Compendium of Cancer Genome Aberrations

Systemic chronic active EBV disease

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

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] N/A

Individual Region Genomic Gain/Loss/LOH

  • Multiple different chromosomal aberrations have been reported, approximately 7% of cases[5]
  • Intragenic deletions in the EBV genome may be detected (~35% of cases)[6]. 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)[6]
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%).[6]
  • DDX3X mutations are the most commonly implicated known driver mutations[6]
  • 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.[6]
  • Presence of a driver mutation associated with shorter overall survival[6]
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 [6] TSG[7] Recurrent (~18%)[6] D, P No Presence of a driver mutation associated with shorter overall survival[6]
KMT2D Truncating mutations[6] TSG[7] Recurrent (~5%)[6] D,P No Presence of a driver mutation associated with shorter overall survival[6]
BCOR/ BCORL1 Predominantly truncating mutations [6] TSG[7] Rare D,P No Presence of a driver mutation associated with shorter overall survival[6]
TET2 Truncating mutations[6] TSG[7] Rare D,P No Presence of a driver mutation associated with shorter overall survival[6]
KDM6A Truncating mutations, missense (p.P887L)[6] TSG[7] Rare D,P No Presence of a driver mutation associated with shorter overall survival[6]

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

Put your text here

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
See Gene Mutation section above

Genetic Diagnostic Testing Methods

  • The WHO 5th edition essential diagnostic criteria include:[3]
    • Persistent (greater than 3 months) infectious mononucleosis-like symptoms
    • Increased EBV DNA in the peripheral blood or EBER-positive cells in affected organs with evidence of EBV infection in T or NK-cells
    • Exclusion of known immunodeficiency, malignancy, or autoimmune disorders
  • The International Consensus Classification (ICC) revised diagnostic criteria include:[8]
    • Persistent (greater than 3 months) infectious mononucleosis-like symptoms
    • Increased EBV DNA (>10,000 IU/mL) in the peripheral blood
    • Histologic evidence of organ disease
    • Detection of EBV RNA or viral protein in T or NK-cells in affected tissues
    • Exclusion of known immunodeficiency, malignancy, or autoimmune disorders
  • Both the WHO 5th edition and ICC include detection of increased EBV DNA in the peripheral blood and/or EBV RNA (EBER) or viral protein in T or NK-cells of affected tissues.[3][8]
    • Whole blood or peripheral blood mononuclear cells are preferred for EBV DNA PCR testing, as serum or plasma are less sensitive for CAEBV disease[9]
    • In tissues, using a double stain for B, T, or NK-cell markers and EBV is recommended.
  • TCR-gene rearrangements can be tested via PCR-Capillary Electrophoresis or NGS methods
  • DNA mutations (SNV/Indels) can be detected using NGS

Familial Forms

  • CAEBV shows an increased prevalence in populations from Asia and natives from Central and South America, suggesting a potential for genetic polymorphisms in immune-modulating genes to play a role in disease pathogenesis[10] [11]
  • Germline mutations have only rarely been detected in CAEBV[12]

Additional Information

  • EBV clonality testing showed monoclonality (84%), oligoclonality (11%), or polyclonality (5%).[13] 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 3.2 "BlueBooksOnline".
  4. ↑ 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)
  5. ↑ 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.
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 6.15 6.16 6.17 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)
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "OncoKB™ - MSK's Precision Oncology Knowledge Base".
  8. ↑ 8.0 8.1 Arber DA, Borowitz MJ, Cook JR, et al. The International Consensus Classification of Myeloid and Lymphoid Neoplasms.; 2025.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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)
  13. ↑ 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

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s):


*Citation of this Page: “Systemic chronic active EBV disease”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 11/17/2025, https://ccga.io/index.php/HAEM5:Systemic_chronic_active_EBV_disease.

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