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Aggressive mature natural killer cell neoplasms: from epidemiology todiagnosis

Abstract

Mature natural killer (NK) cell neoplasms are classified by the World Health Organization into NK/T cell lymphoma, nasal type (NKTCL), aggressive NK-cellleukemia (ANKCL) and chronic lymphoproliferative disorders of NK-cells, thelatter being considered provisionally. NKTCL and ANKCL are rare diseases, withhigher prevalence in Asia, Central and South America. Most NKTCL presentextranodal, as a destructive tumor affecting the nose and upper aerodigestivetract (nasal NKTCL) or any organ or tissue (extranasal NKTCL) whereas ANKCLmanifests as a systemic disease with multiorgan involvement and naturallyevolutes to death in a few weeks. The histopathological hallmark of theseaggressive NK-cell tumors is a polymorphic neoplastic infiltrate withangiocentricity, angiodestruction and tissue necrosis. The tumor cells havecytoplasmatic azurophilic granules and usually show a CD45+bright,CD2+, sCD3-, cytCD3epsilon+,CD56+bright, CD16−/+, cytotoxic granulesmolecules+ phenotype. T-cell receptor genes are in germ-lineconfiguration. Epstein-Barr virus (EBV) -encoded membrane proteins and earlyregion EBV RNA are usually detected on lymphoma cells, with a pattern suggestiveof a latent viral infection type II. Complex chromosomal abnormalities arefrequent and loss of chromosomes 6q, 11q, 13q, and 17p are recurrentaberrations. The rarity of the NK-cell tumors limits our ability to standardizethe procedures for the diagnosis and clinical management and efforts should bemade to encourage multi-institutional registries.

Resumo

As neoplasias de células natural killer (NK) maduras foramclassificadas pela Organização Mundial de Saúde em trêsentidades: o linfoma de células NK/T tipo nasal (NKTCL), a leucemiaagressiva de células NK (ANKCL) e as doenças linfoproliferativascrónicas de células NK, estas últimas consideradas umaentidade provisória. Os NKTCL e a ANKCL são doenças raras,mais prevalentes na Ásia, na América Central e na América doSul. A maioria dos NKTCL tem uma apresentação extra-ganglionar, naforma de tumor destrutivo que atinge o nariz e o trato aerodigestivo alto(forma nasal) ou qualquer órgão ou tecido (forma extranasal). AANKCL manifesta-se como uma doença sistémica que evolui para amorte em poucas semanas. Do ponto de vista histopatológico, estasneoplasias caraterizam-se por um infiltrado polimórfico, comangiocentricidade, destruição vascular e necrose tecidular. Ascélulas tumorais têm grânulos azurófilos no citoplasma eo seu imunofenótipo (CD45+forte, CD2+,sCD3-, cytCD3epsilon+, CD56+forte,CD16−/+, proteínas dos grânuloscitotóxicos+) é caraterístico. Os genes quecodificam para o recetor das células T estão emconfiguração nativa. As células tumorais expressam geralmenteproteínas da membrana e ARN do vírus Epstein Barr, com umpadrão sugestivo de uma infecção vírica latente tipo II.As alterações cromossómicas são complexas, e algumas,como deleções nos braços longos dos cromossomas 6, 11 e 13 edo braço curto do cromossoma 17, ocorrem de forma recorrente. Araridade dos tumores de células NK limita a nossa capacidade parauniformizar os procedimentos de diagnóstico e a abordagem clínica,sendo necessário desenvolver esforços para promover os registosmulticêntricos.

Introduction

Lymphoproliferative disorders of natural killer (NK) cells are rare diseases whichaccount for less than 5% of all lymphoid neoplasms and comprise differentclinical entities [117].

The World Health Organization (WHO) classification of tumors of hematopoietic andlymphoid tissues, updated in 2008, has made advances in their classification.Accordingly, three disease conditions originating from mature NK-cells were proposedbased on their distinct clinical and pathological features [18]. These include two aggressive mature NK-cell neoplasms – extranodalNK/T cell lymphoma, nasal type (NKTCL) [19], and aggressive NK-cell leukemia (ANKCL) [20] – and one provisional entity – chronic lymphoproliferativedisorders of NK-cells (CLPD-NK) [21] (Table 1). The first two entities are indexedindividually in the 10th revision of the International Classification of Diseases(ICD-10) [22] and in the 3rd edition of the ICD for Oncology (ICD-O-3) [23], as well as in Orphanet databases [24]. In addition, two diseases were proposed in the past as originating fromNK-cell precursors, based mainly on the blastic appearance and the CD56+immature immunophenotype of the neoplastic cells. The first, NK-cell lymphoblasticleukemia / lymphoma [25], in fact comprise an heterogeneous group of immature disordersoriginating from NK-, T- and/or myeloid cell precursors, and is now being consideredin the group of the acute leukemia of ambiguous lineage; the other, blasticplasmacytoid dendritic cell neoplasm, previously designed blastic NK-cell lymphoma,arises from plasmacytoid dendritic cells and should no longer be considered aNK-cell malignancy [26].

Table 1 Natural killer cell neoplasms according to the World Health Organizationclassification of tumors of hematopoietic and lymphoid tissues

Nasal type NKTCL, originates in nasal and extranasal organs and tissues and accountfor the majority of cases, with only exceptional cases presenting primarily in thelymph nodes. ANKCL manifests as a systemic disease with multiorgan failure andrapidly evolutes to death. The diagnosis of these aggressive NK-cell neoplasms isoften difficult and requires both clinical suspicion and a differentiatedlaboratorial approach based in morphological, immunophenotypic and molecularstudies.

We review the epidemiology and the clinical and laboratorial criteria for thediagnosis of NKTCL and ANKCL, with emphasis on tissue histology and on themorphological, immunophenotypic and genetic features of the neoplastic cells.

Review

Epidemiology

Both NKTCL and ANKCL are relatively frequent in Asia, Central and South America,but extremely rare in Europe and North America [117].

Extranodal NK/T-cell lymphoma, nasal type, and ANKCL are relatively frequent inCentral American (e.g. Mexico, Guatemala), South American (e.g. Argentina,Brazil, Peru, Chile) and Eastern (e.g. Hong Kong, Japan, Korea) countries, wherethey may account for up to 10% of the non Hodgkin’s lymphoma (NHL),whereas very uncommon in North America and Europe, where they represent lessthan 1% of the NHLa[1, 2, 2729]. Moreover, in series from the United States in which the ethnicbackground was recorded, most patients with NKTCL were of Asian or Hispanicdescent [30]. Few epidemiological data is available in Europe, where itsprevalence has been estimated to be lower than 1–9 cases / 1.000.000inhabitants.

Aggressive NK-cell neoplasms are almost always associated to Epstein Barr Virus(EBV) and similarly to that occurring in Hodgkin’s lymphoma andnasopharyngeal carcinoma, the neoplastic NK-cells usually have a type II latencypattern, expression of EBV nuclear antigens (EBNA) and latent membrane proteins(LMP) being limited to EBNA-1, LMP-1, and LMP-2 [31]. In Asia, increase in the risk of developing nasal NKTCL have beendescribed among crop producers and individuals exposed to pesticides [32], also having an increased risk to develop NHL in general [33, 34].

The International Peripheral T-cell Lymphoma Project (IPTCLP) group reported afour-fold higher relative frequency of NKTCL among lymphomas in Asian countriescompared to Western countries, ANKCL being rarer than NKTCL (Table 2). From the 136 cases of NK-cell neoplasms analyzed by thisgroup, collected in different centers from various countries in North America,Europe, and Asia, only 2 (1.5%) corresponded to ANKCL, as compared to 127cases of NKTCL, the remaining 7 cases being unclassifiable according to the WHOschema [35]. Comparatively, based on the Japanese survey of NK-cell neoplasmsdiagnosed from 1994 to 1998 [36], the NK-cell Tumor Study Group reported on a Japanese series of 172NK-cell tumors, which included 22 ANKCL (12.8%) [37]. Few European series of NKTCL were published to date [38, 39] and, in Europe, reports on ANKCL are limited to sporadic cases [4043].

Table 2 Frequencies of NK/T-cell Lymphoma, nasal type, and aggressive NK-cellleukemia in previous published series

Two variants of extranodal NKTCL, have been described, the nasal and theextranasal forms, the first being more frequent in nearly all reported series.In the register from the Japanese survey, only 18% of the NKTCL wereextranasal [37], a higher percentage of extranasal cases (28%) being found amongthe NKTCL reported by the IPTCLP group [35]; in addition, a Brazilian and an Italian series of NKTCL included19% and 12% of extranasal lymphomas, respectively [39, 44] (Table 2).

Clinical features

Extranodal NK/T cell lymphomas, nasal type

The nasal and extranasal forms of NKTCL differ from each other from theclinical point of view (Table 3) [1, 10, 14, 45].

Table 3 Major clinical features of the NK-cell lymphoma, nasal type, andaggressive NK-cell leukemia

Nasal NK/T cell lymphomas

In contrast to that observed in Occidental countries, where the majority ofthe sinonasal lymphomas are B-cell lymphomas, in Asia more than 40% ofthese lymphomas originate from NK-cells. This neoplasm (also known as“lethal midline granuloma” or “midline malignantreticulosis”) commonly affects males and generally manifests as alocalized disease, with mid-facial and/or upper airway destructive lesions [1, 10, 14, 45]. Patients with nasal NKTCL present with nasal signals andsymptoms, including mass, obstruction swelling, or bleeding. The tumor islocally invasive and often infiltrates the surrounding tissues, such as thenasopharynx, the oropharynx, the palate and the orbits; dissemination toother organs may occur in advanced disease stages.

Extranasal NK/T cell lymphomas

The extranasal form is frequently disseminated at the time of the diagnosis,most patients having multiple organs and tissues involved, usually withoutadenopathies [1, 10, 14, 45]. Patients with extranasal NKTCL often have more adverse clinicalfeatures such as an advanced stage and poor performance status, and are morelikely to have cytopenias, when compared to patients with nasal lymphoma [1, 10, 14]. The tumor may involve any anatomic site at the diseasepresentation or during disease progression, including the skin, thegastrointestinal tract, the testis, the lungs, the eyes, the soft tissues,the adrenal glands, the brain, the breast and the tongue [1, 10, 14]. The diagnosis of an extranasal NKTCL requires the exclusion ofoccult nasal disease, which may require nasal endoscopy with randombiopsies.

Bone marrow involvement at the diagnosis is uncommon in NKTCL, in both nasal(<3.5%) and extranasal (<7%) cases [4, 46]. In contrast, the hemophagocytic syndrome is relatively frequent,and often occurs in advanced disease [47].

Nodal NK-cell lymphomas, nasal type

Although nodal NKTCL are not being considered separately in the WHOclassification, a few cases of NKTCL presenting primarily in the lymph nodeshave been described [44, 4852]. Some of these cases were included in extranodal NKTCL series [44, 50] and in series of patients with cytotoxic lymphomas [51]. For instance, in a review of 49 Asian cases of CD56+ neoplasmsfrom which 34 were NKTCL, one had a primary nodal presentation [50] and a Brazilian series of 122 cases NKTCL, from which 23 caseswere extranasal, included 6 nodal cases [44]. In another series of 66 patients with nodal cytotoxic celllymphomas, one had the classic NKTCL phenotype [51]. In addition, cases of nodal lymphomas with a typical NKTCLphenotype and T-cell receptor (TCR) gamma (TCRG) generearrangements in germ-line configuration were described as case reports [48, 49]. However, in other cases, the tumor probably originates fromcytotoxic T-lymphocytes, as in the series of nodal lymphoma with a typicalNKTCL phenotype reported by Takashi et al., from which 4 cases had clonalTCRG gene rearrangements [52]. Nodal NKTCL have a poor prognosis, most patients surviving forless than one year; they usually affect the cervical lymph nodes and thehistology and phenotype are similar to those of extranodal NKTCL.

Aggressive NK-cell leukemia

Aggressive NK-cell leukemia is a very rare and extremely aggressive neoplasm,also with a higher prevalence among Asians [2, 35, 36, 5355]. Men and women are equally affected and the disease usuallymanifest in the third or four decades. Patients usually present extremelyill, with fever and other systemic symptoms, hepatosplenomegaly,pancytopenia and abnormal liver function. Serum levels of lacticdehydrogenase (LDH) and Fas Ligand (FasL) are often markedly increased. Thehemophagocytic syndrome is frequent at diagnosis or during the diseasecourse, resulting from uncontrolled monocyte/macrophage activation inresponse to cytokines produced by the neoplastic NK-cells [5661]. The natural disease course is fulminant, with multiorgan failureand disseminated intravascular coagulation, death occurring usually within afew weeks [62].

Clinical staging

The Ann-Arbor staging system, originally designed for Hodgkin’s lymphoma,is used for clinical staging of the NHL in general (Table 4) [63, 64]. However, this system is not completely satisfactory for NKTCL, as itdoes not take into account the tumor size and the invasion to contiguousstructures, which may be important prognostic features. Consequently, a modifiedtumor-staging system originally proposed for sinonasal B-cell lymphoma wasadopted, which takes into account the local involvement [65] (Table 4).

Table 4 Clinical staging systems used for aggressive NK-cell neoplasms

In order to perform disease staging, patients should be evaluated with routinehematological and biochemical analysis, bilateral bone marrow trephine biopsy,chest radiography, computerized tomography, and digestive endoscopy. Inaddition, magnetic resonance imaging helps to define the local involvement innasal lymphoma, being superior to computerized tomography in determining theextent of soft-tissue infiltration, in differentiating inflamed from neoplastictissue, and in clarifying bone lesions [66]. Positron emission tomography using fluorine-18-fluoro-deoxy-glucoseis useful to investigate systemic spread and to distinguishing lymphoma frominflammatory masses [67].

The ratio of patients presenting limited extranodal disease stages (IEor IIE) versus those with presenting with advanced disease stages(III or IV) is 7:3 for nasal NKTCL and 4:6 for extranasal NKTCL [36].

Laboratorial diagnosis

Histology and cytology

Natural killer/T cell lymphoma, nasal type, are histologically characterizedby angiocentricity and invasion of the blood vessels by lymphoma cells,resulting in ischemic necrosis; the neoplastic cells have a variable sizeand usually appear morphologically immature and the cytological features areheterogeneous, with a variable mixture of inflammatory cells. Azurophilicgranules are usually observed in the cytoplasm of the lymphoma cells usingimprint smears [6]. Aggressive NK-cell leukemia cells are larger than normal largegranular lymphocytes and often have a pale or slightly basophilic cytoplasmwith azurophilic granules and a nucleus with slightly immature chromatin andinconspicuous or distinct nucleoli. As in NKTCL, necrosis, apoptosis,angioinvasion, and angiodestruction are common findings in tissue biopsies [6]. Also frequent is hemophagocytosis, which results fromuncontrolled macrophage stimulation by inflammatory cytokines produced bythe neoplastic cells and may result in the development of a hemophagocyticsyndrome.

Immunophenotype

Most of our knowledge on the immunophenotype of the neoplastic NK-cells inNKTCL [30, 35, 37, 50, 6870] as in ANKCL [2, 50, 5355, 7175], is based on immunohistochemistry studies.

Like normal NK-cells, NKTCL and ANKCL tumor cells do not express CD3 and theTCR on their surface [1]. Nevertheless, they often have the epsilon chain of CD3 in thecytoplasm and, therefore, they may stain positively for CD3 inimmunohistochemistry of paraffin sections, imposing the differentialdiagnosis with T-cell lymphoma [30]. Also as normal NK-cells, tumor NK-cells do not rearrange TCRgenes, which can be shown to be in germ-line configuration by polymerasechain reaction (PCR) analysis. In addition, NKTCL and ANKCL tumor cellsnearly always express CD2 and less often CD7 and CD8, but not CD4 and CD5.From the markers usually used to identify NK-cells, CD56 is the mostfrequently positive, whereas CD16 expression is variable, and CD57 is almostnever found. In addition, cytotoxic granule–associated proteins suchas T-cell–restricted intracellular antigen (TIA-1), granzyme B, andperforin are frequently expressed. The immunophenotypic characteristics ofNKTCL and ANKCL cells seems to be similar, except for a higher frequency ofcyCD3epsilon+ and a lower frequency of CD16+ casesin NKTCL [37].

Only a limited number of studies have evaluated the expression of killerreceptors on the neoplastic NK-cells from patients with NKTCL and ANKCL [7680]. Reverse transcriptase PCR techniques, revealed that most NKTCLtumor cells do express killer lectin type receptors (KLR) transcripts,including those for the CD94 and the NKG2 (most frequently NKG2A/B andNKG2D) receptors [80], a result that was confirmed by immunohistochemical stainings ontissue biopsies [76, 77] and flow cytometry immunophenotyping of NKTCL and ANKCL cells [78]. The expression of killer immunoglobulin like receptors (KIR)seems to be more variable [7678].

Linker for activation of T cells (LAT), a membrane protein that plays animportant role in T-cell activation, which appears early during T-celldevelopment and is present on T- and NK-cells, among others, is expressed inthe great majority of T- and NK-cell neoplasms [81]. CD70, the receptor for CD27, was also found to be expressed bothon NK-cell lines and on NKTCL lymphoma cells [82].

Ki67 is also frequently positive and the percentage of Ki67+ cellshas proven to be a prognostic factor in extranodal NKTCL [83]. The Ki-67 protein (also known as MKI67) is a nuclear markerstrictly associated with cell proliferation, which is present during allactive phases of the cell cycle (G1, S, G2, and mitosis), but is absent fromresting cells (G0) [84].

The fact that interactions between chemokines and chemokine receptors areinvolved in migration of lymphoma cells and tissue invasion have lead to theinvestigation of chemokine receptor expression on NKTCL cells [69, 70, 74, 75]. These studies revealed that NKTCL cells usually express CXCR3,whose main ligand is CXCL11 (IP9, IFN-gamma inducible protein type 9) [6870]. In addition, ANKL cells are simultaneously positive for CXCR1and CCR5, whose major ligands are CXCL1 (interleukin-8, IL-18) and the CCL3(MIP-1alpha, macrophage inflammatory protein type 1 alpha), CCL4 (MIP-1beta)and CCL5 (RANTES, regulated on activation, normal T cell expressed andsecreted) chemokines, respectively [74, 75].

Primary nodal NKTCL have the same phenotypic and genotypic characteristics asextranodal NKTCL, at least for the markers that are frequently tested, mostof them being described as being CD2+, sCD3-,cytCD3epsilon+, CD56+, EBV+ and ashaving the TCR genes in germ-line configuration; moreover, they also usuallyhave a CD4-, CD5-, CD7-, cytotoxicmolecules+ phenotype [48, 49, 52].

In overall, the immunophenotypic features of the neoplastic NK-cells frompatients with NKTCL and ANKCL are different from those of normal peripheralblood NK-cells [85], reactive NK-cells from patients with acute and chronic NK-celllymphocytosis associated with viral infections and tumors [86, 87], and monoclonal CLPD-NK [88].

Chromosomal and genomic abnormalities

Cytogenetic analyses of the NK-cell neoplasms are difficult because of thescarcity of specimens, small-size samples, tissue necrosis and the presenceof inflammatory cells. Despite these difficulties, several studies wereperformed to date [8996], some of them using comparative genomic hybridization and loss ofheterozygosity techniques. Currently, genetic abnormalities specific forNKTCL and ANKL have not yet been identified, although complex chromosomalaberrancies occur in a large fraction of cases, abnormalities of thechromosome 6 being the most frequent finding [89]. In overall, cytogenetic aberrancies are seen in up to 77% ofcases and karyotypic abnormalities observed include pseudodiploidy(57%), hyperdiploidy (30%), and hypodiploidy (13%) [89]. Recurrent abnormal chromosomal losses are 6q16–q25,11q23.1, 11q24-q25, 13q14.11 and 17p13.3, among others; chromosomal gainsinclude 1q21–q44, 2q13-q14, 2q31.1–q32.2, 6p25–p11.1,7q11.2–q34, 7q35-q36 and 17q21.1 [8996]. A common deletion on 6q in the target area 6q21-25 wasidentified, affecting multiple genes that are probably involved inoncogenesis and disease progression [9096].

Concluding remarks

Mature NK cell neoplasms comprise a wide spectrum of entities, from cases with anindolent disease course (chronic NK-cell lymphocytosis) to cases with aggressiveclinical behavior (NKTCL and ANKCL). Aggressive NK-cell neoplasms areEBV-related diseases with a particular geographic distribution, have a typicalimmunophenotype and complex karyotypic abnormalities, often affecting extranodalorgans and tissues, invading and destroying the adjacent structures, causinghemophagocytosis and disseminating thought the body. Due to their rarity, theyare difficult to diagnose and to manage, and except for nasal NKTCL in earlystages, they are refractory to the available therapies and have a very poorprognosis. Thus, multicentric registering studies and clinical trials are neededin order to better understand the disease biology and to develop new therapeuticagents.

Endnotes

a The estimated incidence of NHL varies worldwide, with the highest ratesbeing reported in the most economically developed regions of the world (e.g.Northern America, Australia/New Zealand, and Northern Europe) and the lowest ratesin the least developed regions (e.g. South-Central and Eastern Asia, and theCaribbean). According to data provided by the Cancer Research, UK(http://www.cancerresearchuk.org/, accessed in 10 September 2011),the crude incidence rate in the UK in 2009 was 22 new NHL cases for every 100,000males and 18 for every 100,000 females and within the countries of the EuropeanUnion, the highest age standardized incidence rates for 2008 were estimated to be inLuxembourg for men (around 19 cases per 100,000) and Ireland for women (more than 13cases per 100,000), while the lowest rates were found in Greece for both sexes (eacharound 3 cases per 100,000).

Author’s information

ML is a senior medical doctor, responsible for the Laboratory of Cytometry of theDepartment of Hematology, Hospital de Santo António, Centro Hospitalar doPorto, Porto, Portugal. The Laboratory of Cytometry is a reference laboratory forthe diagnosis of T- and NK-cell disorders. The author has been dedicated to thediagnosis and treatment of T- and NK-cell lymphoproliferative disorders and hasalready published a large number of papers in this field.

Abbreviations

ANKCL:

Aggressive NK-cell leukemia

CCL3:

C-C motif chemokine ligand type 3, alsoknown as MIP-1alpha

CCL4:

C-C motif chemokine ligand type 4, also known asMIP-1beta

CCL5:

C-C motif chemokine ligand type 5, also known as RANTES

CCR5:

C-Cmotif chemokine ligand type 5 (CD195)

CLPD-NK:

Chronic lymphoproliferativedisorders of NK-cells

CXCL1:

C-X-C motif chemokine ligand type 1, also known asIL-18

CXCL11:

C-X-C motif chemokine ligand type 3, also known as IP9

CXCR1:

C-X-Cmotif chemokine ligand receptor type 1 (CD181)

CXCR3:

C-X-C motif chemokine ligandreceptor type 3 (CD183)

EBNA:

Epstein Barr virus nuclear antigens

EBV:

Epstein-Barr virus

FasL:

Fas ligand

ICD:

International Classification of Diseases(now International Statistical Classification of Diseases and Related HealthProblems)

ICD-O:

International Classification of Diseases for Oncology

IL-8:

Interleukin-8 (CXCL1)

IP9:

IFN-gamma inducible protein type 9 (CXCL11)

IPTCLP:

International Peripheral T-cell Lymphoma Project

KIR:

Killer immunoglobulin-likereceptors

KLR:

C-type lectin-like receptors

LAT:

Linker for activation of T cells

LDH:

Lactate dehydrogenase

LGL:

Large Granular Lymphocytes

LMP:

EBV-encoded latentmembrane protein

MIP-1alpha:

Macrophage inflammatory protein type 1 alpha (CCL3)

MIP-1beta:

Macrophage inflammatory protein type 1 beta (CCL4)

NHL:

Non-Hodgkin’s lymphoma

NK:

Natural killer

NKTCL:

NK/T cell lymphoma

PCR:

Polymerase chain reaction

RANTES:

Regulated on activation, normal T cell expressedand secreted (CCL5)

TCR:

T cell receptor

TIA-1:

T-cell–restrictedintracellular antigen

WHO:

World Health Organization.

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Acknowledgements

The author thanks to the medical doctors (Catarina Lau, Maria dos Anjos Teixeira)and other professionals (Ana Helena Santos, João Rodrigues, LurdesOliveira, Maria Luís Queirós, Marlene Santos, Marta Gonçalves andSónia Fonseca) and collaborators (Magdalena Leander) of the CytometryLaboratory, for the support and collaboration concerning NK-cellimmunophenotyping and diagnosis of NK-cells lymphoproliferative disorders. Shealso thanks to the medical doctors who have referred patients for study.

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ML reviewed the literature on the subject, had write and approved the finalmanuscript.

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Lima, M. Aggressive mature natural killer cell neoplasms: from epidemiology todiagnosis. Orphanet J Rare Dis 8, 95 (2013). https://doi.org/10.1186/1750-1172-8-95

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