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| {{DISPLAYTITLE:Aggressive NK-cell leukaemia}} | | {{DISPLAYTITLE:Aggressive NK-cell leukaemia}} |
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| [[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]] | | [[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]] |
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| Case Western Reserve University, Cleveland, OH | | Case Western Reserve University, Cleveland, OH |
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| __TOC__
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| ==WHO Classification of Disease== | | ==WHO Classification of Disease== |
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| Aggressive NK-cell Leukaemia | | Aggressive NK-cell Leukaemia |
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| ==Definition / Description of Disease== | | ==Related Terminology== |
| 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).
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| ==Synonyms / Terminology==
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| Aggressive NK-cell leukaemia/lymphoma
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| ==Epidemiology / Prevalence==
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| 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">{{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" />'''''
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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.}}</blockquote><ref name=":1" /><blockquote class="blockedit">
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| <center><span style="color:Maroon">'''End of V4 Section'''</span>
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| ----
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| </blockquote>
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| ==Clinical Features==
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| Most common presentation is with constitutional symptoms and frequently associated hepatosplenomegaly is noted on physical examination.<ref name=":1" /><ref name=":4" />
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| {| class="wikitable"
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| |'''Signs and Symptoms'''
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| |Constitutional symptoms (weight loss, fever, night sweats)
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| Hepatosplenomegaly common
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| Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome
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| |-
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| |'''Laboratory Findings'''
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| |Markedly elevated serum lactate dehydrogenase (LDH) levels
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| Circulating FASL
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| Variable percentage of circulating leukemic cells
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| Anemia, neutropenia, thrombocytopenia
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| |}
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| <blockquote class="blockedit">{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}</blockquote>
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| '''Signs and Symptoms:'''
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| *Constitutional symptoms, e.g, fever, general malaise
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| *Hepatosplenomegaly common
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| *Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome
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| '''Laboratory Findings:'''
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| *Markedly elevated serum lactate dehydrogenase (LDH) levels
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| *Circulating FASL
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| *Variable % of circulating leukaemic cells
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| *Anaemia, neutropenia, thrombocytopenia
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| <nowiki>*</nowiki>EBV-negative cases may occur ''de novo'' or transform from chronic lymphoproliferative disorder of NK cells
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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.}}</blockquote><ref name=":1" /><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><blockquote class="blockedit">
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| <center><span style="color:Maroon">'''End of V4 Section'''</span>
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| ----
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| <blockquote class="blockedit">
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| <center><span style="color:Maroon">'''End of V4 Section'''</span>
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| ----
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| </blockquote>
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| </blockquote>
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| ==Sites of Involvement==
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| 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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| <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.}}</blockquote><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><blockquote class="blockedit">
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| <center><span style="color:Maroon">'''End of V4 Section'''</span>
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| ----
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| </blockquote>
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| ==Morphologic Features==
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| '''Peripheral Blood'''
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| *Variable; May appear as:
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| **Normal large granular lymphocytes or
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| **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" />
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| '''Bone Marrow:'''
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| *Interstitial or intrasinusoidal infiltrating pattern, which may be extensive, focal or subtle<ref name=":0" />
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| *May have interspersed reactive histiocytes with haemophagocytosis
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| '''Tissue:'''
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| *Diffuse or patchy destructive infiltrates
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| *Monotonous medium sized cells
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| *Round or highly irregular nuclei with condensed chromatin and small nucleoli
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| *Frequently admixed apoptotic bodies
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| *Necrosis common
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| *+/- angioinvasion
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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.}}</blockquote><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><blockquote class="blockedit">
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| <center><span style="color:Maroon">'''End of V4 Section'''</span>
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| ----
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| </blockquote>
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| ==Immunophenotype==
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| The leukaemic cells show demonstrate the following phenotypic expression.<ref name=":1" /><ref name=":0" />
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| {| class="wikitable sortable"
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| |-
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| !Finding!!Marker
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| |-
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| |Positive (universal)||CD2, CD3-epsilon, CD56, CD94, cytotoxic molecules (TIA1, Granzyme B, perforin A), FASL, c-MYC
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| |-
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| |Positive (subset)||CD16 (75%), CD11b, EBER, p53, pSTAT3, PD-L1, BCL2
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| |-
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| |Negative (universal)||surface CD3, CD4, CD5, CD57 (usually), CD158a/b/e, TCR alpha/beta, TCR gamma/delta
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| |-
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| |Negative (subset)||CD7, CD45
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| |}
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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.}}</blockquote><ref name=":1" /><ref name=":0" /><blockquote class="blockedit">
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| <center><span style="color:Maroon">'''End of V4 Section'''</span>
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| ----
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| </blockquote>
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| ==WHO Essential and Desirable Genetic Diagnostic Criteria==
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| <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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| {| class="wikitable"
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| |+
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| |WHO Essential Criteria (Genetics)*
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| |-
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| |WHO Desirable Criteria (Genetics)*
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| |-
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| |Other Classification
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| |}
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| <nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
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| ==Related Terminology==
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| <span style="color:#0070C0">(''Instructions: The table will have the related terminology from the WHO <u>autocompleted</u>.)''</span>
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| {| class="wikitable" | | {| class="wikitable" |
| |+ | | |+ |
| |Acceptable | | |Acceptable |
| | | | |Aggressive NK-cell leukaemia/lymphoma |
| |- | | |- |
| |Not Recommended | | |Not Recommended |
| | | | |NK-large granular lymphocyte leukaemia; aggressive large granular lymphocyte leukaemia |
| |} | | |} |
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| {| class="wikitable sortable" | | {| class="wikitable sortable" |
| |- | | |- |
| !Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)''' | | !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''' | | !Diagnostic, Prognostic, and Therapeutic Significance - D, P, T |
| !'''Established Clinical Significance Per Guidelines - Yes or No (Source)''' | | !Established Clinical Significance Per Guidelines - Yes or No (Source) |
| !'''Clinical Relevance Details/Other Notes''' | | !Clinical Relevance Details/Other Notes |
| |- | | |- |
| |<span class="blue-text">EXAMPLE:</span> | | |<span class="blue-text">EXAMPLE:</span> |
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| |} | | |} |
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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> |
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| {| class="wikitable sortable" | | {| class="wikitable sortable" |
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| !Chromosomal Pattern | | !Chromosomal Pattern |
| !Molecular Pathogenesis | | !Molecular Pathogenesis |
| !'''Prevalence -''' | | !Prevalence - |
| '''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
| | Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
| !'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T''' | | !Diagnostic, Prognostic, and Therapeutic Significance - D, P, T |
| !'''Established Clinical Significance Per Guidelines - Yes or No (Source)''' | | !Established Clinical Significance Per Guidelines - Yes or No (Source) |
| !'''Clinical Relevance Details/Other Notes''' | | !Clinical Relevance Details/Other Notes |
| |- | | |- |
| |<span class="blue-text">EXAMPLE:</span> | | |<span class="blue-text">EXAMPLE:</span> |
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| {| class="wikitable sortable" | | {| class="wikitable sortable" |
| |- | | |- |
| !Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -''' | | !Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence - |
| '''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
| | Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
| !'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T ''' | | !Diagnostic, Prognostic, and Therapeutic Significance - D, P, T |
| !'''Established Clinical Significance Per Guidelines - Yes or No (Source)''' | | !Established Clinical Significance Per Guidelines - Yes or No (Source) |
| !'''Clinical Relevance Details/Other Notes''' | | !Clinical Relevance Details/Other Notes |
| |- | | |- |
| |<span class="blue-text">EXAMPLE:</span>''EGFR'' | | |<span class="blue-text">EXAMPLE:</span>''EGFR'' |
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| {| class="wikitable sortable" | | {| class="wikitable sortable" |
| |- | | |- |
| !Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC / TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations''' | | !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)''' | | !Diagnostic Significance (Yes, No or Unknown) |
| !Prognostic Significance (Yes, No or Unknown) | | !Prognostic Significance (Yes, No or Unknown) |
| !Therapeutic Significance (Yes, No or Unknown) | | !Therapeutic Significance (Yes, No or Unknown) |
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| |?? | | |?? |
| |} | | |} |
| | ==Genetic Diagnostic Testing Methods== |
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| <blockquote class="blockedit">{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote> | | Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.<ref name=":0" /> |
| | ==Familial Forms== |
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| | N/A |
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| *Upregulated JAK/STAT-MYC biosynthesis axis due to upstream STAT3 activation of the MYC transcription program. *
| | ==Additional Information== |
| *Alterations in RAS-MAPK pathway also identified
| | This disease is <u>defined/characterized</u> as detailed below: |
| *Epigenetic modifier genes (e.g ''BCOR, KMT2D/MLL2'', ''SETD2'', ''PRDM9'', ''CREBBP'', and ''TET2'')
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| *DNA damage repair (''TP53, ASXL1, ASXL2, BRINP3)''
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| *mRNA splicing factors ''(PRPF40B)''
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|
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| | *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). |
|
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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.<ref name=":2" /> | | The <u>epidemiology/prevalence</u> of this disease is detailed below: |
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| | *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>''''' |
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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.}}</blockquote><ref name=":2" /><blockquote class="blockedit"> | | The <u>clinical features</u> of this disease are detailed below: |
| <center><span style="color:Maroon">'''End of V4 Section'''</span> | | |
| ----
| | *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. |
| <blockquote class="blockedit"> | | |
| <center><span style="color:Maroon">'''End of V4 Section'''</span> | | Signs and symptoms - Constitutional symptoms (weight loss, fever, night sweats); Hepatosplenomegaly common; Frequently complicated by multiorgan failure, coagulopathy and haemophagocytic syndrome |
| ----
| | |
| </blockquote> | | Laboratory findings - Markedly elevated serum lactate dehydrogenase (LDH) levels; Circulating FASL; Variable percentage of circulating leukemic cells; Anemia, neutropenia, thrombocytopenia |
| </blockquote> | | |
| ==Genetic Diagnostic Testing Methods==
| | The <u>sites of involvement</u> of this disease are detailed below: |
| | |
| | *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> |
| | |
| | The <u>morphologic features</u> of this disease are detailed below: |
| | |
| | '''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 |
| | |
| | The <u>immunophenotype</u> of this disease is detailed below: |
|
| |
|
| Foundation of diagnosis based on morphology with immunophenotyping via flow cytometry +/- immunohistochemistry.<ref name=":0" />
| | *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 |
|
| |
|
| <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.}}</blockquote><ref name=":0" /><blockquote class="blockedit">
| | Positive (subset) - CD16 (75%), CD11b, EBER, p53, pSTAT3, PD-L1, BCL2 |
| <center><span style="color:Maroon">'''End of V4 Section'''</span>
| |
| ---- | |
| </blockquote>
| |
| ==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
| |
|
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| ==Links== | | ==Links== |
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| [[HAEM5:Extranodal NK/T-cell lymphoma|Extranodal NK/T-cell lymphoma]] | | [[HAEM5:Extranodal NK/T-cell lymphoma|Extranodal NK/T-cell lymphoma]] |
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| [[Hepatosplenic T-cell Lymphoma (HSTCL)]] | | [[HAEM5:Hepatosplenic T-cell lymphoma|Hepatosplenic T-cell Lymphoma]] |
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| [[Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK)]] | | [[HAEM5:NK-large granular lymphocytic leukaemia|NK-large Granular Lymphocytic Leukaemia]] |
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| ==References== | | ==References== |
