Compendium of Cancer Genome Aberrations

Extranodal NK/T-cell lymphoma

Haematolymphoid Tumours (WHO Classification, 5th ed.)

Primary Author(s)*

Ian King, PhD, FACMG

Maryam Mehdipour Dalivand, MD

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category T-cell and NK-cell lymphoid proliferations and lymphomas
Family Mature T-cell and NK-cell neoplasms
Type EBV-positive NK-cell and T-cell lymphomas
Subtype(s) Extranodal NK/T-cell lymphoma

Related Terminology

Acceptable Extranodal NK/T-cell lymphoma, nasal type; EBV-positive extranodal NK/T-cell lymphoma
Not Recommended Angiocentric lymphoma; lethal midline granuloma

Gene Rearrangements

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
CTLA4-CD28 CTLA4-CD28 This fusion promotes tumor cell growth and survival by redirecting immune checkpoint signals[1] Chromosome 2q33 29% T: Therapeutically targetable through blockade of the CTLA4/CD28 pathway or its downstream signaling. No In extranodal NK/T-cell lymphoma, the CTLA4–CD28 fusion identifies a molecular subset in which aberrant CD28 costimulatory signaling likely contributes to tumor growth and survival. Clinically, this suggests potential therapeutic vulnerability to agents targeting the CTLA4/CD28 axis or downstream signaling pathways, although it is not specific enough to be a primary diagnostic marker and currently serves more as a biologic and potential predictive marker rather than a routine clinical test.

Individual Region Genomic Gain/Loss/LOH

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
6 Loss ~2.6 Mb interval within 6q21–q25[2] This locus harbors multiple candidate genes including ATG5, AIM1, PRDM1, PTPRK, HACE1 and FOXO3[3][4][5] D: Chromosome 6q loss is a recurrent abnormality in ENKTL that provides supportive molecular evidence of neoplasia and helps distinguish ENKTL from other T/NK-cell proliferations, but it is not sufficient for a standalone diagnosis.[6]

P: Loss of chromosome 6q in ENKTL is associated with deletion of key tumor suppressor genes and correlates with aggressive disease features and poorer survival, making it an adverse prognostic marker.

No Chromosome 6q loss in ENKTL is a recurrent molecular abnormality that supports diagnosis, indicates aggressive clinical behavior. Loss of chromosome 6q in ENKTL is not directly targetable but highlights deletion of tumor suppressor genes and activation of downstream pathways, such as JAK/STAT and NF-κB. This suggests potential susceptibility to pathway-specific therapies in high-risk patients. [7][8]

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[9][10][11][12][13].

Characteristic Chromosomal or Other Global Mutational Patterns

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
Isochromosome 6p[14] Unknown Yes, isochromosome (6p) leads to loss of 6q tumor suppressor genes (PRDM1, FOXO3, HACE1) and gain of 6p genes, which may enhance proliferation.This dual effect is thought to contribute to more aggressive tumor biology compared with simple 6q deletions.[15][16] Unknown N/A
Isochromosome 7q[17] Unknown Unknown Unknown N/A

Gene Mutations (SNV/INDEL)

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
JAK3 Activating mutations Oncogene Common[18] T No Pan-JAK and selective JAK3 inhibitors have been suggested as potential therapeutic options[18][19]. Clinical trials evaluating JAK inhibitors are in progress.
STAT3[20][21][22] Oncogene Recurrent[21][22] T No STAT3 inhibitor may have potential therapeutic benefit in patients with STAT3 activating mutation[23].
TP53[20] Tumor suppressor gene Common[24][25] P No Associated with advanced stage disease
STAT5B[20][21] Oncogene Recurrent[21] No No n/a
PTPRK[5] Other (acts on JAK/STAT pathway; underexpression leads to STAT3 activation[5]) No No n/a
MYC[26] Oncogene No No n/a
PDGFRA[27] Oncogene No No n/a
EZH2[28] Oncogene No No n/a
RAS/KRAS/HRAS Oncogene Rare[29][30] No No n/a
FAS Oncogene Common[31][32] No No n/a
KIT Oncogene Common[29][33] No No n/a
CTNNB1 Oncogene Common[29][34] No No n/a
DDX3X[20] Epigenetic modifier (RNA helicase) Recurrent[20] No No n/a
KMT2D (MLL2)[20] Epigenetic modifier Common[22] No No n/a
ARID1A[20] Epigenetic modifier No No n/a
EP300[20] Epigenetic modifier No No n/a
ASXL3[20] Epigenetic modifier No No n/a
BCOR[22] Epigenetic modifier 38.2%[22] No No n/a
RUNX3[35] Tumor suppressor gene No No n/a
MGA[20] Tumor suppressor gene No No n/a
PRDM1[36][4][37] 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[36] No No n/a
ATG5[36] Tumor suppressor gene No No n/a
AIM1[36] 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[36] No No n/a
FOXO3[36][4] Tumor suppressor gene Mutated in 2/26 NKTCL and 1/9 ANKL[36] No No n/a
HACE1[36][27] Tumor suppressor gene Mutated in 6/9 (67%) cell lines and 5/15 (33%) primary tumors[38] No No n/a

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

N/A

Genes and Main Pathways Involved

Huang, et al described deregulation of several signaling pathways in NK T-cell lymphoma, main ones listed below[27]. A review by De Mel, et al, also outlines key molecular pathways involved in the pathogenesis of ENKTL[39].

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
JAK3, STAT3, and STAT5B; Activating mutations[27][39] JAK/STAT pathway Increased cell growth and proliferation
MYC, RUNX3[39] MYC Increased cell proliferation and survival
AKT and related genes[27] AKT pathway Increased cell growth, proliferation and survival
NF-κB related genes[27][39] NF-κB pathway Increased cell proliferation
PDGFRA[27][39] PDGF pathway Increased cell proliferation and survival
NOTCH1[39] NOTCH1 pathway Increased cell proliferation
AURKA[39] Aurora kinase pathway[26] Increased cell proliferation and cell cycle dysregulation

Genetic Diagnostic Testing Methods

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

Familial Forms

N/A

Additional Information

 
Extranodal NK T-cell lymphoma, nasal type (HPS). Angiocentric and angiodestructive growth pattern.

This disease is defined/characterized as detailed below:

  • Lymphoma of NK or T-cell lineage strongly associated with Epstein-Barr virus[40]. The lineage (NK or T-cell) has no clinical significance[41].
  • Divided into nasal and non-nasal types, the latter most often occurring in the skin and intestinal tract[42][40].
  • It is a destructive angiocentric disease characterized by vascular destruction and necrosis[43].
  • Differential diagnosis: sinonasal carcinomas and other lymphomas of the nasal cavity, such as diffuse large B-cell lymphoma[44].

The epidemiology/prevalence 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[45].

The clinical features of this disease are detailed below:

 
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[46]; B symptoms (fever, weight loss, night sweats) associated with higher clinical stage[47]

Laboratory findings - No specific findings; Cytopenias

The sites of involvement of this disease are detailed below:

  • Most are nasal type involving the upper aerodigestive tract
  • Extranasal type may involve skin, testis, and gastrointestinal tract[46].
  • Bone marrow involvement is uncommon[48].

The morphologic features 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
     
    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[49].
  • Pseudoepitheliomatous hyperplasia of the overlying mucosal epithelium can mimic squamous cell carcinoma[50][51].

The immunophenotype 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[52][53][54][55][56][57][58]

Negative (universal) - CD4, CD8

Negative (subset) - Surface CD3 (subset of T-cell lineage)[46]

Links

5th edition World Health Organization (WHO) classification system

References

  1. ↑ Yoo, Hae Yong; Kim, Pora; Kim, Won Seog; Lee, Seung Ho; Kim, Sangok; Kang, So Young; Jang, Hye Yoon; Lee, Jong-Eun; Kim, Jaesang (2016-06-01). "Frequent CTLA4-CD28 gene fusion in diverse types of T-cell lymphoma". Haematologica. 101 (6): 757–763. doi:10.3324/haematol.2015.139253. ISSN 1592-8721. PMC 5013939. PMID 26819049.
  2. ↑ De Mel, Sanjay; Soon, Gwyneth Shook-Ting; Mok, Yingting; Chung, Tae-Hoon; Jeyasekharan, Anand D.; Chng, Wee-Joo; Ng, Siok-Bian (2018-06-30). "The Genomics and Molecular Biology of Natural Killer/T-Cell Lymphoma: Opportunities for Translation". International Journal of Molecular Sciences. 19 (7): 1931. doi:10.3390/ijms19071931. ISSN 1422-0067.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  3. ↑ Iqbal, J.; Kucuk, C.; Deleeuw, R. J.; Srivastava, G.; Tam, W.; Geng, H.; Klinkebiel, D.; Christman, J. K.; Patel, K. (2009-06). "Genomic analyses reveal global functional alterations that promote tumor growth and novel tumor suppressor genes in natural killer-cell malignancies". Leukemia. 23 (6): 1139–1151. doi:10.1038/leu.2009.3. ISSN 1476-5551. PMID 19194464. {{cite journal}}: Check date values in: |date= (help)
  4. ↑ 4.0 4.1 4.2 Karube, Kennosuke; Nakagawa, Masao; Tsuzuki, Shinobu; Takeuchi, Ichiro; Honma, Keiichiro; Nakashima, Yasuhiro; Shimizu, Norio; Ko, Young-Hyeh; Morishima, Yasuo (2011-09-22). "Identification of FOXO3 and PRDM1 as tumor-suppressor gene candidates in NK-cell neoplasms by genomic and functional analyses". Blood. 118 (12): 3195–3204. doi:10.1182/blood-2011-04-346890. ISSN 1528-0020. PMID 21690554.
  5. ↑ 5.0 5.1 5.2 Chen, Yun-Wen; Guo, Tianhuan; Shen, Lijun; Wong, Kai-Yau; Tao, Qian; Choi, William W. L.; Au-Yeung, Rex K. H.; Chan, Yuen-Piu; Wong, Michelle L. Y. (2015-03-05). "Receptor-type tyrosine-protein phosphatase κ directly targets STAT3 activation for tumor suppression in nasal NK/T-cell lymphoma". Blood. 125 (10): 1589–1600. doi:10.1182/blood-2014-07-588970. ISSN 1528-0020. PMID 25612622.
  6. ↑ Liang, Li; Zhang, Zhang; Wang, Ying; Nong, Lin; Zheng, Yalin; Qu, Linlin; Zhang, Bo; Li, Ting (2015). "The Genetic Deletion of 6q21 and PRDM1 and Clinical Implications in Extranodal NK/T Cell Lymphoma, Nasal Type". BioMed Research International. 2015: 435423. doi:10.1155/2015/435423. ISSN 2314-6141. PMC 4499638. PMID 26221594.{{cite journal}}: CS1 maint: article number as page number (link) CS1 maint: unflagged free DOI (link)
  7. ↑ Costa, Renata de Oliveira; Pereira, Juliana; Lage, Luís Alberto de Pádua Covas; Baiocchi, Otávio César Guimarães (2023-07-17). "Extranodal NK-/T-cell lymphoma, nasal type: what advances have been made in the last decade?". Frontiers in Oncology. 13. doi:10.3389/fonc.2023.1175545. ISSN 2234-943X.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ↑ Tse, Eric; Kwong, Yok-Lam (2017-12). "The diagnosis and management of NK/T-cell lymphomas". Journal of Hematology & Oncology. 10 (1). doi:10.1186/s13045-017-0452-9. ISSN 1756-8722. {{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)
  9. ↑ Nakashima, Yasuhiro; Tagawa, Hiroyuki; Suzuki, Ritsuro; Karnan, Sivasundaram; Karube, Kennosuke; Ohshima, Koichi; Muta, Koichiro; Nawata, Hajime; Morishima, Yasuo (2005-11). "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". Genes, Chromosomes & Cancer. 44 (3): 247–255. doi:10.1002/gcc.20245. ISSN 1045-2257. PMID 16049916. {{cite journal}}: Check date values in: |date= (help)
  10. ↑ Siu, L. L.; Chan, V.; Chan, J. K.; Wong, K. F.; Liang, R.; Kwong, Y. L. (2000-12). "Consistent patterns of allelic loss in natural killer cell lymphoma". The American Journal of Pathology. 157 (6): 1803–1809. doi:10.1016/S0002-9440(10)64818-3. ISSN 0002-9440. PMC 1885756. PMID 11106552. {{cite journal}}: Check date values in: |date= (help)
  11. ↑ Siu, L. L.; Wong, K. F.; Chan, J. K.; Kwong, Y. L. (1999-11). "Comparative genomic hybridization analysis of natural killer cell lymphoma/leukemia. Recognition of consistent patterns of genetic alterations". The American Journal of Pathology. 155 (5): 1419–1425. doi:10.1016/S0002-9440(10)65454-5. ISSN 0002-9440. PMC 1866965. PMID 10550295. {{cite journal}}: Check date values in: |date= (help)
  12. ↑ Wong, K. F.; Zhang, Y. M.; Chan, J. K. (1999-07). "Cytogenetic abnormalities in natural killer cell lymphoma/leukaemia--is there a consistent pattern?". Leukemia & Lymphoma. 34 (3–4): 241–250. doi:10.3109/10428199909050949. ISSN 1042-8194. PMID 10439361. {{cite journal}}: Check date values in: |date= (help)
  13. ↑ Ko, Y. H.; Choi, K. E.; Han, J. H.; Kim, J. M.; Ree, H. J. (2001-04-15). "Comparative genomic hybridization study of nasal-type NK/T-cell lymphoma". Cytometry. 46 (2): 85–91. doi:10.1002/cyto.1069. ISSN 0196-4763. PMID 11309817.
  14. ↑ Tien, H. F.; Su, I. J.; Tang, J. L.; Liu, M. C.; Lee, F. Y.; Chen, Y. C.; Chuang, S. M. (1997-06). "Clonal chromosomal abnormalities as direct evidence for clonality in nasal T/natural killer cell lymphomas". British Journal of Haematology. 97 (3): 621–625. doi:10.1046/j.1365-2141.1997.752711.x. ISSN 0007-1048. PMID 9207410. {{cite journal}}: Check date values in: |date= (help)
  15. ↑ Tse, Eric; Kwong, Yok-Lam (2017-12). "The diagnosis and management of NK/T-cell lymphomas". Journal of Hematology & Oncology. 10 (1). doi:10.1186/s13045-017-0452-9. ISSN 1756-8722. {{cite journal}}: Check date values in: |date= (help)CS1 maint: unflagged free DOI (link)
  16. ↑ De Mel, Sanjay; Soon, Gwyneth Shook-Ting; Mok, Yingting; Chung, Tae-Hoon; Jeyasekharan, Anand D.; Chng, Wee-Joo; Ng, Siok-Bian (2018-06-30). "The Genomics and Molecular Biology of Natural Killer/T-Cell Lymphoma: Opportunities for Translation". International Journal of Molecular Sciences. 19 (7): 1931. doi:10.3390/ijms19071931. ISSN 1422-0067.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  17. ↑ Feldman, Andrew L.; Law, Mark; Grogg, Karen L.; Thorland, Erik C.; Fink, Stephanie; Kurtin, Paul J.; Macon, William R.; Remstein, Ellen D.; Dogan, Ahmet (2008-08). "Incidence of TCR and TCL1 gene translocations and isochromosome 7q in peripheral T-cell lymphomas using fluorescence in situ hybridization". American Journal of Clinical Pathology. 130 (2): 178–185. doi:10.1309/PNXUKA1CFJMVGCN1. ISSN 0002-9173. PMC 3625137. PMID 18628085. {{cite journal}}: Check date values in: |date= (help)
  18. ↑ 18.0 18.1 Koo, Ghee Chong; Tan, Soo Yong; Tang, Tiffany; Poon, Song Ling; Allen, George E.; Tan, Leonard; Chong, Soo Ching; Ong, Whee Sze; Tay, Kevin (2012-07). "Janus kinase 3-activating mutations identified in natural killer/T-cell lymphoma". Cancer Discovery. 2 (7): 591–597. doi:10.1158/2159-8290.CD-12-0028. ISSN 2159-8290. PMID 22705984. {{cite journal}}: Check date values in: |date= (help)
  19. ↑ Nairismägi, M.-L.; Gerritsen, M. E.; Li, Z. M.; Wijaya, G. C.; Chia, B. K. H.; Laurensia, Y.; Lim, J. Q.; Yeoh, K. W.; Yao, X. S. (2018-05). "Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma". Leukemia. 32 (5): 1147–1156. doi:10.1038/s41375-017-0004-x. ISSN 1476-5551. PMC 5940653. PMID 29434279. {{cite journal}}: Check date values in: |date= (help)
  20. ↑ 20.00 20.01 20.02 20.03 20.04 20.05 20.06 20.07 20.08 20.09 Jiang, Lu; Gu, Zhao-Hui; Yan, Zi-Xun; Zhao, Xia; Xie, Yin-Yin; Zhang, Zi-Guan; Pan, Chun-Ming; Hu, Yuan; Cai, Chang-Ping (2015-09). "Exome sequencing identifies somatic mutations of DDX3X in natural killer/T-cell lymphoma". Nature Genetics. 47 (9): 1061–1066. doi:10.1038/ng.3358. ISSN 1546-1718. PMID 26192917. {{cite journal}}: Check date values in: |date= (help)
  21. ↑ 21.0 21.1 21.2 21.3 Küçük, Can; Jiang, Bei; Hu, Xiaozhou; Zhang, Wenyan; Chan, John K. C.; Xiao, Wenming; Lack, Nathan; Alkan, Can; Williams, John C. (2015-01-14). "Activating mutations of STAT5B and STAT3 in lymphomas derived from γδ-T or NK cells". Nature Communications. 6: 6025. doi:10.1038/ncomms7025. ISSN 2041-1723. PMC 7743911. PMID 25586472.
  22. ↑ 22.0 22.1 22.2 22.3 22.4 Lee, Seungbok; Park, Ha Young; Kang, So Young; Kim, Seok Jin; Hwang, Jinha; Lee, Seungho; Kwak, Soo Heon; Park, Kyong Soo; Yoo, Hae Yong (2015-07-10). "Genetic alterations of JAK/STAT cascade and histone modification in extranodal NK/T-cell lymphoma nasal type". Oncotarget. 6 (19): 17764–17776. doi:10.18632/oncotarget.3776. ISSN 1949-2553. PMC 4627344. PMID 25980440.
  23. ↑ Wang, Yali; Zhou, Wenbo; Chen, Jianfeng; Chen, Jinghong; Deng, Peng; Chen, Huang; Sun, Yichen; Yu, Zhaoliang; Pang, Diwen (2023-08). "Preclinical characterization of WB737, a potent and selective STAT3 inhibitor, in natural killer/T-cell lymphoma". MedComm. 4 (4): e284. doi:10.1002/mco2.284. ISSN 2688-2663. PMC 10274570. PMID 37334274. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  24. ↑ Quintanilla-Martinez, L.; Kremer, M.; Keller, G.; Nathrath, M.; Gamboa-Dominguez, A.; Meneses, A.; Luna-Contreras, L.; Cabras, A.; Hoefler, H. (2001-12). "p53 Mutations in nasal natural killer/T-cell lymphoma from Mexico: association with large cell morphology and advanced disease". The American Journal of Pathology. 159 (6): 2095–2105. doi:10.1016/S0002-9440(10)63061-1. ISSN 0002-9440. PMC 1850589. PMID 11733360. {{cite journal}}: Check date values in: |date= (help)
  25. ↑ Hongyo, Tadashi; Hoshida, Yoshihiko; Nakatsuka, Shin-Ichi; Syaifudin, Mukh; Kojya, Shizuo; Yang, Woo-Ick; Min, Yoo-Hong; Chan, Heekyung; Kim, Chan Hwan (2005-02). "p53, K-ras, c-kit and beta-catenin gene mutations in sinonasal NK/T-cell lymphoma in Korea and Japan". Oncology Reports. 13 (2): 265–271. ISSN 1021-335X. PMID 15643509. {{cite journal}}: Check date values in: |date= (help)
  26. ↑ 26.0 26.1 Ng, Siok-Bian; Selvarajan, Viknesvaran; Huang, Gaofeng; Zhou, Jianbiao; Feldman, Andrew L.; Law, Mark; Kwong, Yok-Lam; Shimizu, Norio; Kagami, Yoshitoyo (2011-03). "Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling". The Journal of Pathology. 223 (4): 496–510. doi:10.1002/path.2823. ISSN 1096-9896. PMID 21294123. {{cite journal}}: Check date values in: |date= (help)
  27. ↑ 27.0 27.1 27.2 27.3 27.4 27.5 27.6 Huang, Yenlin; de Reyniès, Aurélien; de Leval, Laurence; Ghazi, Bouchra; Martin-Garcia, Nadine; Travert, Marion; Bosq, Jacques; Brière, Josette; Petit, Barbara (2010-02-11). "Gene expression profiling identifies emerging oncogenic pathways operating in extranodal NK/T-cell lymphoma, nasal type". Blood. 115 (6): 1226–1237. doi:10.1182/blood-2009-05-221275. ISSN 1528-0020. PMC 2826234. PMID 19965620.
  28. ↑ Yan, Junli; Li, Boheng; Lin, Baohong; Lee, Pei Tsung; Chung, Tae-Hoon; Tan, Joy; Bi, Chonglei; Lee, Xue Ting; Selvarajan, Viknesvaran (2016-08-18). "EZH2 phosphorylation by JAK3 mediates a switch to noncanonical function in natural killer/T-cell lymphoma". Blood. 128 (7): 948–958. doi:10.1182/blood-2016-01-690701. ISSN 1528-0020. PMID 27297789.
  29. ↑ 29.0 29.1 29.2 Hoshida, Yoshihiko; Hongyo, Tadashi; Jia, Xinshan; He, Yanjiao; Hasui, Kazuhisa; Dong, Zhiming; Luo, Wen-Juan; Ham, Maria Francisca; Nomura, Taisei (2003-03). "Analysis of p53, K-ras, c-kit, and beta-catenin gene mutations in sinonasal NK/T cell lymphoma in northeast district of China". Cancer Science. 94 (3): 297–301. doi:10.1111/j.1349-7006.2003.tb01436.x. ISSN 1347-9032. PMC 11160272. PMID 12824925. {{cite journal}}: Check date values in: |date= (help)CS1 maint: PMC format (link)
  30. ↑ Takahara, Miki; Kishibe, Kan; Bandoh, Nobuyuki; Nonaka, Satoshi; Harabuchi, Yasuaki (2004-01). "P53, N- and K-Ras, and beta-catenin gene mutations and prognostic factors in nasal NK/T-cell lymphoma from Hokkaido, Japan". Human Pathology. 35 (1): 86–95. doi:10.1016/j.humpath.2003.08.025. ISSN 0046-8177. PMID 14745729. {{cite journal}}: Check date values in: |date= (help)
  31. ↑ Shen, Lijun; Liang, Anthony C. T.; Lu, Liwei; Au, Wing Yan; Kwong, Yok-Lam; Liang, Raymond H. S.; Srivastava, Gopesh (2002-12). "Frequent deletion of Fas gene sequences encoding death and transmembrane domains in nasal natural killer/T-cell lymphoma". The American Journal of Pathology. 161 (6): 2123–2131. doi:10.1016/S0002-9440(10)64490-2. ISSN 0002-9440. PMC 1850920. PMID 12466128. {{cite journal}}: Check date values in: |date= (help)
  32. ↑ Takakuwa, Tetsuya; Dong, Zhiming; Nakatsuka, Shinichi; Kojya, Shizuo; Harabuchi, Yasuaki; Yang, Woo-Ick; Nagata, Shigekazu; Aozasa, Katsuyuki (2002-07-11). "Frequent mutations of Fas gene in nasal NK/T cell lymphoma". Oncogene. 21 (30): 4702–4705. doi:10.1038/sj.onc.1205571. ISSN 0950-9232. PMID 12096347.
  33. ↑ Hongyo, T.; Li, T.; Syaifudin, M.; Baskar, R.; Ikeda, H.; Kanakura, Y.; Aozasa, K.; Nomura, T. (2000-05-01). "Specific c-kit mutations in sinonasal natural killer/T-cell lymphoma in China and Japan". Cancer Research. 60 (9): 2345–2347. ISSN 0008-5472. PMID 10811105.
  34. ↑ Sugimoto, Kei-ji; Kawamata, Norihiko; Sakajiri, Sakura; Oshimi, Kazuo (2002-11). "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". Japanese Journal of Cancer Research: Gann. 93 (11): 1270–1277. doi:10.1111/j.1349-7006.2002.tb01234.x. ISSN 0910-5050. PMC 5926889. PMID 12460470. {{cite journal}}: Check date values in: |date= (help)
  35. ↑ Selvarajan, V.; Osato, M.; Nah, G. S. S.; Yan, J.; Chung, T.-H.; Voon, D. C.-C.; Ito, Y.; Ham, M. F.; Salto-Tellez, M. (2017-10). "RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC". Leukemia. 31 (10): 2219–2227. doi:10.1038/leu.2017.40. ISSN 1476-5551. PMC 5629367. PMID 28119527. {{cite journal}}: Check date values in: |date= (help)
  36. ↑ 36.0 36.1 36.2 36.3 36.4 36.5 36.6 36.7 Huang, Yenlin; de Leval, Laurence; Gaulard, Philippe (2013-03). "Molecular underpinning of extranodal NK/T-cell lymphoma". Best Practice & Research. Clinical Haematology. 26 (1): 57–74. doi:10.1016/j.beha.2013.04.006. ISSN 1532-1924. PMID 23768641. {{cite journal}}: Check date values in: |date= (help)
  37. ↑ Küçük, Can; Iqbal, Javeed; Hu, Xiaozhou; Gaulard, Phillip; De Leval, Laurence; Srivastava, Gopesh; Au, Wing Yan; McKeithan, Timothy W.; Chan, Wing C. (2011-12-13). "PRDM1 is a tumor suppressor gene in natural killer cell malignancies". Proceedings of the National Academy of Sciences of the United States of America. 108 (50): 20119–20124. doi:10.1073/pnas.1115128108. ISSN 1091-6490. PMC 3250125. PMID 22143801.
  38. ↑ Küçük, Can; Hu, Xiaozhou; Iqbal, Javeed; Gaulard, Philippe; Klinkebiel, David; Cornish, Adam; Dave, Bhavana J.; Chan, Wing C. (2013-01). "HACE1 is a tumor suppressor gene candidate in natural killer cell neoplasms". The American Journal of Pathology. 182 (1): 49–55. doi:10.1016/j.ajpath.2012.09.012. ISSN 1525-2191. PMC 3532710. PMID 23142381. {{cite journal}}: Check date values in: |date= (help)
  39. ↑ 39.0 39.1 39.2 39.3 39.4 39.5 39.6 de Mel, Sanjay; Hue, Susan Swee-Shan; Jeyasekharan, Anand D.; Chng, Wee-Joo; Ng, Siok-Bian (2019-04-02). "Molecular pathogenic pathways in extranodal NK/T cell lymphoma". Journal of Hematology & Oncology. 12 (1): 33. doi:10.1186/s13045-019-0716-7. ISSN 1756-8722. PMC 6444858. PMID 30935402.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  40. ↑ 40.0 40.1 Jaffe, E. S.; Krenacs, L.; Kumar, S.; Kingma, D. W.; Raffeld, M. (1999-01). "Extranodal peripheral T-cell and NK-cell neoplasms". American Journal of Clinical Pathology. 111 (1 Suppl 1): S46–55. ISSN 0002-9173. PMID 9894469. {{cite journal}}: Check date values in: |date= (help)
  41. ↑ Wang, Hua; Fu, Bi-Bo; Gale, Robert Peter; Liang, Yang (2021-09). "NK-/T-cell lymphomas". Leukemia. 35 (9): 2460–2468. doi:10.1038/s41375-021-01313-2. ISSN 1476-5551. PMC 8410593. PMID 34117356. {{cite journal}}: Check date values in: |date= (help)
  42. ↑ 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.
  43. ↑ Aviles, A.; Rodriguez, L.; Guzman, R.; Talavera, A.; Garcia, E. L.; Diaz-Maqueo, J. C. (1992). "Angiocentric T-cell lymphoma of the nose, paranasal sinuses and hard palate". Hematological Oncology. 10 (3–4): 141–147. doi:10.1002/hon.2900100303. ISSN 0278-0232. PMID 1398510.
  44. ↑ Steele, Toby O.; Buniel, Maria C.; Mace, Jess C.; El Rassi, Edward; Smith, Timothy L. (2016-09). "Lymphoma of the nasal cavity and paranasal sinuses: A case series". American Journal of Rhinology & Allergy. 30 (5): 335–339. doi:10.2500/ajra.2016.30.4347. ISSN 1945-8932. PMID 27657899. {{cite journal}}: Check date values in: |date= (help)
  45. ↑ Haverkos, Bradley M.; Pan, Zenggang; Gru, Alejandro A.; Freud, Aharon G.; Rabinovitch, Rachel; Xu-Welliver, Meng; Otto, Brad; Barrionuevo, Carlos; Baiocchi, Robert A. (2016-12). "Extranodal NK/T-cell lymphoma, nasal type (ENKTL-NT): An update on epidemiology, clinical presentation, and natural history in North American and European cases". Current hematologic malignancy reports. 11 (6): 514–527. doi:10.1007/s11899-016-0355-9. ISSN 1558-8211. PMC 5199232. PMID 27778143. {{cite journal}}: Check date values in: |date= (help)
  46. ↑ 46.0 46.1 46.2 Thida AM, Gohari P. Extranodal NK-Cell Lymphoma. [Updated 2023 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK559207/
  47. ↑ Takahara, Miki; Kumai, Takumi; Kishibe, Kan; Nagato, Toshihiro; Harabuchi, Yasuaki (2021-06-25). "Extranodal NK/T-Cell Lymphoma, Nasal Type: Genetic, Biologic, and Clinical Aspects with a Central Focus on Epstein-Barr Virus Relation". Microorganisms. 9 (7): 1381. doi:10.3390/microorganisms9071381. ISSN 2076-2607. PMC 8304202. PMID 34202088.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  48. ↑ Wong, K. F.; Chan, J. K.; Cheung, M. M.; So, J. C. (2001-02). "Bone marrow involvement by nasal NK cell lymphoma at diagnosis is uncommon". American Journal of Clinical Pathology. 115 (2): 266–270. doi:10.1309/E5PR-6A9R-Q02N-8QVW. ISSN 0002-9173. PMID 11211616. {{cite journal}}: Check date values in: |date= (help)
  49. ↑ 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). https://doi.org/10.1186/s13000-018-0765-1
  50. ↑ Ling, Yi-Hong; Zhu, Chong-Mei; Wen, Shi-Hong; Luo, Rong-Zhen; Li, Peng; Cao, Yun; Rao, Hui-Lan; Lin, Su-Xia; Cai, Mu-Yan (2015-09). "Pseudoepitheliomatous hyperplasia mimicking invasive squamous cell carcinoma in extranodal natural killer/T-cell lymphoma: a report of 34 cases". Histopathology. 67 (3): 404–409. doi:10.1111/his.12656. ISSN 1365-2559. PMID 25619876. {{cite journal}}: Check date values in: |date= (help)
  51. ↑ Xiang, Chun-Xiang; Chen, Zi-Hang; Zhao, Sha; Gao, Li-Min; Tao, Qing; Zuo, Zhuo; Liu, Xiao-Yu; Liu, Wei-Ping (2019-07). "Laryngeal Extranodal Nasal-type Natural Killer/T-cell Lymphoma: A Clinicopathologic Study of 31 Cases in China". The American Journal of Surgical Pathology. 43 (7): 995–1004. doi:10.1097/PAS.0000000000001266. ISSN 1532-0979. PMID 31045893. {{cite journal}}: Check date values in: |date= (help)
  52. ↑ Li, Shaoying; Feng, Xiaoli; Li, Ting; Zhang, Shuang; Zuo, Zhuang; Lin, Pei; Konoplev, Sergej; Bueso-Ramos, Carlos E.; Vega, Francisco (2013-01). "Extranodal NK/T-cell lymphoma, nasal type: a report of 73 cases at MD Anderson Cancer Center". The American Journal of Surgical Pathology. 37 (1): 14–23. doi:10.1097/PAS.0b013e31826731b5. ISSN 1532-0979. PMID 23232851. {{cite journal}}: Check date values in: |date= (help)
  53. ↑ Jhuang, Jie-Yang; Chang, Sheng-Tsung; Weng, Shih-Feng; Pan, Shien-Tung; Chu, Pei-Yi; Hsieh, Pin-Pen; Wei, Chih-Hsin; Chou, Shih-Cheng; Koo, Chiew-Loon (2015-02). "Extranodal natural killer/T-cell lymphoma, nasal type in Taiwan: a relatively higher frequency of T-cell lineage and poor survival for extranasal tumors". Human Pathology. 46 (2): 313–321. doi:10.1016/j.humpath.2014.11.008. ISSN 1532-8392. PMID 25554090. {{cite journal}}: Check date values in: |date= (help)
  54. ↑ Pongpruttipan, Tawatchai; Sukpanichnant, Sanya; Assanasen, Thamathorn; Wannakrairot, Pongsak; Boonsakan, Paisarn; Kanoksil, Wasana; Kayasut, Kanita; Mitarnun, Winyou; Khuhapinant, Archrob (2012-04). "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". The American Journal of Surgical Pathology. 36 (4): 481–499. doi:10.1097/PAS.0b013e31824433d8. ISSN 1532-0979. PMID 22314189. {{cite journal}}: Check date values in: |date= (help)
  55. ↑ Jaffe, E. S.; Chan, J. K.; Su, I. J.; Frizzera, G.; Mori, S.; Feller, A. C.; Ho, F. C. (1996-01). "Report of the Workshop on Nasal and Related Extranodal Angiocentric T/Natural Killer Cell Lymphomas. Definitions, differential diagnosis, and epidemiology". The American Journal of Surgical Pathology. 20 (1): 103–111. doi:10.1097/00000478-199601000-00012. ISSN 0147-5185. PMID 8540601. {{cite journal}}: Check date values in: |date= (help)
  56. ↑ Ohshima, K.; Suzumiya, J.; Shimazaki, K.; Kato, A.; Tanaka, T.; Kanda, M.; Kikuchi, M. (1997-11). "Nasal T/NK cell lymphomas commonly express perforin and Fas ligand: important mediators of tissue damage". Histopathology. 31 (5): 444–450. doi:10.1046/j.1365-2559.1997.2880887.x. ISSN 0309-0167. PMID 9416485. {{cite journal}}: Check date values in: |date= (help)
  57. ↑ Takata, Katsuyoshi; Hong, Min-Eui; Sitthinamsuwan, Panitta; Loong, Florence; Tan, Soo-Yong; Liau, Jau-Yu; Hsieh, Pin-Pen; Ng, Siok-Bian; Yang, Sheau-Fang (2015-01). "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". The American Journal of Surgical Pathology. 39 (1): 1–12. doi:10.1097/PAS.0000000000000312. ISSN 1532-0979. PMID 25188863. {{cite journal}}: Check date values in: |date= (help)
  58. ↑ Kuo, Tseng-Tong; Shih, Lee-Yung; Tsang, Ngan-Ming (2004-10). "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". International Journal of Surgical Pathology. 12 (4): 375–387. doi:10.1177/106689690401200410. ISSN 1066-8969. PMID 15494863. {{cite journal}}: Check date values in: |date= (help)

Notes

*Citation of this Page: King I, Dalivand MM. “Extranodal NK/T-cell lymphoma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 04/21/2026, https://ccga.io/index.php/HAEM5:Extranodal_NK/T-cell_lymphoma.


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Prior Author(s): Teodora Popa, MD, Amanda Xu, MD

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