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)

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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
EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: 3'ABL1 / 5'BCR	EXAMPLE: der(22)	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add reference)	EXAMPLE: Yes	EXAMPLE: No	EXAMPLE: Yes	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

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
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:1-159,335,973 [hg38]	EXAMPLE: chr7	EXAMPLE: Yes	EXAMPLE: Yes	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 reference).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:1-145,138,636 [hg38]	EXAMPLE: chr8	EXAMPLE: No	EXAMPLE: No	EXAMPLE: No	EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).

Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: Yes	EXAMPLE: No	EXAMPLE: No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

Gene Mutations (SNV / INDEL)

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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
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification	EXAMPLE: Yes	EXAMPLE: No	EXAMPLE: No	EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).

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

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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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