View source for HAEM5:Adult T-cell leukaemia/lymphoma

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[[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:Adult T-cell Leukemia/Lymphoma]].
}}</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)*==

Prasad R. Kopparapu, PhD and Ferrin C. Wheeler, PhD, FACMG

Vanderbilt University Medical Center 

__TOC__

==WHO Classification of Disease==

{| class="wikitable"
!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
|Mature T-cell and NK-cell leukaemias
|-
|Subtype(s)
|Adult T-cell leukaemia/lymphoma
|}

==Definition / Description of Disease==

Adult T-cell Leukemia/Lymphoma (ATLL) is a systemic, aggressive T-cell malignancy cause by chronic infection of human T lymphotropic virus 1 (HTLV-1) with poor prognosis<ref>Thiele, J. et al., (2017). Adult T-cell leukemia/lymphoma, 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, p363-367</ref>. 

==Synonyms / Terminology==

Adult T-cell leukemia, Adult T-cell lymphoma, HTLV-1 associated adult T-cell leukemia-lymphoma.

==Epidemiology / Prevalence==

ATLL is endemic in many parts of Southwestern Japan, the Caribbean basin, Sub-Saharan Africa, South America, Romania, Northern Iran, parts of the Middle East and Australo-Melanesia<ref name=":0">{{Cite journal|last=Gessain|first=Antoine|last2=Cassar|first2=Olivier|date=2012|title=Epidemiological Aspects and World Distribution of HTLV-1 Infection|url=https://pubmed.ncbi.nlm.nih.gov/23162541|journal=Frontiers in Microbiology|volume=3|pages=388|doi=10.3389/fmicb.2012.00388|issn=1664-302X|pmc=3498738|pmid=23162541}}</ref><ref>{{Cite journal|last=Mehta-Shah|first=Neha|last2=Ratner|first2=Lee|last3=Horwitz|first3=Steven M.|date=08 2017|title=Adult T-Cell Leukemia/Lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/28796966|journal=Journal of Oncology Practice|volume=13|issue=8|pages=487–492|doi=10.1200/JOP.2017.021907|issn=1935-469X|pmc=6366298|pmid=28796966}}</ref>.

ATLL occurs only in adults between 30 to 90 years of age with an average age of 58 years. The male-to-female ratio is 1.5:1<ref>{{Cite journal|last=Rocquain|first=Julien|last2=Carbuccia|first2=Nadine|last3=Trouplin|first3=Virginie|last4=Raynaud|first4=Stéphane|last5=Murati|first5=Anne|last6=Nezri|first6=Meyer|last7=Tadrist|first7=Zoulika|last8=Olschwang|first8=Sylviane|last9=Vey|first9=Norbert|date=2010-08-02|title=Combined mutations of ASXL1, CBL, FLT3, IDH1, IDH2, JAK2, KRAS, NPM1, NRAS, RUNX1, TET2 and WT1 genes in myelodysplastic syndromes and acute myeloid leukemias|url=https://pubmed.ncbi.nlm.nih.gov/20678218|journal=BMC cancer|volume=10|pages=401|doi=10.1186/1471-2407-10-401|issn=1471-2407|pmc=2923633|pmid=20678218}}</ref>.

Transmission occurs through breast milk, sexual fluids, peripheral blood and blood products<ref name=":0" />.

==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)

<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'''
|<span class="blue-text">EXAMPLE:</span> Cytopenias

<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The content below was from the old template. Please incorporate above.}}

ATLL is classified into four clinical subtypes: Acute, Lymphoma, Chronic and Smoldering<ref name=":3">{{Cite journal|last=Shimoyama|first=M.|date=1991-11|title=Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984-87)|url=https://pubmed.ncbi.nlm.nih.gov/1751370|journal=British Journal of Haematology|volume=79|issue=3|pages=428–437|doi=10.1111/j.1365-2141.1991.tb08051.x|issn=0007-1048|pmid=1751370}}</ref>. 

<u>Acute</u>: Most common type (65% of patients) with elevated WBC count, skin rash and generalized lymphadenopathy, hypercalcemia, hepatosplenomegaly, elevated LDH and frequent opportunistic infections like pneumocystis jirovecii pneumonia and strongyloidiasis.

<u>Lymphoma</u>: The lymphomatous variant is characterized by lymphadenopathy, absence of lymphocytosis, possible extranodal lesions with minimal peripheral blood involvement and less frequent hypercalcemia.

<u>Chronic</u>: The chronic variant can progress to acute or lymphomatous subtype. This variant manifests with lymphocytosis and exfoliative skin lesions.  Atypical lymphocytes are fewer in number in peripheral blood. There can be mild hepatosplenomegaly and lymphadenopathy. Hypercalcemia is not observed, and no involvement of CNS, bone and gastrointestinal tract, and neither ascites nor pleural effusion.

<u>Smoldering</u>: This variant may also progress to the acute subtype upon long duration. This variant may present with skin or lung lesions. More than 5% circulating abnormal T-cell lymphocytes can be found in the absence of leukocytosis. No manifestation of hypercalcemia, hepatosplenomegaly or lymphadenopathy.

</blockquote>
==Sites of Involvement==

In addition to lymph node involvement, there is involvement in extranodal sites like spleen, skin, lung, liver, gastrointestinal tract and CNS, making this a systemic disease with peripheral blood involvement<ref>{{Cite journal|last=Bunn|first=P. A.|last2=Schechter|first2=G. P.|last3=Jaffe|first3=E.|last4=Blayney|first4=D.|last5=Young|first5=R. C.|last6=Matthews|first6=M. J.|last7=Blattner|first7=W.|last8=Broder|first8=S.|last9=Robert-Guroff|first9=M.|date=1983-08-04|title=Clinical course of retrovirus-associated adult T-cell lymphoma in the United States|url=https://pubmed.ncbi.nlm.nih.gov/6602943|journal=The New England Journal of Medicine|volume=309|issue=5|pages=257–264|doi=10.1056/NEJM198308043090501|issn=0028-4793|pmid=6602943}}</ref>. 

==Morphologic Features==

The morphological features of ATLL in skin include erythema, papules, and nodules based on macroscopic examination and perivascular infiltration of atypical lymphoid cells, diffuse infiltration of medium to large sized atypical lymphoid cells and infiltration of large atypical lymphoid cell as per histopathological observations. 

Lymph node lesions present as pleomorphic small, medium and large cell types, anaplastic and an angioimmunoblastic T-cell lymphoma type.

Infiltration of atypical lymphoid cells with irregular or round nuclei is seen in the bone marrow cavity with detection of hypercalcemia.

In liver, infiltration of atypical medium to large sized lymphoid cells with irregular nuclei is seen.

Diffuse, pleomorphic and anaplastic type cells can infiltrate the stomach destroying the gastric glands.

In peripheral blood, “flower like” cells that have multilobed nucleus with basophilic cytoplasm can be observed by Giemsa staining<ref>{{Cite journal|last=Ohshima|first=Koichi|date=2007-06|title=Pathological features of diseases associated with human T-cell leukemia virus type I|url=https://pubmed.ncbi.nlm.nih.gov/17388788|journal=Cancer Science|volume=98|issue=6|pages=772–778|doi=10.1111/j.1349-7006.2007.00456.x|issn=1347-9032|pmid=17388788}}</ref>.

==Immunophenotype==

In most patients, tumor cells exhibit phenotype of mature CD4+ T cells by expressing CD2, CD3, CD5, CD25, CD45RO, CD29, T-cell receptor αβ, FOXP3, CD52,  and HLA-DR<ref>{{Cite journal|last=Roncador|first=G.|last2=Garcia|first2=J. F.|last3=Garcia|first3=J. F.|last4=Maestre|first4=L.|last5=Lucas|first5=E.|last6=Menarguez|first6=J.|last7=Ohshima|first7=K.|last8=Nakamura|first8=S.|last9=Banham|first9=A. H.|date=2005-12|title=FOXP3, a selective marker for a subset of adult T-cell leukaemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/16193085|journal=Leukemia|volume=19|issue=12|pages=2247–2253|doi=10.1038/sj.leu.2403965|issn=0887-6924|pmid=16193085}}</ref><ref>{{Cite journal|last=Ishida|first=Takashi|last2=Utsunomiya|first2=Atae|last3=Iida|first3=Shinsuke|last4=Inagaki|first4=Hiroshi|last5=Takatsuka|first5=Yoshifusa|last6=Kusumoto|first6=Shigeru|last7=Takeuchi|first7=Genji|last8=Shimizu|first8=Shigeki|last9=Ito|first9=Masato|date=2003-09-01|title=Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome|url=https://pubmed.ncbi.nlm.nih.gov/14506150|journal=Clinical Cancer Research: An Official Journal of the American Association for Cancer Research|volume=9|issue=10 Pt 1|pages=3625–3634|issn=1078-0432|pmid=14506150}}</ref>. 

Most cases are CD4+CD8-, but rarely, cases can be CD4-CD8+ or CD4+CD8+. A typical immunophenotype for ATLL is: CD2+, CD3+, CD4+, CD7-, CD8-, CD25+, CD30+/-, TCR αβ+<ref name=":4" />. 

Immunophenotypic characterization of CD3, CD4, CD7 , CD8, and CD25 are the minimum requirement for an ATLL diagnosis.
{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||CD2, CD3, CD5, CD4, CCD4
|-
|Positive (subset)||CD8, CD4, CD30, FOXP3
|-
|Negative (universal)||CD7, CD8, TdT, TCL1, ALK1, B cell  antigens, cytotoxic molecules
|-
|Negative (subset)||CD4,CD8, ALK
|}

==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
!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> 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)
<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.}}

Tandem duplications of  2q33.2 segments cause formation of CTLA4-CD28 and ICOS-CD28 fusion products that render prolonged co-stimulatory signals<ref name=":1">{{Cite journal|last=Kataoka|first=Keisuke|last2=Nagata|first2=Yasunobu|last3=Kitanaka|first3=Akira|last4=Shiraishi|first4=Yuichi|last5=Shimamura|first5=Teppei|last6=Yasunaga|first6=Jun-Ichirou|last7=Totoki|first7=Yasushi|last8=Chiba|first8=Kenichi|last9=Sato-Otsubo|first9=Aiko|date=2015-11|title=Integrated molecular analysis of adult T cell leukemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/26437031|journal=Nature Genetics|volume=47|issue=11|pages=1304–1315|doi=10.1038/ng.3415|issn=1546-1718|pmid=26437031}}</ref>. 

{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|-
|2q33.2 (Tandem Duplication)
|5’ CTLA/3’CD28
|der(2)
|7%
|-
|2q33.2 (Tandem Duplication)
|5’ICOS/3’CD28
|der(2)
|7%
|}		
			
</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)}}

ATLL diagnosis can be made based on seropositivity for HTLV-1 and histologically and/or cytologically proven peripheral T cell lymphoma (PTCL). Diagnosis can also be made by quantifying proviral DNA loads (PVLs) in peripheral blood mononuclear cells using real time PCR. PVL of an infected person can range from 0.01 to 50% or higher. Other diagnostic criteria includes appropriate patient demographic information, hypercalcemia, skin lesions and a leukemic phase.

The prognosis of ATLL is largely dependent on the subtype. The acute and lymphomatous subtypes are aggressive, with a median survival of 6.2 months and 10.2 months, respectively. The less-aggressive chronic and smoldering subtypes have a median survival of approximately 4.5 years<ref name=":3" />. Prognostic factors include clinical variant, age, serum calcium and LDH levels as well as detection of opportunistic infections of parasitic or viral types and p16 gene deletion and p53 mutation.

As ATLL is resistant to most chemotherapy, there is no standard chemotherapy regimen. High dose combination chemotherapy and bone marrow transplantation have been tried previously<ref>{{Cite journal|last=Hishizawa|first=Masakatsu|last2=Kanda|first2=Junya|last3=Utsunomiya|first3=Atae|last4=Taniguchi|first4=Shuichi|last5=Eto|first5=Tetsuya|last6=Moriuchi|first6=Yukiyoshi|last7=Tanosaki|first7=Ryuji|last8=Kawano|first8=Fumio|last9=Miyazaki|first9=Yasushi|date=2010-08-26|title=Transplantation of allogeneic hematopoietic stem cells for adult T-cell leukemia: a nationwide retrospective study|url=https://pubmed.ncbi.nlm.nih.gov/20479287|journal=Blood|volume=116|issue=8|pages=1369–1376|doi=10.1182/blood-2009-10-247510|issn=1528-0020|pmid=20479287}}</ref>. Monoclonal antibody-based therapies against IL-2R (anti-Tac), CCR4 (mogamulizumab) and CD52 (alemtuzumab) have also been attempted along with arsenic trioxide, interferon α and zidovudine<ref>{{Cite journal|last=Hermine|first=Olivier|last2=Ramos|first2=Juan Carlos|last3=Tobinai|first3=Kensei|date=02 2018|title=A Review of New Findings in Adult T-cell Leukemia-Lymphoma: A Focus on Current and Emerging Treatment Strategies|url=https://pubmed.ncbi.nlm.nih.gov/29411267|journal=Advances in Therapy|volume=35|issue=2|pages=135–152|doi=10.1007/s12325-018-0658-4|issn=1865-8652|pmc=5818559|pmid=29411267}}</ref>.

</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>

7
|<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>

8
|<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.}}

ATLL with high number of chromosomal imbalances is associated with poor survival<ref>{{Cite journal|last=Itoyama|first=T.|last2=Chaganti|first2=R. S.|last3=Yamada|first3=Y.|last4=Tsukasaki|first4=K.|last5=Atogami|first5=S.|last6=Nakamura|first6=H.|last7=Tomonaga|first7=M.|last8=Ohshima|first8=K.|last9=Kikuchi|first9=M.|date=2001-06-01|title=Cytogenetic analysis and clinical significance in adult T-cell leukemia/lymphoma: a study of 50 cases from the human T-cell leukemia virus type-1 endemic area, Nagasaki|url=https://pubmed.ncbi.nlm.nih.gov/11369658|journal=Blood|volume=97|issue=11|pages=3612–3620|doi=10.1182/blood.v97.11.3612|issn=0006-4971|pmid=11369658}}</ref><ref>{{Cite journal|last=Tsukasaki|first=K.|last2=Krebs|first2=J.|last3=Nagai|first3=K.|last4=Tomonaga|first4=M.|last5=Koeffler|first5=H. P.|last6=Bartram|first6=C. R.|last7=Jauch|first7=A.|date=2001-06-15|title=Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course|url=https://pubmed.ncbi.nlm.nih.gov/11389029|journal=Blood|volume=97|issue=12|pages=3875–3881|doi=10.1182/blood.v97.12.3875|issn=0006-4971|pmid=11389029}}</ref><ref>{{Cite journal|last=Oshiro|first=Aya|last2=Tagawa|first2=Hiroyuki|last3=Ohshima|first3=Koichi|last4=Karube|first4=Kennosuke|last5=Uike|first5=Naokuni|last6=Tashiro|first6=Yukie|last7=Utsunomiya|first7=Atae|last8=Masuda|first8=Masato|last9=Takasu|first9=Nobuyuki|date=2006-06-01|title=Identification of subtype-specific genomic alterations in aggressive adult T-cell leukemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/16484591|journal=Blood|volume=107|issue=11|pages=4500–4507|doi=10.1182/blood-2005-09-3801|issn=0006-4971|pmid=16484591}}</ref><ref name=":2">{{Cite journal|last=Kataoka|first=Keisuke|last2=Iwanaga|first2=Masako|last3=Yasunaga|first3=Jun-Ichirou|last4=Nagata|first4=Yasunobu|last5=Kitanaka|first5=Akira|last6=Kameda|first6=Takuro|last7=Yoshimitsu|first7=Makoto|last8=Shiraishi|first8=Yuichi|last9=Sato-Otsubo|first9=Aiko|date=01 11, 2018|title=Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/29084771|journal=Blood|volume=131|issue=2|pages=215–225|doi=10.1182/blood-2017-01-761874|issn=1528-0020|pmc=5757690|pmid=29084771}}</ref>. 

{| class="wikitable sortable"
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|-
|1
|Gain
|1q
|-
|2
|Gain
|2p
|-
|3
|Gain
|3p
|-
|4
|Gain
|4q
|-
|6
|Loss
|6q
|-
|7
|Gain
|7p, 7q
|-
|9
|Amp
|9p
|-
|10
|Loss
|10p
|-
|13
|Loss
|13q
|-
|14
|Gain
|14q
|-
|16
|Loss
|16q
|-
|18
|Loss
|18p
|}	
		
</blockquote>
==Characteristic Chromosomal 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>

{| class="wikitable sortable"
|-
!Chromosomal Pattern
!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>

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.}}

Cytogenetic studies show that ATLL often has a complex abnormal karyotype without a single distinct abnormality. Observed recurrent abnormalities include trisomy for 3, 7 or 21 and monosomy for X as well as deletion of Y and abnormalities of chromosome 6 and 14. Chromosome 14 rearrangements involving TCRA and TCRD at 14q11 and TCL1 at 14q32 have been documented<ref>{{Cite journal|date=1987-11|title=Correlation of chromosome abnormalities with histologic and immunologic characteristics in non-Hodgkin's lymphoma and adult T cell leukemia-lymphoma. Fifth International Workshop on Chromosomes in Leukemia-Lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/2889485|journal=Blood|volume=70|issue=5|pages=1554–1564|issn=0006-4971|pmid=2889485}}</ref>. Frequent deletions in known fragile sites have been detected in over 500 patients<ref name=":1" />. 

</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>

{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations

<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).
<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.}}

Over 10% of ATLL cases harbor mostly gain of function mutations. ATLL harbors multiple recurrent mutations in genes involved in the TCR-NF-κB pathway, tumor suppressors, transcription factors involved in cell growth and proliferation, apoptosis, and immune surveillance<ref>{{Cite journal|last=Kogure|first=Yasunori|last2=Kataoka|first2=Keisuke|date=2017-09|title=Genetic alterations in adult T-cell leukemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/28627735|journal=Cancer Science|volume=108|issue=9|pages=1719–1725|doi=10.1111/cas.13303|issn=1349-7006|pmc=5581529|pmid=28627735}}</ref><ref name=":2" /><ref>{{Cite journal|last=Kataoka|first=Keisuke|last2=Nagata|first2=Yasunobu|last3=Kitanaka|first3=Akira|last4=Shiraishi|first4=Yuichi|last5=Shimamura|first5=Teppei|last6=Yasunaga|first6=Jun-Ichirou|last7=Totoki|first7=Yasushi|last8=Chiba|first8=Kenichi|last9=Sato-Otsubo|first9=Aiko|date=2015-11|title=Integrated molecular analysis of adult T cell leukemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/26437031|journal=Nature Genetics|volume=47|issue=11|pages=1304–1315|doi=10.1038/ng.3415|issn=1546-1718|pmid=26437031}}</ref>. 

{| class="wikitable sortable"
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|-
|PLCG1
|
|TCR – NF-κB Signaling
|GOF
|
|-
|PKCB
|
|TCR – NF-κB Signaling
|GOF
|
|-
|CARD11
|
|TCR – NF-κB Signaling
|GOF
|
|-
|VAV1
|
|TCR – NF-κB Signaling
|GOF
|
|-
|CD237
|
|TCR – NF-κB Signaling
|GOF
|
|-
|RHOA
|
|RAS-RAF-ERK pathway
|GOF
|
|-
|IRF4
|
|Transcription Factor
|GOF
|
|-
|NOTCH1
|
|Transcription Factor
|GOF
|
|-
|FBXW7
|
|Transcription Factor
|GOF
|
|-
|STAT3
|
|Transcription Factor
|GOF
|
|-
|TNFAIP3/A20
|
|TCR – NF-κB Signaling
|LOF
|
|-
|NFKBIA/IκBα
|
|TCR – NF-κB Signaling
|LOF
|
|-
|TRAF3
|
|TCR – NF-κB Signaling
|LOF
|
|-
|CBLB
|
|TCR – NF-κB Signaling
|LOF
|
|-
|TP53
|
|Tumor Suppressor
|LOF
|
|-
|CDKN2
|
|Tumor Suppressor
|LOF
|
|-
|GATA3
|
|Transcription Factor
|LOF
|
|-
|EP300
|
|Transcription Factor
|LOF
|
|-
|FAS
|
|Apoptosis
|LOF
|
|-
|WWOX
|
|Apoptosis
|LOF
|
|-
|HLA-B
|
|Immune Surveillance
|LOF
|
|-
|B2M
|
|Immune Surveillance
|LOF
|
|-
|PD-L1
|
|Immune Surveillance
|Amplification
|
|}	
		
===Other Mutations===
{| class="wikitable sortable"
|-
!Type!!Gene/Region/Other
|-
|Concomitant Mutations||<span class="blue-text">EXAMPLE:</span> IDH1 R123H
|-
|Secondary Mutations||<span class="blue-text">EXAMPLE:</span> Trisomy 7
|-
|Mutually Exclusive||<span class="blue-text">EXAMPLE:</span> EGFR Amplification
|}

</blockquote>
==Epigenomic Alterations==

Epigenetic alterations also result in dysregulated TCR/NF-κB signaling in ATLL. DNA hypermethylation of CpG islands is detected in 1/3<sup>rd</sup> of all ATLL patients. As a result, genes involved in Cys2-His2 (C2H2) zinc finger genes and those encoding MHC class I molecules are silenced<ref name=":1" />. 

ATLL patients have high expression of polycomb repressive complex (PRC) 2 components like EZH2, its homolog EZH1 and H3K27 methylase causing accumulation of trimethylation of H3K27 and altering the expression of over half of the genes. The severity of the disease is linked to continued down regulation of genes<ref>{{Cite journal|last=Fujikawa|first=Dai|last2=Nakagawa|first2=Shota|last3=Hori|first3=Makoto|last4=Kurokawa|first4=Naoya|last5=Soejima|first5=Ai|last6=Nakano|first6=Kazumi|last7=Yamochi|first7=Tadanori|last8=Nakashima|first8=Makoto|last9=Kobayashi|first9=Seiichiro|date=2016-04-07|title=Polycomb-dependent epigenetic landscape in adult T-cell leukemia|url=https://pubmed.ncbi.nlm.nih.gov/26773042|journal=Blood|volume=127|issue=14|pages=1790–1802|doi=10.1182/blood-2015-08-662593|issn=1528-0020|pmid=26773042}}</ref>. 

==Genes and Main Pathways Involved==

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>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations
|<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.}}
The most important genes involved in the development and progress of ATLL are the Tax and HBZ contributed by the HTLV-1 virus and genes listed in gene mutations table (above) from the host. The main pathways involved are TCR-NF-κB signaling by gain of function and amplifications in PLCG1, VAV1 and FYN, CD28, PRKCB, CARD11, IRF4 and RHOA; and loss of function mutations or deletions in CBLB, TRAF, TNFAIP3 and CSNK1A1<ref name=":1" />.

Genes involving the immune surveillance program are also heavy altered to evade the immune response either by deletions in MHC class1 molecules, CD58, FAS or constitutive activation of PD-L1.

Genes involved in the Lymphocyte activation and differentiation(IRF4, GATA3, IKZF2) are also altered.

Chemokine receptors including CCR4 and CCR7 are responsible for the infiltration of neoplastic cells into other organs along with activation of PI3K/AKT signaling.

The epigenetic mechanism is also exploited to alter gene expression and promote ATLL progression as explained above.

</blockquote>
==Genetic Diagnostic Testing Methods==

Initial diagnosis of ATLL should include a comprehensive physical exam with skin evaluation and CT scans of the chest, abdomen and pelvis. The laboratory evaluation should include: a complete blood count (CBC), metabolic panel (serum electrolyte levels, calcium, creatinine and blood urea nitrogen) and serum LDH levels. Testing methods including PCR, Flow Cytometry, ELISA, serology, and immunohistochemistry in addition to morphologic studies may be employed to diagnose ATLL<ref name=":4">NCCN Clinical Practice Guidelines in Oncology, T-Cell Lymphomas, Version 1.2021. Available at NCCN.org.</ref>.

==Familial Forms==

Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>

==Additional Information==

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==Links==

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==References==
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==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'': “Adult T-cell leukaemia/lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Adult_T-cell_leukaemia/lymphoma</nowiki>.
[[Category:HAEM5]][[Category:DISEASE]][[Category:Diseases A]]