HAEM4Backup:Systemic EBV-Positive T-cell Lymphoma of Childhood

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Primary Author(s)*

  • Lisa A. Lansdon, PhD & Linda D. Cooley, MD, MBA

Cancer Category/Type

Cancer Sub-Classification / Subtype

  • Systemic EBV-Positive T-cell Lymphoma of Childhood

Definition / Description of Disease[1][2][3][4][5][6]

  • A life-threatening clonal disease resulting from primary Epstein-Barr virus (EBV) infected T-cells or in the setting of systemic chronic active EBV infection (CAEBV)
  • T-lymphocytes infected with EBV infiltrate the liver, spleen, lungs, skin and marrow, resulting in multiorgan failure, sepsis and death
  • Rapidly progressive
  • Most common in children and young adults after a primary EBV infection; can occur in adult patients

Synonyms / Terminology[2][6][7]

  • Fulminant EBV-positive T-cell lymphoproliferative disorder of childhood
  • Sporadic fatal infectious mononucleosis
  • Fulminant hemophagocytic syndrome in children in Taiwan
  • Fatal EBV-associated hemophagocytic syndrome
  • Severe Chronic Active EBV Infection (CAEBV; legacy term)

Epidemiology / Prevalence[1][2][3][4][5][8]

  • Most prevalent in Asia (Japan and Taiwan)
  • Has been reported in Mexico, Central and South America
  • Rare in Western countries
  • Children and young adults
  • No sex predilection

Clinical Features

Signs & Symptoms [1][2][3][4][5][9][10]

  • Acute onset fever that is unresponsive to antibiotics
  • General malaise
  • Splenic and liver enlargement
  • Liver failure/jaundice
  • Lymphadenopathy (uncommon)

Laboratory Findings [2][5]

  • Pancytopenia
  • Abnormal liver function tests
  • Abnormal EBV serology with low or absent anti-VCA IgM antibodies
  • Hemophagocytic syndrome (coagulopathy, multiorgan failure and sepsis)
  • CAEBV infection (in some cases)

Sites of Involvement[6]

Systemic disease with most commonly involved sites:

  • Liver
  • Spleen
  • Lymph nodes
  • Bone marrow
  • Skin
  • Lung

Morphologic Features[2][5]

  • Small T-cells
  • Medium to large lymphoid cells with irregular nuclei and frequent mitoses (less common)
  • Sinusoidal infiltration of liver and spleen with hemophagocytosis
  • Spleen: depleted white pulp
  • Liver: prominent portal and sinusoidal infiltration, cholestasis, steatosis and necrosis
  • Lymph nodes: preserved architecture, sinus histiocytosis and erythrophagocytosis
  • Bone marrow: histiocytic hyperplasia and erythrophagocytosis

Immunophenotype[2][4][6][9][10][11]


Finding Marker
Positive CD2, CD3, TIA1, CD8 (de novo EBV infection), CD4 (severe CAEBV)
Negative CD56

Chromosomal Rearrangements (Gene Fusions)

  • No reported gene fusions

Characteristic Chromosomal Aberrations / Patterns[1][2][3][5][6][11][12][13][14]

  • Monoclonal T-cell receptor gene rearrangements
  • Aneuploidies and chromosomal gains/losses have been observed but no observable patterns to-date; Associated with worse prognosis

Genomic Gain/Loss/LOH

  • N/A

Gene Mutations (SNV/INDEL)[2][5][11]

  • All cases analyzed carry type A EBV with the wildtype or 30 bp deleted product of LMP1

Epigenomics (Methylation)

  • N/A

Genes and Main Pathways Involved

  • N/A

Diagnostic Testing Methods

  • Morphology and immunophenotyping (IHC or flow cytometry)
  • Clonal proliferation of T cells (polyclonal cases have been reported[15])

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

  • N/A

Familial Forms

  • Racial predisposition suggests a genetic background; however, no specific genetic abnormalities have been detected

Other Information

Differential Diagnosis[16][17]

  • Clinical and pathologic features of EBV-HLH and systemic EBV positive T-cell lymphoma of childhood overlap. These entities have been suggested to represent a biologic continuum
  • EBV-HLH is defined by a constellation of clinical symptoms and laboratory changes that might be triggered by EBV-associated lymphomas including aggressive NK-cell leukemia (ANKL) and systemic EBV-positive T-cell lymphoma of childhood
  • EBV-HLH associated with genetic abnormalities (primary HLH) can be excluded by genetic analysis and family history
  • Systemic CAEBV infection is difficult to differentiate from systemic EBV-positive T-cell lymphoma based only on morphologic grounds. The clinical information is necessary to achieve the correct diagnosis
  • ANKL is very similar to systemic EBV-positive T-cell lymphoma but the tumor cells express NK cell markers (CD56+) and do not show monoclonal TCR gene rearrangements

Additional Information[13][18][19]

  • Poor outcomes overall due to cytokine storm in HLH
  • Survival rates lower with disease onset after 8 years and with liver dysfunction at diagnosis
  • Death due to rapid disease progression for which there is no effective treatment
  • No known treatment; some case reports of response to etoposide and dexamethasone-based regimen followed by allogenic hematopoietic stem cell transplantation

Links

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

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References

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  1. ↑ 1.0 1.1 1.2 1.3 Kimura, H.; et al. (2001-07-15). "Clinical and virologic characteristics of chronic active Epstein-Barr virus infection". Blood. 98 (2): 280–286. doi:10.1182/blood.v98.2.280. ISSN 0006-4971. PMID 11435294.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 2.8 Quintanilla-Martinez, L.; et al. (2000-07-15). "Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome". Blood. 96 (2): 443–451. ISSN 0006-4971. PMID 10887104.
  3. ↑ 3.0 3.1 3.2 3.3 Kikuta, H.; et al. (1993-12-01). "Fatal Epstein-Barr virus-associated hemophagocytic syndrome". Blood. 82 (11): 3259–3264. ISSN 0006-4971. PMID 8241498.
  4. ↑ 4.0 4.1 4.2 4.3 Su, I. J.; et al. (1994-06). "Epstein-Barr virus (EBV) infects T lymphocytes in childhood EBV-associated hemophagocytic syndrome in Taiwan". The American Journal of Pathology. 144 (6): 1219–1225. ISSN 0002-9440. PMC 1887465. PMID 8203462. Check date values in: |date= (help)
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Suzuki, Keiko; et al. (2004-05). "Clinicopathological states of Epstein-Barr virus-associated T/NK-cell lymphoproliferative disorders (severe chronic active EBV infection) of children and young adults". International Journal of Oncology. 24 (5): 1165–1174. ISSN 1019-6439. PMID 15067338. Check date values in: |date= (help)
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Hue, Susan Swee-Shan; et al. (2020-01). "Epstein-Barr virus-associated T- and NK-cell lymphoproliferative diseases: an update and diagnostic approach". Pathology. 52 (1): 111–127. doi:10.1016/j.pathol.2019.09.011. ISSN 1465-3931. PMID 31767131. Check date values in: |date= (help)
  7. ↑ 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)
  8. ↑ Kimura, Hiroshi; et al. (2003-02-15). "Prognostic factors for chronic active Epstein-Barr virus infection". The Journal of Infectious Diseases. 187 (4): 527–533. doi:10.1086/367988. ISSN 0022-1899. PMID 12599068.
  9. ↑ 9.0 9.1 Jones, J. F.; et al. (1988-03-24). "T-cell lymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein-Barr virus infections". The New England Journal of Medicine. 318 (12): 733–741. doi:10.1056/NEJM198803243181203. ISSN 0028-4793. PMID 2831453.
  10. ↑ 10.0 10.1 Kanegane, H.; et al. (1998-03-15). "A syndrome of peripheral blood T-cell infection with Epstein-Barr virus (EBV) followed by EBV-positive T-cell lymphoma". Blood. 91 (6): 2085–2091. ISSN 0006-4971. PMID 9490694.
  11. ↑ 11.0 11.1 11.2 Kasahara, Y.; et al. (2001-09-15). "Differential cellular targets of Epstein-Barr virus (EBV) infection between acute EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection". Blood. 98 (6): 1882–1888. doi:10.1182/blood.v98.6.1882. ISSN 0006-4971. PMID 11535525.
  12. ↑ Au, W.-Y.; et al. (2005-02). "Clinicopathologic features and treatment outcome of mature T-cell and natural killer-cell lymphomas diagnosed according to the World Health Organization classification scheme: a single center experience of 10 years". Annals of Oncology: Official Journal of the European Society for Medical Oncology. 16 (2): 206–214. doi:10.1093/annonc/mdi037. ISSN 0923-7534. PMID 15668271. Check date values in: |date= (help)
  13. ↑ 13.0 13.1 Smith, Megan C.; et al. (2014). "The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder". International Journal of Clinical and Experimental Pathology. 7 (9): 5738–5749. ISSN 1936-2625. PMC 4203186. PMID 25337215.
  14. ↑ Chen, J. S.; et al. (1997-09). "Clonal karyotype abnormalities in EBV-associated hemophagocytic syndrome". Haematologica. 82 (5): 572–576. ISSN 0390-6078. PMID 9407723. Check date values in: |date= (help)
  15. ↑ Chen, Guoshu; et al. (2014). "Systemic Epstein-Barr virus positive T-cell lymphoproliferative disease of childhood with hemophagocytic syndrome". International Journal of Clinical and Experimental Pathology. 7 (10): 7110–7113. ISSN 1936-2625. PMC 4230111. PMID 25400806.
  16. ↑ Montes-Mojarro, Ivonne A.; et al. (2020-01). "Epstein - Barr virus positive T and NK-cell lymphoproliferations: Morphological features and differential diagnosis". Seminars in Diagnostic Pathology. 37 (1): 32–46. doi:10.1053/j.semdp.2019.12.004. ISSN 0740-2570. PMID 31889602. Check date values in: |date= (help)
  17. ↑ Cohen, Jeffrey I.; et al. (04 2020). "Epstein-Barr virus NK and T cell lymphoproliferative disease: report of a 2018 international meeting". Leukemia & Lymphoma. 61 (4): 808–819. doi:10.1080/10428194.2019.1699080. ISSN 1029-2403. PMID 31833428. Check date values in: |date= (help)
  18. ↑ 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.
  19. ↑ Yoshida, Masanori; et al. (03 2018). "Successful treatment of systemic EBV positive T-cell lymphoma of childhood using the SMILE regimen". Pediatric Hematology and Oncology. 35 (2): 121–124. doi:10.1080/08880018.2018.1459982. ISSN 1521-0669. PMID 29648917. Check date values in: |date= (help)

EXAMPLE Book

  1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.

Notes

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