Aggressive NK-cell leukemia: Difference between revisions

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{{CMG}} {{AE}} {{MV}}
{{CMG}} {{AE}} {{Sahar}} {{MV}}<br>
{{SK}} ANKL
{{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">[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=9192774&query_hl=4&itool=pubmed_ExternalLink]
== Historical Perspective ==
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]
*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>
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]
*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>
Chan JK. "Natural killer cell neoplasms." '''Anat Pathol'''. 1998;3:77-145. PMID 10389582</ref> 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 include: extensive marrow replacement by leukemic cells
== Classification ==
and reactive histiocytes displaying hemophagocytosis. The mainstay of therapy for aggressive NK-cell leukemia is anthracycline-containing chemotherapy.<ref name="wiki">Aggressive NK-cell leukemia. https://en.wikipedia.org/wiki/Aggressive_NK-cell_leukemia Accessed on May 5, 2016</ref>
*There is no [[classification]] system for aggressive NK-cell leukemia.
 
*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>
== Classification==
*There is no classification system for 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>  
==Pathophysiology==
==Pathophysiology==
*The pathogenesis of aggressive NK-cell leukemia is characterized by the aggressive, systemic proliferation of natural killer cells.  
*The [[pathogenesis]] of aggressive NK-cell leukemia is characterized by the aggressive, systemic proliferation of [[Natural killer cell|natural killer cells]].
*The mutation in oncogene p53 has been associated with the development of aggressive NK-cell leukemia.  
*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 gross pathology, characteristic findings of aggressive NK-cell leukemia, include:
*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]
:*No remarkable findings
*On microscopic histopathological analysis, characteristic findings of aggressive NK-cell leukemia, include:<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>
:*Large cells with abundant blue cytoplasm
*[[CD11b]] and [[CD16]] show variable expression in aggressive NK-cell leukemia.
:*Azurophilic granules
*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]
:*Irregular nuclei
:*Open chromatin
:*Distinct nucleoli
:*CD11b and CD16 show variable expression
*The table below demonstrates the immunophenotype for 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"
::{| border="1" cellpadding="5" cellspacing="0"
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|-
|-
| rowspan="1" | Negative
| rowspan="1" | Negative
| colspan="1" align="center" | [[CD57]]
| colspan="1" align="center" |[[CD57]]
|-
|-
|}
|}
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==Causes==
==Causes==
* There are no established causes for aggressive NK-cell leukemia.
* There are no established causes for aggressive NK-cell leukemia.
==Differentiating Aggressive NK-cell Leukemia from Other Diseases==
==Differentiating Aggressive NK-cell Leukemia from Other Diseases==
*Aggressive NK-cell leukemia must be differentiated from other diseases that cause fever, fatigue, and lymphadenopathy such as:
* 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]].
:*Human immunodeficiency virus
* 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>
:*Chronic neutrophilic leukemia
:*Juvenile myelomonocytic leukemia
 
==Epidemiology and Demographics==
==Epidemiology and Demographics==
* Aggressive NK-cell leukemia is very uncommon.<ref name="wiki">Aggressive NK-cell leukemia. https://en.wikipedia.org/wiki/Aggressive_NK-cell_leukemia Accessed on May 5, 2016</ref>
* 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>
===Age===
* Aggressive NK-cell leukemia is more commonly observed among young adults with median age of 42 years old.
*Aggressive NK-cell leukemia is more commonly observed among middle aged adults.
* 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]]


===Gender===
*
*Aggressive NK-cell leukemia affects men and women equally.
|-
|Stage IV


===Race===
*  
*Aggressive NK-cell leukemia usually affects individuals of the Asians race.
|
 
* [[Bone marrow]] or [[liver]]/ extranodal involvement with widespread involvement
==Risk Factors==
|}
*Common risk factors in the development of aggressive NK-cell leukemia, include:
:*[[Epstein-Barr virus]] (EBV) infection
 
== Natural History, Complications and Prognosis==
*The majority of patients with aggressive NK-cell leukemia are symptomatic at diagnosis.<ref name="wiki">Aggressive NK-cell leukemia. https://en.wikipedia.org/wiki/Aggressive_NK-cell_leukemia Accessed on May 5, 2016</ref>
*Early clinical features include fatigue, night sweats, and fever.
*If left untreated, patients with aggressive NK-cell leukemia may progress to develop recurrent infections.
*Common complications of aggressive NK-cell leukemia, include:
:*[[Coagulopathy|Coagulopathies]]
:*[[Hemophagocytic syndrome]]
:*Multiple organ failure
:*Myelofibrosis
*Prognosis is generally poor, and the median survival rate of patients with aggressive NK-cell leukemia is approximately 12 months.<ref name="wiki">Aggressive NK-cell leukemia. https://en.wikipedia.org/wiki/Aggressive_NK-cell_leukemia Accessed on May 5, 2016</ref>
 
== Diagnosis ==
=== Symptoms ===
=== Symptoms ===
*Aggressive NK-cell leukemia is usually asymptomatic.
*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>
*Symptoms of aggressive NK-cell leukemia may include the following:<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>
:*Fever
:*Swelling in the lymph nodes in the neck
:*Night sweats
:*Persistent fatigue
:*Loss of appetite
:*Nausea
:*Vomiting
 
=== Physical Examination ===
=== Physical Examination ===
*Patients with aggressive NK-cell leukemia usually appear pale and malnourished.  
*[[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:<ref name="wiki">Aggressive NK-cell leukemia. https://en.wikipedia.org/wiki/Aggressive_NK-cell_leukemia Accessed on May 5, 2016</ref>
*Physical examination may be remarkable for [[fever]], [[icterus]], [[hepatosplenomegaly]], and [[lymphadenopathy]].
:*Hepatoesplenomegaly
 
=== Laboratory Findings ===
=== Laboratory Findings ===
*Laboratory findings consistent with the diagnosis of aggressive NK-cell leukemia, include:<ref name="wiki">Aggressive NK-cell leukemia. https://en.wikipedia.org/wiki/Aggressive_NK-cell_leukemia Accessed on May 5, 2016</ref>
*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'''
'''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.
:*Large granular lymphocyte (LGL)  
* There are no cytogenetic abnormalities specific to ANKL.
:*Azurophilic granules and nucleoli of varying prominence
* However, following [[cytogenetic]] abnormalites have been reported more frequently among [[patients]] with aggressive NK-cell leukemia.
:*Nuclei may be irregular and hyperchromatic
**[[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>
===Imaging Findings===
=== Electrocardiogram ===
*There are no imaging findings associated with aggressive NK-cell leukemia.
* 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 ===
=== Other Diagnostic Studies ===
*Aggressive NK-cell leukemia may also be diagnosed using bone marrow biopsy.  
* 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:<ref name="wiki">Aggressive NK-cell leukemia. https://en.wikipedia.org/wiki/Aggressive_NK-cell_leukemia Accessed on May 5, 2016</ref>
* Findings on [[bone marrow biopsy]], include extensive marrow replacement by leukemic cells and reactive [[histiocytes]] displaying [[hemophagocytosis]].
:*Extensive marrow replacement by leukemic cells
:*Reactive histiocytes displaying hemophagocytosis
 
== Treatment ==
== Treatment ==
=== Medical Therapy ===
=== Medical Therapy ===
*The mainstay of therapy for aggressive NK-cell leukemia is anthracycline-containing chemotherapy.<ref name="wiki">Aggressive NK-cell leukemia. https://en.wikipedia.org/wiki/Aggressive_NK-cell_leukemia Accessed on May 5, 2016</ref>
* 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>
*Other novel treatments may include pralatrexate.<ref name="wiki">Aggressive NK-cell leukemia. https://en.wikipedia.org/wiki/Aggressive_NK-cell_leukemia Accessed on May 5, 2016</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 ===
*Surgery is '''not''' recommended among patients with aggressive NK-cell leukemia.
* Surgery is '''not''' recommended among [[patients]] with aggressive NK-cell leukemia.
=== Prevention ===
=== Primary Prevention ===
*There are no primary preventive measures available for aggressive NK-cell leukemia.
* 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==
{{Reflist|2}}
{{Reflist|2}}
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[[Category:Immunology]]

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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