View source for HAEM5:EBV-positive nodal T- and NK-cell lymphoma

{{DISPLAYTITLE:EBV-positive nodal T- and NK-cell lymphoma}}

[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]

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==Primary Author(s)*==
FNU Monika, MBBS; Andrew Siref, MD

Creighton University, Omaha, NE
==WHO Classification of Disease==
<span style="color:#0070C0">(Will be autogenerated; Book will include name of specific book and have a link to the online WHO site)</span>
{| class="wikitable"
!Structure
!Disease
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|Family
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==Definition / Description of Disease==

*EBV-positive nodal T- and NK-cell lymphoma is a rare EBV-positive lymphoma of cytotoxic T- or NK-cell lineage, primarily involving lymph nodes in adults.<ref name=":0">Siok-Bian Ng, et al. EBV-positive nodal T- and NK-cell lymphoma. In: WHO Classification of Tumours Editorial Board. Haematolymphoid tumours [Internet]. Lyon (France): International Agency for Research on Cancer; 2024 [cited 2024 Oct 6]. (WHO classification of tumors series, 5th ed.; vol. 11). Available from: BlueBooksOnline (who.int)</ref>

*Is a distinct entity in the 5th Edition of the WHO classification and as a provisional entity in the International Consensus Classification 2022.<ref name=":3">{{Cite journal|last=Yu|first=Fang|last2=Wang|first2=Jinghan|last3=Ke|first3=Zhonghe|last4=Zhang|first4=Yafei|last5=Xu|first5=Liming|last6=Zhang|first6=Han|last7=Huang|first7=Ke|last8=Cheng|first8=Fei|last9=Yang|first9=Hanjin|date=2024-04|title=EBV-positive Nodal T-Cell and NK-Cell Lymphoma: A Study of 26 Cases Including a Subset With Strong CD30 Expression Mimicking Anaplastic Large Cell Lymphoma|url=https://journals.lww.com/10.1097/PAS.0000000000002184|journal=American Journal of Surgical Pathology|language=en|volume=48|issue=4|pages=406–416|doi=10.1097/PAS.0000000000002184|issn=0147-5185}}</ref><ref>{{Cite journal|last=Kato|first=Seiichi|last2=Hamada|first2=Motoharu|last3=Okamoto|first3=Akinao|last4=Yamashita|first4=Daisuke|last5=Miyoshi|first5=Hiroaki|last6=Arai|first6=Haruto|last7=Satou|first7=Akira|last8=Gion|first8=Yuka|last9=Sato|first9=Yasuharu|date=2024-05-14|title=EBV+ nodal T/NK-cell lymphoma associated with clonal hematopoiesis and structural variations of the viral genome|url=https://ashpublications.org/bloodadvances/article/8/9/2138/515170/EBV-nodal-T-NK-cell-lymphoma-associated-with|journal=Blood Advances|language=en|volume=8|issue=9|pages=2138–2147|doi=10.1182/bloodadvances.2023012019|issn=2473-9529|pmc=PMC11068532|pmid=38429084}}</ref>

==Synonyms / Terminology==
nodal EBV+ cytotoxic T-cell lymphoma; nodal peripheral T-cell lymphoma, EBV-positive; primary nodal EBV-positive T/NK-cell lymphoma.<ref name=":0" />
==Epidemiology / Prevalence==

*Rare lymphoma
*Occurs mostly in eastern Asia
*Affects mainly older adults (median age: 61–64 years) although cases in younger adults have been reported
*The M:F ratio is 1.5–3.8:1 <ref name=":0" /><ref name=":7">{{Cite journal|last=Ha|first=Sang Yun|last2=Sung|first2=Jiyeon|last3=Ju|first3=Hyunjung|last4=Karube|first4=Kennosuke|last5=Kim|first5=Soek Jin|last6=Kim|first6=Won Seog|last7=Seto|first7=Masao|last8=Ko|first8=Young-Hyeh|date=2013-07-01|title=Epstein–Barr virus-positive nodal peripheral T cell lymphomas: Clinicopathologic and gene expression profiling study|url=https://linkinghub.elsevier.com/retrieve/pii/S0344033813000988|journal=Pathology - Research and Practice|volume=209|issue=7|pages=448–454|doi=10.1016/j.prp.2013.04.013|issn=0344-0338}}</ref>

==Clinical Features==
{| class="wikitable"
|'''Signs and Symptoms'''<ref name=":0" /><ref name=":1">{{Cite journal|last=Jeon|first=Yoon Kyung|last2=Kim|first2=Jo-Heon|last3=Sung|first3=Ji-Youn|last4=Han|first4=Jae Ho|last5=Ko|first5=Young-Hyeh|date=2015-07|title=Epstein-Barr virus–positive nodal T/NK-cell lymphoma: an analysis of 15 cases with distinct clinicopathological features|url=https://linkinghub.elsevier.com/retrieve/pii/S0046817715000866|journal=Human Pathology|language=en|volume=46|issue=7|pages=981–990|doi=10.1016/j.humpath.2015.03.002}}</ref><ref name=":2">{{Cite journal|last=Kato|first=Seiichi|last2=Asano|first2=Naoko|last3=Miyata-Takata|first3=Tomoko|last4=Takata|first4=Katsuyoshi|last5=Elsayed|first5=Ahmed Ali|last6=Satou|first6=Akira|last7=Takahashi|first7=Emiko|last8=Kinoshita|first8=Tomohiro|last9=Nakamura|first9=Shigeo|date=2015-04|title=T-cell Receptor (TCR) Phenotype of Nodal Epstein-Barr Virus (EBV)-positive Cytotoxic T-cell Lymphoma (CTL): A Clinicopathologic Study of 39 Cases|url=https://journals.lww.com/00000478-201504000-00004|journal=American Journal of Surgical Pathology|language=en|volume=39|issue=4|pages=462–471|doi=10.1097/PAS.0000000000000323|issn=0147-5185}}</ref><ref>{{Cite journal|last=Yu|first=Fang|last2=Wang|first2=Jinghan|last3=Ke|first3=Zhonghe|last4=Zhang|first4=Yafei|last5=Xu|first5=Liming|last6=Zhang|first6=Han|last7=Huang|first7=Ke|last8=Cheng|first8=Fei|last9=Yang|first9=Hanjin|date=2024-04|title=EBV-positive Nodal T-Cell and NK-Cell Lymphoma: A Study of 26 Cases Including a Subset With Strong CD30 Expression Mimicking Anaplastic Large Cell Lymphoma|url=https://journals.lww.com/10.1097/PAS.0000000000002184|journal=American Journal of Surgical Pathology|language=en|volume=48|issue=4|pages=406–416|doi=10.1097/PAS.0000000000002184|issn=0147-5185}}</ref>
|Lymphadenopathy
Advanced clinical stage III/IV disease at diagnosis (86–88% of cases)

B symptoms (72–80%) 

High or high/intermediate International Prognostic Index (IPI) score (64–87%) 
|-
|'''Laboratory Findings'''
|Anemia
Leukopenia

Thrombocytopenia

Elevated serum lactate dehydrogenase
|}
==Sites of Involvement==

*Primarily lymph nodes (most commonly cervical, inguinal, and axillary), although limited extranodal involvement can be seen<ref name=":0" />
*Liver and/or bone marrow (24–60% of cases); other extranodal sites, such as the skin and gastrointestinal tract, are less commonly involved<ref name=":1" /><ref name=":2" /><ref name=":8">{{Cite journal|last=Yamashita|first=Daisuke|last2=Shimada|first2=Kazuyuki|last3=Takata|first3=Katsuyoshi|last4=Miyata‐Takata|first4=Tomoko|last5=Kohno|first5=Kei|last6=Satou|first6=Akira|last7=Sakakibara|first7=Ayako|last8=Nakamura|first8=Shigeo|last9=Asano|first9=Naoko|date=2018-08|title=Reappraisal of nodal Epstein‐Barr Virus‐negative cytotoxic T‐cell lymphoma: Identification of indolent CD 5 + diseases|url=https://onlinelibrary.wiley.com/doi/10.1111/cas.13652|journal=Cancer Science|language=en|volume=109|issue=8|pages=2599–2610|doi=10.1111/cas.13652|issn=1347-9032|pmc=PMC6113510|pmid=29845715}}</ref>
*No nasal involvement has been reported<ref name=":0" />

==Morphologic Features==

*Architectural effacement of lymph node by a diffuse infiltrate of monotonous medium-sized to large lymphoid cells
*The neoplastic cells have centroblastic appearance with vesicular chromatin
*Less frequently, the neoplastic cells display large pleomorphic or mixed-cell morphology with abundant histiocytes and small lymphocytes in the background<ref name=":0" /><ref>{{Cite journal|last=Attygalle|first=Ayoma D|last2=Cabeçadas|first2=José|last3=Gaulard|first3=Philippe|last4=Jaffe|first4=Elaine S|last5=de Jong|first5=Daphne|last6=Ko|first6=Young Hyeh|last7=Said|first7=Jonathan|last8=Klapper|first8=Wolfram|date=2014-01|title=Peripheral T‐cell and NK ‐cell lymphomas and their mimics; taking a step forward – report on the lymphoma workshop of the XVI th meeting of the European Association for Haematopathology and the Society for Hematopathology|url=https://onlinelibrary.wiley.com/doi/10.1111/his.12251|journal=Histopathology|language=en|volume=64|issue=2|pages=171–199|doi=10.1111/his.12251|issn=0309-0167|pmc=PMC6364972|pmid=24128129}}</ref>
*Lacks classic morphological findings of angioinvasion and necrosis seen in extranodal EBV+ T- and NK-cell lymphomas<ref name=":1" />

==Immunophenotype==
Based on T-cell receptor protein expression and/or clonal TR gene rearrangement, EBV-positive nodal T- and NK-cell lymphoma immunophenotype is more commonly of T-cell lineage rather than NK-cell (> 80% of cases) 
{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||CD3, CD2, CD56 (7–22%), cytotoxic molecules (TIA1, granzyme B, and perforin), EBER (ISH)
|-
|CD4/CD8<ref name=":0" /><ref name=":7" /><ref name=":1" /><ref name=":2" /><ref name=":8" />
|CD4-/CD8- (21%), CD4+/CD8- (8%), CD4-/CD8+ (63-72%)
|-
|TCR<ref name=":0" /><ref name=":7" /><ref name=":1" /><ref name=":2" /><ref name=":8" />||TCRβ (+, 43–64%), TCRγ (+, 0–13%), TCRβ and TCRγ (-, 25%), 
|-
|Positive (subset)
|CD30<ref name=":3" />
|-
|Negative (universal)||CD5
|}<br />
==Chromosomal Rearrangements (Gene Fusions)==
No chromosomal rearrangements are identified.

The combination of the 2 pieces of chromosome 9 formed the fusion of the promoter plus exon 1 of ''DOCK8'' and exons 2-7 of ''PD-L1'' (''DOCK8''/''PD-L1'' fusion). https://doi.org/10.1182/bloodadvances.2023012019
{| class="wikitable sortable"
|-
!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
|-
|NA||NA||NA||NA
|NA
|NA
|NA
|NA
|}
==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. Do not delete table.'') </span>
{| class="wikitable sortable"
|-
!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
|-
|3<ref name=":4" />
|Loss
|3q26.1
|3q26.1
|No
|No
|No
|<br />
|-
|22<ref name=":4" />
|Loss
|22q11.23
|22q11.23
|No
|No
|No
|
|-
|14<ref name=":4" />
|Loss
|14q11.2
|14q11.2
|'''May be'''
|No
|No
|Loss of chr14q11.2 is the most frequent CNA, consistent with this aberration as a marker of T-cell lineage.<ref name=":4">{{Cite journal|last=Ng|first=Siok-Bian|last2=Chung|first2=Tae-Hoon|last3=Kato|first3=Seiichi|last4=Nakamura|first4=Shigeo|last5=Takahashi|first5=Emiko|last6=Ko|first6=Young-Hyeh|last7=Khoury|first7=Joseph D.|last8=Yin|first8=C. Cameron|last9=Soong|first9=Richie|date=2018-02-01|title=Epstein-Barr virus-associated primary nodal T/NK-cell lymphoma shows a distinct molecular signature and copy number changes|url=https://haematologica.org/article/view/8350|journal=Haematologica|language=en|volume=103|issue=2|pages=278–287|doi=10.3324/haematol.2017.180430|issn=1592-8721|pmc=PMC5792272|pmid=29097495}}</ref>
|-
|3<ref name=":5">{{Cite journal|last=Wai|first=Cho Mar Myint|last2=Chen|first2=Shangying|last3=Phyu|first3=The|last4=Fan|first4=Shuangyi|last5=Leong|first5=Sai Mun|last6=Zheng|first6=Wenning|last7=Low|first7=Louis Ching Yi|last8=Choo|first8=Shoa-Nian|last9=Lee|first9=Chi-Kuen|date=2022-01-13|title=Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS|url=https://haematologica.org/article/view/haematol.2021.280003|journal=Haematologica|language=en|volume=107|issue=8|pages=1864–1879|doi=10.3324/haematol.2021.280003|issn=1592-8721|pmc=PMC9335103|pmid=35021606}}</ref>
|Gain
|3p14.1
|3p14.1
|No
|No
|No
|Gain of 3p14.1 is found in 14.3% cases compared to 5.9% and 76.0% of ENKTL and PTCL-NOS cases, respectively
|-
|6<ref name=":5" />
|Gain
|6p22.3
|6p22.3
|No
|No
|No
|Gain of 6p22.3 is found more frequently in ENKTL (20.6%) and PTCL-NOS (58.6%) than in PTCL-EBV (7.1%) (''P''=0.005).
|-
|6<ref name=":5" />
|Gain
|6p22.1
|6p22.1
|No
|No
|No
|Gain of 6p22.1 is seen more in 21.4% of PTCL-EBV cases compared to 8.8% of ENKTL and 58.6% of PTCL-NOS cases
|-
|17<ref name=":5" />
|Gain
|17q21.33
|17q21.33
|No
|No
|No
|
|}
==Characteristic Chromosomal Patterns==
No specific characteristic chromosomal patterns have been described in EBV-positive nodal T- and NK-cell lymphoma.
{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|NA
|NA
|NA
|NA
|NA
|}
==Gene Mutations (SNV / INDEL)==
Based on the recent published literature, the most commonly mutated genes in EBV-positive nodal T- and NK-cell lymphoma identified in the Asian population are given below:
{| class="wikitable sortable"
|-
!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
|-
|''TET2''
|TSG
|64%- 68%<ref name=":5" /><ref name=":6">{{Cite journal|last=Kato|first=Seiichi|last2=Hamada|first2=Motoharu|last3=Okamoto|first3=Akinao|last4=Yamashita|first4=Daisuke|last5=Miyoshi|first5=Hiroaki|last6=Arai|first6=Haruto|last7=Satou|first7=Akira|last8=Gion|first8=Yuka|last9=Sato|first9=Yasuharu|date=2024-05-14|title=EBV+ nodal T/NK-cell lymphoma associated with clonal hematopoiesis and structural variations of the viral genome|url=https://ashpublications.org/bloodadvances/article/8/9/2138/515170/EBV-nodal-T-NK-cell-lymphoma-associated-with|journal=Blood Advances|language=en|volume=8|issue=9|pages=2138–2147|doi=10.1182/bloodadvances.2023012019|issn=2473-9529|pmc=PMC11068532|pmid=38429084}}</ref>
|DNMT3A<ref name=":6" />
|NA
|NA
|'''Yes'''
|No
|Both gene mutations are associated with clonal hematopoiesis and were found to have an overall poor survival in cohort of patients with concurrent mutations<ref name=":6" />
|-
|DNMT3A
|TSG
|32%<ref name=":6" />
|TET2<ref name=":6" />
|NA
|NA
|'''Yes'''
|No
|Same as above
|-
|''PIK3CD''
|
|33%<ref name=":5" />
|NA
|NA
|NA
|NA
|NA
|
|-
|''STAT3''
|Oncogene
|19%<ref name=":5" />
|NA
|NA
|NA
|NA
|NA
|
|-
|''DDX3X''
|TSG
|20%<ref name=":5" />
|NA
|NA
|NA
|NA
|NA
|
|-
|''PTPRD''
|
|18%<ref name=":5" />
|NA
|NA
|NA
|NA
|NA
|
|-
|''SETD2''
|
|8%<ref>{{Cite journal|last=Climent|first=Fina|last2=Nicolae|first2=Alina|last3=de Leval|first3=Laurence|last4=Dirnhofer|first4=Stefan|last5=Leoncini|first5=Lorenzo|last6=Ondrejka|first6=Sarah L.|last7=Soma|first7=Lorinda|last8=Wotherspoon|first8=Andrew|last9=Zamo|first9=Alberto|date=2023-09-01|title=Cytotoxic peripheral T-cell lymphomas and EBV-positive T/NK-cell lymphoproliferative diseases: emerging concepts, recent advances, and the putative role of clonal hematopoiesis. A report of the 2022 EA4HP/SH lymphoma workshop|url=https://link.springer.com/article/10.1007/s00428-023-03616-4|journal=Virchows Archiv|language=en|volume=483|issue=3|pages=333–348|doi=10.1007/s00428-023-03616-4|issn=1432-2307|pmc=PMC10542298|pmid=37646869}}</ref>
|NA
|NA
|NA
|NA
|NA
|
|}<br />
==Epigenomic Alterations==
<br />
==Genes and Main Pathways Involved==
Recent studies have demonstrated that EBV-positive nodal T- and NK-cell lymphoma is characterized by low genomic instability, upregulation of immune pathways (NFκB and check point protein PD-L1) that promote immune evasion, downregulation of EBV miRNAS and T-cell receptor (''TCR'') clonality. Furthermore, gene expression profiling analysis has identified enriched expression of genes related to cytotoxic activation, IL-6/JAK/STAT3 signaling, cell cycle and genomic instability, immune-related pathways, and interferon-α/γ response. NF-κB pathway–associated genes and proteins (''BIRC3'', ''NFKB1'', and ''CD27'') are upregulated. PDL1 (CD274) is also upregulated and is thought to be correlated with IFN-γ, IL-6/JAK/STAT3, and NF-κB pathways upregulation, although there is no gain of 9p24.1. Some of these pathways may be considered as potential therapeutic targets for EBV-positive nodal T- and NK-cell lymphoma as drugs targeting JAK-STAT, NFκB, STAT3, IFNγ, PD1/PD-L1 are either approved by FDA for different cancers or are being evaluated in clinical trials for lymphomas.<ref name=":5" /> 
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|''TET2;'' point mutations<ref name=":6" />
|DNA demethylation; epigenetic modifier
|
|-
|''DNMT3''
|DNA methylation; epigenetic modifier
|
|-
|''STAT3;'' gain-of-function mutation
|JAK-STAT Pathway
|Cell proliferation, migration and apoptosis
|-
|''PIK3CD''
|IL-9 Signaling Pathways; Immune response
|
|-
|''DDX3X''
|Innate Immune System and Toll-like receptor signaling pathway
|
|-
|''PTPRD''
|Protein-protein interactions at synapses and Transmission across Chemical Synapses
|Cell growth, differentiation, mitotic cycle, and oncogenic transformation
|-
|''SETD2''
|Key regulator of DNA mismatch repair in G1 and early S phase
|
|}
==Genetic Diagnostic Testing Methods==
Diagnosis of EBV-positive nodal T- and NK-cell lymphoma requires a combination of clinical evaluation, laboratory tests, imaging studies, and genetic testing to identify diagnostic criteria.

T-cell clonality can be confirmed by PCR, NGS, or flow cytometry. Cytogenetics, FISH and NGS can be helpful in differentiating this lymphoma from other types of EBV-T/NK cell lymphoproliferative disorders.
==Familial Forms==
None.
==Additional Information==
<br />
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