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

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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.

• Is a distinct entity in the Fifth WHO classification and as a provisional entity in the international consensus classification 2022.

Synonyms / Terminology

nodal EBV+ cytotoxic T-cell lymphoma; nodal peripheral T-cell lymphoma, EBV-positive; primary nodal EBV-positive T/NK-cell lymphoma.

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

Clinical Features

Signs and Symptoms	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
• The liver and/or bone marrow (24–60% of cases); other extranodal sites, such as the skin and gastrointestinal tract, are less commonly involved
• No nasal involvement has been reported

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
• Lacks classic morphological findings of angioinvasion and necrosis seen in extranodal positive T- and NK-cell lymphomas

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
Negative (universal)	CD4, CD5
Negative (subset)	TCRβ and TCRγ (25%), CD4-/CD8- (21%), CD4+/CD8- (8%), CD4-/CD8+ (64%)

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	Loss	3q26.1	3q26.1	No	No	No	EXAMPLE:
22	Loss	22q11.23	22q11.23	No	No	No
14	Loss	14q11.2	14q11.2	No	No	No	Loss of chr14q11.2 is the most frequent CNA, consistent with this aberration as a marker of T-cell lineage.
3	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	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	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	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%	DNMT3A	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
DNMT3A	TSG	32%	TET2	NA	NA	Yes	No	Same as above
PIK3CD		33%	NA	NA	NA	NA	NA
STAT3		19%
DDX3X		20%
PTPRD		18%
SETD2		8%

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
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE: KMT2C and ARID1A; Inactivating mutations	EXAMPLE: Histone modification, chromatin remodeling	EXAMPLE: Abnormal gene expression program

Genetic Diagnostic Testing Methods

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Familial Forms

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Additional Information

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References

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Notes

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