HAEM5:Systemic EBV-positive T-cell lymphoma of childhood: Difference between revisions

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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 EBV-positive T-cell lymphoma of childhood

Related Terminology


Acceptable	N/A
Not Recommended	Fulminant EBV-positive T-cell lymphoproliferative disorder of childhood; sporadic fatal infectious mononucleosis; severe chronic active EBV (CAEBV) infection; severe CAEBV with monoclonal EBV-positive T-cell proliferation; fatal EBV-associated haemophagocytic syndrome; fulminant haemophagocytic syndrome

Gene Rearrangements

Monoclonal T-cell receptor gene rearrangements in most cases.^[1]^[2] T-cell clonality can also be detected in EBV-associated HLH and other EBV-associated disorders.^[3]

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^[4]	N/A	Common^[1]	D	Yes	The WHO 5th edition notes that diagnosis of SEBVTCL of childhood "may be supported by clonal TR gene rearrangements," and clonal TR gene rearrangements are included as desirable diagnostic criteria.^[5]^[6]

Individual Region Genomic Gain/Loss/LOH

Cytogenetic abnormalities found in 30-35% of cases of SEBVTCL of childhood. The WHO 5th edition and International Consensus Classification note that cytogenetic abnormalities favor a diagnosis of SEBVTCL over EBV-positive nonfamilial HLH.^[7] ^[5]^[6]^[3]
No observable patterns in the cytogenetic/karyotypic abnormalities to-date; cytogenetic abnormalities associated with worse prognosis^[2]^[8]^[9]^[10]

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

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

Gene Mutations (SNV/INDELS)

Somatic mutations have been reported; however, consistent/recurrent mutations are not well-described.^[3]^[11]^[12]
- FYN mutations have been reported in two cases ^[3]^[12]
- Mutations in KMT2D, MFHAS1, STAT3, EP300, ITPKB, DDX3X, NOTCH1, NOTCH2, and TET2 (amongst others) have also been reported^[13]

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
N/A

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

N/A

Genes and Main Pathways Involved

N/A

Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
N/A

Genetic Diagnostic Testing Methods

In the WHO 5th edition, clonal TCR-gene rearrangements are included as desirable diagnostic criteria for the diagnosis of SEBVTCL of childhood^[5]^[6]

Differential Diagnosis with EBV-positive HLH is challenging
- TCR-gene rearrangements and aberrant T-cell phenotypes can be seen in both SEBVTCL of childhood and EBV-positive HLH
- The WHO 5th edition and International Consensus Classification note that cytogenetic abnormalities favor a diagnosis of SEBVTCL over EBV-positive nonfamilial HLH.^[5]^[7]
- Primary/familial EBV-positive HLH can be excluded by family history and genetic analysis^[3]
TCR-gene rearrangements can be detected via PCR or NGS methods. Cytogenetic abnormalities can be detected with karyotype and chromosome microarray (CMA).

Familial Forms

N/A

Additional Information

SEBVTCL of childhood shows an increased prevalence in populations from Asia and Latin America, suggesting a potential genetic etiology. However, no specific genetic abnormalities have been detected^[14]
Typically occurs following primary acute EBV infection; though, it is rarely reported in patients with a history of systemic chronic active EBV (CAEBV)^[3]
Harbors type A EBV with the wildtype or 30bp-deleted product of LMP1^[1]^[15]^[16]

Links

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

References

↑ ^1.0 ^1.1 ^1.2 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.
↑ ^2.0 ^2.1 Coffey, Amy M.; et al. (2019-08). "A clinicopathologic study of the spectrum of systemic forms of EBV-associated T-cell lymphoproliferative disorders of childhood: A single tertiary care pediatric institution experience in North America". Pediatric Blood & Cancer. 66 (8): e27798. doi:10.1002/pbc.27798. ISSN 1545-5017. PMID 31099136. Check date values in: |date= (help)
↑ ^3.0 ^3.1 ^3.2 ^3.3 ^3.4 ^3.5 Dojcinov, Stefan D.; et al. (2023-01-04). "How I Diagnose EBV-Positive B- and T-Cell Lymphoproliferative Disorders". American Journal of Clinical Pathology. 159 (1): 14–33. doi:10.1093/ajcp/aqac105. ISSN 1943-7722. PMID 36214507 Check |pmid= value (help).
↑ 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)
↑ ^5.0 ^5.1 ^5.2 ^5.3 The WHO Classification of Tumours Editorial Board, ed. Haematolymphoid Tumours: Who Classification of Tumours. 5th ed. International Agency for Research on Cancer; 2024.
↑ ^6.0 ^6.1 ^6.2 "BlueBooksOnline".
↑ ^7.0 ^7.1 Arber DA, Borowitz MJ, Cook JR, et al. The International Consensus Classification of Myeloid and Lymphoid Neoplasms.; 2025.
↑ 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)
↑ 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.
↑ 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)
↑ Saleem, Atif; et al. (2020-03-01). "Novel IRF8 and PD-L1 molecular aberrations in systemic EBV-positive T-cell lymphoma of childhood". Human Pathology: Case Reports. 19: 200356. doi:10.1016/j.ehpc.2020.200356. ISSN 2214-3300.
↑ ^12.0 ^12.1 Asmussen, Anders; et al. (2024-01). "Severe lympho-depletion, abrogated thymopoiesis and systemic EBV positive T-cell lymphoma of childhood, a case". Leukemia & Lymphoma. 65 (1): 118–122. doi:10.1080/10428194.2023.2264425. ISSN 1029-2403. PMID 37871127 Check |pmid= value (help). Check date values in: |date= (help)
↑ Gao, Li-Min; et al. (2019). "Somatic mutations in KMT2D and TET2 associated with worse prognosis in Epstein-Barr virus-associated T or natural killer-cell lymphoproliferative disorders". Cancer Biology & Therapy. 20 (10): 1319–1327. doi:10.1080/15384047.2019.1638670. ISSN 1555-8576. PMC 6783120. PMID 31311407.
↑ 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)
↑ 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.
↑ 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)

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

*Citation of this Page: “Systemic EBV-positive T-cell lymphoma of childhood”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 11/20/2025, https://ccga.io/index.php/HAEM5:Systemic_EBV-positive_T-cell_lymphoma_of_childhood.

[:1-1] 1.0 ^1.1 ^1.2 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.

[:7-2] 2.0 ^2.1 Coffey, Amy M.; et al. (2019-08). "A clinicopathologic study of the spectrum of systemic forms of EBV-associated T-cell lymphoproliferative disorders of childhood: A single tertiary care pediatric institution experience in North America". Pediatric Blood & Cancer. 66 (8): e27798. doi:10.1002/pbc.27798. ISSN 1545-5017. PMID 31099136. Check date values in: |date= (help)

[:10-3] 3.0 ^3.1 ^3.2 ^3.3 ^3.4 ^3.5 Dojcinov, Stefan D.; et al. (2023-01-04). "How I Diagnose EBV-Positive B- and T-Cell Lymphoproliferative Disorders". American Journal of Clinical Pathology. 159 (1): 14–33. doi:10.1093/ajcp/aqac105. ISSN 1943-7722. PMID 36214507 Check |pmid= value (help).

[4] 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)

[:3-5] 5.0 ^5.1 ^5.2 ^5.3 The WHO Classification of Tumours Editorial Board, ed. Haematolymphoid Tumours: Who Classification of Tumours. 5th ed. International Agency for Research on Cancer; 2024.

[:6-6] 6.0 ^6.1 ^6.2 "BlueBooksOnline".

[:0-7] 7.0 ^7.1 Arber DA, Borowitz MJ, Cook JR, et al. The International Consensus Classification of Myeloid and Lymphoid Neoplasms.; 2025.

[:5-8] 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)

[:9-9] 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.

[10] 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)

[11] Saleem, Atif; et al. (2020-03-01). "Novel IRF8 and PD-L1 molecular aberrations in systemic EBV-positive T-cell lymphoma of childhood". Human Pathology: Case Reports. 19: 200356. doi:10.1016/j.ehpc.2020.200356. ISSN 2214-3300.

[:2-12] 12.0 ^12.1 Asmussen, Anders; et al. (2024-01). "Severe lympho-depletion, abrogated thymopoiesis and systemic EBV positive T-cell lymphoma of childhood, a case". Leukemia & Lymphoma. 65 (1): 118–122. doi:10.1080/10428194.2023.2264425. ISSN 1029-2403. PMID 37871127 Check |pmid= value (help). Check date values in: |date= (help)

[13] Gao, Li-Min; et al. (2019). "Somatic mutations in KMT2D and TET2 associated with worse prognosis in Epstein-Barr virus-associated T or natural killer-cell lymphoproliferative disorders". Cancer Biology & Therapy. 20 (10): 1319–1327. doi:10.1080/15384047.2019.1638670. ISSN 1555-8576. PMC 6783120. PMID 31311407.

[14] 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)

[:8-15] 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.

[16] 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)

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HAEM5:Systemic EBV-positive T-cell lymphoma of childhood: Difference between revisions

Latest revision as of 12:46, 20 November 2025

Contents

Primary Author(s)*

WHO Classification of Disease

Related Terminology

Gene Rearrangements

Individual Region Genomic Gain/Loss/LOH

Characteristic Chromosomal or Other Global Mutational Patterns

Gene Mutations (SNV/INDELS)

Epigenomic Alterations

Genes and Main Pathways Involved

Genetic Diagnostic Testing Methods

Familial Forms

Additional Information

Links

References

Notes

Navigation menu

@@ Line 1: / Line 1: @@
 {{DISPLAYTITLE:Systemic EBV-positive T-cell lymphoma of childhood}}
 [[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
-{{Under Construction}}
-<blockquote class='blockedit'>{{Box-round|title=Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification|This page was converted to the new template on 2023-12-07. The original page can be found at [[HAEM4:Systemic EBV-Positive T-cell Lymphoma of Childhood]].
-}}</blockquote>
-<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ 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 to a table, click within the table and select the > symbol that appears to be given options. 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 </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>
 ==Primary Author(s)*==
-*Lisa A. Lansdon, PhD & Linda D. Cooley, MD, MBA
+*Karin Miller, MD
-__TOC__
 ==WHO Classification of Disease==
@@ Line 37: / Line 27: @@
 |}
-==Definition / Description of Disease==
+==Related Terminology==
-*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
-<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":0">{{Cite journal|last=Kimura|first=H.|last2=Hoshino|first2=Y.|last3=Kanegane|first3=H.|last4=Tsuge|first4=I.|last5=Okamura|first5=T.|last6=Kawa|first6=K.|last7=Morishima|first7=T.|date=2001-07-15|title=Clinical and virologic characteristics of chronic active Epstein-Barr virus infection|url=https://pubmed.ncbi.nlm.nih.gov/11435294|journal=Blood|volume=98|issue=2|pages=280–286|doi=10.1182/blood.v98.2.280|issn=0006-4971|pmid=11435294}}</ref><ref name=":1">{{Cite journal|last=Quintanilla-Martinez|first=L.|last2=Kumar|first2=S.|last3=Fend|first3=F.|last4=Reyes|first4=E.|last5=Teruya-Feldstein|first5=J.|last6=Kingma|first6=D. W.|last7=Sorbara|first7=L.|last8=Raffeld|first8=M.|last9=Straus|first9=S. E.|date=2000-07-15|title=Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/10887104|journal=Blood|volume=96|issue=2|pages=443–451|issn=0006-4971|pmid=10887104}}</ref><ref name=":2">{{Cite journal|last=Kikuta|first=H.|last2=Sakiyama|first2=Y.|last3=Matsumoto|first3=S.|last4=Oh-Ishi|first4=T.|last5=Nakano|first5=T.|last6=Nagashima|first6=T.|last7=Oka|first7=T.|last8=Hironaka|first8=T.|last9=Hirai|first9=K.|date=1993-12-01|title=Fatal Epstein-Barr virus-associated hemophagocytic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/8241498|journal=Blood|volume=82|issue=11|pages=3259–3264|issn=0006-4971|pmid=8241498}}</ref><ref name=":3">{{Cite journal|last=Su|first=I. J.|last2=Chen|first2=R. L.|last3=Lin|first3=D. T.|last4=Lin|first4=K. S.|last5=Chen|first5=C. C.|date=1994-06|title=Epstein-Barr virus (EBV) infects T lymphocytes in childhood EBV-associated hemophagocytic syndrome in Taiwan|url=https://pubmed.ncbi.nlm.nih.gov/8203462|journal=The American Journal of Pathology|volume=144|issue=6|pages=1219–1225|issn=0002-9440|pmc=1887465|pmid=8203462}}</ref><ref name=":4">{{Cite journal|last=Suzuki|first=Keiko|last2=Ohshima|first2=Koichi|last3=Karube|first3=Kennosuke|last4=Suzumiya|first4=Junji|last5=Ohga|first5=Shouichi|last6=Ishihara|first6=Shigehiko|last7=Tamura|first7=Kazuo|last8=Kikuchi|first8=Masahiro|date=2004-05|title=Clinicopathological states of Epstein-Barr virus-associated T/NK-cell lymphoproliferative disorders (severe chronic active EBV infection) of children and young adults|url=https://pubmed.ncbi.nlm.nih.gov/15067338|journal=International Journal of Oncology|volume=24|issue=5|pages=1165–1174|issn=1019-6439|pmid=15067338}}</ref><ref name=":5">{{Cite journal|last=Hue|first=Susan Swee-Shan|last2=Oon|first2=Ming Liang|last3=Wang|first3=Shi|last4=Tan|first4=Soo-Yong|last5=Ng|first5=Siok-Bian|date=2020-01|title=Epstein-Barr virus-associated T- and NK-cell lymphoproliferative diseases: an update and diagnostic approach|url=https://pubmed.ncbi.nlm.nih.gov/31767131|journal=Pathology|volume=52|issue=1|pages=111–127|doi=10.1016/j.pathol.2019.09.011|issn=1465-3931|pmid=31767131}}</ref><blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Synonyms / Terminology==
-*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)
-<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":1" /><ref name=":5" /><ref>{{Cite journal|last=Ohshima|first=Koichi|last2=Kimura|first2=Hiroshi|last3=Yoshino|first3=Tadashi|last4=Kim|first4=Chul Woo|last5=Ko|first5=Young H.|last6=Lee|first6=Seung-Suk|last7=Peh|first7=Suat-Cheng|last8=Chan|first8=John K. C.|last9=CAEBV Study Group|date=2008-04|title=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|url=https://pubmed.ncbi.nlm.nih.gov/18324913|journal=Pathology International|volume=58|issue=4|pages=209–217|doi=10.1111/j.1440-1827.2008.02213.x|issn=1440-1827|pmid=18324913}}</ref><blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Epidemiology / Prevalence==
-*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
-<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" /><ref>{{Cite journal|last=Kimura|first=Hiroshi|last2=Morishima|first2=Tsuneo|last3=Kanegane|first3=Hirokazu|last4=Ohga|first4=Shouichi|last5=Hoshino|first5=Yo|last6=Maeda|first6=Akihiko|last7=Imai|first7=Shosuke|last8=Okano|first8=Motohiko|last9=Morio|first9=Tomohiro|date=2003-02-15|title=Prognostic factors for chronic active Epstein-Barr virus infection|url=https://pubmed.ncbi.nlm.nih.gov/12599068|journal=The Journal of Infectious Diseases|volume=187|issue=4|pages=527–533|doi=10.1086/367988|issn=0022-1899|pmid=12599068}}</ref><blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Clinical Features==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
 {| class="wikitable"
-|'''Signs and Symptoms'''
+|+
-|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)
+|Acceptable
+|N/A
-<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)
-<span class="blue-text">EXAMPLE:</span> Fatigue
-<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
 |-
-|'''Laboratory Findings'''
+|Not Recommended
-|<span class="blue-text">EXAMPLE:</span> Cytopenias
+|Fulminant EBV-positive T-cell lymphoproliferative disorder of childhood; sporadic fatal infectious mononucleosis; severe chronic active EBV (CAEBV) infection; severe CAEBV with monoclonal EBV-positive T-cell proliferation; fatal EBV-associated haemophagocytic syndrome; fulminant haemophagocytic syndrome
-<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
 |}
+==Gene Rearrangements==
-<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}</blockquote>
+Monoclonal T-cell receptor gene rearrangements in most cases.<ref name=":1">{{Cite journal|last=Quintanilla-Martinez|first=L.|last2=Kumar|first2=S.|last3=Fend|first3=F.|last4=Reyes|first4=E.|last5=Teruya-Feldstein|first5=J.|last6=Kingma|first6=D. W.|last7=Sorbara|first7=L.|last8=Raffeld|first8=M.|last9=Straus|first9=S. E.|date=2000-07-15|title=Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/10887104|journal=Blood|volume=96|issue=2|pages=443–451|issn=0006-4971|pmid=10887104}}</ref><ref name=":7">{{Cite journal|last=Coffey|first=Amy M.|last2=Lewis|first2=Annisa|last3=Marcogliese|first3=Andrea N.|last4=Elghetany|first4=M. Tarek|last5=Punia|first5=Jyotinder N.|last6=Chang|first6=Chung-Che|last7=Allen|first7=Carl E.|last8=McClain|first8=Kenneth L.|last9=Gaikwad|first9=Amos S.|date=2019-08|title=A clinicopathologic study of the spectrum of systemic forms of EBV-associated T-cell lymphoproliferative disorders of childhood: A single tertiary care pediatric institution experience in North America|url=https://pubmed.ncbi.nlm.nih.gov/31099136|journal=Pediatric Blood & Cancer|volume=66|issue=8|pages=e27798|doi=10.1002/pbc.27798|issn=1545-5017|pmid=31099136}}</ref> T-cell clonality can also be detected in EBV-associated HLH and other EBV-associated disorders.<ref name=":10">{{Cite journal|last=Dojcinov|first=Stefan D.|last2=Quintanilla-Martinez|first2=Leticia|date=2023-01-04|title=How I Diagnose EBV-Positive B- and T-Cell Lymphoproliferative Disorders|url=https://pubmed.ncbi.nlm.nih.gov/36214507|journal=American Journal of Clinical Pathology|volume=159|issue=1|pages=14–33|doi=10.1093/ajcp/aqac105|issn=1943-7722|pmid=36214507}}</ref>
-Signs & Symptoms <ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":3" /><ref name=":4" /><ref name=":6">{{Cite journal|last=Jones|first=J. F.|last2=Shurin|first2=S.|last3=Abramowsky|first3=C.|last4=Tubbs|first4=R. R.|last5=Sciotto|first5=C. G.|last6=Wahl|first6=R.|last7=Sands|first7=J.|last8=Gottman|first8=D.|last9=Katz|first9=B. Z.|date=1988-03-24|title=T-cell lymphomas containing Epstein-Barr viral DNA in patients with chronic Epstein-Barr virus infections|url=https://pubmed.ncbi.nlm.nih.gov/2831453|journal=The New England Journal of Medicine|volume=318|issue=12|pages=733–741|doi=10.1056/NEJM198803243181203|issn=0028-4793|pmid=2831453}}</ref><ref name=":7">{{Cite journal|last=Kanegane|first=H.|last2=Bhatia|first2=K.|last3=Gutierrez|first3=M.|last4=Kaneda|first4=H.|last5=Wada|first5=T.|last6=Yachie|first6=A.|last7=Seki|first7=H.|last8=Arai|first8=T.|last9=Kagimoto|first9=S.|date=1998-03-15|title=A syndrome of peripheral blood T-cell infection with Epstein-Barr virus (EBV) followed by EBV-positive T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/9490694|journal=Blood|volume=91|issue=6|pages=2085–2091|issn=0006-4971|pmid=9490694}}</ref>
-*Acute onset fever that is unresponsive to antibiotics
-*General malaise
-*Splenic and liver enlargement
-*Liver failure/jaundice
-*Lymphadenopathy (uncommon)
-Laboratory Findings <ref name=":1" /><ref name=":4" />
-*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)
-<blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Sites of Involvement==
-Systemic disease with most commonly involved sites:
-*Liver
-*Spleen
-*Lymph nodes
-*Bone marrow
-*Skin
-*Lung
-<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":5" /><blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Morphologic Features==
-*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
-<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":1" /><ref name=":4" /><blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Immunophenotype==
-<br />
 {| class="wikitable sortable"
 |-
-!Finding!!Marker
+!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
 |-
-|Positive||CD2, CD3, TIA1, CD8 (''de novo'' EBV infection), CD4 (severe CAEBV)
+|T-cell Receptor (TCR) Gene Rearrangements
-|-
+|N/A
-|Negative||CD56
+|V(D)J rearrangement of T-cell receptor loci<ref>{{Cite journal|last=van Dongen|first=J. J. M.|last2=Langerak|first2=A. W.|last3=Brüggemann|first3=M.|last4=Evans|first4=P. a. S.|last5=Hummel|first5=M.|last6=Lavender|first6=F. L.|last7=Delabesse|first7=E.|last8=Davi|first8=F.|last9=Schuuring|first9=E.|date=2003-12|title=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|url=https://pubmed.ncbi.nlm.nih.gov/14671650|journal=Leukemia|volume=17|issue=12|pages=2257–2317|doi=10.1038/sj.leu.2403202|issn=0887-6924|pmid=14671650}}</ref>
+|N/A
+|Common<ref name=":1" />
+|D
+|Yes
+|The WHO 5th edition notes that diagnosis of SEBVTCL of childhood "may be supported by clonal TR gene rearrangements," and clonal TR gene rearrangements are included as desirable diagnostic criteria.<ref name=":3">The WHO Classification of Tumours Editorial Board, ed. ''Haematolymphoid Tumours: Who Classification of Tumours''. 5th ed. International Agency for Research on Cancer; 2024.</ref><ref name=":6">{{Cite journal|title=BlueBooksOnline|url=https://tumourclassification.iarc.who.int/chapters/63}}</ref>
 |}
+==Individual Region Genomic Gain/Loss/LOH==
+* Cytogenetic abnormalities found in 30-35% of cases of SEBVTCL of childhood. The WHO 5th edition and International Consensus Classification note that cytogenetic abnormalities favor a diagnosis of SEBVTCL over EBV-positive nonfamilial HLH.<ref name=":0">Arber DA, Borowitz MJ, Cook JR, et al. ''The International Consensus Classification of Myeloid and Lymphoid Neoplasms''.; 2025.</ref> <ref name=":3" /><ref name=":6" /><ref name=":10" />
-<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":1" /><ref name=":3" /><ref name=":5" /><ref name=":6" /><ref name=":7" /><ref name=":8">{{Cite journal|last=Kasahara|first=Y.|last2=Yachie|first2=A.|last3=Takei|first3=K.|last4=Kanegane|first4=C.|last5=Okada|first5=K.|last6=Ohta|first6=K.|last7=Seki|first7=H.|last8=Igarashi|first8=N.|last9=Maruhashi|first9=K.|date=2001-09-15|title=Differential cellular targets of Epstein-Barr virus (EBV) infection between acute EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection|url=https://pubmed.ncbi.nlm.nih.gov/11535525|journal=Blood|volume=98|issue=6|pages=1882–1888|doi=10.1182/blood.v98.6.1882|issn=0006-4971|pmid=11535525}}</ref><blockquote class="blockedit">
+* No observable patterns in the cytogenetic/karyotypic abnormalities to-date; cytogenetic abnormalities associated with worse prognosis<ref name=":7" /><ref name=":5">{{Cite journal|last=Hue|first=Susan Swee-Shan|last2=Oon|first2=Ming Liang|last3=Wang|first3=Shi|last4=Tan|first4=Soo-Yong|last5=Ng|first5=Siok-Bian|date=2020-01|title=Epstein-Barr virus-associated T- and NK-cell lymphoproliferative diseases: an update and diagnostic approach|url=https://pubmed.ncbi.nlm.nih.gov/31767131|journal=Pathology|volume=52|issue=1|pages=111–127|doi=10.1016/j.pathol.2019.09.011|issn=1465-3931|pmid=31767131}}</ref><ref name=":9">{{Cite journal|last=Smith|first=Megan C.|last2=Cohen|first2=Daniel N.|last3=Greig|first3=Bruce|last4=Yenamandra|first4=Ashwini|last5=Vnencak-Jones|first5=Cindy|last6=Thompson|first6=Mary Ann|last7=Kim|first7=Annette S.|date=2014|title=The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder|url=https://pubmed.ncbi.nlm.nih.gov/25337215|journal=International Journal of Clinical and Experimental Pathology|volume=7|issue=9|pages=5738–5749|issn=1936-2625|pmc=4203186|pmid=25337215}}</ref><ref>{{Cite journal|last=Chen|first=J. S.|last2=Tzeng|first2=C. C.|last3=Tsao|first3=C. J.|last4=Su|first4=W. C.|last5=Chen|first5=T. Y.|last6=Jung|first6=Y. C.|last7=Su|first7=I. J.|date=1997-09|title=Clonal karyotype abnormalities in EBV-associated hemophagocytic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/9407723|journal=Haematologica|volume=82|issue=5|pages=572–576|issn=0390-6078|pmid=9407723}}</ref>
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Chromosomal Rearrangements (Gene Fusions)==
-Put your text here and fill in the table
 {| class="wikitable sortable"
 |-
-!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
+!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
-!Diagnostic Significance (Yes, No or Unknown)
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
-!Prognostic Significance (Yes, No or Unknown)
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
-!Therapeutic Significance (Yes, No or Unknown)
+!Clinical Relevance Details/Other Notes
-!Notes
 |-
-|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
+|N/A
-<span class="blue-text">EXAMPLE:</span> 30% (add reference)
+|
-|Yes
+|
-|No
+|
-|Yes
+|
-|<span class="blue-text">EXAMPLE:</span>
+|
+|
-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).
-|}
-<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}</blockquote>
-*No reported gene fusions
-<blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:
-* Chromosomal Rearrangements (Gene Fusions)
-* Individual Region Genomic Gain/Loss/LOH
-* Characteristic Chromosomal Patterns
-* Gene Mutations (SNV/INDEL)}}</blockquote>
-*N/A
-<blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Individual Region Genomic Gain / Loss / LOH==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.'') </span>
-{| class="wikitable sortable"
-|-
-!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
-|-
-|<span class="blue-text">EXAMPLE:</span>
-|<span class="blue-text">EXAMPLE:</span> Loss
-|<span class="blue-text">EXAMPLE:</span>
-chr7:1- 159,335,973 [hg38]
-|<span class="blue-text">EXAMPLE:</span>
-chr7
-|Yes
-|Yes
-|No
-|<span class="blue-text">EXAMPLE:</span>
-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).
-|-
-|<span class="blue-text">EXAMPLE:</span>
-|<span class="blue-text">EXAMPLE:</span> Gain
-|<span class="blue-text">EXAMPLE:</span>
-chr8:1-145,138,636 [hg38]
-|<span class="blue-text">EXAMPLE:</span>
-chr8
-|No
-|No
-|No
-|<span class="blue-text">EXAMPLE:</span>
-Common recurrent secondary finding for t(8;21) (add reference).
 |}
-<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}</blockquote>
+<blockquote class="blockedit"><center>
-*N/A
-<blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
 </blockquote>
-==Characteristic Chromosomal Patterns==
+==Characteristic Chromosomal or Other Global Mutational Patterns==
-Put your text here <span style="color:#0070C0">(''EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.'')</span>
+N/A
 {| class="wikitable sortable"
 |-
 !Chromosomal Pattern
-!Diagnostic Significance (Yes, No or Unknown)
+!Molecular Pathogenesis
-!Prognostic Significance (Yes, No or Unknown)
+!Prevalence -
-!Therapeutic Significance (Yes, No or Unknown)
+Common >20%, Recurrent 5-20% or Rare <5% (Disease)
-!Notes
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
+!Clinical Relevance Details/Other Notes
 |-
-|<span class="blue-text">EXAMPLE:</span>
+|N/A
+|
-Co-deletion of 1p and 18q
+|
-|Yes
+|
-|No
+|
-|No
+|
-|<span class="blue-text">EXAMPLE:</span>
-See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
 |}
-<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The content below was from the old template. Please incorporate above.}}</blockquote>
+== Gene Mutations (SNV/INDELS) ==
-*Monoclonal T-cell receptor gene rearrangements
-*Aneuploidies and chromosomal gains/losses have been observed but no observable patterns to-date; Associated with worse prognosis
-<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":0" /><ref name=":1" /><ref name=":2" /><ref name=":4" /><ref name=":5" /><ref name=":8" /><ref>{{Cite journal|last=Au|first=W.-Y.|last2=Ma|first2=S.-Y.|last3=Chim|first3=C.-S.|last4=Choy|first4=C.|last5=Loong|first5=F.|last6=Lie|first6=A. K. W.|last7=Lam|first7=C. C. K.|last8=Leung|first8=A. Y. H.|last9=Tse|first9=E.|date=2005-02|title=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|url=https://pubmed.ncbi.nlm.nih.gov/15668271|journal=Annals of Oncology: Official Journal of the European Society for Medical Oncology|volume=16|issue=2|pages=206–214|doi=10.1093/annonc/mdi037|issn=0923-7534|pmid=15668271}}</ref><ref name=":9">{{Cite journal|last=Smith|first=Megan C.|last2=Cohen|first2=Daniel N.|last3=Greig|first3=Bruce|last4=Yenamandra|first4=Ashwini|last5=Vnencak-Jones|first5=Cindy|last6=Thompson|first6=Mary Ann|last7=Kim|first7=Annette S.|date=2014|title=The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder|url=https://pubmed.ncbi.nlm.nih.gov/25337215|journal=International Journal of Clinical and Experimental Pathology|volume=7|issue=9|pages=5738–5749|issn=1936-2625|pmc=4203186|pmid=25337215}}</ref><ref>{{Cite journal|last=Chen|first=J. S.|last2=Tzeng|first2=C. C.|last3=Tsao|first3=C. J.|last4=Su|first4=W. C.|last5=Chen|first5=T. Y.|last6=Jung|first6=Y. C.|last7=Su|first7=I. J.|date=1997-09|title=Clonal karyotype abnormalities in EBV-associated hemophagocytic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/9407723|journal=Haematologica|volume=82|issue=5|pages=572–576|issn=0390-6078|pmid=9407723}}</ref><blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-<blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-</blockquote>
-==Gene Mutations (SNV / INDEL)==
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable. Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Do not delete table.'') </span>
+* Somatic mutations have been reported; however, consistent/recurrent mutations are not well-described.<ref name=":10" /><ref>{{Cite journal|last=Saleem|first=Atif|last2=Joshi|first2=Rohan|last3=Lei|first3=Li|last4=Lezama|first4=Lhara|last5=Raghavan|first5=Shyam S.|last6=Neishaboori|first6=Nastaran|last7=Roy|first7=Mohana|last8=Schroers-Martin|first8=Joe|last9=Charville|first9=Gregory W.|date=2020-03-01|title=Novel IRF8 and PD-L1 molecular aberrations in systemic EBV-positive T-cell lymphoma of childhood|url=https://www.sciencedirect.com/science/article/pii/S2214330020300055|journal=Human Pathology: Case Reports|volume=19|pages=200356|doi=10.1016/j.ehpc.2020.200356|issn=2214-3300}}</ref><ref name=":2">{{Cite journal|last=Asmussen|first=Anders|last2=Quintanilla-Martinez|first2=Leticia|last3=Larsen|first3=Martin|last4=Fagerberg|first4=Christina|last5=Bækvad-Hansen|first5=Marie|last6=Juul|first6=Maja Bech|last7=Rewers|first7=Kate|last8=Raaschou-Jensen|first8=Klas|last9=Barnkob|first9=Mike Bogetofte|date=2024-01|title=Severe lympho-depletion, abrogated thymopoiesis and systemic EBV positive T-cell lymphoma of childhood, a case|url=https://pubmed.ncbi.nlm.nih.gov/37871127|journal=Leukemia & Lymphoma|volume=65|issue=1|pages=118–122|doi=10.1080/10428194.2023.2264425|issn=1029-2403|pmid=37871127}}</ref>
+** ''FYN'' mutations have been reported in two cases <ref name=":10" /><ref name=":2" />
+** Mutations in ''KMT2D'', ''MFHAS1'', ''STAT3'', ''EP300'', ''ITPKB'', ''DDX3X'', ''NOTCH1'', ''NOTCH2'', and ''TET2'' (amongst others) have also been reported<ref>{{Cite journal|last=Gao|first=Li-Min|last2=Zhao|first2=Sha|last3=Zhang|first3=Wen-Yan|last4=Wang|first4=Mi|last5=Li|first5=Hui-Fang|last6=Lizaso|first6=Anle|last7=Liu|first7=Wei-Ping|date=2019|title=Somatic mutations in KMT2D and TET2 associated with worse prognosis in Epstein-Barr virus-associated T or natural killer-cell lymphoproliferative disorders|url=https://pmc.ncbi.nlm.nih.gov/articles/PMC6783120/|journal=Cancer Biology & Therapy|volume=20|issue=10|pages=1319–1327|doi=10.1080/15384047.2019.1638670|issn=1555-8576|pmc=6783120|pmid=31311407}}</ref>
 {| class="wikitable sortable"
 |-
-!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
+!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
-!'''Diagnostic Significance (Yes, No or Unknown)'''
+Common >20%, Recurrent 5-20% or Rare <5% (Disease)
-!Prognostic Significance (Yes, No or Unknown)
+!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
-!Therapeutic Significance (Yes, No or Unknown)
+!Established Clinical Significance Per Guidelines - Yes or No (Source)
-!Notes
+!Clinical Relevance Details/Other Notes
 |-
-|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations
+|N/A
+|
-<span class="blue-text">EXAMPLE:</span>
+|
+|
-EGFR; Exon 20 mutations
-<span class="blue-text">EXAMPLE:</span> BRAF; Activating mutations
-|<span class="blue-text">EXAMPLE:</span> TSG
-|<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
-<span class="blue-text">EXAMPLE:</span> 30% (add Reference)
-|<span class="blue-text">EXAMPLE:</span> IDH1 R123H
-|<span class="blue-text">EXAMPLE:</span> EGFR amplification
 |
 |
 |
-|<span class="blue-text">EXAMPLE:</span>  Excludes hairy cell leukemia (HCL) (add reference).
+|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
-<br />
-|}
-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.
-<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}</blockquote>
-*All cases analyzed carry type A EBV with the wildtype or 30 bp deleted product of ''LMP1''
-<blockquote class='blockedit'>{{Box-round|title=Unassigned References|The following referenees were placed in the header. Please place them into the appropriate locations in the text.}}</blockquote><ref name=":1" /><ref name=":4" /><ref name=":8" /><blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-<blockquote class="blockedit">
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-</blockquote>
-==Epigenomic Alterations==
-*N/A
-==Genes and Main Pathways Involved==
+== Epigenomic Alterations ==
+N/A
-Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
+== Genes and Main Pathways Involved ==
+N/A
 {| class="wikitable sortable"
 |-
 !Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 |-
-|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations
+|N/A
-|<span class="blue-text">EXAMPLE:</span> MAPK signaling
+|
-|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
+|
-|-
-|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
-|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
-|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
-|-
-|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
-|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
-|<span class="blue-text">EXAMPLE:</span>  Abnormal gene expression program
 |}
-<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}</blockquote>
+== Genetic Diagnostic Testing Methods ==
+* In the WHO 5th edition, clonal TCR-gene rearrangements are included as ''desirable'' diagnostic criteria for the diagnosis of SEBVTCL of childhood<ref name=":3" /><ref name=":6" />
+* Differential Diagnosis with EBV-positive HLH is challenging
+** TCR-gene rearrangements and aberrant T-cell phenotypes can be seen in both SEBVTCL of childhood and EBV-positive HLH
+** The WHO 5th edition and International Consensus Classification note that cytogenetic abnormalities favor a diagnosis of SEBVTCL over EBV-positive nonfamilial HLH.<ref name=":3" /><ref name=":0" />
+** Primary/familial EBV-positive HLH can be excluded by family history and genetic analysis<ref name=":10" />
+* TCR-gene rearrangements can be detected via PCR or NGS methods. Cytogenetic abnormalities can be detected with karyotype and chromosome microarray (CMA).
-*N/A
+== Familial Forms ==
-<blockquote class="blockedit">
+N/A
-<center><span style="color:Maroon">'''End of V4 Section'''</span>
-----
-</blockquote>
-==Genetic Diagnostic Testing Methods==
-*Morphology and immunophenotyping (IHC or flow cytometry)
+== Additional Information ==
-*Clonal proliferation of T cells (polyclonal cases have been reported<ref>{{Cite journal|last=Chen|first=Guoshu|last2=Chen|first2=Li|last3=Qin|first3=Xiaohua|last4=Huang|first4=Zhuoya|last5=Xie|first5=Xiaoling|last6=Li|first6=Guowei|last7=Xu|first7=Bing|date=2014|title=Systemic Epstein-Barr virus positive T-cell lymphoproliferative disease of childhood with hemophagocytic syndrome|url=https://pubmed.ncbi.nlm.nih.gov/25400806|journal=International Journal of Clinical and Experimental Pathology|volume=7|issue=10|pages=7110–7113|issn=1936-2625|pmc=4230111|pmid=25400806}}</ref>)
-==Familial Forms==
+* SEBVTCL of childhood shows an increased prevalence in populations from Asia and Latin America, suggesting a potential genetic etiology. However, no specific genetic abnormalities have been detected<ref>{{Cite journal|last=Montes-Mojarro|first=Ivonne A.|last2=Kim|first2=Wook Youn|last3=Fend|first3=Falko|last4=Quintanilla-Martinez|first4=Leticia|date=2020-01|title=Epstein - Barr virus positive T and NK-cell lymphoproliferations: Morphological features and differential diagnosis|url=https://pubmed.ncbi.nlm.nih.gov/31889602|journal=Seminars in Diagnostic Pathology|volume=37|issue=1|pages=32–46|doi=10.1053/j.semdp.2019.12.004|issn=0740-2570|pmid=31889602}}</ref>
+* Typically occurs following primary acute EBV infection; though, it is rarely reported in patients with a history of systemic chronic active EBV (CAEBV)<ref name=":10" />
+* Harbors type A EBV with the wildtype or 30bp-deleted product of ''LMP1''<ref name=":1" /><ref name=":8">{{Cite journal|last=Kasahara|first=Y.|last2=Yachie|first2=A.|last3=Takei|first3=K.|last4=Kanegane|first4=C.|last5=Okada|first5=K.|last6=Ohta|first6=K.|last7=Seki|first7=H.|last8=Igarashi|first8=N.|last9=Maruhashi|first9=K.|date=2001-09-15|title=Differential cellular targets of Epstein-Barr virus (EBV) infection between acute EBV-associated hemophagocytic lymphohistiocytosis and chronic active EBV infection|url=https://pubmed.ncbi.nlm.nih.gov/11535525|journal=Blood|volume=98|issue=6|pages=1882–1888|doi=10.1182/blood.v98.6.1882|issn=0006-4971|pmid=11535525}}</ref><ref>{{Cite journal|last=Suzuki|first=Keiko|last2=Ohshima|first2=Koichi|last3=Karube|first3=Kennosuke|last4=Suzumiya|first4=Junji|last5=Ohga|first5=Shouichi|last6=Ishihara|first6=Shigehiko|last7=Tamura|first7=Kazuo|last8=Kikuchi|first8=Masahiro|date=2004-05|title=Clinicopathological states of Epstein-Barr virus-associated T/NK-cell lymphoproliferative disorders (severe chronic active EBV infection) of children and young adults|url=https://pubmed.ncbi.nlm.nih.gov/15067338|journal=International Journal of Oncology|volume=24|issue=5|pages=1165–1174|issn=1019-6439|pmid=15067338}}</ref>
-*Racial predisposition suggests a genetic background; however, no specific genetic abnormalities have been detected
+== Links ==
+[[HAEM4:EBV-Positive T-cell and NK-cell Lymphoproliferative Diseases of Childhood]]<center><center>
-==Additional Information==
-Differential Diagnosis<ref>{{Cite journal|last=Montes-Mojarro|first=Ivonne A.|last2=Kim|first2=Wook Youn|last3=Fend|first3=Falko|last4=Quintanilla-Martinez|first4=Leticia|date=2020-01|title=Epstein - Barr virus positive T and NK-cell lymphoproliferations: Morphological features and differential diagnosis|url=https://pubmed.ncbi.nlm.nih.gov/31889602|journal=Seminars in Diagnostic Pathology|volume=37|issue=1|pages=32–46|doi=10.1053/j.semdp.2019.12.004|issn=0740-2570|pmid=31889602}}</ref><ref>{{Cite journal|last=Cohen|first=Jeffrey I.|last2=Iwatsuki|first2=Keiji|last3=Ko|first3=Young-Hyeh|last4=Kimura|first4=Hiroshi|last5=Manoli|first5=Irini|last6=Ohshima|first6=Koichi|last7=Pittaluga|first7=Stefania|last8=Quintanilla-Martinez|first8=Leticia|last9=Jaffe|first9=Elaine S.|date=04 2020|title=Epstein-Barr virus NK and T cell lymphoproliferative disease: report of a 2018 international meeting|url=https://pubmed.ncbi.nlm.nih.gov/31833428|journal=Leukemia & Lymphoma|volume=61|issue=4|pages=808–819|doi=10.1080/10428194.2019.1699080|issn=1029-2403|pmid=31833428}}</ref>
-*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<ref name=":9" /><ref>{{Cite journal|last=Kimura|first=Hiroshi|last2=Ito|first2=Yoshinori|last3=Kawabe|first3=Shinji|last4=Gotoh|first4=Kensei|last5=Takahashi|first5=Yoshiyuki|last6=Kojima|first6=Seiji|last7=Naoe|first7=Tomoki|last8=Esaki|first8=Shinichi|last9=Kikuta|first9=Atsushi|date=2012-01-19|title=EBV-associated T/NK-cell lymphoproliferative diseases in nonimmunocompromised hosts: prospective analysis of 108 cases|url=https://pubmed.ncbi.nlm.nih.gov/22096243|journal=Blood|volume=119|issue=3|pages=673–686|doi=10.1182/blood-2011-10-381921|issn=1528-0020|pmid=22096243}}</ref><ref>{{Cite journal|last=Yoshida|first=Masanori|last2=Osumi|first2=Tomoo|last3=Imadome|first3=Ken-Ichi|last4=Tomizawa|first4=Daisuke|last5=Kato|first5=Motohiro|last6=Miyazawa|first6=Noritaka|last7=Ito|first7=Reiko|last8=Nakazawa|first8=Atsuko|last9=Matsumoto|first9=Kimikazu|date=03 2018|title=Successful treatment of systemic EBV positive T-cell lymphoma of childhood using the SMILE regimen|url=https://pubmed.ncbi.nlm.nih.gov/29648917|journal=Pediatric Hematology and Oncology|volume=35|issue=2|pages=121–124|doi=10.1080/08880018.2018.1459982|issn=1521-0669|pmid=29648917}}</ref>
-*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==
+== References ==
+<center><center>
+<center><center>
+<center><references />
-[[HAEM4:EBV-Positive T-cell and NK-cell Lymphoproliferative Diseases of Childhood]]
+<br />
-Put your links here (use "Link" icon at top of page)
+==Notes==
+<nowiki>*</nowiki>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 [[Leadership|''<u>Associate Editor</u>'']] 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.
-==References==
+Prior Author(s): Lisa A. Lansdon, PhD & Linda D. Cooley, MD, MBA
-(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted.''</span> <span style="color:#0070C0">''If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />
-'''
-==Notes==
-<nowiki>*</nowiki>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 CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
 <nowiki>*</nowiki>''Citation of this Page'': “Systemic EBV-positive T-cell lymphoma of childhood”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Systemic_EBV-positive_T-cell_lymphoma_of_childhood</nowiki>.
-[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases S]]
+[[Category:HAEM5]]
+[[Category:DISEASE]]
+[[Category:Diseases S]]

HAEM5:Systemic EBV-positive T-cell lymphoma of childhood: Difference between revisions

Latest revision as of 12:46, 20 November 2025

Primary Author(s)*

WHO Classification of Disease

Related Terminology

Gene Rearrangements

Individual Region Genomic Gain/Loss/LOH

Characteristic Chromosomal or Other Global Mutational Patterns

Gene Mutations (SNV/INDELS)

Epigenomic Alterations

Genes and Main Pathways Involved

Genetic Diagnostic Testing Methods

Familial Forms

Additional Information

Links

References

Notes

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