EBV-positive nodal T- and NK-cell lymphoma
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
(Will be autogenerated; Book will include name of specific book and have a link to the online WHO site)
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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.[1]
- Is a distinct entity in the Fifth 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]
- The 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 positive 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 of a T-cell lineage rather than NK-cell (> 80% of cases)
| Finding | Marker |
|---|---|
| Positive (universal) | CD3, CD2, CD8 (63–72%) and CD56 (7–22%) cytotoxic molecules (TIA1, granzyme B, and perforin), EBER (ISH) |
| Positive (subset) | TCRβ (43–64%), TCRγ (0–13%), CD30[2] |
| Negative (universal) | CD4, CD5 |
| Negative (subset) | TCRβ and TCRγ (25%), CD4-/CD8- (21%), CD4+/CD8- (8%), CD4-/CD8+ (64%)[6] |
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
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| 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 | EXAMPLE:
|
| 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 are identified 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 | 20%[11] | NA | NA | NA | NA | NA | ||
| PTPRD | 18%[11] | NA | NA | NA | NA | NA | ||
| SETD2 | 8%[13] | NA | NA | NA | NA | NA |
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Epigenomic Alterations
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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, and downregulation of EBV miRNAS , T-cell receptor (TCR) signaling
| 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 | ||
| PTPRD | ||
| SETD2 |
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
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Additional Information
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Links
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References
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Notes
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- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 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) - ↑ 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 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 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) - ↑ 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 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)