EBV-positive nodal T- and NK-cell lymphoma
Haematolymphoid Tumours (WHO Classification, 5th ed.)
 | This page is under construction |
(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click nearby within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)
Primary Author(s)*
FNU Monika, MBBS; Andrew Siref, MD
Creighton University, Omaha, NE
WHO Classification of Disease
(Will be autogenerated; Book will include name of specific book and have a link to the online WHO site)
| Structure | Disease |
|---|---|
| Book | |
| Category | |
| Family | |
| Type | |
| Subtype(s) |
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.[1]
- Is a distinct entity in the 5th Edition of the WHO classification and as a provisional entity in the International Consensus Classification 2022.[2][3]
Synonyms / Terminology
nodal EBV+ cytotoxic T-cell lymphoma; nodal peripheral T-cell lymphoma, EBV-positive; primary nodal EBV-positive T/NK-cell lymphoma.[1]
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 [1][4]
Clinical Features
| Signs and Symptoms[1][5][6][7] | 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[1]
- Liver and/or bone marrow (24–60% of cases); other extranodal sites, such as the skin and gastrointestinal tract, are less commonly involved[5][6][8]
- No nasal involvement has been reported[1]
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[1][9]
- Lacks classic morphological findings of angioinvasion and necrosis seen in extranodal EBV+ T- and NK-cell lymphomas[5]
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)
| Finding | Marker |
|---|---|
| Positive (universal) | CD3, CD2, CD56 (7–22%), cytotoxic molecules (TIA1, granzyme B, and perforin), EBER (ISH) |
| CD4/CD8[1][4][5][6][8] | CD4-/CD8- (21%), CD4+/CD8- (8%), CD4-/CD8+ (63-72%) |
| TCR[1][4][5][6][8] | TCRβ (+, 43–64%), TCRγ (+, 0–13%), TCRβ and TCRγ (-, 25%), |
| Positive (subset) | CD30[2] |
| Negative (universal) | CD5 |
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
| 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 (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.)
| 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[10] | Loss | 3q26.1 | 3q26.1 | No | No | No | |
| 22[10] | Loss | 22q11.23 | 22q11.23 | No | No | No | |
| 14[10] | 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.[10] |
| 3[11] | 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[11] | 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[11] | 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[11] | 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.
| 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:
| 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%[11][12] | DNMT3A[12] | 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[12] |
| DNMT3A | TSG | 32%[12] | TET2[12] | NA | NA | Yes | No | Same as above |
| PIK3CD | 33%[11] | NA | NA | NA | NA | NA | ||
| STAT3 | Oncogene | 19%[11] | NA | NA | NA | NA | NA | |
| DDX3X | TSG | 20%[11] | NA | NA | NA | NA | NA | |
| PTPRD | 18%[11] | NA | NA | NA | NA | NA | ||
| SETD2 | 8%[13] | NA | NA | NA | NA | NA |
Epigenomic Alterations
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.[11]
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| TET2; point mutations[12] | 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
Links
(use the "Link" icon that looks like two overlapping circles at the top of the page) (Instructions: Highlight text to which you want to add a link in this section or elsewhere, select the "Link" icon at the top of the page, and search the name of the internal page to which you want to link this text, or enter an external internet address by including the "http://www." portion.)
References
(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference.)
Notes
*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.
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 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)
- ↑ 2.0 2.1 Yu, Fang; et al. (2024-04). "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". American Journal of Surgical Pathology. 48 (4): 406–416. doi:10.1097/PAS.0000000000002184. ISSN 0147-5185. Check date values in:
|date=(help) - ↑ Kato, Seiichi; et al. (2024-05-14). "EBV+ nodal T/NK-cell lymphoma associated with clonal hematopoiesis and structural variations of the viral genome". Blood Advances. 8 (9): 2138–2147. doi:10.1182/bloodadvances.2023012019. ISSN 2473-9529. PMC PMC11068532 Check
|pmc=value (help). PMID 38429084 Check|pmid=value (help).CS1 maint: PMC format (link) - ↑ 4.0 4.1 4.2 Ha, Sang Yun; et al. (2013-07-01). "Epstein–Barr virus-positive nodal peripheral T cell lymphomas: Clinicopathologic and gene expression profiling study". Pathology - Research and Practice. 209 (7): 448–454. doi:10.1016/j.prp.2013.04.013. ISSN 0344-0338.
- ↑ 5.0 5.1 5.2 5.3 5.4 Jeon, Yoon Kyung; et al. (2015-07). "Epstein-Barr virus–positive nodal T/NK-cell lymphoma: an analysis of 15 cases with distinct clinicopathological features". Human Pathology. 46 (7): 981–990. doi:10.1016/j.humpath.2015.03.002. Check date values in:
|date=(help) - ↑ 6.0 6.1 6.2 6.3 Kato, Seiichi; et al. (2015-04). "T-cell Receptor (TCR) Phenotype of Nodal Epstein-Barr Virus (EBV)-positive Cytotoxic T-cell Lymphoma (CTL): A Clinicopathologic Study of 39 Cases". American Journal of Surgical Pathology. 39 (4): 462–471. doi:10.1097/PAS.0000000000000323. ISSN 0147-5185. Check date values in:
|date=(help) - ↑ Yu, Fang; et al. (2024-04). "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". American Journal of Surgical Pathology. 48 (4): 406–416. doi:10.1097/PAS.0000000000002184. ISSN 0147-5185. Check date values in:
|date=(help) - ↑ 8.0 8.1 8.2 Yamashita, Daisuke; et al. (2018-08). "Reappraisal of nodal Epstein‐Barr Virus‐negative cytotoxic T‐cell lymphoma: Identification of indolent CD 5 + diseases". Cancer Science. 109 (8): 2599–2610. doi:10.1111/cas.13652. ISSN 1347-9032. PMC 6113510. PMID 29845715. Check date values in:
|date=(help)CS1 maint: PMC format (link) - ↑ Attygalle, Ayoma D; et al. (2014-01). "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". Histopathology. 64 (2): 171–199. doi:10.1111/his.12251. ISSN 0309-0167. PMC 6364972. PMID 24128129. Check date values in:
|date=(help)CS1 maint: PMC format (link) - ↑ 10.0 10.1 10.2 10.3 Ng, Siok-Bian; et al. (2018-02-01). "Epstein-Barr virus-associated primary nodal T/NK-cell lymphoma shows a distinct molecular signature and copy number changes". Haematologica. 103 (2): 278–287. doi:10.3324/haematol.2017.180430. ISSN 1592-8721. PMC 5792272. PMID 29097495.CS1 maint: PMC format (link)
- ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 11.9 Wai, Cho Mar Myint; et al. (2022-01-13). "Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS". Haematologica. 107 (8): 1864–1879. doi:10.3324/haematol.2021.280003. ISSN 1592-8721. PMC PMC9335103 Check
|pmc=value (help). PMID 35021606 Check|pmid=value (help).CS1 maint: PMC format (link) - ↑ 12.0 12.1 12.2 12.3 12.4 12.5 Kato, Seiichi; et al. (2024-05-14). "EBV+ nodal T/NK-cell lymphoma associated with clonal hematopoiesis and structural variations of the viral genome". Blood Advances. 8 (9): 2138–2147. doi:10.1182/bloodadvances.2023012019. ISSN 2473-9529. PMC PMC11068532 Check
|pmc=value (help). PMID 38429084 Check|pmid=value (help).CS1 maint: PMC format (link) - ↑ Climent, Fina; et al. (2023-09-01). "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". Virchows Archiv. 483 (3): 333–348. doi:10.1007/s00428-023-03616-4. ISSN 1432-2307. PMC PMC10542298 Check
|pmc=value (help). PMID 37646869 Check|pmid=value (help).CS1 maint: PMC format (link)