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{{Infobox_Disease |
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  Image          = |
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  DiseasesDB    = |
  ICD10          = |
  ICD9          = |
  ICDO          = 9948/3 |
  OMIM          = |
  MedlinePlus    = |
  eMedicineSubj  = ent |
  eMedicineTopic = 776 |
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{{SI}}
{{CMG}}
__NOTOC__
__NOTOC__
 
{{SI}}                                                                 
 
{{CMG}} {{AE}} {{Sahar}} {{MV}}<br>
'''Synonyms and related key words''': Aggressive Natural Killer cell leukemia
{{SK}} ANKL
 
==Overview==
==Overview==
 
Aggressive NK-cell leukemia is a [[disease]] with an aggressive, systemic proliferation of [[natural killer cells|natural killer cells (NK cells)]] and a rapidly declining clinical course. There is no [[classification]] system for aggressive NK-cell leukemia. The [[pathogenesis]] of aggressive NK-cell leukemia is characterized by the proliferation of [[Natural killer cell|natural killer cells]]. Aggressive NK-cell leukemia is very uncommon, and is most commonly seen among middle aged adults.  The most common [[Risk factor|risk factors]] in the development of aggressive NK-cell leukemia is the [[Epstein-Barr virus|Epstein-Barr virus (EBV)]] [[infection]]. The majority of [[Patient|patients]] with aggressive NK-cell leukemia are [[symptomatic]] at [[diagnosis]]. Early clinical features include [[fatigue]], [[Night sweat|night sweats]], and [[fever]]. [[Physical examination]] among [[Patient|patients]] with aggressive NK-cell leukemia may be remarkable for [[hepatosplenomegaly]]. Aggressive NK-cell leukemia may also be [[Diagnosis|diagnosed]] using [[bone marrow biopsy]], findings of which can include extensive [[marrow]] replacement by [[Leukemia|leukemic]] [[Cell (biology)|cells]] and reactive [[Histiocyte|histiocytes]] displaying [[hemophagocytosis]]. The mainstay of [[therapy]] for aggressive NK-cell leukemia is [[anthracycline]]-containing [[chemotherapy]].
'''Aggressive NK-cell leukemia''' is a disease with an aggressive, systemic proliferation of [[natural killer cells]] (NK cells) and a rapidly declining clinical course.<ref name="cha1">
== Historical Perspective ==
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9192774&query_hl=4&itool=pubmed_ExternalLink]
*In 1986, Dr. Fernandez and his colleagues reported the first case of aggressive NK-cell leukemia.<ref name="pmid3955237">{{cite journal |vauthors=Fernandez LA, Pope B, Lee C, Zayed E |title=Aggressive natural killer cell leukemia in an adult with establishment of an NK cell line |journal=Blood |volume=67 |issue=4 |pages=925–30 |date=April 1986 |pmid=3955237 |doi= |url=}}</ref>
Chan JK, Sin VC, Wong KF, Ng CS, Tsang WY, Chan CH, Cheung MM, Lau WH. "Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm." '''Blood'''. 1997 Jun 15;89(12):4501-13. PMID 9192774</ref><ref name="ima1">
*In 1989, Dr. Kawa and his colleagues first reported the [[association]] between [[EBV]] virus and aggressive NK-cell leukemia.<ref name="Kawa-HaIshihara1989">{{cite journal|last1=Kawa-Ha|first1=K|last2=Ishihara|first2=S|last3=Ninomiya|first3=T|last4=Yumura-Yagi|first4=K|last5=Hara|first5=J|last6=Murayama|first6=F|last7=Tawa|first7=A|last8=Hirai|first8=K|title=CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein-Barr viral DNA.|journal=Journal of Clinical Investigation|volume=84|issue=1|year=1989|pages=51–55|issn=0021-9738|doi=10.1172/JCI114168}}</ref>
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=2375924&query_hl=6&itool=pubmed_ExternalLink]
== Classification ==
Imamura N, Kusunoki Y, Kawa-Ha K, Yumura K, Hara J, Oda K, Abe K, Dohy H, Inada T, Kajihara H, ''et al''. "Aggressive natural killer cell leukaemia/lymphoma: report of four cases and review of the literature. Possible existence of a new clinical entity originating from the third lineage of lymphoid cells." '''Br J Haematol'''. 1990 May;75(1):49-59. PMID 2375924</ref><ref name="cha2">
*There is no [[classification]] system for aggressive NK-cell leukemia.
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10389582&query_hl=10&itool=pubmed_ExternalLink]
*This [[disorder]] is [[Classification|classified]] as a large granular [[lymphocyte]] (LGL) leukemia according to third WHO [[classification]].<ref name="Ishida2018">{{cite journal|last1=Ishida|first1=Fumihiro|title=Aggressive NK-Cell Leukemia|journal=Frontiers in Pediatrics|volume=6|year=2018|issn=2296-2360|doi=10.3389/fped.2018.00292}}</ref>
==Pathophysiology==
*The [[pathogenesis]] of aggressive NK-cell leukemia is characterized by the aggressive, systemic proliferation of [[Natural killer cell|natural killer cells]].
*Although the exact association of [[EBV]] and aggressive NK-cell leukemia remain to be cleared, [[EBV]] has been suggested to play a role in its [[pathogenesis]].<ref name="SiuWong1999">{{cite journal|last1=Siu|first1=Lisa L.P.|last2=Wong|first2=Kit-Fai|last3=Chan|first3=John K.C.|last4=Kwong|first4=Yok-Lam|title=Comparative Genomic Hybridization Analysis of Natural Killer Cell Lymphoma/Leukemia|journal=The American Journal of Pathology|volume=155|issue=5|year=1999|pages=1419–1425|issn=00029440|doi=10.1016/S0002-9440(10)65454-5}}</ref>
*On [[microscopic]] [[Histopathology|histopathological]] analysis, characteristic findings of aggressive NK-cell leukemia include large [[Cell (biology)|cells]] with abundant blue [[cytoplasm]], [[azurophilic granules]], irregular [[Cell nucleus|nuclei]], open [[chromatin]], and distinct [[Nucleolus|nucleoli]].<ref name="cha2">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10389582&query_hl=10&itool=pubmed_ExternalLink]
Chan JK. "Natural killer cell neoplasms." '''Anat Pathol'''. 1998;3:77-145. PMID 10389582</ref>
*[[CD11b]] and [[CD16]] show variable expression in aggressive NK-cell leukemia.
*The table below demonstrates the [[Immunophenotyping|immunophenotype]] for [[Patient|patients]] with aggressive NK-cell leukemia.<ref name="cha2">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10389582&query_hl=10&itool=pubmed_ExternalLink]
Chan JK. "Natural killer cell neoplasms." '''Anat Pathol'''. 1998;3:77-145. PMID 10389582</ref>
Chan JK. "Natural killer cell neoplasms." '''Anat Pathol'''. 1998;3:77-145. PMID 10389582</ref>
 
::{| border="1" cellpadding="5" cellspacing="0"
It is also called ''aggressive NK-cell lymphoma'', or ''large granular lymphocyte leukemia, NK-cell type''<ref name="who1">[http://www.iarc.fr/WHO-BlueBooks/BBwebsite/bb3.html] Jaffe E.S., Harris N.L., Stein H., Vardiman J.W. (eds): '''World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of Haemopoietic and Lymphoid Tissues.''' IARC Press: Lyon 2001 </ref>
 
===Synonyms===
Aggressive NK-cell leukemia/lymphoma, large granular lymphocyte leukemia, NK-cell type<ref name="who1">[http://www.iarc.fr/WHO-BlueBooks/BBwebsite/bb3.html] Jaffe E.S., Harris N.L., Stein H., Vardiman J.W. (eds): '''World Health Organization Classification of Tumors. Pathology and Genetics of Tumours of Haemopoietic and Lymphoid Tissues.''' IARC Press: Lyon 2001 </ref>
 
===ICD-O code===
9948/3<ref name="who1"/>
 
===Definition===
'''Aggressive NK-cell leukemia''' is a disease with an aggressive, systemic proliferation of [[natural killer cells]] (NK cells) and a rapidly declining clinical course.<ref name="cha1">
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9192774&query_hl=4&itool=pubmed_ExternalLink]
Chan JK, Sin VC, Wong KF, Ng CS, Tsang WY, Chan CH, Cheung MM, Lau WH. "Nonnasal lymphoma expressing the natural killer cell marker CD56: a clinicopathologic study of 49 cases of an uncommon aggressive neoplasm." '''Blood'''. 1997 Jun 15;89(12):4501-13. PMID: 9192774</ref><ref name="ima1">
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=2375924&query_hl=6&itool=pubmed_ExternalLink]
Imamura N, Kusunoki Y, Kawa-Ha K, Yumura K, Hara J, Oda K, Abe K, Dohy H, Inada T, Kajihara H, ''et al''. "Aggressive natural killer cell leukaemia/lymphoma: report of four cases and review of the literature. Possible existence of a new clinical entity originating from the third lineage of lymphoid cells." '''Br J Haematol'''. 1990 May;75(1):49-59. PMID: 2375924</ref><ref name="cha2">
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10389582&query_hl=10&itool=pubmed_ExternalLink]
Chan JK. "Natural killer cell neoplasms." '''Anat Pathol'''. 1998;3:77-145. PMID: 10389582</ref>
 
==Epidemiology==
This rare form a leukemia is more common among Asians in comparison to other ethnic groups. It is typically diagnosed in adolescents and young adults, with a slight predominance in males.<ref name="cha1"/><ref name="ima1"/><ref name="cha2"/><ref name="kwo1">
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=7817949&query_hl=18&itool=pubmed_ExternalLink]
Kwong YL, Wong KF, Chan LC, Liang RH, Chan JK, Lin CK, Chan TK. "Large granular lymphocyte leukemia. A study of nine cases in a Chinese population." '''Am J Clin Pathol'''. 1995 Jan;103(1):76-81. PMID: 7817949</ref><ref name="kwo2">
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9375032&query_hl=22&itool=pubmed_ExternalLink]
Kwong YL, Chan AC, Liang RH. "Natural killer cell lymphoma/leukemia: pathology and treatment."  '''Hematol Oncol'''. 1997 May;15(2):71-9. PMID: 9375032</ref><ref name="gel1">
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8088773&query_hl=24&itool=pubmed_ExternalLink]
Gelb AB, van de Rijn M, Regula DP Jr, Cornbleet JP, Kamel OW, Horoupian DS, Cleary ML, Warnke RA. "Epstein-Barr virus-associated natural killer-large granular lymphocyte leukemia." '''Hum Pathol'''. 1994 Sep;25(9):953-60. PMID: 8088773</ref><ref name="osh1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8762811&query_hl=26&itool=pubmed_ExternalLink]
Oshimi K. "Lymphoproliferative disorders of natural killer cells." '''Int J Hematol.''' 1996 Jun;63(4):279-90. PMID: 8762811</ref>
 
==Clinical features==
 
===Etiology===
This disease has a strong association with the [[Epstein-Barr virus]] (EBV)<ref name="gel1"/>, but the true pathogenesis of this disease has yet to be described. The cell of origin is believed to be an [[NK cell]].<ref name="who1"/> Blastoid NK cell lymphoma appears to be a different entity and shows no association with EBV.<ref name="cha1"/>
 
===Presentation===
Patients usually present with constitutional symptoms ([[malaise]], [[weight loss]], [[fatigue (medical)|fatigue]]), and [[hepatosplenomegaly]] is commonly found on physical exam. [[Lymphadenopathy]] is also found to a lesser extent. Due to the aggressive nature of the disease, patients may initially present at a more advanced stage, with [[coagulopathies]], hemophagocytic syndrome, and multi-organ failure.<ref name="cha1"/><ref name="ima1"/><ref name="kwo1"/><ref name="kob1">
[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=8854571&query_hl=29&itool=pubmed_ExternalLink]
Kobayashi Y, Uehara S, Inamori K, Shirato R, Ozawa K, Sklar J, Asano S. "Hemophagocytosis as a para-neoplastic syndrome in NK cell leukemia." '''Int J Hematol'''. 1996 Aug;64(2):135-42. PMID: 8854571</ref><ref name="oku1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=1746541&query_hl=31&itool=pubmed_ExternalLink]
Okuda T, Sakamoto S, Deguchi T, Misawa S, Kashima K, Yoshihara T, Ikushima S, Hibi S, Imashuku S. "Hemophagocytic syndrome associated with aggressive natural killer cell leukemia." '''Am J Hematol'''. 1991 Dec;38(4):321-3. PMID: 1746541</ref>
 
===Laboratory findings===
Leukemic cells are invariably present in samples of peripheral [[blood]] to a variable extent. [[Pancytopenia]] ([[anemia]], [[neutropenia]], [[thrombocytopenia]]) is commonly seen as well.<ref name="who1"/> 
 
===Sites of involvement===
This disease is typically found and diagnosed in peripheral [[blood]], and while it can involve any organ, it is usually found in the [[spleen]], [[liver]], and [[bone marrow]].<ref name="who1"/>
 
==Morphology==
 
===Peripheral blood===
The leukemic cells have a diameter mildly greater than a [[large granular lymphocyte]] (LGL) and have azurophilic granules and nucleoli of varying prominence. Nuclei may be irregular and hyperchromatic.<ref name="who1"/>
 
===Bone marrow===
Bone marrow involvement runs the spectrum between an inconspicuous infiltrate to extensive marrow replacement by leukemic cells. Reactive [[histiocytes]] displaying [[hemophagocytosis]] can been seen interspersed in the [[neoplastic]] infiltrate.<ref name="who1"/>
 
===Other organs===
Leukemic involvement of organs is typically destructive on tissue sections with necrosis and possibly angioinvasion, and the monotonous infiltrate may be diffuse or patchy.<ref name="who1"/> 
 
==Molecular findings==
 
===Immunophenotype===
The immunophenotype of this disease is the same as extranodal NK/T-cell lymphoma, nasal type and is shown in the table below. [[CD11b]] and [[CD16]] show variable expression.<ref name = "cha1"/><ref name="osh1"/>
 
{| border="1" cellpadding="5" cellspacing="0"
|-
|-
| rowspan="1"| '''Status'''
| rowspan="1" | '''Status'''
| colspan="1" align="center"| '''Antigens'''
| colspan="1" align="center" | '''Antigens'''
|-
|-
| rowspan="1"| Positive
| rowspan="1" | Positive
| colspan="1" align="center"| [[CD2]], [[CD3ε]], [[CD56]], [[perforin]], [[granzyme B]], [[TIA-1]]
| colspan="1" align="center" | [[CD2]], [[CD3ε]], [[CD56]], [[perforin]], [[granzyme B]], [[TIA-1]], [[CCR5]]
|-
|-
| rowspan="1"| Negative
| rowspan="1" | Negative
| colspan="1" align="center"| [[CD57]]
| colspan="1" align="center" |[[CD57]]
|-
|-
|}
|}


===Genetic findings===
==Causes==
Due to the [[myeloid]] lineage, clonal rearrangements of [[lymphoid]] (T cell receptor; B cell receptor) genes are not seen.<ref name="who1"/> The genome of the [[Epstein Barr virus]] (EBV) is detected in many cases<ref name="gel1"/>, along with a variety of chromosomal abnormalities.<ref name="won1">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10439361&query_hl=38&itool=pubmed_ExternalLink]
* There are no established causes for aggressive NK-cell leukemia.
Wong KF, Zhang YM, Chan JK. "Cytogenetic abnormalities in natural killer cell lymphoma/leukaemia--is there a consistent pattern?" '''Leuk Lymphoma'''. 1999 Jul;34(3-4):241-50. PMID: 10439361</ref>
==Differentiating Aggressive NK-cell Leukemia from Other Diseases==
* Aggressive NK-cell leukemia must be differentiated from other [[Disease|diseases]] that cause [[fever]], [[fatigue]], and [[lymphadenopathy]] such as [[human Immunodeficiency Virus (HIV)|Human immunodeficiency virus]], [[chronic neutrophilic leukemia]], and [[juvenile myelomonocytic leukemia]].
* Aggressive NK-cell leukemia should also be differentiated from other lymphoprolierative [[disorders]] originating from [[natural killer cells]] including extranodal NK/T cell lymphoma, nasal type (NKTCL) and [[chronic lymphoproliferative disorder of NK cells]] (CLPD-NK).<ref>{{cite book | last = Swerdlow | first = Steven | title = WHO classification of tumours of haematopoietic and lymphoid tissues | publisher = International Agency for Research on Cancer | location = Lyon | year = 2017 | isbn = 9789283244943 }}</ref>
==Epidemiology and Demographics==
* Aggressive NK-cell leukemia is a rare [[disorder]].<ref name="SuzukiSuzumiya2004">{{cite journal|last1=Suzuki|first1=R|last2=Suzumiya|first2=J|last3=Nakamura|first3=S|last4=Aoki|first4=S|last5=Notoya|first5=A|last6=Ozaki|first6=S|last7=Gondo|first7=H|last8=Hino|first8=N|last9=Mori|first9=H|last10=Sugimori|first10=H|last11=Kawa|first11=K|last12=Oshimi|first12=K|title=Aggressive natural killer-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells|journal=Leukemia|volume=18|issue=4|year=2004|pages=763–770|issn=0887-6924|doi=10.1038/sj.leu.2403262}}</ref><ref name="pmid29263371">{{cite journal |vauthors=Tang YT, Wang D, Luo H, Xiao M, Zhou HS, Liu D, Ling SP, Wang N, Hu XL, Luo Y, Mao X, Ao QL, Huang J, Zhang W, Sheng LS, Zhu LJ, Shang Z, Gao LL, Zhang PL, Zhou M, Zhou KG, Qiu LG, Liu QF, Zhang HY, Li JY, Jin J, Fu L, Zhao WL, Chen JP, Du X, Huang G, Wang QF, Zhou JF, Huang L |title=Aggressive NK-cell leukemia: clinical subtypes, molecular features, and treatment outcomes |journal=Blood Cancer J |volume=7 |issue=12 |pages=660 |date=December 2017 |pmid=29263371 |pmc=5802497 |doi=10.1038/s41408-017-0021-z |url=}}</ref>
* Aggressive NK-cell leukemia is more commonly observed among young adults with median age of 42 years old.
* Aggressive NK-cell leukemia affects men more frequently than women.
* Aggressive NK-cell leukemia usually affects individuals of the Asian [[race]].<ref name="Lima2013">{{cite journal|last1=Lima|first1=Margarida|title=Aggressive mature natural killer cell neoplasms: from epidemiology to diagnosis|journal=Orphanet Journal of Rare Diseases|volume=8|issue=1|year=2013|pages=95|issn=1750-1172|doi=10.1186/1750-1172-8-95}}</ref>
== Risk Factors ==
* Common [[Risk factor|risk factors]] in the development of aggressive NK-cell leukemia include [[Epstein-Barr virus|Epstein-Barr virus (EBV)]] [[infection]]<ref name="SuzukiSuzumiya2004">{{cite journal|last1=Suzuki|first1=R|last2=Suzumiya|first2=J|last3=Nakamura|first3=S|last4=Aoki|first4=S|last5=Notoya|first5=A|last6=Ozaki|first6=S|last7=Gondo|first7=H|last8=Hino|first8=N|last9=Mori|first9=H|last10=Sugimori|first10=H|last11=Kawa|first11=K|last12=Oshimi|first12=K|title=Aggressive natural killer-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells|journal=Leukemia|volume=18|issue=4|year=2004|pages=763–770|issn=0887-6924|doi=10.1038/sj.leu.2403262}}</ref><ref name="Kawa-HaIshihara1989">{{cite journal|last1=Kawa-Ha|first1=K|last2=Ishihara|first2=S|last3=Ninomiya|first3=T|last4=Yumura-Yagi|first4=K|last5=Hara|first5=J|last6=Murayama|first6=F|last7=Tawa|first7=A|last8=Hirai|first8=K|title=CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein-Barr viral DNA.|journal=Journal of Clinical Investigation|volume=84|issue=1|year=1989|pages=51–55|issn=0021-9738|doi=10.1172/JCI114168}}</ref>
== Screening ==
*There is insufficient evidence to recommend routine [[screening]] for aggressive NK-cell leukemia.
== Natural History, Complications, and Prognosis==
*The majority of [[Patient|patients]] with aggressive NK-cell leukemia are [[symptomatic]] at the time of [[diagnosis]].<ref name="Lima2013">{{cite journal|last1=Lima|first1=Margarida|title=Aggressive mature natural killer cell neoplasms: from epidemiology to diagnosis|journal=Orphanet Journal of Rare Diseases|volume=8|issue=1|year=2013|pages=95|issn=1750-1172|doi=10.1186/1750-1172-8-95}}</ref>
*Early clinical features include [[fatigue]], [[night sweats]], and [[fever]].
*If left untreated, [[Patient|patients]] with aggressive NK-cell leukemia may progress to develop recurrent [[Infection|infections]].
*Common [[complications]] of aggressive NK-cell leukemia, include [[coagulopathy|Coagulopathies]], [[hemophagocytic syndrome]], [[multiple organ failure]], and [[myelofibrosis]].<ref name="LiTian2014">{{cite journal|last1=Li|first1=Chunrui|last2=Tian|first2=Ye|last3=Wang|first3=Jue|last4=Zhu|first4=Li|last5=Huang|first5=Liang|last6=Wang|first6=Na|last7=Xu|first7=Danmei|last8=Cao|first8=Yang|last9=Li|first9=Jianyong|last10=Zhou|first10=Jianfeng|title=Abnormal immunophenotype provides a key diagnostic marker: a report of 29 cases of de novo aggressive natural killer cell leukemia|journal=Translational Research|volume=163|issue=6|year=2014|pages=565–577|issn=19315244|doi=10.1016/j.trsl.2014.01.010}}</ref>
*[[Prognosis]] is generally poor, and the [[median]] [[survival rate]] of [[patients]] with aggressive NK-cell leukemia is few months.
== Diagnosis ==
=== Staging ===
* The table below shows the staging system for aggressive NK-cell leukemia according to the Ann Arbor [[staging]] system.<ref name="ListerCrowther1989">{{cite journal|last1=Lister|first1=T A|last2=Crowther|first2=D|last3=Sutcliffe|first3=S B|last4=Glatstein|first4=E|last5=Canellos|first5=G P|last6=Young|first6=R C|last7=Rosenberg|first7=S A|last8=Coltman|first8=C A|last9=Tubiana|first9=M|title=Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting.|journal=Journal of Clinical Oncology|volume=7|issue=11|year=1989|pages=1630–1636|issn=0732-183X|doi=10.1200/JCO.1989.7.11.1630}}</ref>
{| class="wikitable"
|+
|-
| style="background: #4479BA; width: 100px;" align="center"| {{fontcolor|#FFF|'''Stage'''}}
| style="background: #4479BA; width: 350px;" align="center"| {{fontcolor|#FFF|'''Staging Criteria'''}}
|-
|Stage I
|
* Confined to one [[lymph node]]
|-
|Stage II
|
* Confined to more than one [[lymph node]]
*On one side of the [[diaphragm]]
|-
|Stage III
|
* Confined to lymphatic tissue or [[spleen]]
* On both sides of the [[diaphragm]]


==Current articles==
*
|-
|Stage IV


*[http://scholar.google.com/scholar?q=Aggressive+NK-cell+leukemia&hl=en&lr=&scoring=r&as_ylo=2002 Google Scholar]
*
|
* [[Bone marrow]] or [[liver]]/ extranodal involvement with widespread involvement
|}
=== Symptoms ===
*Symptoms of aggressive NK-cell leukemia may include [[fever]], swelling in the [[Lymph node|lymph nodes]] in the [[neck]], [[night sweats]], persistent [[fatigue]], [[anorexia|Loss of appetite]], [[weight loss]], [[nausea]], [[vomiting]], [[icterus|Yellow discoloration of the sclera]], and [[hepatosplenomegaly|Enlarged liver or spleen]].<ref name="pmid12495907">{{cite journal |vauthors=Song SY, Kim WS, Ko YH, Kim K, Lee MH, Park K |title=Aggressive natural killer cell leukemia: clinical features and treatment outcome |journal=Haematologica |volume=87 |issue=12 |pages=1343–5 |date=December 2002 |pmid=12495907 |doi= |url=}}</ref><ref name="pmid2846089">{{cite journal |vauthors=Sheridan W, Winton EF, Chan WC, Gordon DS, Vogler WR, Phillips C, Bongiovanni KF, Waldmann TA |title=Leukemia of non-T lineage natural killer cells |journal=Blood |volume=72 |issue=5 |pages=1701–7 |date=November 1988 |pmid=2846089 |doi= |url=}}</ref>
=== Physical Examination ===
*[[Patients]] with aggressive NK-cell leukemia usually appear [[icteric]] and malnourished.<ref name="LiTian2014">{{cite journal|last1=Li|first1=Chunrui|last2=Tian|first2=Ye|last3=Wang|first3=Jue|last4=Zhu|first4=Li|last5=Huang|first5=Liang|last6=Wang|first6=Na|last7=Xu|first7=Danmei|last8=Cao|first8=Yang|last9=Li|first9=Jianyong|last10=Zhou|first10=Jianfeng|title=Abnormal immunophenotype provides a key diagnostic marker: a report of 29 cases of de novo aggressive natural killer cell leukemia|journal=Translational Research|volume=163|issue=6|year=2014|pages=565–577|issn=19315244|doi=10.1016/j.trsl.2014.01.010}}</ref><ref name="Lima2013">{{cite journal|last1=Lima|first1=Margarida|title=Aggressive mature natural killer cell neoplasms: from epidemiology to diagnosis|journal=Orphanet Journal of Rare Diseases|volume=8|issue=1|year=2013|pages=95|issn=1750-1172|doi=10.1186/1750-1172-8-95}}</ref>
*Physical examination may be remarkable for [[fever]], [[icterus]], [[hepatosplenomegaly]], and [[lymphadenopathy]].
=== Laboratory Findings ===
*Laboratory findings consistent with the [[diagnosis]] of aggressive NK-cell leukemia include:<ref name="NazarullahDon2016">{{cite journal|last1=Nazarullah|first1=Alia|last2=Don|first2=Michelle|last3=Linhares|first3=Yuliya|last4=Alkan|first4=Serhan|last5=Huang|first5=Qin|title=Aggressive NK-cell leukemia: A rare entity with diagnostic and therapeutic challenge|journal=Human Pathology: Case Reports|volume=4|year=2016|pages=32–37|issn=22143300|doi=10.1016/j.ehpc.2015.08.001}}</ref>
'''Peripheral Blood Smear''' may show large granular [[lymphocyte]] (LGL), fine or coarse [[azurophilic granules]] and [[nucleoli]] of varying prominence, and nuclei may be irregular and hyperchromatic.
* There are no cytogenetic abnormalities specific to ANKL.
* However, following [[cytogenetic]] abnormalites have been reported more frequently among [[patients]] with aggressive NK-cell leukemia.
**[[chromosomes]] 6q and 11q <ref name="WongZhang2009">{{cite journal|last1=Wong|first1=K. F.|last2=Zhang|first2=Y. M.|last3=Chan|first3=J. K. C.|title=Cytogenetic Abnormalities in Natural Killer Cell LymphomaLeukaemia - Is There a Consistent Pattern?|journal=Leukemia & Lymphoma|volume=34|issue=3-4|year=2009|pages=241–250|issn=1042-8194|doi=10.3109/10428199909050949}}</ref>
*[[Complete blood count]] ([[CBC]]) may show [[cytopenias]].<ref name="pmid8324214">{{cite journal |vauthors=Loughran TP |title=Clonal diseases of large granular lymphocytes |journal=Blood |volume=82 |issue=1 |pages=1–14 |date=July 1993 |pmid=8324214 |doi= |url=}}</ref>
=== Electrocardiogram ===
* There are no [[ECG]] findings associated with aggressive NK-cell leukemia.
=== X-ray ===
There are no [[x-ray]] findings associated with aggressive NK-cell leukemia.
=== Echocardiography or Ultrasound ===
* There are no [[echocardiography]]/[[ultrasound]] findings associated with aggressive NK-cell leukemia.
=== CT scan ===
* There are no [[CT scan]] findings associated with aggressive NK-cell leukemia.
=== MRI ===
* There are no [[MRI]] findings associated with aggressive NK-cell leukemia.
=== Other Imaging Findings===
* There are no other [[imaging]] findings associated with aggressive NK-cell leukemia.
=== Other Diagnostic Studies ===
* Aggressive NK-cell leukemia may also be diagnosed using [[bone marrow biopsy]].<ref name="pmid12648073">{{cite journal |vauthors=Morice WG, Kurtin PJ, Leibson PJ, Tefferi A, Hanson CA |title=Demonstration of aberrant T-cell and natural killer-cell antigen expression in all cases of granular lymphocytic leukaemia |journal=Br. J. Haematol. |volume=120 |issue=6 |pages=1026–36 |date=March 2003 |pmid=12648073 |doi=10.1046/j.1365-2141.2003.04201.x |url=}}</ref>
* Findings on [[bone marrow biopsy]], include extensive marrow replacement by leukemic cells and reactive [[histiocytes]] displaying [[hemophagocytosis]].
== Treatment ==
=== Medical Therapy ===
* The mainstay of therapy for aggressive NK-cell leukemia is [[anthracycline]]-containing [[chemotherapy]].<ref name="pmid30364049">{{cite journal |vauthors=Ishida F |title=Aggressive NK-Cell Leukemia |journal=Front Pediatr |volume=6 |issue= |pages=292 |date=2018 |pmid=30364049 |pmc=6191480 |doi=10.3389/fped.2018.00292 |url=}}</ref>
*[[L-Asparaginase|L-asparaginase]] containing [[chemotherapy]] regimen followed by [[allogeneic stem cell transplantation]] shows to slightly prolong life, but relapse is almost assured.<ref name="pmid22360679">{{cite journal |vauthors=Ishida F, Ko YH, Kim WS, Suzumiya J, Isobe Y, Oshimi K, Nakamura S, Suzuki R |title=Aggressive natural killer cell leukemia: therapeutic potential of L-asparaginase and allogeneic hematopoietic stem cell transplantation |journal=Cancer Sci. |volume=103 |issue=6 |pages=1079–83 |date=June 2012 |pmid=22360679 |doi=10.1111/j.1349-7006.2012.02251.x |url=}}</ref>
* Other novel treatments may include [[pralatrexate]].
* None of the aforementioned treatment regimens have been curative.
*[[Allogeneic]] [[bone marrow transplantation]] has been reported successful in some cases.<ref name="pmid9674865">{{cite journal |vauthors=Takami A, Nakao S, Yachie A, Kasahara Y, Okumura H, Miura Y, Sugimori N, Zeng W, Wang H, Kotani T, Shiobara S, Matsuda T |title=Successful treatment of Epstein-Barr virus-associated natural killer cell large granular lymphocytic leukaemia using allogeneic peripheral blood stem cell transplantation |journal=Bone Marrow Transplant. |volume=21 |issue=12 |pages=1279–82 |date=June 1998 |pmid=9674865 |doi=10.1038/sj.bmt.1701262 |url=}}</ref>
=== Surgery ===
* Surgery is '''not''' recommended among [[patients]] with aggressive NK-cell leukemia.
=== Primary Prevention ===
* There are no [[Primary prevention|primary preventive]] measures available for aggressive NK-cell leukemia.
=== Secondary Prevention ===
* There are no [[Secondary prevention|secondary preventive]] measures available for aggressive NK-cell leukemia.


==References==
==References==
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Latest revision as of 14:25, 22 October 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2] Associate Editor(s)-in-Chief: Sahar Memar Montazerin, M.D.[3] Maria Fernanda Villarreal, M.D. [4]
Synonyms and keywords: ANKL

Overview

Aggressive NK-cell leukemia is a disease with an aggressive, systemic proliferation of natural killer cells (NK cells) and a rapidly declining clinical course. There is no classification system for aggressive NK-cell leukemia. The pathogenesis of aggressive NK-cell leukemia is characterized by the proliferation of natural killer cells. Aggressive NK-cell leukemia is very uncommon, and is most commonly seen among middle aged adults. The most common risk factors in the development of aggressive NK-cell leukemia is the Epstein-Barr virus (EBV) infection. The majority of patients with aggressive NK-cell leukemia are symptomatic at diagnosis. Early clinical features include fatigue, night sweats, and fever. Physical examination among patients with aggressive NK-cell leukemia may be remarkable for hepatosplenomegaly. Aggressive NK-cell leukemia may also be diagnosed using bone marrow biopsy, findings of which can include extensive marrow replacement by leukemic cells and reactive histiocytes displaying hemophagocytosis. The mainstay of therapy for aggressive NK-cell leukemia is anthracycline-containing chemotherapy.

Historical Perspective

  • In 1986, Dr. Fernandez and his colleagues reported the first case of aggressive NK-cell leukemia.[1]
  • In 1989, Dr. Kawa and his colleagues first reported the association between EBV virus and aggressive NK-cell leukemia.[2]

Classification

Pathophysiology

Status Antigens
Positive CD2, CD3ε, CD56, perforin, granzyme B, TIA-1, CCR5
Negative CD57

Causes

  • There are no established causes for aggressive NK-cell leukemia.

Differentiating Aggressive NK-cell Leukemia from Other Diseases

Epidemiology and Demographics

  • Aggressive NK-cell leukemia is a rare disorder.[7][8]
  • Aggressive NK-cell leukemia is more commonly observed among young adults with median age of 42 years old.
  • Aggressive NK-cell leukemia affects men more frequently than women.
  • Aggressive NK-cell leukemia usually affects individuals of the Asian race.[9]

Risk Factors

Screening

  • There is insufficient evidence to recommend routine screening for aggressive NK-cell leukemia.

Natural History, Complications, and Prognosis

Diagnosis

Staging

  • The table below shows the staging system for aggressive NK-cell leukemia according to the Ann Arbor staging system.[11]
Stage Staging Criteria
Stage I
Stage II
Stage III
Stage IV

Symptoms

Physical Examination

Laboratory Findings

  • Laboratory findings consistent with the diagnosis of aggressive NK-cell leukemia include:[14]

Peripheral Blood Smear may show large granular lymphocyte (LGL), fine or coarse azurophilic granules and nucleoli of varying prominence, and nuclei may be irregular and hyperchromatic.

Electrocardiogram

  • There are no ECG findings associated with aggressive NK-cell leukemia.

X-ray

There are no x-ray findings associated with aggressive NK-cell leukemia.

Echocardiography or Ultrasound

CT scan

  • There are no CT scan findings associated with aggressive NK-cell leukemia.

MRI

  • There are no MRI findings associated with aggressive NK-cell leukemia.

Other Imaging Findings

  • There are no other imaging findings associated with aggressive NK-cell leukemia.

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

  • Surgery is not recommended among patients with aggressive NK-cell leukemia.

Primary Prevention

Secondary Prevention

References

  1. ↑ Fernandez LA, Pope B, Lee C, Zayed E (April 1986). "Aggressive natural killer cell leukemia in an adult with establishment of an NK cell line". Blood. 67 (4): 925–30. PMID 3955237.
  2. ↑ 2.0 2.1 Kawa-Ha, K; Ishihara, S; Ninomiya, T; Yumura-Yagi, K; Hara, J; Murayama, F; Tawa, A; Hirai, K (1989). "CD3-negative lymphoproliferative disease of granular lymphocytes containing Epstein-Barr viral DNA". Journal of Clinical Investigation. 84 (1): 51–55. doi:10.1172/JCI114168. ISSN 0021-9738.
  3. ↑ Ishida, Fumihiro (2018). "Aggressive NK-Cell Leukemia". Frontiers in Pediatrics. 6. doi:10.3389/fped.2018.00292. ISSN 2296-2360.
  4. ↑ Siu, Lisa L.P.; Wong, Kit-Fai; Chan, John K.C.; Kwong, Yok-Lam (1999). "Comparative Genomic Hybridization Analysis of Natural Killer Cell Lymphoma/Leukemia". The American Journal of Pathology. 155 (5): 1419–1425. doi:10.1016/S0002-9440(10)65454-5. ISSN 0002-9440.
  5. ↑ 5.0 5.1 [1] Chan JK. "Natural killer cell neoplasms." Anat Pathol. 1998;3:77-145. PMID 10389582
  6. ↑ Swerdlow, Steven (2017). WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer. ISBN 9789283244943.
  7. ↑ 7.0 7.1 Suzuki, R; Suzumiya, J; Nakamura, S; Aoki, S; Notoya, A; Ozaki, S; Gondo, H; Hino, N; Mori, H; Sugimori, H; Kawa, K; Oshimi, K (2004). "Aggressive natural killer-cell leukemia revisited: large granular lymphocyte leukemia of cytotoxic NK cells". Leukemia. 18 (4): 763–770. doi:10.1038/sj.leu.2403262. ISSN 0887-6924.
  8. ↑ Tang YT, Wang D, Luo H, Xiao M, Zhou HS, Liu D, Ling SP, Wang N, Hu XL, Luo Y, Mao X, Ao QL, Huang J, Zhang W, Sheng LS, Zhu LJ, Shang Z, Gao LL, Zhang PL, Zhou M, Zhou KG, Qiu LG, Liu QF, Zhang HY, Li JY, Jin J, Fu L, Zhao WL, Chen JP, Du X, Huang G, Wang QF, Zhou JF, Huang L (December 2017). "Aggressive NK-cell leukemia: clinical subtypes, molecular features, and treatment outcomes". Blood Cancer J. 7 (12): 660. doi:10.1038/s41408-017-0021-z. PMC 5802497. PMID 29263371.
  9. ↑ 9.0 9.1 9.2 Lima, Margarida (2013). "Aggressive mature natural killer cell neoplasms: from epidemiology to diagnosis". Orphanet Journal of Rare Diseases. 8 (1): 95. doi:10.1186/1750-1172-8-95. ISSN 1750-1172.
  10. ↑ 10.0 10.1 Li, Chunrui; Tian, Ye; Wang, Jue; Zhu, Li; Huang, Liang; Wang, Na; Xu, Danmei; Cao, Yang; Li, Jianyong; Zhou, Jianfeng (2014). "Abnormal immunophenotype provides a key diagnostic marker: a report of 29 cases of de novo aggressive natural killer cell leukemia". Translational Research. 163 (6): 565–577. doi:10.1016/j.trsl.2014.01.010. ISSN 1931-5244.
  11. ↑ Lister, T A; Crowther, D; Sutcliffe, S B; Glatstein, E; Canellos, G P; Young, R C; Rosenberg, S A; Coltman, C A; Tubiana, M (1989). "Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting". Journal of Clinical Oncology. 7 (11): 1630–1636. doi:10.1200/JCO.1989.7.11.1630. ISSN 0732-183X.
  12. ↑ Song SY, Kim WS, Ko YH, Kim K, Lee MH, Park K (December 2002). "Aggressive natural killer cell leukemia: clinical features and treatment outcome". Haematologica. 87 (12): 1343–5. PMID 12495907.
  13. ↑ Sheridan W, Winton EF, Chan WC, Gordon DS, Vogler WR, Phillips C, Bongiovanni KF, Waldmann TA (November 1988). "Leukemia of non-T lineage natural killer cells". Blood. 72 (5): 1701–7. PMID 2846089.
  14. ↑ Nazarullah, Alia; Don, Michelle; Linhares, Yuliya; Alkan, Serhan; Huang, Qin (2016). "Aggressive NK-cell leukemia: A rare entity with diagnostic and therapeutic challenge". Human Pathology: Case Reports. 4: 32–37. doi:10.1016/j.ehpc.2015.08.001. ISSN 2214-3300.
  15. ↑ Wong, K. F.; Zhang, Y. M.; Chan, J. K. C. (2009). "Cytogenetic Abnormalities in Natural Killer Cell LymphomaLeukaemia - Is There a Consistent Pattern?". Leukemia & Lymphoma. 34 (3–4): 241–250. doi:10.3109/10428199909050949. ISSN 1042-8194.
  16. ↑ Loughran TP (July 1993). "Clonal diseases of large granular lymphocytes". Blood. 82 (1): 1–14. PMID 8324214.
  17. ↑ Morice WG, Kurtin PJ, Leibson PJ, Tefferi A, Hanson CA (March 2003). "Demonstration of aberrant T-cell and natural killer-cell antigen expression in all cases of granular lymphocytic leukaemia". Br. J. Haematol. 120 (6): 1026–36. doi:10.1046/j.1365-2141.2003.04201.x. PMID 12648073.
  18. ↑ Ishida F (2018). "Aggressive NK-Cell Leukemia". Front Pediatr. 6: 292. doi:10.3389/fped.2018.00292. PMC 6191480. PMID 30364049.
  19. ↑ Ishida F, Ko YH, Kim WS, Suzumiya J, Isobe Y, Oshimi K, Nakamura S, Suzuki R (June 2012). "Aggressive natural killer cell leukemia: therapeutic potential of L-asparaginase and allogeneic hematopoietic stem cell transplantation". Cancer Sci. 103 (6): 1079–83. doi:10.1111/j.1349-7006.2012.02251.x. PMID 22360679.
  20. ↑ Takami A, Nakao S, Yachie A, Kasahara Y, Okumura H, Miura Y, Sugimori N, Zeng W, Wang H, Kotani T, Shiobara S, Matsuda T (June 1998). "Successful treatment of Epstein-Barr virus-associated natural killer cell large granular lymphocytic leukaemia using allogeneic peripheral blood stem cell transplantation". Bone Marrow Transplant. 21 (12): 1279–82. doi:10.1038/sj.bmt.1701262. PMID 9674865.
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