Extranodal NK/T-cell lymphoma, nasal type: Difference between revisions

| name = Extranodal NK-T-cell lymphoma

| image = Histopathology of extranodal NK-T cell lymphoma, nasal = type.png

| pronounce =

| field = [[Hematology]] and [[Oncology]]

| symptoms =

| complications =

| onset =

| duration =
| types =

'''Extranodal NK/T-cell lymphoma, nasal type''' ('''ENKTCL-NT''') (also termed '''angiocentric lymphoma''', '''nasal-type NK lymphoma''', '''NK/T-cell lymphoma''', '''polymorphic/malignant midline reticulosis''',<ref name="Bolognia">{{cite book |author1=Rapini, Ronald P. |author2=Bolognia, Jean L. |author3=Jorizzo, Joseph L. |title=Dermatology: 2-Volume Set |publisher=Mosby |location=St. Louis |year=2007 |pages= |isbn=978-1-4160-2999-1 |oclc= |doi= |accessdate=}}</ref> and '''[[lethal midline granuloma]]'''<ref name="pmid22744721">{{cite journal | vauthors = Li DM, Lun LD | title = Mucor irregularis infection and lethal midline granuloma: a case report and review of published literature | journal = Mycopathologia | volume = 174 | issue = 5–6 | pages = 429–39 | date = December 2012 | pmid = 22744721 | doi = 10.1007/s11046-012-9559-2 | urls2cid = 14415645 }}</ref>) is a rare type of [[lymphoma]] that commonly involves midline areas of the nasal cavity, oral cavity, and/or [[pharynx]]<ref name="pmid30213402">{{cite journal | vauthors = Yamaguchi M, Oguchi M, Suzuki R | title = Extranodal NK/T-cell lymphoma: Updates in biology and management strategies | journal = Best Practice & Research. Clinical Haematology | volume = 31 | issue = 3 | pages = 315–321 | date = September 2018 | pmid = 30213402 | doi = 10.1016/j.beha.2018.07.002 | urls2cid = 52272644 }}</ref> At these sites, the disease often takes the form of massive, [[necrotic]], and extremely disfiguring lesions. However, ENKTCL-NT can also involve the eye, [[larynx]], lung, [[gastrointestinal tract]], skin, and various other tissues.<ref name="pmid24438142">{{cite journal | vauthors = Park S, Ko YH | title = Epstein-Barr virus-associated T/natural killer-cell lymphoproliferative disorders | journal = The Journal of Dermatology | volume = 41 | issue = 1 | pages = 29–39 | date = January 2014 | pmid = 24438142 | doi = 10.1111/1346-8138.12322 | urls2cid = 42534926 }}</ref> ENKTCL-NT mainly afflictsaffects adults; it is relatively common in Asia and to lesser extents Mexico, Central America, and South America but is rare in Europe and North America.<ref name="pmid28477890">{{cite journal | vauthors = Goodlad JR | title = Epstein-Barr Virus-associated Lymphoproliferative Disorders in the Skin | journal = Surgical Pathology Clinics | volume = 10 | issue = 2 | pages = 429–453 | date = June 2017 | pmid = 28477890 | doi = 10.1016/j.path.2017.01.001 | url = }}</ref> In Korea, ENKTCL-NT often involves the skin and is reported to be the most common form of cutaneous [[lymphoma]] after [[mycosis fungoides]].<ref name="Andrews">{{cite book |author1=James, William D. |author2=Berger, Timothy G. |title=Andrews' Diseases of the Skin: clinical Dermatology |publisher=Saunders Elsevier |location= |year=2006 |pages= |isbn=978-0-7216-2921-6 |oclc= |doi= |accessdate=|display-authors=etal}}</ref>

ENKTCL-NT is classified as an [[Epstein-BarrEpstein–Barr virus-associatedvirus–associated lymphoproliferative diseases|Epstein-Barr virus-associated lymphoproliferative disease]].<ref name="pmid29885408">{{cite journal | vauthors = Rezk SA, Zhao X, Weiss LM | title = Epstein -– Barr virus -– associated lymphoid proliferations, a 2018 update | journal = Human Pathology | volume = 79| issue = | pages = 18–41| date = June 2018 | pmid = 29885408 | doi = 10.1016/j.humpath.2018.05.020 | urls2cid = 47010934 }}</ref> It is due to the [[malignant transformation]] of either one of two types of [[lymphocytes]], [[NK cell]]s or a [[T cell]] variant termed [[cytotoxic T cell]]s, that are infected with the [[Epstein-BarrEpstein–Barr virus]] (EBV). Typically, the viral infection, which afflictsaffects >90% of the world population, occurs years before evidence of ENKTCL-NT, is carried in cells in a [[Infection#Subclinical versus clinical (latent versus apparent)|latent]], asymptomatic form, and for unclear reasons becomes active in causing the disease. Following the virus's activation, the infected cells acquire numerous genetic abnormalities which may play an important role in the development and/or progression of ENKTCL-NT.<ref name="pmid30125149">{{cite journal | vauthors = Farrell PJ | title = Epstein-Barr Virus and Cancer | journal = Annual Review of Pathology | volume = 14| issue = | pages = 29–53| date = August 2018 | pmid = 30125149 | doi = 10.1146/annurev-pathmechdis-012418-013023 | urls2cid = 52051261 }}</ref>

''''Epstein-Barr virus-positive nodal NK/T cell lymphoma''' (EBV+ nodal NKTCL) was considered to be one form of ENKTCL-NT since it is a malignancy of EBV-infected NK or T cells. However, EBV+ nodal NKTCL is manifested primarily by its involvement in [[lymph nodes]]; it also has clinical, pathological, pathophysiological, and genetic features that differ significantly from those of ENKTCL-NT. The [[World Health Organization]], 2016, therefore reclassified this lymphoma as a variant of a disease to which its features more closely resemble, [[peripheral T-cell lymphoma not otherwise specified]].<ref name="pmid29885408"/>

While a rare disease, particularly in North America, ENKTCL-NT has recently gained much interest. Clinical studies have found that newer [[chemotherapeutic]] regimens greatly improved survival in cases of early disease. While, survival in advanced cases is still extremely poor, generally being only a few months,<ref name="pmid29761078">{{cite journal | vauthors = Hu B, Oki Y | title = Novel Immunotherapy Options for Extranodal NK/T-Cell Lymphoma | journal = Frontiers in Oncology | volume = 8 | issue = | pages = 139 | date = 2018 | pmid = 29761078 | pmc = 5937056 | doi = 10.3389/fonc.2018.00139 | urldoi-access = free }}</ref> recent studies suggest that new regimens directed at gene mutation and expression abnormalities may improve survival.<ref name="pmid29761078"/><ref name="pmid29966370">{{cite journal | vauthors = de Mel S, Soon GS, Mok Y, Chung TH, Jeyasekharan AD, Chng WJ, Ng SB | title = The Genomics and Molecular Biology of Natural Killer/T-Cell Lymphoma: Opportunities for Translation | journal = International Journal of Molecular Sciences | volume = 19 | issue = 7 | pages = 1931| date = June 2018 | pmid = 29966370 | pmc = 6073933 | doi = 10.3390/ijms19071931 | urldoi-access = free }}</ref> Further study of these new regimens has important implications not only for ENKTCL-NT but also for other NK/T cell malignancies.

Extranodal NK/T-cell lymphoma, nasal type occurs primarily in Asians and South Americans; it is comparatively uncommon in other areas. AfflictedAffected patients (median age 50–60 years old; males predominate) most often (~80% of cases) present with nasal bleeding, upper airway obstruction, perforation of the [[hard palate]], and/or disfiguring, necrotic lesions of the nasal cavity, [[nasopharynx]] (including [[Waldeyer's tonsillar ring]]), [[paranasal sinuses]], palate,<ref name="pmid21628857">{{cite journal | vauthors = Kwong YL | title = The diagnosis and management of extranodal NK/T-cell lymphoma, nasal-type and aggressive NK-cell leukemia | journal = Journal of Clinical and Experimental Hematopathology : JCEH | volume = 51 | issue = 1 | pages = 21–8 | date = 2011 | pmid = 21628857 | doi = 10.3960/jslrt.51.21|url doi-access = free }}</ref> and/or [[Orbit (anatomy)|eye socket]].<ref name="pmid28410601"/> Less often, patients present with these findings plus signs and symptoms involving extranasal sites such as the skin, upper respiratory tract, [[gastrointestinal tract]], uterus, testes, and/or elsewhere.<ref name="pmid28893938">{{cite journal | vauthors = Shannon-Lowe C, Rickinson AB, Bell AI | title = Epstein-Barr virus-associated lymphomas | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 372 | issue = 1732 | pages = 20160271| date = October 2017 | pmid = 28893938 | pmc = 5597738 | doi = 10.1098/rstb.2016.0271 | url = }}</ref> Rarely, individuals present with evidence of involvement in the later sites without those involving the head/neck area. On further study these individuals may be found to have occult involvement in the head and neck or to develop such involvement. However, ~10 present of patients present with only skin lesions such as a solitary or multiple subcutaneous masses (which may be ulcerated) in the arms or legs<ref name="pmid28477890"/> while another ~10% present with masses in the lower [[gastrointestinal tract]] (which may be accompanied by bleeding or obstruction), salivary glands, testes, muscles, or other organs without evidence of lesions in the head/neck areas. In these cases, there is relatively little involvement of lymph nodes except as a result of direct invasiosninvasion from non-nodal sites.<ref name="pmid28410601"/> Thirty-five to forty-five percent of patients present with a history of [[malaise]], [[fever]], [[night sweat]]s, and/or [[weight loss]]. Most (70-7570–75%) patients are diagnosed with early stage I or II disease while the rest have far more serious stage III or IV disease. Rarely, patients with stage III or IV disease have evidence of a life -threatening complication, [[hemophagocytic lymphohistiocytosis]].<ref name="pmid28679966">{{cite journal | vauthors = Yamaguchi M, Miyazaki K | title = Current treatment approaches for NK/T-cell lymphoma | journal = Journal of Clinical and Experimental Hematopathology : JCEH | volume = 57 | issue = 3 | pages = 98–108 | date = December 2017 | pmid = 28679966 | pmc = 6144191 | doi = 10.3960/jslrt.17018 | url = }}</ref> Also in rare cases, patients evidence a widespread disease that includes malignant cell infiltrations in the liver, spleen, lymph nodes, bone marrow, and/or blood. These case are, or may soon progress to, a related but potentially fatal disease, [[aggressive NK-cell leukemia]].<ref name="pmid28410601"/>

About 45% of patients present with elevated levels of serum [[lactate dehydrogenase]]; elevation in this serum enzyme is a poor prognostic indicator.<ref name="pmid28679966"/> Patients with ENKTCL-NT also have elevated levels of plasma EBV [[DNA]]. Quantification of these levels at diagnosis correlates with the extent of their tumor load while serially assaying these levels during treatment gives evidence of the tumors response to treatment and residual disease.<ref name="pmid28410601"/> Rarely, patients show laboratory evidence of hemophagocytic lymphohistiocytosis such as: decreased circulating [[red blood cells]], [[leukocytes]], and/or [[platelets]]; increased serum levels of [[liver function tests|liver-derived enzymes]], [[ferritin]], and/or [[Hypertriglyceridemia|triglycerides]]; decreased serum levels of [[fibrinogen]]; and/or hemophagocytosis, i.e. engulfment of blood cells by tissue [[histiocytes]] in the liver, spleen, bone morrow, and/or other tissues.<ref name="pmid28982299">{{cite journal | vauthors = Jin Z, Wang Y, Wang J, Wu L, Pei R, Lai W, Wang Z | title = Multivariate analysis of prognosis for patients with natural killer/T cell lymphoma-associated hemophagocytic lymphohistiocytosis | journal = Hematology (Amsterdam, Netherlands) | volume = 23 | issue = 4 | pages = 228–234 | date = May 2018 | pmid = 28982299 | doi = 10.1080/10245332.2017.1385191 | urldoi-access = free }}</ref> or [[aggressive NK-cell leukemia]] (e.g. decreased circulating red blood cells, leukocytes, and/or platelets, increased circulating large, granule-containing malignant NK cells, and infiltrations of the latter cells in bone marrow and other tissues).<ref name="pmid28410601"/>

ENKTCL-NT is a disease of malignant NK or, very much less often, [[cytotoxic T cells]]. Unlike most other [[lymphoma]]s, which typically develop in and involve [[Lymphatic system#Lymphoid tissue|lymphatic tissues]] (particularly [[lymph node]]s and [[spleen]]), ENKTCL-NT commonly develops in non-lymphatic tissues. This difference in distribution probably reflects the occupancy of the [[T cell]] and [[B cell]] precursors to most lymphomas in lymphatic tissues versus the frequent occupancy of the NK and cytotoxic T cells precursors to ENTCL-NT in non-lymphatic tissues.<ref name="pmid28410601">{{cite journal | vauthors = Tse E, Kwong YL | title = The diagnosis and management of NK/T-cell lymphomas | journal = Journal of Hematology & Oncology | volume = 10 | issue = 1 | pages = 85 | date = April 2017 | pmid = 28410601 | pmc = 5391564 | doi = 10.1186/s13045-017-0452-9 | urldoi-access = free }}</ref>

ENKTCL-NT is thought to arise from the expression of EBV genes in the infected NK or cytotoxic T cells and the ability of these genes to cause the cells they infect to overexpress and acquire mutations in key genes that regulate cell growth, immortalization, invasiveness, and ability to evade normal control mechanisms, particularly [[Immune system#Tumor immunology|immune surveillance]]. Since these gene-related abnormalities are multiple and vary between patients, it is not clear which contribute to the development and/or progression of ENKTLCENKTCL-NT. Clinical studies are therefore examining [[targeted therapy]] tactics to determine which gene abnormalities contribute to, and which drugs targeting these abnormalities are useful in treating, ENKTCL-NT.<ref name="pmid30134235"/>

Infected cells carry ~10 cytosolic EBV [[Plasmid#Episomes|episomes]], i.e. gene-bearing viral [[DNA]] particles. In the premalignant precursor NK and cytotoxic T cells of ENKTCL-NT, these episomes express only some of their many latency genes, i.e. genes which promote the virus's [[viral latency|latency]] rather than [[Lytic cycle|lytic]] phase of infectivity. EBV has three different latency phases, I, II, and III, in each of which different sets of latency genes are expressed to establish different controls on the cells which they infect. In the premalignant cells of ENKTCL-NT, EBV express latency II genes such as EBNA-1, LMP-1, LMP-2A, and LMP-2B protein-producing genes; EBER-1 and EBER-2 [[non-coding RNA]]-producing genes (see [[Epstein-BarrEpstein–Barr virus#latency|EBV non-coding RNAs]]); and certain BART [[microRNA]]-producing genes (see [[Epstein-BarrEpstein–Barr virus#Protein/genes|EBV microRNAs]]). LMP1 protein induces infected cells to overexpress genes that produce [[cMyc]],<ref name="pmid29966370"/> [[NF-κB]], and [[BCL2]] proteins which when overexpressed block these cells' apoptosis (i.e. cell death) response to injury or the host's immune system and promote their survival and proliferation;<ref name="pmid29885408"/> LMP2A and LMP2B proteins induce infected cells to overexpress the genes that make [[AKT]] and [[B cell receptor]] proteins and to activate the NF-κ pathway<ref name="pmid29761078"/> which when over-activated blocks these cells' apoptosis response and promotes their survival and proliferation; EBER 1 and 2 non-coding RNAs induce infected cells to overexpress the gene that makes the [[interleukin 10]] protein which when overexpressed may promote its parent cells to proliferate and avoid the host's immune system;<ref name="pmid29885408"/> and certain BART microRNAs may help infected cells avoid attack by the hosts immune system<ref name="pmid30125149"/> and modify their [[notch signaling pathway]] thereby promoting their proliferation.<ref name="pmid29518976">{{cite journal | vauthors = Dojcinov SD, Fend F, Quintanilla-Martinez L | title = EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts | journal = Pathogens (Basel, Switzerland) | volume = 7 | issue = 1 | pages = 28| date = March 2018 | pmid = 29518976 | pmc = 5874754 | doi = 10.3390/pathogens7010028 | urldoi-access = free }}</ref> In consequence, the EBV latency II genes force infected cells to become immortal, proliferate excessively, invade tissues, and avoid attack by the hosts' [[immune system#Tumor immunology|immune system]]. Due at leaseleast in part to these imposed factors, the infected cells may acquire other genetic abnormalities that further promote their malignant behavior.<ref name="pmid28410601"/><ref name="pmid30134235">{{cite journal | vauthors = Zhang Y, Li C, Xue W, Zhang M, Li Z | title = Frequent Mutations in Natural Killer/T Cell Lymphoma | journal = Cellular Physiology and Biochemistry | volume = 49 | issue = 1 | pages = 1–16 | date = 2018 | pmid = 30134235 | doi = 10.1159/000492835 | urldoi-access = free }}</ref>

The rapidly proliferating and immortalized EBV-infected NK/T cells accumulate numerous changes in the expression or activity of their genes by acquisition of chromosome deletions, gene mutations, and changes in gene expression.{{citation needed|date=November 2021}}

===== Chromosomes =====

[[Deletion (genetics)|Deletions]] in the long (i.e. "q") arm at position 21-2521–25 (notated as 6q21-25) from one of the two [[chromosome 6]]'s was an early finding in occasional cases of ENKTCL-NT. This deletion removes one of the two copies of several [[tumor suppressor]] genes (i.e. genes that protect cells from becoming malignant) such as ''[[HACE1]], [[PRDM1]], [[FOXO3]],'' and ''[[PTPRK]].'' Subsequent studies showed that the disease is also occasionally associated with losses in the short arm of chromosome 8 at position 11.23 (8p11.23) which for unclear reasons are associated with a poor prognosis, and occasional losses at position 11l.2 in the q arm of chromosome 14 (14q11.2) which correlates with the ENKTCL-NT malignancy being of cytotoxic T cell origin.<ref name="pmid29966370"/> EBV-infected NK and T cells may also occasionally develop [[chromosome segregation]] errors during [[mitosis]] and consequently divide into daughter cells which possess too few or too many [[chromosomes]] and thereby exhibit chaotic losses or increases in the expression of the genes located on these chromosomes.<ref name="pmid29966370"/>

===== Mutated genes =====

[[DNA sequencing#High-throughput sequencing (HTS) methods|Second generation sequencing methods]] have uncovered numerous genes which are mutated in the malignant cells of ENKTCL-NT. These mutated genes and their product proteins have the following '''a)''' mutation rates in ENKTCL-NT; '''b)''' normal functions; '''c)''' [[gain of functionmutation|gains]] or [[loss of function|losses]] of activity; '''d)''' pro-malignant effects on EN/T cells and '''e)''' clinical impacts on the course of ENKTCL-NT:

| ''[[TP53]]'' || [[p53 upregulated modulator of apoptosis|p53]] || 13-6213–62% || [[tumor suppressor]] || [[gain of functionmutation|gain]] || promotes cell proliferation, survival, migration, invasiveness, and metastasis || correlates with advanced stage and poor prognosis<ref name="pmid30134235"/>

| ''[[DDX3X]]'' || DDX3X || 12-2012–20% || tumor suppressor || [[loss of function|loss]] || lost ability to inhibit proliferation || correlates with advanced stage and poor prognosis<ref name="pmid30134235"/>

| ''[[STAT3]]'' || STAT3 || 8-268–26% || [[JAK-STAT signaling pathway]] component || gain || promotes cell proliferation and survival || unknown<ref name="pmid30134235"/>

| ''[[STAT5B]]'' || STAT5B || ~2-62–6% || JAK-STAT signaling pathway component || gain || promotes cell proliferation and survival || unknown<ref name="pmid30134235"/>

| ''[[MGAJAK3]]'' || MAX dimerization proteinJAK3 || ~80–35% || tumorJAK-STAT suppressorsignaling pathway component || lossgain || unknownpromotes cell proliferation and survival || unknown<ref name="pmid30134235"/>

| ''[[MLL2Mga, max dimerization protein|MGA]]'' || MAX MLL2dimerization protein || 7-80~8% || [[histone methyltransferase]], tumor suppressor || loss || reduces [[cellular differentiation]], possibly promoting cell proliferation and survivalunknown || unknown<ref name="pmid30134235"/>

| ''[[BCL-6 corepressor|BCORMLL2]]'' || BCL-6 corepressorMLL2 || 21-327–80% || inhibits BCL-5, may regulate [[apoptosishistone methyltransferase]], tumor suppressor || loss || mayreduces increase[[cellular differentiation]], possibly promoting cell proliferation and survival || unknown<ref name="pmid30134235"/>

| ''[[ARID1A]]'' || ARID1A || 4-84–8% || a [[SWI/SNF]] protein that regulates expression of other proteins || loss || unknown || unknown<ref name="pmid30134235"/>

In the above table, ARID1A protein stands for AT-rich interactive domain-containing protein 1A and ECSIT protein stands for evolutionarily conserved signaling intermediate in Toll pathway; mitochondrial. A gain of function mutation in the ECSIT gene that changes the amino acid at the 140 position in its product protein from [[valine]] to [[alanine]] (i.e. V140A) is associated with a high incidence of ENKTCL-NT being complicated by the development of life-threatening [[Hemophagocytic lymphohistiocytosis]] and thereby a relatively high mortality rate.<ref name="pmid30213402"/> Numerous other genes are rarely (i.e. ≤2% of cases) mutated in ENKTCL-NT. These include include ''[[JAK1]], [[MLL3]], [[ARID1A]], [[EP300]], [[ASXL3]], [[Moesin|MSN]], [[FAT4]], [[NARS (gene)|NARS]], [[IL6R]], [[MGAM]], CHPF2,'' (see<ref>{{Cite web | url=https://www.ncbi.nlm.nih.gov/gene/54480 | title=CHPF2 chondroitin polymerizing factor 2 &#91;Homo sapiens (human)&#93; -– Gene -– NCBI}}</ref>) and ''MIR17HG'' ((see<ref>{{Cite web | url=https://www.ncbi.nlm.nih.gov/gene/407975 | title=MIR17HG miR-17-92a-1 cluster host gene &#91;Homo sapiens (human)&#93; -– Gene -– NCBI}}</ref>).<ref name="pmid30134235"/>

===== Overexpressed genes =====

ENKTCL-NT malignant cells overexpress [[NF-κB]], a cellular signaling [[transcription factor]] that when [[Downregulation and upregulation|up-regulated]] promotes these cells' proliferation and survival. They also overexpress: '''1)''' [[aurora kinase A]], a [[serine/threonine-specific protein kinase]] that when up-regulated in the cancer setting promotes these cells' invasiveness and to develop [[chromosome segregation]] errors during [[mitosis]] that result in daughter cells having too few or too many [[chromosome]]; '''2)''' members of the [[inhibitor of apoptosis]] family of proteins including [[survivin]],<ref name="pmid29966370"/> [[Bcl-xL]], and [[MCL1]]<ref name="pmid18778369">{{cite journal | vauthors = Yasuda H, Sugimoto K, Imai H, Isobe Y, Sasaki M, Kojima Y, Nakamura S, Oshimi K | title = Expression levels of apoptosis-related proteins and Ki-67 in nasal NK / T-cell lymphoma | journal = European Journal of Haematology | volume = 82 | issue = 1 | pages = 39–45 | date = January 2009 | pmid = 18778369 | doi = 10.1111/j.1600-0609.2008.01152.x | urldoi-access = free }}</ref> which when up-regulated suppress [[programmed cell death]] to promote these cell's survival and resistance to attack by the host immune system;<ref name="pmid28577912">{{cite journal | vauthors = Peery RC, Liu JY, Zhang JT | title = Targeting survivin for therapeutic discovery: past, present, and future promises | journal = Drug Discovery Today | volume = 22 | issue = 10 | pages = 1466–1477 | date = October 2017 | pmid = 28577912 | doi = 10.1016/j.drudis.2017.05.009 | urlhdl = 1805/15547 | hdl-access = free }}</ref><ref name="pmid29149100">{{cite journal | vauthors = Kale J, Osterlund EJ, Andrews DW | title = BCL-2 family proteins: changing partners in the dance towards death | journal = Cell Death and Differentiation | volume = 25 | issue = 1 | pages = 65–80 | date = January 2018 | pmid = 29149100 | pmc = 5729540 | doi = 10.1038/cdd.2017.186 | url = }}</ref> '''3)''' [[P-glycoprotein|multidrug resistance protein 1]], a surface membrane protein that when up-regulated causes these cells to greatly increases the export of [[anthracycline]]s such as [[Doxorubicin|Adriamycin]] and [[daunorubicin|Daunomycin]] thereby rendering them resistant to this class of [[chemotherapy]] drugs; '''4)''' EZH2, a [[histone methyltransferase]] that when up-regulated indirectly promotes these cells' growth; '''5)''' [[RUNX3|runt-related transcription factor 3]] that when up-regulated indirectly promotes the survival and proliferation of these cells;<ref name="pmid29966370"/> and '''6)''' [[programmed death-ligand 1]] (PD-L1), that when up-regulated increases the ability of these cells to avoid attack by the host's immune system.<ref name="pmid29368155">{{cite journal | vauthors = Suzuki R | title = NK/T Cell Lymphoma: Updates in Therapy | journal = Current Hematologic Malignancy Reports | volume = 13 | issue = 1 | pages = 7–12 | date = February 2018 | pmid = 29368155 | doi = 10.1007/s11899-018-0430-5 | urls2cid = 3805195 }}</ref>

=== Signaling pathways ===

Studies on cultured malignant NK cells and/or patient tissue specimens find that numerous genes are [[Methylation#Epigenetic methylation|hypermethylated]] at their [[Promoter (genetics)|promoter sites]] and therefore are [[Gene silencing|silenced]], i.e. make less or none of their protein products. This silencing has been detected in numerous proteins expressed by cultured NK cells (e.g. ''[[BCL2L11]], [[DAPK1]], [[PTPN6]], [[TET2]], [[SOCS6]], [[PRDM1]], [[AIM1]], [[HACE]], [[CDKN2B|p15]], [[p16]], [[p73]], [[MLH1]], [[Retinoic acid receptor beta|RARB]], and [[ASNS]]'') and the ''MIR146A'' gene for its miR-146a [[microRNA]] product. Studies conducted on the expression of microRNAs in cultured malignant NK cells have also revealed that many are either over- or under-expressed compared to non-malignant cultured NK cells. This dysregulation of thsethese microRNA genes may reflect the action of products expressed by certain EBV genes and/or the overexpression of the infected cells' ''MYC'' gene. In all cases, the epigenetic dysregulation of these genes requires further study to determine its significance for the development and progression of ENKTCL-NT.<ref name="pmid29966370"/>

On microscopic examination, involved tissues show commonly show areas of [[necrosis]] and cellular infiltrates that are centered around and often injure or destroy small blood vessels. The infiltrates contain large granule-containing lymphocytes that express cell surface [[CD2]], [[T-cell surface glycoprotein CD3 epsilon chain|cytoplasmic CD3ε]], and cell surface [[Neural cell adhesion molecule|CD56]] as well the cytotoplasmiccytoplasmic intracellular proteins, [[perforin]], [[granzyme B]], and T cell intracellular antigen-1 (TIA-1). These cells exhibit evidence of EBV infection as determined by ''[[In situ hybridization|''in situ hybridization]]'' assays to detect one of the virus's latent products, typically EBER-1/2 micoRNAs.<ref name="pmid28410601"/> Identification of the genetic abnormalities cited above in the cells may be of help in establishing the diagnoses and be of use for selecting novel therapeutic approaches to individual patients.<ref name="pmid29966370"/> Non-malignant inflammatory [[white blood cells]], including [[eosinophil]]s, are also commonly found in these infiltrates.<ref name="pmid28410601"/>

The diagnosis of ENKTCL-NT depends on histological findings that biopsied tissue infiltrates contain lymphocytes that express CD3ε, cytotoxic molecules (granzyme B, perforin, TIA1), and EBV.<ref name="pmid29966370"/> [[Bone marrow examination]] is recommended to determine its involvement in this disorder. Whole body [[PET-CT]] scans are recommended to determine the extent of disease at presentation as well as to follow the effects of therapeutic interventions. The tumor load of each individual's disease as well as response to therapies has also been estimated by assaying plasma levels of EBV DNA.<ref name="pmid28410601"/> ENKTCL-NT can be mimicked by two benign diseases which involve the excessive proliferation of non-malignant NK cells in the GI tract viz., [[Natural killer cell enteropathy]], a disease wherein NK cell infiltrative lesions occur in the intestine, colon, stomach, and/or esophagus, and [[Natural killer cell enteropathy|lymphomatoid gastropathy]], a disease wherein these cells infiltrative lesions are limited to the stomach.<ref name="pmid30212873">{{cite journal | vauthors = Xia D, Morgan EA, Berger D, Pinkus GS, Ferry JA, Zukerberg LR|author4-link=Geraldine Pinkus | title = NK-Cell Enteropathy and Similar Indolent Lymphoproliferative Disorders: A Case Series With Literature Review | journal = American Journal of Clinical Pathology | volume = 151 | issue = 1 | pages = 75–85 | date = January 2019 | pmid = 30212873 | doi = 10.1093/ajcp/aqy108 | urldoi-access = free }}</ref> FindingsAnother thatlymphoproliferative differentiatedisorder theseof benignthe diseasesGI fromtract, [[indolent T cell lymphoproliferative disorder of the gastrointestinal tract]] may also mimic ENKTCL-NT. areThis givenchronic disorder involves the proliferation of CD+4, CD8+, CD4-/CD8-, or CD4+/CD8+ T cells in theirthe Wikipediamucosal layers of the GI tract to give a variety of GI tract symptoms. While generally a persistent and benign disorder, a small but significant percentage of cases have progressed to aggressive [[lymphoma]]s.<ref name="pmid27353398">{{cite journal | vauthors = Matnani R, Ganapathi KA, Lewis SK, Green PH, Alobeid B, Bhagat G | title = Indolent T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract: a review and update | journal = Hematological Oncology | volume = 35 | issue = 1 | pages = 3–16 | date = March 2017 | pmid = 27353398 | doi = 10.1002/hon.2317 | s2cid = 21364706 | doi-access = free }}</ref><ref name="pmid29592893">{{cite journal | vauthors = Sharma A, Oishi N, Boddicker RL, Hu G, Benson HK, Ketterling RP, Greipp PT, Knutson DL, Kloft-Nelson SM, He R, Eckloff BW, Jen J, Nair AA, Davila JI, Dasari S, Lazaridis KN, Bennani NN, Wu TT, Nowakowski GS, Murray JA, Feldman AL | title = Recurrent STAT3-JAK2 fusions in indolent T-cell lymphoproliferative disorder of the gastrointestinal tract | journal = Blood | volume = 131 | issue = 20 | pages = 2262–2266 | date = May 2018 | pmid = 29592893 | pmc = 5958657 | doi = 10.1182/blood-2018-01-830968 }}</ref> The disease may be incidentally diagnosed upon histopathology os sinus contents removed from [[sinusitis]] surgery.

== Course of ENKTCL-NT ==

The course of the untreated disease is heavily dependent on its clinical stage at diagnosis. Patients presenting with highly localized stage I nasal disease usually have nasal but no other symptoms; these individuals commonly show no progression of their disease over long periods of time. Other patients with limited (i.e. stage I or II) disease involving other sites in the head area are more likely to sufferhave a relatively slow progression of their disease while patients with stage III or IV disease have a more rapidly progressive disease with a poor prognosis. Patients presenting with ENKTCL-NT that does not involve the head area typically have a disseminated and aggressively progressive disease with a very poor prognosis.<ref name="pmid21628857"/> Patients with stage I or II localized disease that have been treated with the recently defined chemotherapeutic protocols have 5 year survivals of ~70-8970–89%<ref name="pmid29761078"/> while those with advanced stage III or IV disseminated disease treated with these protocols have 5 year survivals of 50%.<ref name="pmid29368155"/> Patients who relapse or are resistant to these protocols have had overall survivals of just a few months.<ref name="pmid29761078"/>

Three prognostic models, NK-PI, PINK (i.e. prognostic index of natural killer lymphomas), and PINK-E) for ENKTCL-NT have evolved over the past 12 years. The latest model, PINK-E, which applies to patients treated with recently defined regimens, lists 5 risk factors (age >60, state III or IV disease, no nasal involvement, distant lymph node involvement, and detectable blood levels of EBV DNA) to define patients as low, intermediate, and high risk based on their having 0-10–1, 2, or 3-53–5 risk factors, respectively. Overall 3 year survival in these 3 respective groups were 81, 55, and 28%.<ref name="pmid29368155"/> Patients, particularly those in the advanced poor risk groups may develop hemophagocytic lymphohistiocytosis or have their disease progress to aggressive NK-cell leukemia. Both conditions are life-threatening and far less responsive to treatment.<ref name="pmid28410601"/>

The treatment of ENKTCL- NT employs [[chemotherapy]] plus, where indicated, [[radiotherapy]]. Early chemotherapies relied on [[CHOP (chemotherapy)|CHOP]] (i.e. [[cyclophosphamide]], an [[anthracycline]] (primarily [[adriamycin]]), [[vincristine]], and [[prednisolone]]) or chop-like regimens. These were only marginally successful because, as it was latterlater discovered, the malignant NK cells in ENKTCL-NT over-express [[P-glycoprotein|multidrug resistance protein 1]]. This protein exports various molecules, including antracyclines[[anthracycline]]s and [[vincristine]], from its parent cells and thereby renders these cells resistant to [[adriamycin]]<ref name="pmid28410601"/> and vincristine<ref name="pmid21143116">{{cite journal | vauthors = He SM, Li R, Kanwar JR, Zhou SF | title = Structural and functional properties of human multidrug resistance protein 1 (MRP1/ABCC1) | journal = Current Medicinal Chemistry | volume = 18 | issue = 3 | pages = 439–81 | date = 2011 | pmid = 21143116 | doi = 10.2174/092986711794839197| url = }}</ref> and therefore to CHOP and CHOP-like regimens.<ref name="pmid28410601"/> Subsequent studies discovered that [[Asparaginase|L-asparaginase]]<ref name="pmid28410601"/> (NK cells do not express L-asaraginase<ref name="pmid29761078"/>) and, to a lesser extent, [[Platinum-based antineoplastic|platinum-based antineoplastic drugs]] (e.g.carboplatin)<ref name="pmid28679966"/> were active on theses cells. Accordingly, several chemotherapeutic regimens were tested and found to give much better results than previous regimens. However, these regimens have bot undergone [[Clinical trials#phases|phase 3 clinical trials]] that examine their effectiveness relative to other regimens. The following regimens are recommended by many studies and the [[European Society for Medical Oncology]] Clinical Practice guidelines<ref name="pmid28679966"/> or [[National Comprehensive Cancer Network]]:<ref name=NCCN>add NCCN ref</ref>

* [[Epstein-BarrEpstein–Barr virus-associatedvirus–associated lymphoproliferative diseases#Extranodal NK/T cell lymphoma, nasal type|Epstein-Barr virus-associated extranodal NK/T cell lymphoma, nasal type]]

| DiseasesDB =

| ICD10 = {{ICD10|C|86.0}}

| ICD9 =

| ICDO = {{ICDO|9719|3}}

| OMIM =

| MedlinePlus =

| eMedicineSubj =

| eMedicineTopic =

| MeshID = D054391

[[Category:Epstein–Barr virus-associatedvirus–associated diseases]]