HAEM5:Aggressive NK-cell leukaemia: Difference between revisions

<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]].

==Related Terminology==

|+

|Acceptable

|Not Recommended

|NK-large granular lymphocyte leukaemia; aggressive large granular lymphocyte leukaemia

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.

!Driver Gene!!Fusion(s) and Common Partner Genes!!Molecular Pathogenesis!!Typical Chromosomal Alteration(s)

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!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)

!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T

!Established Clinical Significance Per Guidelines - Yes or No (Source)

|<span class="blue-text">EXAMPLE:</span>

|<span class="blue-text">EXAMPLE:</span> Loss

|<span class="blue-text">EXAMPLE:</span>

|<span class="blue-text">EXAMPLE:</span>

|<span class="blue-text">EXAMPLE:</span> D, P

|<span class="blue-text">EXAMPLE:</span>

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 references).

|<span class="blue-text">EXAMPLE:</span>

|<span class="blue-text">EXAMPLE:</span> Gain

|<span class="blue-text">EXAMPLE:</span>

|<span class="blue-text">EXAMPLE:</span>

|<span class="blue-text">EXAMPLE:</span> D, P

|<span class="blue-text">EXAMPLE:</span>

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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">{{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=":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><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>

==Characteristic Chromosomal or Other Global Mutational Patterns==

!Chromosomal Pattern

!Molecular Pathogenesis

!Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

!Clinical Relevance Details/Other Notes

|<span class="blue-text">EXAMPLE:</span>

|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

|<span class="blue-text">EXAMPLE:</span> D, P

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|<span class="blue-text">EXAMPLE:</span>

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!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  

!Established Clinical Significance Per Guidelines - Yes or No (Source)

!Clinical Relevance Details/Other Notes

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<br />

|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)

|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations

|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations

|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene

|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)

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|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.

|<span class="blue-text">EXAMPLE:</span> T

|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

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.<ref name=":2" /><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>''

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">{{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>

!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)

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The <u>morphologic features</u> of this disease are detailed below:

*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.<ref name=":1" />

'''Tissue:'''

The <u>immunophenotype</u> of this disease is detailed below:

*The leukaemic cells show demonstrate the following phenotypic expression.<ref name=":1" /><ref name=":0" />

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

[[HAEM5:Hepatosplenic T-cell lymphoma|Hepatosplenic T-cell Lymphoma]]

[[HAEM5:NK-large granular lymphocytic leukaemia|NK-large Granular Lymphocytic Leukaemia]]