HAEM5:NK-large granular lymphocytic leukaemia: Difference between revisions
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[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]] | [[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]] | ||
==Primary Author(s)*== | ==Primary Author(s)*== | ||
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{| class="wikitable" | {| class="wikitable" | ||
|Acceptable | |Acceptable | ||
|Chronic lymphoproliferative disorder of NK cells; chronic NK-large granular lymphocyte lymphoproliferative disorder | |Chronic lymphoproliferative disorder of NK cells; chronic NK-large granular lymphocyte lymphoproliferative disorder | ||
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!Clinical Relevance Details/Other Notes | !Clinical Relevance Details/Other Notes | ||
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!Clinical Relevance Details/Other Notes | !Clinical Relevance Details/Other Notes | ||
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!Clinical Relevance Details/Other Notes | !Clinical Relevance Details/Other Notes | ||
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==Gene Mutations (SNV/INDEL)== | ==Gene Mutations (SNV/INDEL)== | ||
{| class="wikitable sortable" | {| class="wikitable sortable" | ||
|- | |- | ||
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!Clinical Relevance Details/Other Notes | !Clinical Relevance Details/Other Notes | ||
|- | |- | ||
|STAT3 | |''STAT3'' | ||
|Exons 12-21 encoding the Src homology 2 (SH2 domain on two hotspots: D661 and Y640), driver mutation <ref name=":1" /> | |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 name=":8" /> to 30% <ref name=":2" /> | |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> | ||
(NK-LGL) | (NK-LGL) | ||
|D,P | |D,P | ||
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Higher frequency of symptomatic disease; no difference in overall survival <ref name=":2" /> | Higher frequency of symptomatic disease; no difference in overall survival <ref name=":2" /> | ||
Also seen in T-LGL <ref name=":2" /> | Also seen in T-LGL <ref name=":2" /> | ||
Commonly associated with CD16high/CD57low or cytotoxic memory NK-LGL's <ref name=":3" /> | 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 | |''TET2'' | ||
|Loss of function <ref name=":4" /> | |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" /> | ||
|Common: 28% <ref name=":5" /> - 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" /> | ||
(NK-LGL) | (NK-LGL) | ||
|D | |D | ||
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Associated with thrombocytopenia <ref name=":4" /> | Associated with thrombocytopenia <ref name=":4" /> | ||
|- | |- | ||
|CCL22 | |''CCL22'' | ||
|Gain of function <ref name=":6" /> | |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> | ||
| | | | ||
|Common: 21.5% <ref name=":6" /> | |Common: 21.5% <ref name=":6" /> | ||
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|Specific to NK-LGL <ref name=":3" /> | |Specific to NK-LGL <ref name=":3" /> | ||
|- | |- | ||
|TNFAIP3 | |''TNFAIP3'' | ||
|Loss of function <ref name=":4" /> | |Loss of function <ref name=":4" /> | ||
|TSG | |TSG | ||
|Recurrent: 6% <ref name=":9" /> - 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) | (NK-LGL) | ||
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|- | |- | ||
|PI3K pathway genes | |''PI3K'' pathway genes | ||
|PIK3CD activating mutation, PIK3AP1 mutation not previously described <ref name=":5" /> | |PIK3CD activating mutation, PIK3AP1 mutation not previously described <ref name=":5" /> | ||
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|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 | |''STAT5b'' | ||
|Exon 16 missense N642H mutation in the SH2 domain, driver mutation <ref name=":1" /> | |Exon 16 missense N642H mutation in the SH2 domain, driver mutation <ref name=":1" /> | ||
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|}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. | |}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. | ||
==Epigenomic Alterations== | |||
TET2 shows increased methylated regions in clonal NK-LGLs compared to normal NK-cells <ref name=":5" /> | |||
==Genes and Main Pathways Involved== | |||
{| class="wikitable sortable" | {| 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" /> | |||
| | |||
|} | |} | ||
==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 | *Absence of T-cell receptor gene rearrangements by PCR<ref name=":7" />. | ||
*Sanger Sequencing. | *Sanger Sequencing. | ||
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==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" /> | *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" /> | *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" /> | |||
<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 | ||
Negative - surface CD3, EBV | |||
==Links== | ==Links== | ||
N/A | N/A | ||
==References== | ==References== | ||
<references /> | <references /> | ||
< | ==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>. | |||
<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): | ||
[[Category:HAEM5]] | [[Category:HAEM5]] | ||
[[Category:DISEASE]] | [[Category:DISEASE]] | ||
[[Category:Diseases N]] | [[Category:Diseases N]] | ||