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Created page with "==Primary Author(s)*== Shanelle De Lancy, MD, Shashirekha Shetty, PhD __TOC__ ==Cancer Category/Type== Mature T- and NK-cell neoplasms ==Cancer Sub-Classification / Subty..."

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==Primary Author(s)*==

Shanelle De Lancy, MD, Shashirekha Shetty, PhD

__TOC__

==Cancer Category/Type==

Mature T- and NK-cell neoplasms

==Cancer Sub-Classification / Subtype==

Aggressive NK-cell Leukaemia

==Definition / Description of Disease==

*Proliferation of NK-cells
*Associated with EBV infection, but EBV may be negative in a subset of patients
*Aggressive clinical course with poor response to chemotherapy
*Relapse common in patients that achieve complete remission (+/- bone marrow transplantation)

==Synonyms / Terminology==

Aggressive NK-cell leukaemia/lymphoma

==Epidemiology / Prevalence<ref name=":1" />==

*Young to middle-aged adults
*Median age: 40 years; Peaks in 3rd and 5th decades
*More prevalent in Asian, 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>
*No gender predilection
*EBV-negative cases tend to occur in older patients, with no significant difference in Asian vs. non-Asian populations<ref name=":2" />
*Median survival: <2 months

==Clinical Features<ref name=":1" /><ref>{{Cite journal|last=Kim|first=Wook Youn|last2=Montes-Mojarro|first2=Ivonne A.|last3=Fend|first3=Falko|last4=Quintanilla-Martinez|first4=Leticia|date=2019|title=Epstein-Barr Virus-Associated T and NK-Cell Lymphoproliferative Diseases|url=https://pubmed.ncbi.nlm.nih.gov/30931288|journal=Frontiers in Pediatrics|volume=7|pages=71|doi=10.3389/fped.2019.00071|issn=2296-2360|pmc=6428722|pmid=30931288}}</ref>==

'''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

<nowiki>*</nowiki>EBV-negative cases may occur ''de novo'' or transform from chronic lymphoproliferative disorder of NK cells

==Sites of Involvement<ref>{{Cite journal|last=Hue|first=Susan Swee-Shan|last2=Oon|first2=Ming Liang|last3=Wang|first3=Shi|last4=Tan|first4=Soo-Yong|last5=Ng|first5=Siok-Bian|date=2020-01|title=Epstein–Barr virus-associated T- and NK-cell lymphoproliferative diseases: an update and diagnostic approach|url=https://linkinghub.elsevier.com/retrieve/pii/S0031302519304210|journal=Pathology|language=en|volume=52|issue=1|pages=111–127|doi=10.1016/j.pathol.2019.09.011}}</ref>==

*Peripheral blood
*Bone marrow
*Liver
*Spleen
*Lymph nodes

but may involve any organ including skin, lungs, soft tissue and omentum

==Morphologic Features<ref name=":1">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.</ref>==

'''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

'''Bone Marrow:'''

*Interstitial or intrasinusoidal infiltrating pattern, which may be extensive, focal or subtle<ref name=":0" />
*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

==Immunophenotype<ref name=":1" /><ref name=":0" />==

{| class="wikitable sortable"
|-
!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
|}

==Chromosomal Rearrangements (Gene Fusions)==
N/A

==Characteristic Chromosomal Aberrations / Patterns<ref name=":2" />==

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.

==Genomic Gain/Loss/LOH<ref name=":0" /><ref name=":1" />==

{| class="wikitable sortable"
|-
!Chromosome!!Gain/Loss/Amp/LOH<br />
|-
|1q23.1-q23.2
|Gain
|-
|1q31.3-q44
|Gain
|-
|7p15.1-q22.3
|Loss
|-
|17p13.1
|Loss
|}

==Gene Mutations (SNV/INDEL)<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" />==

{| class="wikitable sortable"
|-
!Gene!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence <ref name=":2" />
|-
|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<ref name=":3">{{Cite journal|last=Huang|first=Liang|last2=Liu|first2=Dan|last3=Wang|first3=Na|last4=Ling|first4=Shaoping|last5=Tang|first5=Yuting|last6=Wu|first6=Jun|last7=Hao|first7=Lingtong|last8=Luo|first8=Hui|last9=Hu|first9=Xuelian|date=2018-02|title=Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia|url=http://www.nature.com/articles/cr2017146|journal=Cell Research|language=en|volume=28|issue=2|pages=172–186|doi=10.1038/cr.2017.146|issn=1001-0602|pmc=PMC5799812|pmid=29148541}}</ref>
*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''

==Epigenomics (Methylation)<ref name=":2" /><ref name=":3" />==

Mutations seen in epigenetic regulatory molecules:

*RNA helicase ''DDX3X'' (28%)
*''TET2'' (28%)
*''CREBBP'' (21%)
*''MLL2'' (21%)

==Genes and Main Pathways Involved<ref name=":2" />==

*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)''

<nowiki>*</nowiki>Thought in some cases to be as a result of highly expressed EBV-encoded small RNAs (EBERs) causing release of IL-10.

==Diagnostic Testing Methods<ref name=":0" />==

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

==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)<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>==

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

==Familial Forms==

N/A

==Other Information==
N/A

==Links==

[[Extranodal NK/T-cell Lymphoma, Nasal Type|Extranodal NK/T-cell lymphoma]]

[[Hepatosplenic T-cell Lymphoma (HSTCL)]]

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

==References==
<references /><br />
==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.

HAEM4Backup:Aggressive NK-cell Leukemia - Revision history

Bailey.Glen: Created page with "==Primary Author(s)*== Shanelle De Lancy, MD, Shashirekha Shetty, PhD __TOC__ ==Cancer Category/Type== Mature T- and NK-cell neoplasms ==Cancer Sub-Classification / Subty..."

Bailey.Glen: Created page with "==Primary Author(s)*== Shanelle De Lancy, MD, Shashirekha Shetty, PhD TOC ==Cancer Category/Type== Mature T- and NK-cell neoplasms ==Cancer Sub-Classification / Subty..."