EBV-positive nodal T- and NK-cell lymphoma
Primary Author(s)*
FNU Monika, MBBS; Andrew Siref, MD
Creighton University, Omaha, NE
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Haematolymphoid Tumours (5th ed.) |
| Category | T-cell and NK-cell lymphoid proliferations and lymphomas |
| Family | Mature T-cell and NK-cell neoplasms |
| Type | EBV-positive T-cell and NK-cell lymphomas |
| Subtype(s) | EBV-positive nodal T- and NK-cell lymphoma |
Related Terminology
| Acceptable | Nodal EBV+ cytotoxic T-cell lymphoma; nodal peripheral T-cell lymphoma, EBV-positive; primary nodal EBV-positive T/NK-cell lymphoma |
| Not Recommended | Peripheral T-cell lymphoma NOS, EBV-positive |
Gene Rearrangements
No chromosomal rearrangements are identified.
| Driver Gene | Fusion(s) and Common Partner Genes | Molecular Pathogenesis | Typical Chromosomal Alteration(s) | Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|---|
| N/A | N/A | N/A | N/A | N/A | N/A | N/A | N/A |
Individual Region Genomic Gain/Loss/LOH
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)
| 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 | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| EXAMPLE:
7 |
EXAMPLE: Loss | EXAMPLE:
chr7 |
EXAMPLE:
Unknown |
EXAMPLE: D, P | EXAMPLE: No | EXAMPLE:
Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references). |
| EXAMPLE:
8 |
EXAMPLE: Gain | EXAMPLE:
chr8 |
EXAMPLE:
Unknown |
EXAMPLE: D, P | EXAMPLE:
Common recurrent secondary finding for t(8;21) (add references). | |
| EXAMPLE:
17 |
EXAMPLE: Amp | EXAMPLE:
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb] |
EXAMPLE:
ERBB2 |
EXAMPLE: D, P, T | EXAMPLE:
Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined. | |
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[1] | Loss | 3q26.1 | 3q26.1 | No | No | No | |
| 22[1] | Loss | 22q11.23 | 22q11.23 | No | No | No | |
| 14[1] | 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.[1] |
| 3[2] | 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[2] | 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[2] | 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[2] | Gain | 17q21.33 | 17q21.33 | No | No | No |
Characteristic Chromosomal or Other Global Mutational Patterns
No specific characteristic chromosomal patterns have been described in EBV-positive nodal T- and NK-cell lymphoma.
| Chromosomal Pattern | Molecular Pathogenesis | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|
| N/A | N/A | N/A | N/A | N/A | N/A |
Gene Mutations (SNV/INDEL)
Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)
| Gene | Genetic Alteration | Tumor Suppressor Gene, Oncogene, Other | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| EXAMPLE:EGFR
|
EXAMPLE: Exon 18-21 activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (lung cancer) | EXAMPLE: T | EXAMPLE: Yes (NCCN) | EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references). |
| EXAMPLE: TP53; Variable LOF mutations
|
EXAMPLE: Variable LOF mutations | EXAMPLE: Tumor Supressor Gene | EXAMPLE: Common (breast cancer) | EXAMPLE: P | EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer. | |
| EXAMPLE: BRAF; Activating mutations | EXAMPLE: Activating mutations | EXAMPLE: Oncogene | EXAMPLE: Common (melanoma) | EXAMPLE: T | ||
Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
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%[2][3] | DNMT3A[3] | 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[3] |
| DNMT3A | TSG | 32%[3] | TET2[3] | NA | NA | Yes | No | Same as above |
| PIK3CD | 33%[2] | NA | NA | NA | NA | NA | ||
| STAT3 | Oncogene | 19%[2] | NA | NA | NA | NA | NA | |
| DDX3X | TSG | 20%[2] | NA | NA | NA | NA | NA | |
| PTPRD | 18%[2] | NA | NA | NA | NA | NA | ||
| SETD2 | 8%[4] | NA | NA | NA | NA | NA |
Epigenomic Alterations
N/A
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.[2]
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| TET2; point mutations[3] | 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
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
EBV-positive nodal T- and NK-cell lymphoma is provisional entity in the International Consensus Classification 2022.[5]
Links
References
- ↑ 1.0 1.1 1.2 1.3 Ng, Siok-Bian; Chung, Tae-Hoon; Kato, Seiichi; Nakamura, Shigeo; Takahashi, Emiko; Ko, Young-Hyeh; Khoury, Joseph D.; Yin, C. Cameron; Soong, Richie (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.
{{cite journal}}: CS1 maint: PMC format (link) - ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 Wai, Cho Mar Myint; Chen, Shangying; Phyu, The; Fan, Shuangyi; Leong, Sai Mun; Zheng, Wenning; Low, Louis Ching Yi; Choo, Shoa-Nian; Lee, Chi-Kuen (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 9335103. PMID 35021606.
{{cite journal}}: CS1 maint: PMC format (link) - ↑ 3.0 3.1 3.2 3.3 3.4 3.5 Kato, Seiichi; Hamada, Motoharu; Okamoto, Akinao; Yamashita, Daisuke; Miyoshi, Hiroaki; Arai, Haruto; Satou, Akira; Gion, Yuka; Sato, Yasuharu (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 11068532. PMID 38429084.
{{cite journal}}: CS1 maint: PMC format (link) - ↑ Climent, Fina; Nicolae, Alina; de Leval, Laurence; Dirnhofer, Stefan; Leoncini, Lorenzo; Ondrejka, Sarah L.; Soma, Lorinda; Wotherspoon, Andrew; Zamo, Alberto (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 10542298. PMID 37646869.
{{cite journal}}: CS1 maint: PMC format (link) - ↑ Campo, Elias; Jaffe, Elaine S.; Cook, James R.; Quintanilla-Martinez, Leticia; Swerdlow, Steven H.; Anderson, Kenneth C.; Brousset, Pierre; Cerroni, Lorenzo; de Leval, Laurence (2022-09-15). "The International Consensus Classification of Mature Lymphoid Neoplasms: a report from the Clinical Advisory Committee". Blood. 140 (11): 1229–1253. doi:10.1182/blood.2022015851. ISSN 1528-0020. PMC 9479027. PMID 35653592.
Notes
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Prior Author(s):