Compendium of Cancer Genome Aberrations

Systemic chronic active EBV disease

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Karin Miller, MD

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 lymphoid proliferations and lymphomas of childhood
Subtype(s) Systemic chronic active EBV disease

Related Terminology

Acceptable N/A
Not Recommended Chronic active EBV infection; severe chronic active EBV infection; chronic active EBV disease (T- and NK-cell phenotype); chronic active EBV infection of T- and NK-cell type, systemic form

Gene Rearrangements

Approximately half of CAEBV cases show monoclonal T-cell gene rearrangements.

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
T-cell Receptor (TCR) Gene Rearrangements N/A V(D)J rearrangement of T-cell receptor loci [1] N/A Monoclonality detected in ~47% of cases[2] D The WHO 5th edition notes that, "cases with monomorphic and monoclonal proliferation have a poorer outcome than those with polymorphic and polyclonal proliferation."[3][4][5] N/A

Individual Region Genomic Gain/Loss/LOH

  • Multiple different chromosomal aberrations have been reported, approximately 7% of cases[6]
  • Frequent copy number alterations (CNAs) have recently been described in a subtype of NK-cell CAEBV with a poor prognosis that also showed a high CPG-island methylation pattern and higher tumor mutational burden (TMB).[7]
  • Intragenic deletions in the EBV genome may be detected (~35% of cases)[8]. Intragenic deletions in EBV were also detected in other EBV-associated neoplasms, but were not reported in patients with infectious mononucleosis or posttransplant lymphoproliferative disorder (PTLD)[8]
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
N/A N/A N/A N/A N/A N/A N/A

Characteristic Chromosomal or Other Global Mutational Patterns

N/A

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)

  • Somatic mutations can be detected in a subset of CAEBV cases (~29%).[8]
  • DDX3X mutations are the most commonly implicated known driver mutations. [8]
    • Mutations in KMT2D, KMT2B, BCOR/BCORL1, TET2, KDM6A, NFKB1, and ARID1a have also been described.[8][9]
  • In one study, identical driver mutations were detected in different cell lineages (T, B, and NK), demonstrating that EBV infected a common lymphoid progenitor in CAEBV patients. Acquisition of somatic, driver mutations in these pre-malignant, EBV-infected cells subsequently leads to clonal evolution in multiple cell lines.[8]
  • Presence of a driver mutation associated with shorter overall survival[8]
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
DDX3X Truncating mutations and pathogenic missense and in-frame deletions have been reported [8] TSG[10] Recurrent (~18%)[8] D, P No Presence of a driver mutation associated with shorter overall survival[8]
KMT2D Truncating mutations[8] TSG[10] Recurrent (~5%)[8] D,P No Presence of a driver mutation associated with shorter overall survival[8]
BCOR/ BCORL1 Predominantly truncating mutations [8] TSG[10] Rare D,P No Presence of a driver mutation associated with shorter overall survival[8]
TET2 Truncating mutations[8] TSG[10] Rare D,P No Presence of a driver mutation associated with shorter overall survival[8]
KDM6A Truncating mutations, missense (p.P887L)[8] TSG[10] Rare D,P No Presence of a driver mutation associated with shorter overall survival[8]

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.

Epigenomic Alterations

A high CPG-island methylation pattern has been described in a subtype of NK-cell CAEBV with a poor prognosis; these high methylation cases also showed higher tumor mutational burden (TMB) and frequent copy number alterations (CNAs).[7]

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
DDX3X Encodes RNA helicase Involved in cell signaling, transcriptional regulation, and viral replication. [11]

Exact role in CAEBV-pathogenesis not fully elucidated.[7]

Genetic Diagnostic Testing Methods

  • Both the WHO 5th edition and International Consensus Classification (ICC) include detection of increased EBV DNA in the peripheral blood (>10,000 IU/mL in ICC criteria) and/or EBV RNA (EBER) or viral protein in T or NK-cells of affected tissues.[3][4][12]
    • Whole blood or peripheral blood mononuclear cells are preferred for EBV DNA PCR testing, as serum or plasma are less sensitive for CAEBV disease[13]
    • In tissues, using a double stain for B, T, or NK-cell markers and EBV is recommended.

Familial Forms

  • Germline mutations have only rarely been detected in CAEBV[14]

Additional Information

  • CAEBV shows an increased prevalence in populations from Asia and Latin America, suggesting a potential for genetic polymorphisms in immune-modulating genes to play a role in disease pathogenesis.[15] [16]
  • EBV clonality testing showed monoclonality (84%), oligoclonality (11%), or polyclonality (5%).[17] TCR clonality testing is described above (see gene rearrangements)

Links

HAEM4:EBV-Positive T-cell and NK-cell Lymphoproliferative Diseases of Childhood

References

  1. ↑ van Dongen, J. J. M.; et al. (2003-12). "Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936". Leukemia. 17 (12): 2257–2317. doi:10.1038/sj.leu.2403202. ISSN 0887-6924. PMID 14671650. Check date values in: |date= (help)
  2. ↑ Kimura, Hiroshi; et al. (2012-01-19). "EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases". Blood. 119 (3): 673–686. doi:10.1182/blood-2011-10-381921. ISSN 1528-0020. PMID 22096243.
  3. ↑ 3.0 3.1 The WHO Classification of Tumours Editorial Board, ed. Haematolymphoid Tumours: Who Classification of Tumours. 5th ed. International Agency for Research on Cancer; 2024.
  4. ↑ 4.0 4.1 "BlueBooksOnline".
  5. ↑ Ohshima, Koichi; et al. (2008-04). "Proposed categorization of pathological states of EBV-associated T/natural killer-cell lymphoproliferative disorder (LPD) in children and young adults: overlap with chronic active EBV infection and infantile fulminant EBV T-LPD". Pathology International. 58 (4): 209–217. doi:10.1111/j.1440-1827.2008.02213.x. ISSN 1440-1827. PMID 18324913. Check date values in: |date= (help)
  6. ↑ Kimura, Hiroshi; et al. (2012-01-19). "EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases". Blood. 119 (3): 673–686. doi:10.1182/blood-2011-10-381921. ISSN 1528-0020. PMID 22096243.
  7. ↑ 7.0 7.1 7.2 Akazawa, Ryo; et al. (2025-11-06). "Multiomics analysis reveals the genetic and epigenetic features of high-risk NK cell-type chronic active EBV infection". Blood. 146 (19): 2336–2349. doi:10.1182/blood.2024026805. ISSN 1528-0020. PMID 40737598 Check |pmid= value (help).
  8. ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 8.12 8.13 8.14 8.15 8.16 8.17 8.18 Okuno, Yusuke; et al. (2019-03). "Defective Epstein-Barr virus in chronic active infection and haematological malignancy". Nature Microbiology. 4 (3): 404–413. doi:10.1038/s41564-018-0334-0. ISSN 2058-5276. PMID 30664667. Check date values in: |date= (help)
  9. ↑ Akazawa, Ryo; et al. (2025-11-06). "Multiomics analysis reveals the genetic and epigenetic features of high-risk NK cell-type chronic active EBV infection". Blood. 146 (19): 2336–2349. doi:10.1182/blood.2024026805. ISSN 1528-0020. PMID 40737598 Check |pmid= value (help).
  10. ↑ 10.0 10.1 10.2 10.3 10.4 "OncoKB™ - MSK's Precision Oncology Knowledge Base".
  11. ↑ Bollard, Catherine M.; et al. (2018-06-28). "How I treat T-cell chronic active Epstein-Barr virus disease". Blood. 131 (26): 2899–2905. doi:10.1182/blood-2018-03-785931. ISSN 1528-0020. PMC 6024635. PMID 29712633.
  12. ↑ Arber DA, Borowitz MJ, Cook JR, et al. The International Consensus Classification of Myeloid and Lymphoid Neoplasms.; 2025.
  13. ↑ Kimura, Hiroshi; et al. (2017). "Chronic Active Epstein-Barr Virus Disease". Frontiers in Immunology. 8: 1867. doi:10.3389/fimmu.2017.01867. ISSN 1664-3224. PMC 5770746. PMID 29375552.
  14. ↑ Okuno, Yusuke; et al. (2019-03). "Defective Epstein-Barr virus in chronic active infection and haematological malignancy". Nature Microbiology. 4 (3): 404–413. doi:10.1038/s41564-018-0334-0. ISSN 2058-5276. PMID 30664667. Check date values in: |date= (help)
  15. ↑ Kimura, Hiroshi; et al. (2017). "Chronic Active Epstein-Barr Virus Disease". Frontiers in Immunology. 8: 1867. doi:10.3389/fimmu.2017.01867. ISSN 1664-3224. PMC 5770746. PMID 29375552.
  16. ↑ Kimura, Hiroshi (2006). "Pathogenesis of chronic active Epstein-Barr virus infection: is this an infectious disease, lymphoproliferative disorder, or immunodeficiency?". Reviews in Medical Virology. 16 (4): 251–261. doi:10.1002/rmv.505. ISSN 1052-9276. PMID 16791843.
  17. ↑ Kimura, Hiroshi; et al. (2012-01-19). "EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases". Blood. 119 (3): 673–686. doi:10.1182/blood-2011-10-381921. ISSN 1528-0020. PMID 22096243.

Notes

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*Citation of this Page: “Systemic chronic active EBV disease”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 11/19/2025, https://ccga.io/index.php/HAEM5:Systemic_chronic_active_EBV_disease.

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