Compendium of Cancer Genome Aberrations

HAEM5:Extranodal NK/T-cell lymphoma: Difference between revisions

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{{DISPLAYTITLE:Extranodal NK/T-cell lymphoma}}
{{DISPLAYTITLE:Extranodal NK/T-cell lymphoma}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]


==Primary Author(s)*==
==Primary Authors*==


Teodora Popa, MD, Queen's University
Teodora Popa, MD, Queen's University


Amanda Xu, MD, Queen's University  
Amanda Xu, MD, Queen's University  
__TOC__
==WHO Classification of Disease==
==WHO Classification of Disease==


Line 30: Line 26:
|-
|-
|Subtype(s)
|Subtype(s)
|Extranodal NK/T-cell lymphoma
|
|}
|}
==Related Terminology==


==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 was 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
Not recommended: angiocentric lymphoma; lethal midline granuloma (historical)
==Epidemiology / Prevalence==
* Most prevalent in East Asia and Latin America.
* Represents less than 1% of non-Hodgkin lymphomas in the United States
** 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"
{| class="wikitable"
|'''Signs and Symptoms'''
|+
|Nasal mass, nasal obstruction, nasal bleeding
|Acceptable
Hoarseness, dysphagia, halitosis, airway obstruction, dysphonia
|Extranodal NK/T-cell lymphoma, nasal type; EBV-positive extranodal NK/T-cell lymphoma
|-
|Not Recommended
|Angiocentric lymphoma; lethal midline granuloma
|}


Abdominal pain, GI bleeding, bowel perforation
==Gene Rearrangements==
 
{| class="wikitable sortable"
B symptoms (fever, weight loss, night sweats)
|-
!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
|-
|-
|'''Laboratory Findings'''
|
|No specific findings
|
Cytopenias
|
|
|
|
|
|
|}
|}


==Sites of Involvement==
==Individual Region Genomic Gain/Loss/LOH==
 
* Most are nasal type involving the upper aerodigestive tract
* Extranasal type may involve 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==
[[File:Extranodal NK T-cell lymphoma, nasal type.png|thumb|Extranodal NK T-cell lymphoma, nasal type (HPS). Angiocentric and angiodestructive growth pattern.]]
[[File:Extranodal NK T-cell lymphoma, nasal type.vsi(17.8X) snapshot.png|thumb|Extranodal NK T-cell lymphoma, nasal type (HPS). Angiocentric and angiodestructive growth pattern.]]
 
*Diffuse infiltrate composed of admixture of small, medium, or large and anaplastic cells.
*Cells have irregularly folded nuclei and moderate pale cytoplasm.
*Loss of mucosal glands.
*Angiocentric and angiodestructive growth pattern with coagulative necrosis.
*Usually see apoptotic cells and 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==
[[File:IHC NKTCL.png|thumb|Extranodal NK T-cell lymphoma stained with CD2 (top left), CD56 (red chromogen; top right), EBER in-situ hybridization (bottom left) and TIA1 (bottom right).]]
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"
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
!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
|-
|-
|Positive (universal)||CD2, CD56, cytoplasmic CD3ε, cytotoxic markers (TIA-1, granzyme B, perforin)  
|<span class="blue-text">EXAMPLE:</span>
EBER / EBV
7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>
chr7
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|<span class="blue-text">EXAMPLE:</span> 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 references).
|-
|-
|Positive (subset)||TCR αβ/γδ, HLA-DR, CD25, pSTAT3, CXCL13, IRF4/MUM1, CD16, Fas, FasL, MATK, CD30
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|
|<span class="blue-text">EXAMPLE:</span>
Common recurrent secondary finding for t(8;21) (add references).
|-
|-
|Negative (universal)||CD4, CD8
|<span class="blue-text">EXAMPLE:</span>
17
|<span class="blue-text">EXAMPLE:</span> Amp
|<span class="blue-text">EXAMPLE:</span>
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|<span class="blue-text">EXAMPLE:</span>
''ERBB2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|<span class="blue-text">EXAMPLE:</span>
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
|-
|-
|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"
{| class="wikitable sortable"
Line 150: Line 122:
|Loss
|Loss
|
|
|6q21-25
|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>
|Unknown
|Unknown
|Unknown
|Unknown
Line 156: Line 128:
|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>.
|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==
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>.
 
==Characteristic Chromosomal or Other Global Mutational Patterns==
{| class="wikitable sortable"
|-
!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
|-
|<span class="blue-text">EXAMPLE:</span>
Co-deletion of 1p and 18q
|<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).
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|<span class="blue-text">EXAMPLE:</span> D, P
|
|
|-
|<span class="blue-text">EXAMPLE:</span>
Microsatellite instability - hypermutated
|
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
|
|-
|
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|
|
|
|}


{| class="wikitable sortable"
{| class="wikitable sortable"
Line 178: Line 185:
|N/A
|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.
==Gene Mutations (SNV/INDEL)==
{| class="wikitable sortable"
|-
!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
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''


<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|<span class="blue-text">EXAMPLE:</span> T
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|<span class="blue-text">EXAMPLE:</span> P
|
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|
|-
|
|
|
|
|
|
|
|}
{| class="wikitable sortable"
{| 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!!Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)!!Prevalence (COSMIC /  TCGA / Other)!!Concomitant Mutations!!Mutually Exclusive Mutations
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
Line 195: Line 243:
|
|
|
|
|
|Unknown
|
|Unknown
|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.
|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.
|
|
Line 202: Line 250:
|''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>
|''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>
|Oncogene
|Oncogene
|26%<ref name=":4" />
|6-26%<ref name=":3" /><ref name=":4" />
|
|
|
|
|
|
|Unknown
|Unknown
|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>.
|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>.
|
|
Line 212: Line 260:
|''STAT5B''<ref name=":2" /><ref name=":3" />
|''STAT5B''<ref name=":2" /><ref name=":3" />
|Oncogene
|Oncogene
|6%<ref name=":3" />
|
|
|
|
|
|Unknown
|
|Unknown
|
|Unknown
|
|
|
|-
|-
Line 225: Line 273:
|
|
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|Unknown
|
|Unknown
|
|Unknown
|
|
|-
|-
Line 235: Line 283:
|
|
|
|
|
|Unknown
|
|Unknown
|
|Unknown
|
|
|-
|-
|''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>
|''PDGFRA''<ref name=":13" />
|Oncogene
|
|
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|''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
|
|
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|-
|''PDGFRA''<ref name=":13" />
|''RAS/KRAS/HRAS''
|Oncogene
|Oncogene
|<5%<ref name=":14">{{Cite journal|last=Hoshida|first=Yoshihiko|last2=Hongyo|first2=Tadashi|last3=Jia|first3=Xinshan|last4=He|first4=Yanjiao|last5=Hasui|first5=Kazuhisa|last6=Dong|first6=Zhiming|last7=Luo|first7=Wen-Juan|last8=Ham|first8=Maria Francisca|last9=Nomura|first9=Taisei|date=2003-03|title=Analysis of p53, K-ras, c-kit, and beta-catenin gene mutations in sinonasal NK/T cell lymphoma in northeast district of China|url=https://pubmed.ncbi.nlm.nih.gov/12824925|journal=Cancer Science|volume=94|issue=3|pages=297–301|doi=10.1111/j.1349-7006.2003.tb01436.x|issn=1347-9032|pmc=PMC11160272|pmid=12824925}}</ref><ref>{{Cite journal|last=Takahara|first=Miki|last2=Kishibe|first2=Kan|last3=Bandoh|first3=Nobuyuki|last4=Nonaka|first4=Satoshi|last5=Harabuchi|first5=Yasuaki|date=2004-01|title=P53, N- and K-Ras, and beta-catenin gene mutations and prognostic factors in nasal NK/T-cell lymphoma from Hokkaido, Japan|url=https://pubmed.ncbi.nlm.nih.gov/14745729|journal=Human Pathology|volume=35|issue=1|pages=86–95|doi=10.1016/j.humpath.2003.08.025|issn=0046-8177|pmid=14745729}}</ref>
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|''FAS''
|Oncogene
|50-60%<ref>{{Cite journal|last=Shen|first=Lijun|last2=Liang|first2=Anthony C. T.|last3=Lu|first3=Liwei|last4=Au|first4=Wing Yan|last5=Kwong|first5=Yok-Lam|last6=Liang|first6=Raymond H. S.|last7=Srivastava|first7=Gopesh|date=2002-12|title=Frequent deletion of Fas gene sequences encoding death and transmembrane domains in nasal natural killer/T-cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/12466128|journal=The American Journal of Pathology|volume=161|issue=6|pages=2123–2131|doi=10.1016/S0002-9440(10)64490-2|issn=0002-9440|pmc=1850920|pmid=12466128}}</ref><ref>{{Cite journal|last=Takakuwa|first=Tetsuya|last2=Dong|first2=Zhiming|last3=Nakatsuka|first3=Shinichi|last4=Kojya|first4=Shizuo|last5=Harabuchi|first5=Yasuaki|last6=Yang|first6=Woo-Ick|last7=Nagata|first7=Shigekazu|last8=Aozasa|first8=Katsuyuki|date=2002-07-11|title=Frequent mutations of Fas gene in nasal NK/T cell lymphoma|url=https://pubmed.ncbi.nlm.nih.gov/12096347|journal=Oncogene|volume=21|issue=30|pages=4702–4705|doi=10.1038/sj.onc.1205571|issn=0950-9232|pmid=12096347}}</ref>
|
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|-
|''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>
|''KIT''
|Oncogene
|Oncogene
|5-71% (China)
22% (Japan)<ref name=":14" /><ref>{{Cite journal|last=Hongyo|first=T.|last2=Li|first2=T.|last3=Syaifudin|first3=M.|last4=Baskar|first4=R.|last5=Ikeda|first5=H.|last6=Kanakura|first6=Y.|last7=Aozasa|first7=K.|last8=Nomura|first8=T.|date=2000-05-01|title=Specific c-kit mutations in sinonasal natural killer/T-cell lymphoma in China and Japan|url=https://pubmed.ncbi.nlm.nih.gov/10811105|journal=Cancer Research|volume=60|issue=9|pages=2345–2347|issn=0008-5472|pmid=10811105}}</ref>
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|''CTNNB1''
|Oncogene
|16-30%<ref name=":14" /><ref>{{Cite journal|last=Sugimoto|first=Kei-ji|last2=Kawamata|first2=Norihiko|last3=Sakajiri|first3=Sakura|last4=Oshimi|first4=Kazuo|date=2002-11|title=Molecular analysis of oncogenes, ras family genes (N-ras, K-ras, H-ras), myc family genes (c-myc, N-myc) and mdm2 in natural killer cell neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/12460470|journal=Japanese Journal of Cancer Research: Gann|volume=93|issue=11|pages=1270–1277|doi=10.1111/j.1349-7006.2002.tb01234.x|issn=0910-5050|pmc=5926889|pmid=12460470}}</ref>
|
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|-
|''DDX3X''<ref name=":2" />
|''DDX3X''<ref name=":2" />
|Other (RNA helicase)
|Epigenetic modifier (RNA helicase)
|20%<ref name=":2" />
|20%<ref name=":2" />
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|''KMT2D (MLL2)''<ref name=":2" />
|Epigenetic modifier
|38.2%<ref name=":4" />
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|-
|''TP53''<ref name=":2" />
|''ARID1A''<ref name=":2" />
|Tumor suppressor gene
|Epigenetic modifier
|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>
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|''EP300''<ref name=":2" />
|Epigenetic modifier
|
|
|
|
|Yes, associated with advanced stage disease<ref name=":11" />.
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|-
|''MGA''<ref name=":2" />
|''ASXL3''<ref name=":2" />
|Tumor suppressor gene
|Epigenetic modifier
|
|
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|''BCOR''<ref name=":4" />
|Epigenetic modifier
|38.2%<ref name=":4" />
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|-
|''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>
|''TP53''<ref name=":2" />
|Tumor suppressor gene
|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>
|
|
|
|
|Unknown
|Yes, associated with advanced stage disease<ref name=":11" />.
|Unknown
|
|
|-
|''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>
|Tumor suppressor gene
|
|
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|-
|''ATG5''<ref name=":9" />
|''MGA''<ref name=":2" />
|Tumor suppressor gene
|Tumor suppressor gene
|
|
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|''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
|Methylated in NK-92, KHYG-1, SNK-1, SNK-6 cell lines, 12/17 cases; Deleted in 8/18 cases; Mutated in NK-92 and KAI3 cell lines, 1/26 cases<ref name=":9" />
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|-
|''AIM1''<ref name=":9" />
|''ATG5''<ref name=":9" />
|Tumor suppressor gene
|Tumor suppressor gene
|
|
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|''AIM1''<ref name=":9" />
|Tumor suppressor gene
|Methylated in NK-92, HANK1, NK-YS, SNK-1, YT cell lines; Mutated in in SNK-1 and SNK-6 cell lines<ref name=":9" />
|
|
|
|
|Unknown
|Unknown
|Unknown
|
|
|-
|-
|''FOXO3''<ref name=":9" /><ref name=":7" />
|''FOXO3''<ref name=":9" /><ref name=":7" />
|Tumor suppressor gene
|Tumor suppressor gene
|Mutated in 2/26 NKTCL and 1/9 ANKL<ref name=":9" />
|
|
|
|
|
|Unknown
|
|Unknown
|
|Unknown
|
|
|
|-
|-
|''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>
|''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
|Tumor suppressor gene
|Mutated in 6/9 (67%) cell lines and 5/15 (33%) primary tumors<ref>{{Cite journal|last=Küçük|first=Can|last2=Hu|first2=Xiaozhou|last3=Iqbal|first3=Javeed|last4=Gaulard|first4=Philippe|last5=Klinkebiel|first5=David|last6=Cornish|first6=Adam|last7=Dave|first7=Bhavana J.|last8=Chan|first8=Wing C.|date=2013-01|title=HACE1 is a tumor suppressor gene candidate in natural killer cell neoplasms|url=https://pubmed.ncbi.nlm.nih.gov/23142381|journal=The American Journal of Pathology|volume=182|issue=1|pages=49–55|doi=10.1016/j.ajpath.2012.09.012|issn=1525-2191|pmc=3532710|pmid=23142381}}</ref>
|
|
|
|
|
|Unknown
|
|Unknown
|
|Unknown
|
|
|
|}
|}
Line 359: Line 498:


==Genes and Main Pathways Involved==
==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>.
[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 name=":15">{{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"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|''JAK3'', ''STAT3'', and ''STAT5B''; Activating mutations
|''JAK3'', ''STAT3'', and ''STAT5B''; Activating mutations<ref name=":13" /><ref name=":15" />
|JAK/STAT pathway
|JAK/STAT pathway
|Increased cell growth and proliferation
|Increased cell growth and proliferation
|-
|-
|''MYC, RUNX3''
|''MYC, RUNX3''<ref name=":15" />
|MYC
|MYC
|Increased cell proliferation and survival
|Increased cell proliferation and survival
|-
|-
|''AKT'' and related genes
|''AKT'' and related genes<ref name=":13" />
|AKT pathway
|AKT pathway
|Increased cell growth, proliferation and survival
|Increased cell growth, proliferation and survival
|-
|-
|NF-κB related genes
|NF-κB related genes<ref name=":13" /><ref name=":15" />
|NF-κB pathway
|NF-κB pathway
|Increased cell proliferation
|Increased cell proliferation
|-
|-
|''PDGFRA''
|''PDGFRA''<ref name=":13" /><ref name=":15" />
|PDGF pathway
|PDGF pathway
|Increased cell proliferation and survival
|Increased cell proliferation and survival
|-
|-
|''NOTCH1''
|''NOTCH1''<ref name=":15" />
|NOTCH1 pathway
|NOTCH1 pathway
|Increased cell proliferation
|Increased cell proliferation
|-
|-
|AURKA
|AURKA<ref name=":15" />
|Aurora kinase pathway<ref name=":12" />
|Aurora kinase pathway<ref name=":12" />
|Increased cell proliferation and cell cycle dysregulation
|Increased cell proliferation and cell cycle dysregulation
Line 394: Line 533:
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


* Not routinely performed.
*Select cases may require TCR gene rearrangement studies; otherwise, not routinely performed.
* Select cases may require TCR gene rearrangement studies.
*EBV PCR testing may be used for disease monitoring


==Familial Forms==
==Familial Forms==
Line 402: Line 541:


==Additional Information==
==Additional Information==
[[File:Extranodal NK T-cell lymphoma, nasal type.png|thumb|Extranodal NK T-cell lymphoma, nasal type (HPS). Angiocentric and angiodestructive growth pattern.]]This disease is <u>defined/characterized</u> as detailed below:
*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>. The lineage (NK or T-cell) has no clinical significance<ref name=":16">{{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>.
*Divided into nasal and non-nasal types, the latter most often occurring in the skin and intestinal tract<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><ref name=":6" />.
*It is a destructive angiocentric disease characterized by vascular destruction and necrosis<ref name=":17">{{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>.
*Differential diagnosis: sinonasal carcinomas and other lymphomas of the nasal cavity, such as diffuse large B-cell lymphoma<ref name=":18">{{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>.
The <u>epidemiology/prevalence</u> of this disease is detailed below:
*Most prevalent in East Asia and Latin America.
*Represents less than 1% of non-Hodgkin lymphomas in the United States
**Highest incidence among Asian Pacific Islanders and Hispanic populations<ref name=":19">{{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>.
The <u>clinical features</u> of this disease are detailed below: [[File:Extranodal NK T-cell lymphoma, nasal type.vsi(17.8X) snapshot.png|thumb|Extranodal NK T-cell lymphoma, nasal type (HPS). Angiocentric and angiodestructive growth pattern.]]
Signs and symptoms - Nasal mass, nasal obstruction, nasal bleeding; Hoarseness, dysphagia, halitosis, airway obstruction, dysphonia; Abdominal pain, GI bleeding, bowel 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>; B symptoms (fever, weight loss, night sweats) associated with higher clinical stage<ref name=":20">{{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>
Laboratory findings - No specific findings; Cytopenias
The <u>sites of involvement</u> of this disease are detailed below:
*Most are nasal type involving the upper aerodigestive tract
*Extranasal type may involve skin, testis, and gastrointestinal tract<ref name=":0" />.
*Bone marrow involvement is uncommon<ref name=":21">{{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>.
The <u>morphologic features</u> of this disease are detailed below:
*Diffuse infiltrate composed of admixture of small, medium, or large and anaplastic cells.
*Cells have irregularly folded nuclei and moderate pale cytoplasm.
*Loss of mucosal glands.
*Angiocentric and angiodestructive growth pattern with coagulative necrosis.
*Usually see apoptotic cells and mitotic figures[[File:IHC NKTCL.png|thumb|Extranodal NK T-cell lymphoma stained with CD2 (top left), CD56 (red chromogen; top right), EBER in-situ hybridization (bottom left) and TIA1 (bottom right).]]
The pitfalls can include:
*Mucosal ulceration and superimposed inflammation can mimic an inflammatory process, particularly in less aggressive cases<ref name=":22">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 name=":23">{{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 name=":24">{{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>.
The <u>immunophenotype</u> of this disease is detailed below:
Positive (universal) - EBER / EBV
Positive (majority) - cytoplasmic CD3ε, CD2, CD56, granzyme B, and TIA-1
Positive (subset) - TCR αβ/γδ, HLA-DR, CD25, pSTAT3, CXCL13, IRF4/MUM1, CD16, Fas, FasL, MATK, CD30<ref name=":25">{{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 name=":26">{{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 name=":27">{{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 name=":28">{{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 name=":29">{{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 name=":30">{{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 name=":31">{{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>
Negative (universal) - CD4, CD8


N/A
Negative (subset) - Surface CD3 (subset of T-cell lineage)<ref name=":0" />


==Links==
==Links==
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==Notes==
==Notes==
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<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:HAEM5]]
[[Category:DISEASE]]
[[Category:DISEASE]]
[[Category:Diseases E]]
[[Category:Diseases E]]
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