!Prognostic Significance (Yes, No or Unknown)
 
!Prognostic Significance (Yes, No or Unknown)
 
!Therapeutic Significance (Yes, No or Unknown)
 
!Therapeutic Significance (Yes, No or Unknown)
 
!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE
+
|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>
−
 
+
|
−
7
+
|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>
−
|EXAMPLE Loss
+
|
−
|EXAMPLE
+
|
−
 
 
−
chr7:1- 159,335,973 [hg38]
 
−
|EXAMPLE
 
−
 
 
−
chr7
 
 
|Yes
 
|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" />
 +
|
 
|Yes
 
|Yes
−
|No
+
|Unknown
−
|EXAMPLE
+
|Resistance to immunosuppressive agents have been observed; no current therapeutic target <ref name=":5" />
 +
| - Also seen in T-LGL
 +
- Commonly associated with CD16 low phenotype
  
−
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).
+
- Associated with thrombocytopenia <ref name=":4" />
 
|-
 
|-
−
|EXAMPLE
+
|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>
−
 
+
|
−
8
+
|21.5% <ref name=":6" />
−
|EXAMPLE Gain
+
|
−
|EXAMPLE
+
|
−
 
 
−
chr8:1-145,138,636 [hg38]
 
−
|EXAMPLE
 
−
 
 
−
chr8
 
 
|No
 
|No
 
|No
 
|No
 
|No
 
|No
−
|EXAMPLE
+
| - Specific to NK-LGL <ref name=":3" />
−
 
 
−
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>
 
−
 
 
−
{| class="wikitable sortable"
 
 
|-
 
|-
−
!Chromosomal Pattern
+
|TNFAIP3; loss of function <ref name=":4" />
−
!Diagnostic Significance (Yes, No or Unknown)
+
|TSG
−
!Prognostic Significance (Yes, No or Unknown)
+
|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" />
−
!Therapeutic Significance (Yes, No or Unknown)
+
|
−
!Notes
+
|
−
|-
+
|No
−
|EXAMPLE
 
−
 
 
−
Co-deletion of 1p and 18q
 
−
|Yes
 
 
|No
 
|No
 
|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)==
 
−
 
 
−
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>
 
−
 
 
−
{| class="wikitable sortable"
 
−
|-
 
−
!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
 
 
|-
 
|-
−
|EXAMPLE: TP53; Variable LOF mutations
+
|PI3K pathway genes; PIK3CD activating mutation, PIK3AP1 mutation not previously described <ref name=":5" />
−
 
 
−
EXAMPLE:
 
−
 
 
−
EGFR; Exon 20 mutations
 
−
 
 
−
EXAMPLE: BRAF; Activating mutations
 
−
|EXAMPLE: TSG
 
−
|EXAMPLE: 20% (COSMIC)
 
−
 
 
−
EXAMPLE: 30% (add Reference)
 
−
|EXAMPLE: IDH1 R123H
 
−
|EXAMPLE: EGFR amplification
 
 
|
 
|
 +
|3 patients (5%) <ref name=":5" />
 
|
 
|
 
|
 
|
−
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
+
|No
−
<br />
+
|No
−
|}
+
|No
−
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.
+
|PIK3CD mutations are observed as de novo germline mutations causing activated PI3 kinase delta syndrome <ref name=":5" />
−
 
 
−
 
 
−
<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"
 
−
|-
 
−
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence
 
−
!Additional information
 
 
|-
 
|-
−
|STAT3||
+
|STAT5b; exon 16 missense N642H mutation in the SH2 domain, driver mutation <ref name=":1" />
−
* exons 12-21
 
−
 
 
−
* 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>
 
 
|
 
|
−
|-
+
|1 patient <ref name=":1" />
−
|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>
 
 
|
 
|
−
* Exon 16
 
−
 
−
* Missense N642H mutation in the SH2 domain<ref name=":1" />
 
 
|
 
|
−
|Driver mutation<ref name=":1" />
+
|Unknown
−
|1 patient<ref name=":1" />
+
|Unknown; progressed to aggressive disease and died due to disease <ref name=":1" />
 +
|No current approved therapeutic targets <ref name=":1" />
 
|
 
|
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*Progressed to aggressive disease<ref name=":1" />
 
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|}
 
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===Other Mutations===
 
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{| class="wikitable sortable"
 
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|-
 
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!Type!!Gene/Region/Other
 
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|-
 
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|Concomitant Mutations||EXAMPLE IDH1 R123H
 
−
|-
 
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|Secondary Mutations||EXAMPLE Trisomy 7
 
−
|-
 
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|Mutually Exclusive||EXAMPLE EGFR Amplification
 
 
|}
 
|}
 +
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
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*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==
  
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Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table.'')</span>
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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==
−
|-
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!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>.
−
|-
 
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|EXAMPLE: BRAF and MAP2K1; Activating mutations
 
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|EXAMPLE: MAPK signaling
 
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|EXAMPLE: Increased cell growth and proliferation
 
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|-
 
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|EXAMPLE: CDKN2A; Inactivating mutations
 
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|EXAMPLE: Cell cycle regulation
 
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|EXAMPLE: Unregulated cell division
 
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|-
 
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|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
 
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|EXAMPLE:  Histone modification, chromatin remodeling
 
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|EXAMPLE:  Abnormal gene expression program
 
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|}
 
  
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<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}
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*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" />.
  
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* Most patients carry heavy mutational burden
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*Absence of T-cell receptor gene rearrangement studies <ref name=":7" />.
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*
 
  
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</blockquote>
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*Sanger Sequencing.
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==Genetic Diagnostic Testing Methods==
 
  
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Put your text here
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*Whole Genome Sequencing.
  
 
==Familial Forms==
 
==Familial Forms==
  
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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>
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None
  
 
==Additional Information==
 
==Additional Information==
  
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None
  
 
==Links==
 
==Links==
  
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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>
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<br />
  
 
==References==
 
==References==
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(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 />
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<references />
  
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'''
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<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 CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
 
<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>.
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[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases N]]
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[[Category:HAEM5]]
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[[Category:DISEASE]]
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[[Category:Diseases N]]

Latest revision as of 17:35, 6 September 2024


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

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. [1]

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) [1]

Epidemiology / Prevalence

  • Median age: 60 years
  • Does not show sex, racial, geographical, or genetic predisposition [1]

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 [1]

Laboratory Findings Lymphocytosis, variable neutropenia and/or anemia [1]

Sites of Involvement

  • Peripheral blood and bone marrow
  • Uncommon: spleen [1]

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. [1]

Immunophenotype [1]

Finding Marker
Positive CD16
Positive cytoplasmic CD3-epsilon
Positive (frequent) CD56
Positive Cytotoxic markers

(TIA1, granzyme B & granzyme M)

Positive CD94
Decreased to negative CD2, CD7, CD57, CD161
Negative surface CD3
Restricted or lack of expression KIR isoforms (CD158a, b, c)
Negative EBV

Chromosomal Rearrangements (Gene Fusions)

None

Individual Region Genomic Gain / Loss / LOH

None

Characteristic Chromosomal Patterns

None

Gene Mutations (SNV / INDEL)

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 [2] Variable: 9% [3] to 30% [4] Yes Higher frequency of symptomatic disease; no difference in overall survival [4] No current approved therapeutic targets [2] - Also seen in T-LGL [4]

- Commonly associated  with CD16high/CD57low or cytotoxic memory NK-LGL's [5]

TET2; loss of function [6] Other: TET2 induces an oxidation of 5mC into 5hmc in active DNA demethylation [6] 28% [7] - 34% [6] STAT3 [6] Yes Unknown Resistance to immunosuppressive agents have been observed; no current therapeutic target [7] - Also seen in T-LGL

- Commonly associated with CD16 low phenotype

- Associated with thrombocytopenia [6]

CCL22; gain of function [8] 21.5% [8] No No No - Specific to NK-LGL [5]
TNFAIP3; loss of function [6] TSG 6% [9] - 10% [6] No No No
PI3K pathway genes; PIK3CD activating mutation, PIK3AP1 mutation not previously described [7] 3 patients (5%) [7] No No No PIK3CD mutations are observed as de novo germline mutations causing activated PI3 kinase delta syndrome [7]
STAT5b; exon 16 missense N642H mutation in the SH2 domain, driver mutation [2] 1 patient [2] Unknown Unknown; progressed to aggressive disease and died due to disease [2] No current approved therapeutic targets [2]

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 [7]

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. [5]

Genetic Diagnostic Testing Methods

  • Assessing for restricted expression of KIR isoforms, is often used as a surrogate for clonality [10].
  • Mutational screen for STAT3, STAT5b, TET2, TNFAIP3 and CCL22 mutations may be more helpful when compared to KIR analysis on diagnostic work-up [5].
  • Absence of T-cell receptor gene rearrangement studies [10].
  • Sanger Sequencing.
  • Whole Genome Sequencing.

Familial Forms

None

Additional Information

None

Links


References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Cite error: Invalid <ref> tag; no text was provided for refs named :0
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 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.
  3. ↑ 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).
  4. ↑ 4.0 4.1 4.2 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.
  5. ↑ 5.0 5.1 5.2 5.3 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).
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 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).
  7. ↑ 7.0 7.1 7.2 7.3 7.4 7.5 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).
  8. ↑ 8.0 8.1 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)
  9. ↑ 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)
  10. ↑ 10.0 10.1 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.


Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “NK-large granular lymphocytic leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:NK-large_granular_lymphocytic_leukaemia.

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