HAEM5:Aggressive NK-cell leukaemia: Difference between revisions

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Aggressive NK-cell Leukaemia  
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).<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> 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">{{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> EBV-negative cases may occur de novo or transform from chronic lymphoproliferative disorder of NK cells.'''''<ref name=":4">{{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>'''''
==Clinical Features==
Most common presentation is with constitutional symptoms and frequently associated hepatosplenomegaly is noted on physical examination.<ref name=":1" /><ref name=":4" /> 
{| class="wikitable"
|'''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
|}
<nowiki>*</nowiki>EBV-negative cases may occur ''de novo'' or transform from chronic lymphoproliferative disorder of NK cells
==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.<ref name=":5">{{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>
==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.<ref name=":1" />
'''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==
The leukaemic cells show demonstrate the following phenotypic expression.<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
|}
==WHO Essential and Desirable Genetic Diagnostic Criteria==
==WHO Essential and Desirable Genetic Diagnostic Criteria==
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</span>
<span style="color:#0070C0">(''Instructions: The table will have the diagnostic criteria from the WHO book <u>autocompleted</u>; remove any <u>non</u>-genetics related criteria. If applicable, add text about other classification'' ''systems that define this entity and specify how the genetics-related criteria differ.'')</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" /><ref name=":1" /><ref name=":0" />
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>


{| class="wikitable sortable"
{| class="wikitable sortable"
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|??
|??
|}
|}
==Genetic Diagnostic Testing Methods==
Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.<ref name=":0" />
==Familial Forms==
N/A
==Additional Information==
This disease is <u>defined/characterized</u> as detailed below:
* 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).
The <u>epidemiology/prevalence</u> of this disease is detailed below:
* 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" /> 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">{{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>'''''
The <u>clinical features</u> of this disease are detailed below:
* Most common presentation is with constitutional symptoms and frequently associated hepatosplenomegaly is noted on physical examination.<ref name=":1" /><ref name=":4" />  EBV-negative cases may occur ''de novo'' or transform from chronic lymphoproliferative disorder of NK cells.
Signs and symptoms - Constitutional symptoms (weight loss, fever, night sweats); Hepatosplenomegaly common; Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome


<blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>
Laboratory findings - Markedly elevated serum lactate dehydrogenase (LDH) levels; Circulating FASL; Variable percentage of circulating leukemic cells; Anemia, neutropenia, thrombocytopenia


The <u>sites of involvement</u> of this disease are detailed below:


*Upregulated JAK/STAT-MYC biosynthesis axis due to upstream STAT3 activation of the MYC transcription program. *
* 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">{{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>
*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)''


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


<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" />
'''Peripheral Blood'''
==Genetic Diagnostic Testing Methods==
 
*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" />
 
'''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
 
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 (universal) - CD2, CD3-epsilon, CD56, CD94, cytotoxic molecules (TIA1, Granzyme B, perforin A), FASL, c-MYC


Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.<ref name=":0" />
Positive (subset) - CD16 (75%), CD11b, EBER, p53, pSTAT3, PD-L1, BCL2
==Familial Forms==


N/A
Negative (universal) - surface CD3, CD4, CD5, CD57 (usually), CD158a/b/e, TCR alpha/beta, TCR gamma/delta


==Additional Information==
Negative (subset) - CD7, CD45
N/A


==Links==
==Links==