Difference between revisions of "HAEM5:Aggressive NK-cell leukaemia"

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{{DISPLAYTITLE:Aggressive NK-cell leukaemia}}
 
{{DISPLAYTITLE:Aggressive NK-cell 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 2023-12-07. The original page can be found at [[HAEM4:Aggressive NK-cell Leukemia]].
+
<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:Aggressive NK-cell Leukemia]].
 
}}</blockquote>
 
}}</blockquote>
  
−
<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples). Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>
+
<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ HGVS-based nomenclature for variants], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>
  
 
==Primary Author(s)*==
 
==Primary Author(s)*==
Line 20: Line 20:
 
==WHO Classification of Disease==
 
==WHO Classification of Disease==
  
−
Aggressive NK-cell leukaemia
+
Aggressive NK-cell Leukaemia
  
 
==Definition / Description of Disease==
 
==Definition / Description of Disease==
Line 30: Line 30:
  
 
==Epidemiology / Prevalence==
 
==Epidemiology / Prevalence==
−
Aggressive NK-cell leukaemia impacts young to middle-aged adults with peak incidence during 3rd and 5th decades of life (Mean age: 40 years).<ref name=":1" /> There is no gender predilection and most prevalent in Asia, Central and South America.<ref name=":0">{{Cite journal|last=El Hussein|first=Siba|last2=Patel|first2=Keyur P.|last3=Fang|first3=Hong|last4=Thakral|first4=Beenu|last5=Loghavi|first5=Sanam|last6=Kanagal-Shamanna|first6=Rashmi|last7=Konoplev|first7=Sergej|last8=Jabbour|first8=Elias J.|last9=Medeiros|first9=L. Jeffrey|date=09 2020|title=Genomic and Immunophenotypic Landscape of Aggressive NK-Cell Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/32590457|journal=The American Journal of Surgical Pathology|volume=44|issue=9|pages=1235–1243|doi=10.1097/PAS.0000000000001518|issn=1532-0979|pmid=32590457}}</ref> EBV-negative cases tend to occur in older patients, with no significant difference in Asian vs. non-Asian populations.<ref name=":2" /> Median survival is very short, <2 months.
+
Aggressive NK-cell leukaemia impacts young to middle-aged adults with peak incidence during 3rd and 5th decades of life (Mean age: 40 years).<ref name=":1" /> There is no gender predilection and most prevalent in Asia, Central and South America.<ref name=":0">{{Cite journal|last=El Hussein|first=Siba|last2=Patel|first2=Keyur P.|last3=Fang|first3=Hong|last4=Thakral|first4=Beenu|last5=Loghavi|first5=Sanam|last6=Kanagal-Shamanna|first6=Rashmi|last7=Konoplev|first7=Sergej|last8=Jabbour|first8=Elias J.|last9=Medeiros|first9=L. Jeffrey|date=09 2020|title=Genomic and Immunophenotypic Landscape of Aggressive NK-Cell Leukemia|url=https://pubmed.ncbi.nlm.nih.gov/32590457|journal=The American Journal of Surgical Pathology|volume=44|issue=9|pages=1235–1243|doi=10.1097/PAS.0000000000001518|issn=1532-0979|pmid=32590457}}</ref> Median survival is very short, <2 months. EBV-negative cases tend to occur in older patients, with no significant difference in Asian vs. non-Asian populations.<ref name=":2" /> EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells.'''''<ref name=":4" />'''''
  
  
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==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>
+
Most common presentation is with constitutional symptoms and frequently associated hepatosplenomegaly is noted on physical examination.<ref name=":1" /><ref name=":4" />
 
{| class="wikitable"
 
{| class="wikitable"
 
|'''Signs and Symptoms'''
 
|'''Signs and Symptoms'''
 
|Constitutional symptoms (weight loss, fever, night sweats)
 
|Constitutional symptoms (weight loss, fever, night sweats)
  
−
Hepatosplenomegaly common<ref name=":1" />
+
Hepatosplenomegaly common
  
 
Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome
 
Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome
−
 
−
'''''<nowiki>*</nowiki>EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells<ref name=":4" />'''''
 
 
|-
 
|-
 
|'''Laboratory Findings'''
 
|'''Laboratory Findings'''
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==Sites of Involvement==
 
==Sites of Involvement==
  
−
Peripheral blood, bone marrow, liver, spleen, and lymph nodes. Extranodal involvement sites are organs including skin, lungs, soft tissue and omentum can be seen.<ref name=":5" />
+
Peripheral blood, bone marrow, liver, spleen, and lymph nodes are frequently involved. Extranodal involvement sites are organs including skin, lungs, soft tissue and omentum has also been reported.<ref name=":5" />
  
  
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==Immunophenotype==
 
==Immunophenotype==
  
−
The leukaemic cells .......
+
The leukaemic cells show demonstrate the following phenotypic expression.<ref name=":1" /><ref name=":0" />
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
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==Chromosomal Rearrangements (Gene Fusions)==
 
==Chromosomal Rearrangements (Gene Fusions)==
  
−
Put your text here and fill in the table
+
Due to the rarity of this lymphoma the data in recurrent chromosomal rearrangement is extremely scant. There have been chromosomal rearrangements reported in association with the aggressive NK-cell leukaemia, however, none of them are considered specific for the disease.
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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!Therapeutic Significance (Yes, No or Unknown)
 
!Therapeutic Significance (Yes, No or Unknown)
 
!Notes
 
!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).
 
 
|}
 
|}
 
 
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−
<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>{{Cite journal|last=Dufva|first=Olli|last2=Kankainen|first2=Matti|last3=Kelkka|first3=Tiina|last4=Sekiguchi|first4=Nodoka|last5=Awad|first5=Shady Adnan|last6=Eldfors|first6=Samuli|last7=Yadav|first7=Bhagwan|last8=Kuusanmäki|first8=Heikki|last9=Malani|first9=Disha|date=04 19, 2018|title=Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target|url=https://pubmed.ncbi.nlm.nih.gov/29674644|journal=Nature Communications|volume=9|issue=1|pages=1567|doi=10.1038/s41467-018-03987-2|issn=2041-1723|pmc=5908809|pmid=29674644}}</ref></blockquote>
+
<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=":6">{{Cite journal|last=Dufva|first=Olli|last2=Kankainen|first2=Matti|last3=Kelkka|first3=Tiina|last4=Sekiguchi|first4=Nodoka|last5=Awad|first5=Shady Adnan|last6=Eldfors|first6=Samuli|last7=Yadav|first7=Bhagwan|last8=Kuusanmäki|first8=Heikki|last9=Malani|first9=Disha|date=04 19, 2018|title=Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target|url=https://pubmed.ncbi.nlm.nih.gov/29674644|journal=Nature Communications|volume=9|issue=1|pages=1567|doi=10.1038/s41467-018-03987-2|issn=2041-1723|pmc=5908809|pmid=29674644}}</ref></blockquote>
 
</blockquote>
 
</blockquote>
 
==Individual Region Genomic Gain / Loss / LOH==
 
==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>
+
There have been a few chromosomal abnormalities associated with aggressive NK-cell leukaemia as listed below, however, the specificity along with prognostic and therapeutic significance is unknown.<ref name=":2" />
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE
+
|1
−
 
+
|Gain
−
7
+
|1q23.1-q23.2
−
|EXAMPLE Loss
+
|
−
|EXAMPLE
+
|No
−
 
+
|Unknown
−
chr7:1- 159,335,973 [hg38]
+
|Unknown
−
|EXAMPLE
+
|
−
 
+
|-
−
chr7
+
|1
−
|Yes
+
|Gain
−
|Yes
+
|1q31.3-q44
 +
|
 
|No
 
|No
−
|EXAMPLE
+
|Unknown
−
 
+
|Unknown
−
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
+
|7
−
 
+
|Loss
−
8
+
|7p15.1-q22.3
−
|EXAMPLE Gain
+
|
−
|EXAMPLE
 
−
 
 
−
chr8:1-145,138,636 [hg38]
 
−
|EXAMPLE
 
−
 
 
−
chr8
 
 
|No
 
|No
 +
|Unknown
 +
|Unknown
 +
|
 +
|-
 +
|17
 +
|Loss
 +
|17p13.1
 +
|
 
|No
 
|No
 +
|Unknown
 +
|Unknown
 +
|
 +
|-
 +
|6
 +
|Loss
 +
|6q16.1–q27
 +
|
 
|No
 
|No
−
|EXAMPLE
+
|Unknown
−
 
+
|Unknown
−
Common recurrent secondary finding for t(8;21) (add reference).
+
|
 
|}
 
|}
  
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==Characteristic Chromosomal Patterns==
 
==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>
+
Due to rare nature of disease, cytogenetics data is limited. The common abnormalities include del(6)(q21q25) and del(11q), however, none of these abnormalities are specific and their clinical significance is unknown.<ref name=":2" /> Complex karyotypes with unbalanced rearrangements are frequently seen.
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 261: Line 261:
 
!Therapeutic Significance (Yes, No or Unknown)
 
!Therapeutic Significance (Yes, No or Unknown)
 
!Notes
 
!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).
 
 
|}
 
|}
  
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</blockquote>
 
</blockquote>
 
==Gene Mutations (SNV / INDEL)==
 
==Gene Mutations (SNV / INDEL)==
 +
Mutations in the ''JAK-STAT'' pathway appear to be mutually exclusive.<ref name=":3" /> Most ''STAT3'' and ''STAT5B''  mutations localized to exons 20 and 21 encoding the Src homology 2 (SH2) domain, which causes ''STAT'' dimerization. Other mutations identified: 9p copy gains (containing ''JAK2),'' point mutation in protein tyrosine phosphatase (''PTPRK'') (tumor suppressor that negatively regulates ''STAT3''). mutations in ''PTPN4'' and ''PTPN23.<ref name=":2" /><ref name=":7" />''
  
−
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>
+
Molecular abnormalities present possible therapeutic implications. Dufva et al identified high sensitivity of ANKL cell lines to JAK and BCL2 inhibition. Other possibly effective drug classes are heat shock protein 90 (HSP90) inhibitors, polo-like kinase (PLK) inhibitors, aurora kinase (AURK) inhibitors, cyclin-dependent kinase inhibitors, and histone deacetylase inhibitors.<ref name=":6" />
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE: TP53; Variable LOF mutations
+
|JAK/STAT/c-MYC pathway (including ''STAT3, STAT5B, STAT5A, JAK2, JAK3, STAT6, SOCS31, SOCS3'' and ''PTPN11'')
−
 
+
|Oncogene
−
EXAMPLE:
+
|21 - 66.6%
−
 
+
|
−
EGFR; Exon 20 mutations
+
|
−
 
 
−
EXAMPLE: BRAF; Activating mutations
 
−
|EXAMPLE: TSG
 
−
|EXAMPLE: 20% (COSMIC)
 
−
 
 
−
EXAMPLE: 30% (add Reference)
 
−
|EXAMPLE: IDH1 R123H
 
−
|EXAMPLE: EGFR amplification
 
 
|
 
|
 
|
 
|
 
|
 
|
−
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
+
|Gain of function
 
<br />
 
<br />
 +
|-
 +
|RAS/MAPK pathway
 +
|Oncogene
 +
|16.7 - 29%
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|Gain of function
 +
|-
 +
|''TP53''
 +
|Tumor suppressor gene
 +
|7 -50%
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|Loss of function
 +
|-
 +
|''BCL2''
 +
|Oncogene
 +
|NA
 +
|
 +
|
 +
|
 +
|
 +
|
 +
|Gain of function
 
|}
 
|}
 
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.
 
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.
Line 352: Line 365:
  
  
−
<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=":2">{{Cite journal|last=El Hussein|first=Siba|last2=Medeiros|first2=L. Jeffrey|last3=Khoury|first3=Joseph D.|date=10 09, 2020|title=Aggressive NK Cell Leukemia: Current State of the Art|url=https://pubmed.ncbi.nlm.nih.gov/33050313|journal=Cancers|volume=12|issue=10|doi=10.3390/cancers12102900|issn=2072-6694|pmc=7600035|pmid=33050313}}</ref><ref>{{Cite journal|last=Gao|first=Juehua|last2=Zhang|first2=Yanming|last3=Yaseen|first3=Nabeel R.|last4=Fang|first4=Yuqiang|last5=Lu|first5=Xinyan|last6=Sukhanova|first6=Madina|last7=Chen|first7=Qing|last8=Chen|first8=Yi-Hua|date=2020-11|title=Comprehensive molecular genetic studies of Epstein-Barr virus-negative aggressive Natural killer-cell leukemia/lymphoma|url=https://linkinghub.elsevier.com/retrieve/pii/S0046817720301702|journal=Human Pathology|language=en|volume=105|pages=20–30|doi=10.1016/j.humpath.2020.08.008}}</ref><ref name=":3" /></blockquote>
+
<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=":2">{{Cite journal|last=El Hussein|first=Siba|last2=Medeiros|first2=L. Jeffrey|last3=Khoury|first3=Joseph D.|date=10 09, 2020|title=Aggressive NK Cell Leukemia: Current State of the Art|url=https://pubmed.ncbi.nlm.nih.gov/33050313|journal=Cancers|volume=12|issue=10|doi=10.3390/cancers12102900|issn=2072-6694|pmc=7600035|pmid=33050313}}</ref><ref name=":7">{{Cite journal|last=Gao|first=Juehua|last2=Zhang|first2=Yanming|last3=Yaseen|first3=Nabeel R.|last4=Fang|first4=Yuqiang|last5=Lu|first5=Xinyan|last6=Sukhanova|first6=Madina|last7=Chen|first7=Qing|last8=Chen|first8=Yi-Hua|date=2020-11|title=Comprehensive molecular genetic studies of Epstein-Barr virus-negative aggressive Natural killer-cell leukemia/lymphoma|url=https://linkinghub.elsevier.com/retrieve/pii/S0046817720301702|journal=Human Pathology|language=en|volume=105|pages=20–30|doi=10.1016/j.humpath.2020.08.008}}</ref><ref name=":3" /></blockquote>
 
</blockquote>
 
</blockquote>
 
==Epigenomic Alterations==
 
==Epigenomic Alterations==
  
−
 
+
Mutations seen in epigenetic regulatory molecules including RNA helicase ''DDX3X'' (28%), ''TET2'' (28%), ''CREBBP'' (21%), and ''MLL2'' (21%) have been reported.<ref name=":2" /><ref name=":3" />
−
Mutations seen in epigenetic regulatory molecules:
 
−
 
 
−
*RNA helicase ''DDX3X'' (28%)
 
−
*''TET2'' (28%)
 
−
*''CREBBP'' (21%)
 
−
*''MLL2'' (21%)
 
  
  
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==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>
+
The disease pathogenesis is regulated by a complex interplay between diverse molecular pathways especially that involving the upregulated JAK/STAT-MYC biosynthesis axis due to upstream STAT3 activation of the MYC transcription program. Thought in some cases to be as a result of highly expressed EBV-encoded small RNAs (EBERs) causing release of IL-10.<ref name=":2" />
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
|-
 
|-
−
|EXAMPLE: BRAF and MAP2K1; Activating mutations
+
|STAT3 activation of the MYC transcription program
−
|EXAMPLE: MAPK signaling
+
|JAK/STAT-MYC biosynthesis axis
−
|EXAMPLE: Increased cell growth and proliferation
+
|Increased cell survival and proliferation
 
|-
 
|-
−
|EXAMPLE: CDKN2A; Inactivating mutations
+
|Alterations in RAS-MAPK pathway
−
|EXAMPLE: Cell cycle regulation
+
|RAS-MAPK pathway
−
|EXAMPLE: Unregulated cell division
+
|Increased cell survival and proliferation
 
|-
 
|-
−
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
+
|''BCOR, KMT2D/MLL2'', ''SETD2'', ''PRDM9'', ''CREBBP'', and ''TET2''
−
|EXAMPLE:  Histone modification, chromatin remodeling
+
|Epigenetic modifier genes
−
|EXAMPLE:  Abnormal gene expression program
+
|Altering the epigenetic landscape
 +
|-
 +
|''TP53, ASXL1, ASXL2, BRINP3''
 +
|DNA damage repair
 +
|??
 +
|-
 +
|''PRPF40B''
 +
|mRNA splicing factors
 +
|??
 
|}
 
|}
  
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−
<nowiki>*</nowiki>Thought in some cases to be as a result of highly expressed EBV-encoded small RNAs (EBERs) causing release of IL-10.
+
<nowiki>*</nowiki>Thought in some cases to be as a result of highly expressed EBV-encoded small RNAs (EBERs) causing release of IL-10.<ref name=":2" />
  
  
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==Genetic Diagnostic Testing Methods==
 
==Genetic Diagnostic Testing Methods==
  
−
 
+
Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.<ref name=":0" />
−
Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.
 
  
  

Latest revision as of 16:50, 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:Aggressive NK-cell Leukemia.

(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)

Primary Author(s)*

Shanelle De Lancy, MD, Rabail Aslam, MD, Shashirekha Shetty, PhD

Case Western Reserve University, Cleveland, OH

WHO Classification of Disease

Aggressive NK-cell Leukaemia

Definition / Description of Disease

Aggressive NK-cell leukaemia is a malignant proliferation of NK-cells, often associated with EBV infection, however, a subset of cases could be EBV negative. The disease has an extremely aggressive clinical course with poor response to chemotherapy, frequent relapses noted in patient who have had previously achieved complete remission (+/- bone marrow transplantation).

Synonyms / Terminology

Aggressive NK-cell leukaemia/lymphoma

Epidemiology / Prevalence

Aggressive NK-cell leukaemia impacts young to middle-aged adults with peak incidence during 3rd and 5th decades of life (Mean age: 40 years).[1] There is no gender predilection and most prevalent in Asia, Central and South America.[2] Median survival is very short, <2 months. EBV-negative cases tend to occur in older patients, with no significant difference in Asian vs. non-Asian populations.[3] EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells.[4]


editUnassigned References
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[1]

Clinical Features

Most common presentation is with constitutional symptoms and frequently associated hepatosplenomegaly is noted on physical examination.[1][4]

Signs and Symptoms Constitutional symptoms (weight loss, fever, night sweats)

Hepatosplenomegaly common

Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome

Laboratory Findings Markedly elevated serum lactate dehydrogenase (LDH) levels

Circulating FASL

Variable percentage of circulating leukemic cells

Anemia, neutropenia, thrombocytopenia


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Signs and Symptoms:

  • Constitutional symptoms, e.g, fever, general malaise
  • Hepatosplenomegaly common
  • Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome

Laboratory Findings:

  • Markedly elevated serum lactate dehydrogenase (LDH) levels
  • Circulating FASL
  • Variable % of circulating leukaemic cells
  • Anaemia, neutropenia, thrombocytopenia


*EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells


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[1][4]

Sites of Involvement

Peripheral blood, bone marrow, liver, spleen, and lymph nodes are frequently involved. Extranodal involvement sites are organs including skin, lungs, soft tissue and omentum has also been reported.[5]


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[5]

Morphologic Features

Peripheral Blood

  • Variable; May appear as:
    • Normal large granular lymphocytes or
    • Intermediate to large cells with atypical nuclei (enlarged, irregular folding, open chromatin or distinct nucleoli) and moderate pale or lightly basophilic cytoplasm containing fine, coarse or no azurophilic granules.[1]

Bone Marrow:

  • Interstitial or intrasinusoidal infiltrating pattern, which may be extensive, focal or subtle[2]
  • May have interspersed reactive histiocytes with haemophagocytosis

Tissue:

  • Diffuse or patchy destructive infiltrates
  • Monotonous medium sized cells
  • Round or highly irregular nuclei with condensed chromatin and small nucleoli
  • Frequently admixed apoptotic bodies
  • Necrosis common
  • +/- angioinvasion


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[1]

Immunophenotype

The leukaemic cells show demonstrate the following phenotypic expression.[1][2]

Finding Marker
Positive (universal) CD2, CD3-epsilon, CD56, CD94, cytotoxic molecules (TIA1, Granzyme B, perforin A), FASL, c-MYC
Positive (subset) CD16 (75%), CD11b, EBER, p53, pSTAT3, PD-L1, BCL2
Negative (universal) surface CD3, CD4, CD5, CD57 (usually), CD158a/b/e, TCR alpha/beta, TCR gamma/delta
Negative (subset) CD7, CD45


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[1][2]

Chromosomal Rearrangements (Gene Fusions)

Due to the rarity of this lymphoma the data in recurrent chromosomal rearrangement is extremely scant. There have been chromosomal rearrangements reported in association with the aggressive NK-cell leukaemia, however, none of them are considered specific for the disease.

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


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N/A


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  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)


Molecular abnormalities present possible therapeutic implications.

Dufva et al identified high sensitivity of ANKL cell lines to JAK and BCL2 inhibition.

Other possibly effective drug classes:

  • Heat shock protein 90 (HSP90) inhibitors
  • Polo-like kinase (PLK) inhibitors
  • Aurora kinase (AURK) inhibitors
  • Cyclin-dependent kinase inhibitors
  • Histone deacetylase inhibitors


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[6]

Individual Region Genomic Gain / Loss / LOH

There have been a few chromosomal abnormalities associated with aggressive NK-cell leukaemia as listed below, however, the specificity along with prognostic and therapeutic significance is unknown.[3]

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
1 Gain 1q23.1-q23.2 No Unknown Unknown
1 Gain 1q31.3-q44 No Unknown Unknown
7 Loss 7p15.1-q22.3 No Unknown Unknown
17 Loss 17p13.1 No Unknown Unknown
6 Loss 6q16.1–q27 No Unknown Unknown
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Chromosome Gain/Loss/Amp/LOH
1q23.1-q23.2 Gain
1q31.3-q44 Gain
7p15.1-q22.3 Loss
17p13.1 Loss


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[2][1]

Characteristic Chromosomal Patterns

Due to rare nature of disease, cytogenetics data is limited. The common abnormalities include del(6)(q21q25) and del(11q), however, none of these abnormalities are specific and their clinical significance is unknown.[3] Complex karyotypes with unbalanced rearrangements are frequently seen.

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
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Due to rare nature of disease, cytogenetics data is limited. However, common abnormalities include del(6)(q21q25) and del(11q).

Complex karyotypes with unbalanced rearrangements are frequently seen.


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[3]

Gene Mutations (SNV / INDEL)

Mutations in the JAK-STAT pathway appear to be mutually exclusive.[7] Most STAT3 and STAT5B mutations localized to exons 20 and 21 encoding the Src homology 2 (SH2) domain, which causes STAT dimerization. Other mutations identified: 9p copy gains (containing JAK2), point mutation in protein tyrosine phosphatase (PTPRK) (tumor suppressor that negatively regulates STAT3). mutations in PTPN4 and PTPN23.[3][8]

Molecular abnormalities present possible therapeutic implications. Dufva et al identified high sensitivity of ANKL cell lines to JAK and BCL2 inhibition. Other possibly effective drug classes are heat shock protein 90 (HSP90) inhibitors, polo-like kinase (PLK) inhibitors, aurora kinase (AURK) inhibitors, cyclin-dependent kinase inhibitors, and histone deacetylase inhibitors.[6]

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
JAK/STAT/c-MYC pathway (including STAT3, STAT5B, STAT5A, JAK2, JAK3, STAT6, SOCS31, SOCS3 and PTPN11) Oncogene 21 - 66.6% Gain of function


RAS/MAPK pathway Oncogene 16.7 - 29% Gain of function
TP53 Tumor suppressor gene 7 -50% Loss of function
BCL2 Oncogene NA Gain of function

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.


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Gene Oncogene/Tumor Suppressor/Other Presumed Mechanism (LOF/GOF/Other; Driver/Passenger) Prevalence [3]
JAK/STAT/c-MYC pathway (including STAT3, STAT5B, STAT5A, JAK2, JAK3, STAT6, SOCS31, SOCS3 and PTPN11) Oncogene Gain of function 21 - 66.6%
RAS/MAPK pathway Oncogene Gain of function 16.7 - 29%
TP53 Tumor suppressor Loss of function 7 -50%
BCL2 Oncogene Gain of function N/A

JAK/STAT/c-MYC

  • Mutations in the JAK-STAT pathway appear to be mutually exclusive[7]
  • Most STAT3 and STAT5B mutations localized to exons 20 and 21 encoding the Src homology 2 (SH2) domain, which causes STAT dimerization
  • Other mutations identified:
    • 9p copy gains (containing JAK2)
    • point mutation in protein tyrosine phosphatase (PTPRK) (tumor suppressor that negatively regulates STAT3)
    • mutations in PTPN4 and PTPN23


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[3][8][7]

Epigenomic Alterations

Mutations seen in epigenetic regulatory molecules including RNA helicase DDX3X (28%), TET2 (28%), CREBBP (21%), and MLL2 (21%) have been reported.[3][7]


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[3][7]

Genes and Main Pathways Involved

The disease pathogenesis is regulated by a complex interplay between diverse molecular pathways especially that involving the upregulated JAK/STAT-MYC biosynthesis axis due to upstream STAT3 activation of the MYC transcription program. Thought in some cases to be as a result of highly expressed EBV-encoded small RNAs (EBERs) causing release of IL-10.[3]

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
STAT3 activation of the MYC transcription program JAK/STAT-MYC biosynthesis axis Increased cell survival and proliferation
Alterations in RAS-MAPK pathway RAS-MAPK pathway Increased cell survival and proliferation
BCOR, KMT2D/MLL2, SETD2, PRDM9, CREBBP, and TET2 Epigenetic modifier genes Altering the epigenetic landscape
TP53, ASXL1, ASXL2, BRINP3 DNA damage repair ??
PRPF40B mRNA splicing factors ??
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  • Upregulated JAK/STAT-MYC biosynthesis axis due to upstream STAT3 activation of the MYC transcription program. *
  • Alterations in RAS-MAPK pathway also identified
  • Epigenetic modifier genes (e.g BCOR, KMT2D/MLL2, SETD2, PRDM9, CREBBP, and TET2)
  • DNA damage repair (TP53, ASXL1, ASXL2, BRINP3)
  • mRNA splicing factors (PRPF40B)


*Thought in some cases to be as a result of highly expressed EBV-encoded small RNAs (EBERs) causing release of IL-10.[3]


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[3]

Genetic Diagnostic Testing Methods

Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.[2]


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[2]

Familial Forms

N/A

Additional Information

N/A

Links

Extranodal NK/T-cell lymphoma

Hepatosplenic T-cell Lymphoma (HSTCL)

Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK)

References

(use the "Cite" icon at the top of the page) (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. 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.)

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Chan, JKC et al., (2017). Aggressive NK-cell leukaemia, 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, p353-354.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 El Hussein, Siba; et al. (09 2020). "Genomic and Immunophenotypic Landscape of Aggressive NK-Cell Leukemia". The American Journal of Surgical Pathology. 44 (9): 1235–1243. doi:10.1097/PAS.0000000000001518. ISSN 1532-0979. PMID 32590457 Check |pmid= value (help). Check date values in: |date= (help)
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 El Hussein, Siba; et al. (10 09, 2020). "Aggressive NK Cell Leukemia: Current State of the Art". Cancers. 12 (10). doi:10.3390/cancers12102900. ISSN 2072-6694. PMC 7600035 Check |pmc= value (help). PMID 33050313 Check |pmid= value (help). Check date values in: |date= (help)
  4. ↑ 4.0 4.1 4.2 Kim, Wook Youn; et al. (2019). "Epstein-Barr Virus-Associated T and NK-Cell Lymphoproliferative Diseases". Frontiers in Pediatrics. 7: 71. doi:10.3389/fped.2019.00071. ISSN 2296-2360. PMC 6428722. PMID 30931288.
  5. ↑ 5.0 5.1 Hue, Susan Swee-Shan; et al. (2020-01). "Epstein–Barr virus-associated T- and NK-cell lymphoproliferative diseases: an update and diagnostic approach". Pathology. 52 (1): 111–127. doi:10.1016/j.pathol.2019.09.011. Check date values in: |date= (help)
  6. ↑ 6.0 6.1 Dufva, Olli; et al. (04 19, 2018). "Aggressive natural killer-cell leukemia mutational landscape and drug profiling highlight JAK-STAT signaling as therapeutic target". Nature Communications. 9 (1): 1567. doi:10.1038/s41467-018-03987-2. ISSN 2041-1723. PMC 5908809. PMID 29674644. Check date values in: |date= (help)
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Huang, Liang; et al. (2018-02). "Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia". Cell Research. 28 (2): 172–186. doi:10.1038/cr.2017.146. ISSN 1001-0602. PMC 5799812. PMID 29148541. Check date values in: |date= (help)CS1 maint: PMC format (link)
  8. ↑ 8.0 8.1 Gao, Juehua; et al. (2020-11). "Comprehensive molecular genetic studies of Epstein-Barr virus-negative aggressive Natural killer-cell leukemia/lymphoma". Human Pathology. 105: 20–30. doi:10.1016/j.humpath.2020.08.008. Check date values in: |date= (help)


Notes

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