View source for HAEM5:Extranodal NK/T-cell lymphoma

{{DISPLAYTITLE:Extranodal NK/T-cell lymphoma}}

[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]

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<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)*==

Teodora Popa, MD, Queen's University

Amanda Xu, MD, Queen's University 

__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
|EBV-positive NK-cell and T-cell lymphomas
|-
|Subtype(s)
|Extranodal NK/T-cell lymphoma
|}

==Definition / Description of Disease==

Extranodal NK/T-cell lymphoma (ENKTL) is a distinct entity in the [https://tumourclassification.iarc.who.int/chaptercontent/63/258 5th edition World Health Organization (WHO) classification system]. It is referred to as "extranodal NK/T-cell lymphoma, nasal type" in the 2016 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues revised 4th edition<ref name=":5">Chan J. K. C., et al., (2017). Extranodal NK/T-cell lymphoma, nasal type, 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. Revised 4th Edition. IARC Press: Lyon, France, p.368-371.</ref>.

*ENKTL is a lymphoma of NK or T-cell lineage strongly associated with Epstein-Barr virus<ref name=":6">{{Cite journal|last=Jaffe|first=E. S.|last2=Krenacs|first2=L.|last3=Kumar|first3=S.|last4=Kingma|first4=D. W.|last5=Raffeld|first5=M.|date=1999-01|title=Extranodal peripheral T-cell and NK-cell neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/9894469|journal=American Journal of Clinical Pathology|volume=111|issue=1 Suppl 1|pages=S46–55|issn=0002-9173|pmid=9894469}}</ref>.
*It is a destructive angiocentric disease characterized by vascular destruction and necrosis<ref>{{Cite journal|last=Aviles|first=A.|last2=Rodriguez|first2=L.|last3=Guzman|first3=R.|last4=Talavera|first4=A.|last5=Garcia|first5=E. L.|last6=Diaz-Maqueo|first6=J. C.|date=1992|title=Angiocentric T-cell lymphoma of the nose, paranasal sinuses and hard palate|url=https://pubmed.ncbi.nlm.nih.gov/1398510|journal=Hematological Oncology|volume=10|issue=3-4|pages=141–147|doi=10.1002/hon.2900100303|issn=0278-0232|pmid=1398510}}</ref>.
*It can be clinically divided into nasal and non-nasal types, the latter most often occurring in the skin and intestinal tract<ref name=":5" /><ref name=":6" />.
*The lineage (NK or T-cell) has no clinical significance<ref>{{Cite journal|last=Wang|first=Hua|last2=Fu|first2=Bi-Bo|last3=Gale|first3=Robert Peter|last4=Liang|first4=Yang|date=2021-09|title=NK-/T-cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/34117356|journal=Leukemia|volume=35|issue=9|pages=2460–2468|doi=10.1038/s41375-021-01313-2|issn=1476-5551|pmc=8410593|pmid=34117356}}</ref>.

*The differential diagnosis includes sinonasal carcinomas and other lymphomas of the nasal cavity, such as diffuse large B-cell lymphoma<ref>{{Cite journal|last=Steele|first=Toby O.|last2=Buniel|first2=Maria C.|last3=Mace|first3=Jess C.|last4=El Rassi|first4=Edward|last5=Smith|first5=Timothy L.|date=2016-09|title=Lymphoma of the nasal cavity and paranasal sinuses: A case series|url=https://pubmed.ncbi.nlm.nih.gov/27657899|journal=American Journal of Rhinology & Allergy|volume=30|issue=5|pages=335–339|doi=10.2500/ajra.2016.30.4347|issn=1945-8932|pmid=27657899}}</ref>.

==Synonyms / Terminology==

Extranodal NK/T-cell lymphoma, nasal type; EBV-positive extranodal NK/T-cell lymphoma; angiocentric lymphoma (not recommended); lethal midline granuloma (historical)

==Epidemiology / Prevalence==

ENKTL is most prevalent in East Asia and Latin America. It represents less than 1% of non-Hodgkin lymphomas in the United States, with the highest incidence among Asian Pacific Islanders and Hispanic populations<ref>{{Cite journal|last=Haverkos|first=Bradley M.|last2=Pan|first2=Zenggang|last3=Gru|first3=Alejandro A.|last4=Freud|first4=Aharon G.|last5=Rabinovitch|first5=Rachel|last6=Xu-Welliver|first6=Meng|last7=Otto|first7=Brad|last8=Barrionuevo|first8=Carlos|last9=Baiocchi|first9=Robert A.|date=2016-12|title=Extranodal NK/T-cell lymphoma, nasal type (ENKTL-NT): An update on epidemiology, clinical presentation, and natural history in North American and European cases|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5199232/|journal=Current hematologic malignancy reports|volume=11|issue=6|pages=514–527|doi=10.1007/s11899-016-0355-9|issn=1558-8211|pmc=5199232|pmid=27778143}}</ref>.

==Clinical Features==

Common clinical presentations of nasal-type ENKTL include nasal mass, obstruction, and bleeding. Patients with abdominal involvement may present with abdominal pain, gastrointestinal (GI) bleed, or perforation<ref name=":0">Thida AM, Gohari P. Extranodal NK-Cell Lymphoma. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: <nowiki>https://www.ncbi.nlm.nih.gov/books/NBK559207/</nowiki></ref>. The presence of B symptoms is associated with higher clinical stage<ref>{{Cite journal|last=Takahara|first=Miki|last2=Kumai|first2=Takumi|last3=Kishibe|first3=Kan|last4=Nagato|first4=Toshihiro|last5=Harabuchi|first5=Yasuaki|date=2021-06-25|title=Extranodal NK/T-Cell Lymphoma, Nasal Type: Genetic, Biologic, and Clinical Aspects with a Central Focus on Epstein-Barr Virus Relation|url=https://pubmed.ncbi.nlm.nih.gov/34202088|journal=Microorganisms|volume=9|issue=7|pages=1381|doi=10.3390/microorganisms9071381|issn=2076-2607|pmc=8304202|pmid=34202088}}</ref>.
{| class="wikitable"
|'''Signs and Symptoms'''
|Nasal mass, nasal obstruction, nasal bleeding
Hoarseness, dysphagia, halitosis, airway obstruction, dysphonia

Abdominal pain, GI bleeding, bowel perforation

B symptoms (fever, weight loss, night sweats)
|-
|'''Laboratory Findings'''
|No specific findings
Cytopenias
|}

==Sites of Involvement==

Most cases of ENKTL are nasal type, meaning they involve the upper aerodigestive tract. Extranasal ENKTL may involve the skin, testis, and gastrointestinal tract<ref name=":0" />. Bone marrow involvement is uncommon<ref>{{Cite journal|last=Wong|first=K. F.|last2=Chan|first2=J. K.|last3=Cheung|first3=M. M.|last4=So|first4=J. C.|date=2001-02|title=Bone marrow involvement by nasal NK cell lymphoma at diagnosis is uncommon|url=https://pubmed.ncbi.nlm.nih.gov/11211616|journal=American Journal of Clinical Pathology|volume=115|issue=2|pages=266–270|doi=10.1309/E5PR-6A9R-Q02N-8QVW|issn=0002-9173|pmid=11211616}}</ref>.

==Morphologic Features==

*Diffuse lymphomatous infiltrate composed of small, medium, or large and anaplastic cells (or a mix of small and large cells). The cells have irregularly folded nuclei and moderate pale cytoplasm.
*Loss of mucosal glands.
*Angiocentric and angiodestructive growth pattern.
*Coagulative necrosis and apoptosis.
*Mitotic figures.

Pitfalls:

*Mucosal ulceration and superimposed inflammation can mimic an inflammatory process, particularly in less aggressive cases<ref>Devins, K., Schuster, S.J., Caponetti, G.C. ''et al.'' Rare case of low-grade extranodal NK/T-cell lymphoma, nasal type, arising in the setting of chronic rhinosinusitis and harboring a novel N-terminal ''KIT'' mutation. ''Diagn Pathol'' 13, 92 (2018). <nowiki>https://doi.org/10.1186/s13000-018-0765-1</nowiki></ref>.
*Pseudoepitheliomatous hyperplasia of the overlying mucosal epithelium can mimic squamous cell carcinoma<ref>{{Cite journal|last=Ling|first=Yi-Hong|last2=Zhu|first2=Chong-Mei|last3=Wen|first3=Shi-Hong|last4=Luo|first4=Rong-Zhen|last5=Li|first5=Peng|last6=Cao|first6=Yun|last7=Rao|first7=Hui-Lan|last8=Lin|first8=Su-Xia|last9=Cai|first9=Mu-Yan|date=2015-09|title=Pseudoepitheliomatous hyperplasia mimicking invasive squamous cell carcinoma in extranodal natural killer/T-cell lymphoma: a report of 34 cases|url=https://pubmed.ncbi.nlm.nih.gov/25619876|journal=Histopathology|volume=67|issue=3|pages=404–409|doi=10.1111/his.12656|issn=1365-2559|pmid=25619876}}</ref><ref>{{Cite journal|last=Xiang|first=Chun-Xiang|last2=Chen|first2=Zi-Hang|last3=Zhao|first3=Sha|last4=Gao|first4=Li-Min|last5=Tao|first5=Qing|last6=Zuo|first6=Zhuo|last7=Liu|first7=Xiao-Yu|last8=Liu|first8=Wei-Ping|date=2019-07|title=Laryngeal Extranodal Nasal-type Natural Killer/T-cell Lymphoma: A Clinicopathologic Study of 31 Cases in China|url=https://pubmed.ncbi.nlm.nih.gov/31045893|journal=The American Journal of Surgical Pathology|volume=43|issue=7|pages=995–1004|doi=10.1097/PAS.0000000000001266|issn=1532-0979|pmid=31045893}}</ref>.

==Immunophenotype==

The majority of cases are positive for cytoplasmic CD3ε, CD2, granzyme B, and TIA-1. Most ENKTLs are of NK-lineage and express CD56. Cases of T-lineage express T-cell receptor (TCR) and show clonal TCR gene rearrangements. All cases are EBV positive by in situ hybridization for Epstein-Barr virus-encoded small RNA (EBER). Other markers that may be expressed include HLA-DR, CD25, pSTAT3, CXCL13, IRF4/MUM1, CD16, Fas, FasL, MATK, and CD30<ref>{{Cite journal|last=Li|first=Shaoying|last2=Feng|first2=Xiaoli|last3=Li|first3=Ting|last4=Zhang|first4=Shuang|last5=Zuo|first5=Zhuang|last6=Lin|first6=Pei|last7=Konoplev|first7=Sergej|last8=Bueso-Ramos|first8=Carlos E.|last9=Vega|first9=Francisco|date=2013-01|title=Extranodal NK/T-cell lymphoma, nasal type: a report of 73 cases at MD Anderson Cancer Center|url=https://pubmed.ncbi.nlm.nih.gov/23232851|journal=The American Journal of Surgical Pathology|volume=37|issue=1|pages=14–23|doi=10.1097/PAS.0b013e31826731b5|issn=1532-0979|pmid=23232851}}</ref><ref>{{Cite journal|last=Jhuang|first=Jie-Yang|last2=Chang|first2=Sheng-Tsung|last3=Weng|first3=Shih-Feng|last4=Pan|first4=Shien-Tung|last5=Chu|first5=Pei-Yi|last6=Hsieh|first6=Pin-Pen|last7=Wei|first7=Chih-Hsin|last8=Chou|first8=Shih-Cheng|last9=Koo|first9=Chiew-Loon|date=2015-02|title=Extranodal natural killer/T-cell lymphoma, nasal type in Taiwan: a relatively higher frequency of T-cell lineage and poor survival for extranasal tumors|url=https://pubmed.ncbi.nlm.nih.gov/25554090|journal=Human Pathology|volume=46|issue=2|pages=313–321|doi=10.1016/j.humpath.2014.11.008|issn=1532-8392|pmid=25554090}}</ref><ref>{{Cite journal|last=Pongpruttipan|first=Tawatchai|last2=Sukpanichnant|first2=Sanya|last3=Assanasen|first3=Thamathorn|last4=Wannakrairot|first4=Pongsak|last5=Boonsakan|first5=Paisarn|last6=Kanoksil|first6=Wasana|last7=Kayasut|first7=Kanita|last8=Mitarnun|first8=Winyou|last9=Khuhapinant|first9=Archrob|date=2012-04|title=Extranodal NK/T-cell lymphoma, nasal type, includes cases of natural killer cell and αβ, γδ, and αβ/γδ T-cell origin: a comprehensive clinicopathologic and phenotypic study|url=https://pubmed.ncbi.nlm.nih.gov/22314189|journal=The American Journal of Surgical Pathology|volume=36|issue=4|pages=481–499|doi=10.1097/PAS.0b013e31824433d8|issn=1532-0979|pmid=22314189}}</ref><ref>{{Cite journal|last=Jaffe|first=E. S.|last2=Chan|first2=J. K.|last3=Su|first3=I. J.|last4=Frizzera|first4=G.|last5=Mori|first5=S.|last6=Feller|first6=A. C.|last7=Ho|first7=F. C.|date=1996-01|title=Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas. Definitions, differential diagnosis, and epidemiology|url=https://pubmed.ncbi.nlm.nih.gov/8540601|journal=The American Journal of Surgical Pathology|volume=20|issue=1|pages=103–111|doi=10.1097/00000478-199601000-00012|issn=0147-5185|pmid=8540601}}</ref><ref>{{Cite journal|last=Ohshima|first=K.|last2=Suzumiya|first2=J.|last3=Shimazaki|first3=K.|last4=Kato|first4=A.|last5=Tanaka|first5=T.|last6=Kanda|first6=M.|last7=Kikuchi|first7=M.|date=1997-11|title=Nasal T/NK cell lymphomas commonly express perforin and Fas ligand: important mediators of tissue damage|url=https://pubmed.ncbi.nlm.nih.gov/9416485|journal=Histopathology|volume=31|issue=5|pages=444–450|doi=10.1046/j.1365-2559.1997.2880887.x|issn=0309-0167|pmid=9416485}}</ref><ref>{{Cite journal|last=Takata|first=Katsuyoshi|last2=Hong|first2=Min-Eui|last3=Sitthinamsuwan|first3=Panitta|last4=Loong|first4=Florence|last5=Tan|first5=Soo-Yong|last6=Liau|first6=Jau-Yu|last7=Hsieh|first7=Pin-Pen|last8=Ng|first8=Siok-Bian|last9=Yang|first9=Sheau-Fang|date=2015-01|title=Primary cutaneous NK/T-cell lymphoma, nasal type and CD56-positive peripheral T-cell lymphoma: a cellular lineage and clinicopathologic study of 60 patients from Asia|url=https://pubmed.ncbi.nlm.nih.gov/25188863|journal=The American Journal of Surgical Pathology|volume=39|issue=1|pages=1–12|doi=10.1097/PAS.0000000000000312|issn=1532-0979|pmid=25188863}}</ref><ref>{{Cite journal|last=Kuo|first=Tseng-Tong|last2=Shih|first2=Lee-Yung|last3=Tsang|first3=Ngan-Ming|date=2004-10|title=Nasal NK/T cell lymphoma in Taiwan: a clinicopathologic study of 22 cases, with analysis of histologic subtypes, Epstein-Barr virus LMP-1 gene association, and treatment modalities|url=https://pubmed.ncbi.nlm.nih.gov/15494863|journal=International Journal of Surgical Pathology|volume=12|issue=4|pages=375–387|doi=10.1177/106689690401200410|issn=1066-8969|pmid=15494863}}</ref>.

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||CD2, CD56, cytoplasmic CD3ε, cytotoxic markers (TIA-1, granzyme B, perforin) 
EBER / EBV
|-
|Positive (subset)||TCR αβ/γδ, HLA-DR, CD25, pSTAT3, CXCL13, IRF4/MUM1, CD16, Fas, FasL, MATK, CD30
|-
|Negative (universal)||CD4, CD8
|-
|Negative (subset)||Surface CD3 (subset of T-cell lineage)<ref name=":0" />
|}

==Chromosomal Rearrangements (Gene Fusions)==

No specific chromosomal translocation has been identified in ENKTL.

{| 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
|-
|N/A||N/A||N/A||N/A
|N/A
|N/A
|N/A
|N/A
|}		
			
==Individual Region Genomic Gain / Loss / LOH==

ENKTL shows recurring deletion at 6q21-25<ref>{{Cite journal|last=Wong|first=K. F.|last2=Chan|first2=J. K.|last3=Kwong|first3=Y. L.|date=1997-09|title=Identification of del(6)(q21q25) as a recurring chromosomal abnormality in putative NK cell lymphoma/leukaemia|url=https://pubmed.ncbi.nlm.nih.gov/9326190|journal=British Journal of Haematology|volume=98|issue=4|pages=922–926|doi=10.1046/j.1365-2141.1997.3223139.x|issn=0007-1048|pmid=9326190}}</ref><ref>{{Cite journal|last=Ohshima|first=Koichi|last2=Haraokaa|first2=Seiji|last3=Ishihara|first3=Shigehiko|last4=Ohgami|first4=Akiko|last5=Yoshioka|first5=Shingo|last6=Suzumiya|first6=Junji|last7=Kikuchi|first7=Masahiro|date=2002-02|title=Analysis of chromosome 6q deletion in EBV-associated NK cell leukaemia/lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/11999560|journal=Leukemia & Lymphoma|volume=43|issue=2|pages=293–300|doi=10.1080/10428190290006062|issn=1042-8194|pmid=11999560}}</ref>.

Other less common chromosomal alterations include gain of 1p, 2q, 6p, 10q, 11q, 12q, 13q, 17q, 19p, 20q, and Xp; and loss of 1p36, 2p16, 4q12, 4q31-32, 5p14, 5q34-35, 6q13-14, 6q16-27, 11q22-23, 12q, 13q12-14, 13q14-34, 17p13, and entire chromosome X<ref>{{Cite journal|last=Nakashima|first=Yasuhiro|last2=Tagawa|first2=Hiroyuki|last3=Suzuki|first3=Ritsuro|last4=Karnan|first4=Sivasundaram|last5=Karube|first5=Kennosuke|last6=Ohshima|first6=Koichi|last7=Muta|first7=Koichiro|last8=Nawata|first8=Hajime|last9=Morishima|first9=Yasuo|date=2005-11|title=Genome-wide array-based comparative genomic hybridization of natural killer cell lymphoma/leukemia: different genomic alteration patterns of aggressive NK-cell leukemia and extranodal Nk/T-cell lymphoma, nasal type|url=https://pubmed.ncbi.nlm.nih.gov/16049916|journal=Genes, Chromosomes & Cancer|volume=44|issue=3|pages=247–255|doi=10.1002/gcc.20245|issn=1045-2257|pmid=16049916}}</ref><ref>{{Cite journal|last=Siu|first=L. L.|last2=Chan|first2=V.|last3=Chan|first3=J. K.|last4=Wong|first4=K. F.|last5=Liang|first5=R.|last6=Kwong|first6=Y. L.|date=2000-12|title=Consistent patterns of allelic loss in natural killer cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/11106552|journal=The American Journal of Pathology|volume=157|issue=6|pages=1803–1809|doi=10.1016/S0002-9440(10)64818-3|issn=0002-9440|pmc=1885756|pmid=11106552}}</ref><ref>{{Cite journal|last=Siu|first=L. L.|last2=Wong|first2=K. F.|last3=Chan|first3=J. K.|last4=Kwong|first4=Y. L.|date=1999-11|title=Comparative genomic hybridization analysis of natural killer cell lymphoma/leukemia. Recognition of consistent patterns of genetic alterations|url=https://pubmed.ncbi.nlm.nih.gov/10550295|journal=The American Journal of Pathology|volume=155|issue=5|pages=1419–1425|doi=10.1016/S0002-9440(10)65454-5|issn=0002-9440|pmc=1866965|pmid=10550295}}</ref><ref>{{Cite journal|last=Wong|first=K. F.|last2=Zhang|first2=Y. M.|last3=Chan|first3=J. K.|date=1999-07|title=Cytogenetic abnormalities in natural killer cell lymphoma/leukaemia--is there a consistent pattern?|url=https://pubmed.ncbi.nlm.nih.gov/10439361|journal=Leukemia & Lymphoma|volume=34|issue=3-4|pages=241–250|doi=10.3109/10428199909050949|issn=1042-8194|pmid=10439361}}</ref><ref>{{Cite journal|last=Ko|first=Y. H.|last2=Choi|first2=K. E.|last3=Han|first3=J. H.|last4=Kim|first4=J. M.|last5=Ree|first5=H. J.|date=2001-04-15|title=Comparative genomic hybridization study of nasal-type NK/T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/11309817|journal=Cytometry|volume=46|issue=2|pages=85–91|doi=10.1002/cyto.1069|issn=0196-4763|pmid=11309817}}</ref>.

{| 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
|-
|6
|Loss
|
|6q21-25
|Unknown
|Unknown
|Unknown
|This locus harbours multiple candidate tumour suppressor genes including ''ATG5'', ''AIM1'', ''PRDM1'', ''PTPRK'', ''HACE1'', and ''FOXO3''<ref>{{Cite journal|last=Iqbal|first=J.|last2=Kucuk|first2=C.|last3=Deleeuw|first3=R. J.|last4=Srivastava|first4=G.|last5=Tam|first5=W.|last6=Geng|first6=H.|last7=Klinkebiel|first7=D.|last8=Christman|first8=J. K.|last9=Patel|first9=K.|date=2009-06|title=Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies|url=https://pubmed.ncbi.nlm.nih.gov/19194464|journal=Leukemia|volume=23|issue=6|pages=1139–1151|doi=10.1038/leu.2009.3|issn=1476-5551|pmid=19194464}}</ref><ref name=":7">{{Cite journal|last=Karube|first=Kennosuke|last2=Nakagawa|first2=Masao|last3=Tsuzuki|first3=Shinobu|last4=Takeuchi|first4=Ichiro|last5=Honma|first5=Keiichiro|last6=Nakashima|first6=Yasuhiro|last7=Shimizu|first7=Norio|last8=Ko|first8=Young-Hyeh|last9=Morishima|first9=Yasuo|date=2011-09-22|title=Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses|url=https://pubmed.ncbi.nlm.nih.gov/21690554|journal=Blood|volume=118|issue=12|pages=3195–3204|doi=10.1182/blood-2011-04-346890|issn=1528-0020|pmid=21690554}}</ref><ref name=":1">{{Cite journal|last=Chen|first=Yun-Wen|last2=Guo|first2=Tianhuan|last3=Shen|first3=Lijun|last4=Wong|first4=Kai-Yau|last5=Tao|first5=Qian|last6=Choi|first6=William W. L.|last7=Au-Yeung|first7=Rex K. H.|last8=Chan|first8=Yuen-Piu|last9=Wong|first9=Michelle L. Y.|date=2015-03-05|title=Receptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/25612622|journal=Blood|volume=125|issue=10|pages=1589–1600|doi=10.1182/blood-2014-07-588970|issn=1528-0020|pmid=25612622}}</ref>.
|}
==Characteristic Chromosomal Patterns==

{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|Isochromosome 6p<ref>{{Cite journal|last=Tien|first=H. F.|last2=Su|first2=I. J.|last3=Tang|first3=J. L.|last4=Liu|first4=M. C.|last5=Lee|first5=F. Y.|last6=Chen|first6=Y. C.|last7=Chuang|first7=S. M.|date=1997-06|title=Clonal chromosomal abnormalities as direct evidence for clonality in nasal T/natural killer cell lymphomas|url=https://pubmed.ncbi.nlm.nih.gov/9207410|journal=British Journal of Haematology|volume=97|issue=3|pages=621–625|doi=10.1046/j.1365-2141.1997.752711.x|issn=0007-1048|pmid=9207410}}</ref>
|Unknown
|Unknown
|Unknown
|N/A
|-
|Isochromosome 7q<ref>{{Cite journal|last=Feldman|first=Andrew L.|last2=Law|first2=Mark|last3=Grogg|first3=Karen L.|last4=Thorland|first4=Erik C.|last5=Fink|first5=Stephanie|last6=Kurtin|first6=Paul J.|last7=Macon|first7=William R.|last8=Remstein|first8=Ellen D.|last9=Dogan|first9=Ahmet|date=2008-08|title=Incidence of TCR and TCL1 gene translocations and isochromosome 7q in peripheral T-cell lymphomas using fluorescence in situ hybridization|url=https://pubmed.ncbi.nlm.nih.gov/18628085|journal=American Journal of Clinical Pathology|volume=130|issue=2|pages=178–185|doi=10.1309/PNXUKA1CFJMVGCN1|issn=0002-9173|pmc=3625137|pmid=18628085}}</ref>
|Unknown
|Unknown
|Unknown
|N/A
|}
==Gene Mutations (SNV / INDEL)==

Recurrent mutations have been identified in several genes, some of which are listed below. This is not an exhaustive list. Currently, molecular testing for these alterations is not routinely performed.

{| 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
|-
|''JAK3''<ref name=":10">{{Cite journal|last=Koo|first=Ghee Chong|last2=Tan|first2=Soo Yong|last3=Tang|first3=Tiffany|last4=Poon|first4=Song Ling|last5=Allen|first5=George E.|last6=Tan|first6=Leonard|last7=Chong|first7=Soo Ching|last8=Ong|first8=Whee Sze|last9=Tay|first9=Kevin|date=2012-07|title=Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/22705984|journal=Cancer Discovery|volume=2|issue=7|pages=591–597|doi=10.1158/2159-8290.CD-12-0028|issn=2159-8290|pmid=22705984}}</ref><ref>{{Cite journal|last=Bouchekioua|first=A.|last2=Scourzic|first2=L.|last3=de Wever|first3=O.|last4=Zhang|first4=Y.|last5=Cervera|first5=P.|last6=Aline-Fardin|first6=A.|last7=Mercher|first7=T.|last8=Gaulard|first8=P.|last9=Nyga|first9=R.|date=2014-02|title=JAK3 deregulation by activating mutations confers invasive growth advantage in extranodal nasal-type natural killer cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/23689514|journal=Leukemia|volume=28|issue=2|pages=338–348|doi=10.1038/leu.2013.157|issn=1476-5551|pmid=23689514}}</ref>
|Oncogene
|35.4%<ref name=":10" />
|
|
|
|
|Pan-JAK and selective JAK3 inhibitors have been suggested as potential therapeutic options<ref name=":10" /><ref>{{Cite journal|last=Nairismägi|first=M.-L.|last2=Gerritsen|first2=M. E.|last3=Li|first3=Z. M.|last4=Wijaya|first4=G. C.|last5=Chia|first5=B. K. H.|last6=Laurensia|first6=Y.|last7=Lim|first7=J. Q.|last8=Yeoh|first8=K. W.|last9=Yao|first9=X. S.|date=2018-05|title=Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/29434279|journal=Leukemia|volume=32|issue=5|pages=1147–1156|doi=10.1038/s41375-017-0004-x|issn=1476-5551|pmc=5940653|pmid=29434279}}</ref>. [https://clinicaltrials.gov/study/NCT02974647 Clinical trials evaluating JAK inhibitors] are in progress.
|
|-
|''STAT3''<ref name=":2">{{Cite journal|last=Jiang|first=Lu|last2=Gu|first2=Zhao-Hui|last3=Yan|first3=Zi-Xun|last4=Zhao|first4=Xia|last5=Xie|first5=Yin-Yin|last6=Zhang|first6=Zi-Guan|last7=Pan|first7=Chun-Ming|last8=Hu|first8=Yuan|last9=Cai|first9=Chang-Ping|date=2015-09|title=Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/26192917|journal=Nature Genetics|volume=47|issue=9|pages=1061–1066|doi=10.1038/ng.3358|issn=1546-1718|pmid=26192917}}</ref><ref name=":3">{{Cite journal|last=Küçük|first=Can|last2=Jiang|first2=Bei|last3=Hu|first3=Xiaozhou|last4=Zhang|first4=Wenyan|last5=Chan|first5=John K. C.|last6=Xiao|first6=Wenming|last7=Lack|first7=Nathan|last8=Alkan|first8=Can|last9=Williams|first9=John C.|date=2015-01-14|title=Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells|url=https://pubmed.ncbi.nlm.nih.gov/25586472|journal=Nature Communications|volume=6|pages=6025|doi=10.1038/ncomms7025|issn=2041-1723|pmc=7743911|pmid=25586472}}</ref><ref name=":4">{{Cite journal|last=Lee|first=Seungbok|last2=Park|first2=Ha Young|last3=Kang|first3=So Young|last4=Kim|first4=Seok Jin|last5=Hwang|first5=Jinha|last6=Lee|first6=Seungho|last7=Kwak|first7=Soo Heon|last8=Park|first8=Kyong Soo|last9=Yoo|first9=Hae Yong|date=2015-07-10|title=Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type|url=https://pubmed.ncbi.nlm.nih.gov/25980440|journal=Oncotarget|volume=6|issue=19|pages=17764–17776|doi=10.18632/oncotarget.3776|issn=1949-2553|pmc=4627344|pmid=25980440}}</ref>
|
|26%<ref name=":4" />
|
|
|
|
|STAT3 inhibitor may have potential therapeutic benefit in patients with STAT3 activating mutation<ref>{{Cite journal|last=Wang|first=Yali|last2=Zhou|first2=Wenbo|last3=Chen|first3=Jianfeng|last4=Chen|first4=Jinghong|last5=Deng|first5=Peng|last6=Chen|first6=Huang|last7=Sun|first7=Yichen|last8=Yu|first8=Zhaoliang|last9=Pang|first9=Diwen|date=2023-08|title=Preclinical characterization of WB737, a potent and selective STAT3 inhibitor, in natural killer/T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/37334274|journal=MedComm|volume=4|issue=4|pages=e284|doi=10.1002/mco2.284|issn=2688-2663|pmc=PMC10274570|pmid=37334274}}</ref>.
|
|-
|''STAT5B''<ref name=":2" /><ref name=":3" />
|
|
|
|
|
|
|
|
|-
|''PTPRK''<ref name=":1" />
|Other (acts on JAK/STAT pathway; underexpression leads to STAT3 activation<ref name=":1" />)
|
|
|
|
|
|
|
|-
|''MYC''<ref name=":12">{{Cite journal|last=Ng|first=Siok-Bian|last2=Selvarajan|first2=Viknesvaran|last3=Huang|first3=Gaofeng|last4=Zhou|first4=Jianbiao|last5=Feldman|first5=Andrew L.|last6=Law|first6=Mark|last7=Kwong|first7=Yok-Lam|last8=Shimizu|first8=Norio|last9=Kagami|first9=Yoshitoyo|date=2011-03|title=Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling|url=https://pubmed.ncbi.nlm.nih.gov/21294123|journal=The Journal of Pathology|volume=223|issue=4|pages=496–510|doi=10.1002/path.2823|issn=1096-9896|pmid=21294123}}</ref>
|Oncogene
|
|
|
|
|
|
|
|-
|''RUNX3''<ref>{{Cite journal|last=Selvarajan|first=V.|last2=Osato|first2=M.|last3=Nah|first3=G. S. S.|last4=Yan|first4=J.|last5=Chung|first5=T.-H.|last6=Voon|first6=D. C.-C.|last7=Ito|first7=Y.|last8=Ham|first8=M. F.|last9=Salto-Tellez|first9=M.|date=2017-10|title=RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC|url=https://pubmed.ncbi.nlm.nih.gov/28119527|journal=Leukemia|volume=31|issue=10|pages=2219–2227|doi=10.1038/leu.2017.40|issn=1476-5551|pmc=5629367|pmid=28119527}}</ref>
|
|
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|-
|''PDGFRA''<ref name=":13" />
|Oncogene
|
|
|
|
|
|
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|-
|''EZH2''<ref>{{Cite journal|last=Yan|first=Junli|last2=Li|first2=Boheng|last3=Lin|first3=Baohong|last4=Lee|first4=Pei Tsung|last5=Chung|first5=Tae-Hoon|last6=Tan|first6=Joy|last7=Bi|first7=Chonglei|last8=Lee|first8=Xue Ting|last9=Selvarajan|first9=Viknesvaran|date=2016-08-18|title=EZH2 phosphorylation by JAK3 mediates a switch to noncanonical function in natural killer/T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/27297789|journal=Blood|volume=128|issue=7|pages=948–958|doi=10.1182/blood-2016-01-690701|issn=1528-0020|pmid=27297789}}</ref>
|Oncogene
|
|
|
|
|
|
|
|-
|''DDX3X''<ref name=":2" />
|Other (RNA helicase)
|20%<ref name=":2" />
|
|
|
|
|
|
|-
|''TP53''<ref name=":2" />
|Tumor suppressor gene
|24-62%<ref name=":11">{{Cite journal|last=Quintanilla-Martinez|first=L.|last2=Kremer|first2=M.|last3=Keller|first3=G.|last4=Nathrath|first4=M.|last5=Gamboa-Dominguez|first5=A.|last6=Meneses|first6=A.|last7=Luna-Contreras|first7=L.|last8=Cabras|first8=A.|last9=Hoefler|first9=H.|date=2001-12|title=p53 Mutations in nasal natural killer/T-cell lymphoma from Mexico: association with large cell morphology and advanced disease|url=https://pubmed.ncbi.nlm.nih.gov/11733360|journal=The American Journal of Pathology|volume=159|issue=6|pages=2095–2105|doi=10.1016/S0002-9440(10)63061-1|issn=0002-9440|pmc=1850589|pmid=11733360}}</ref><ref name=":8">{{Cite journal|last=Hongyo|first=Tadashi|last2=Hoshida|first2=Yoshihiko|last3=Nakatsuka|first3=Shin-Ichi|last4=Syaifudin|first4=Mukh|last5=Kojya|first5=Shizuo|last6=Yang|first6=Woo-Ick|last7=Min|first7=Yoo-Hong|last8=Chan|first8=Heekyung|last9=Kim|first9=Chan Hwan|date=2005-02|title=p53, K-ras, c-kit and beta-catenin gene mutations in sinonasal NK/T-cell lymphoma in Korea and Japan|url=https://pubmed.ncbi.nlm.nih.gov/15643509|journal=Oncology Reports|volume=13|issue=2|pages=265–271|issn=1021-335X|pmid=15643509}}</ref>
|
|
|
|Yes, associated with advanced stage disease<ref name=":11" />.
|
|
|-
|''MGA''<ref name=":2" />
|Tumor suppressor gene
|
|
|
|
|
|
|
|-
|''PRDM1''<ref name=":9">{{Cite journal|last=Huang|first=Yenlin|last2=de Leval|first2=Laurence|last3=Gaulard|first3=Philippe|date=2013-03|title=Molecular underpinning of extranodal NK/T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/23768641|journal=Best Practice & Research. Clinical Haematology|volume=26|issue=1|pages=57–74|doi=10.1016/j.beha.2013.04.006|issn=1532-1924|pmid=23768641}}</ref><ref name=":7" /><ref>{{Cite journal|last=Küçük|first=Can|last2=Iqbal|first2=Javeed|last3=Hu|first3=Xiaozhou|last4=Gaulard|first4=Phillip|last5=De Leval|first5=Laurence|last6=Srivastava|first6=Gopesh|last7=Au|first7=Wing Yan|last8=McKeithan|first8=Timothy W.|last9=Chan|first9=Wing C.|date=2011-12-13|title=PRDM1 is a tumor suppressor gene in natural killer cell malignancies|url=https://pubmed.ncbi.nlm.nih.gov/22143801|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=108|issue=50|pages=20119–20124|doi=10.1073/pnas.1115128108|issn=1091-6490|pmc=3250125|pmid=22143801}}</ref>
|Tumor suppressor gene
|
|
|
|
|
|
|
|-
|''ATG5''<ref name=":9" />
|Tumor suppressor gene
|
|
|
|
|
|
|
|-
|''AIM1''<ref name=":9" />
|Tumor suppressor gene
|
|
|
|
|
|
|
|-
|''FOXO3''<ref name=":9" /><ref name=":7" />
|Tumor suppressor gene
|
|
|
|
|
|
|
|-
|''HACE1''<ref name=":9" /><ref name=":13">{{Cite journal|last=Huang|first=Yenlin|last2=de Reyniès|first2=Aurélien|last3=de Leval|first3=Laurence|last4=Ghazi|first4=Bouchra|last5=Martin-Garcia|first5=Nadine|last6=Travert|first6=Marion|last7=Bosq|first7=Jacques|last8=Brière|first8=Josette|last9=Petit|first9=Barbara|date=2010-02-11|title=Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type|url=https://pubmed.ncbi.nlm.nih.gov/19965620|journal=Blood|volume=115|issue=6|pages=1226–1237|doi=10.1182/blood-2009-05-221275|issn=1528-0020|pmc=2826234|pmid=19965620}}</ref>
|Tumor suppressor gene
|
|
|
|
|
|
|
|}
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.

==Epigenomic Alterations==

A 2015 study by Lu, ''et al'' uncovered recurrent mutations in the RNA helicase gene ''DDX3X'' and other epigenetic modifiers including ''KMT2D (MLL2), ARID1A, EP300'', and ''ASXL3''<ref name=":2" />.

Similarly, a 2015 study by Lee'', et al'' reported that histone modification-related genes, including ''BCOR'' and ''KMT2D (MLL2),'' accounted for 38.2% of 34 ENKTL samples by next-generation sequencing<ref name=":4" />.

==Genes and Main Pathways Involved==
[https://ashpublications.org/blood/article/115/6/1226/26917/Gene-expression-profiling-identifies-emerging Huang, ''et al''] described deregulation of several signaling pathways in NK T-cell lymphoma, main ones listed below<ref name=":13" />. A review by [https://jhoonline.biomedcentral.com/articles/10.1186/s13045-019-0716-7 De Mel, ''et al''], also outlines key molecular pathways involved in the pathogenesis of ENKTL<ref>{{Cite journal|last=de Mel|first=Sanjay|last2=Hue|first2=Susan Swee-Shan|last3=Jeyasekharan|first3=Anand D.|last4=Chng|first4=Wee-Joo|last5=Ng|first5=Siok-Bian|date=2019-04-02|title=Molecular pathogenic pathways in extranodal NK/T cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/30935402|journal=Journal of Hematology & Oncology|volume=12|issue=1|pages=33|doi=10.1186/s13045-019-0716-7|issn=1756-8722|pmc=6444858|pmid=30935402}}</ref>.
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|''JAK3'', ''STAT3'', and ''STAT5B''; Activating mutations
|JAK/STAT pathway
|Increased cell growth and proliferation
|-
|''MYC, RUNX3''
|MYC
|Increased cell proliferation and survival
|-
|''AKT'' and related genes
|AKT pathway
|Increased cell growth, proliferation and survival
|-
|NF-κB related genes
|NF-κB pathway
|Increased cell proliferation
|-
|''PDGFRA''
|PDGF pathway
|Increased cell proliferation and survival
|-
|''NOTCH1''
|NOTCH1 pathway
|Increased cell proliferation
|-
|AURKA
|Aurora kinase pathway<ref name=":12" />
|Increased cell proliferation and cell cycle dysregulation
|}
==Genetic Diagnostic Testing Methods==

Not routinely performed. Select cases may require TCR gene rearrangement studies.

==Familial Forms==

N/A

==Additional Information==

N/A

==Links==

[https://tumourclassification.iarc.who.int/chaptercontent/63/258 5th edition World Health Organization (WHO) classification system]

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