Natural Killer Cell Neoplasms - University of Wisconsinâ€“Madison

Natural Killer Cell Neoplasms

Xiayuan Liang, MD1,2

Douglas K. Graham, MD, PhD3,4

1 Department of Pathology, Children’s Hospital,Denver, Colorado.

2 Department of Pathology, University of ColoradoSchool of Medicine, Denver, Colorado.

3 Section of Hematology/Oncology, Children’sHospital, Denver, Colorado.

4 Department of Pediatrics, University of ColoradoSchool of Medicine, Denver, Colorado.

Natural killer (NK) cell tumors are an uncommon and heterogeneous group of dis-

orders. The World Health Organization (WHO) classified mature NK cell neo-

plasms into 2 types: 1) extranodal NK cell lymphoma, nasal type and 2) aggressive

NK cell leukemia. The mature NK cell tumors are prevalent in Asia and Central

and South America. These tumors show polymorphic neoplastic infiltrate with

angioinvasion and/or angiodestruction, cytoplasmic azurophilic granules, CD2-

positive (CD21)/CD3-negative (CD32)/cCD3e1/CD561 phenotype, and strong

association with Epstein-Barr virus (EBV). Loss of chromosomes 6q, 11q, 13q, and

17p are recurrent aberrations. Although blastic NK cell lymphoma, currently

referred to as CD41/CD561 hematodermic neoplasm, also was included in the NK

cell lymphoma category in the WHO classification scheme, existing evidence indi-

cates a plasmacytoid dendritic cell derivation as opposed to an NK cell origin.

Recently, rare cases of CD561 immature lymphoid tumors have been reported in

the literature. These tumors are characterized by blastic appearance, CD32/CD42/

CD561/CD132/CD332 phenotype, T-cell receptor and immunoglobulin genes in

germline configuration, and no evidence of EBV, suggesting a true immature NK

cell derivation. For this article, the authors reviewed the recent concepts and pro-

gress in clinicopathologic features, pathogenesis, genetic characteristics, diagnosis,

differential diagnosis, treatment approaches, and outcomes of all subtypes of NK

cell neoplasms. Cancer 2008;112:1425–36. � 2008 American Cancer Society.

KEYWORDS: natural killer cell lymphoma, natural killer cell leukemia, naturalkiller cell, natural killer cell tumor, CD56.

N atural killer (NK) cells represent a lineage of non-T lymphocytes

and non-B lymphocytes that mediate a major histocompatibility

complex, nonrestricted cytotoxicity against tumor cells and bacterial

or viral infected cells.1 NK cells constitute <5% of peripheral blood

lymphocytes with large granular lymphocyte (LGL) morphology. NK

cells are derived in bone marrow from hematopoietic stem cells

through the intermediate developmental stages of lymphoid stem

cells, bipotential T/NK progenitor cells, and committed NK progeni-

tor cells.2–4 Therefore, NK cells express variably T-lineage-associated

antigens (CD2 and/or CD7). By definition, NK cells are surface CD3-

negatiave (CD32) and myeloperoxidase (MPO)2, and have germline

configuration of T-cell receptor (TCR) and immunoglobulin (Ig)

genes.5–7 CD16, CD56, and CD57 are NK-associated antigens.

Among these 3 markers, CD56 (neural cell adhesion molecule) is

expressed most consistently.8

NK cell neoplasms are a rare and heterogeneous group of disor-

ders with a broad spectrum of morphologic, immunophenotypic,

and clinical features. The World Health Organization (WHO) classifi-

cation encompasses 3 distinct entities: 1) aggressive NK cell leuke-

mia9; 2) extranodal NK/T-cell lymphoma, nasal type10; and 3) blastic

Address for reprints: Xiayuan Liang, MD, Depart-ment of Pathology, Children’s Hospital, 13123East 16th Avenue, Aurora, CO 80045; Fax: (720)777-7119; E-mail: [email protected]

Received August 3, 2007; revision receivedOctober 11, 2007; accepted October 16, 2007.

ª 2008 American Cancer SocietyDOI 10.1002/cncr.23316Published online 19 February 2008 in Wiley InterScience (www.interscience.wiley.com).

1425

NK cell lymphoma.11 In recent years, the conceptual

view of NK cell neoplasms has changed as the result

of further understanding of the cell derivations and

the characteristics of the malignant counterparts.

Currently, it is believed that blastic NK cell lym-

phoma derives from plasmacytoid dendritic cells

(pDCs) rather than NK cells.12–14 In this article, we

review the recent concepts and progress in clinico-

pathologic features, pathogenesis, cytogenetics, diag-

nosis, differential diagnosis, treatment strategies, and

outcomes of this group of uncommon neoplasms.

Clinicopathologic Categorizations and FeaturesOn the basis of morphology, immunophenotype,

functional NK cell activity, and expression of cyto-

toxic molecules, NK cell neoplasms can be divided

into immature and mature categories.5,7,15–20 In the

last 2 decades, a number of patients with CD56-posi-

tive (CD561) blastoid hematopoietic tumors have

been reported in the literature, suggesting the exis-

tence of neoplasms arising from immature NK

cells.6,16–32 In contrast, it is believed that aggressive

NK cell leukemia and extranodal NK cell lymphoma,

nasal type originate from mature NK cells.5,9,10,15

Precursor NK cell neoplasms and otherhistorically related entitiesPrecursor lymphoblastic lymphoma/leukemia (LBL)-

expressing NK cell-associated antigens was recog-

nized first by Sheibani et al. in 1987.16 Six tumors that

expressed CD16 and CD57 in addition to terminal de-

oxynucleotidyl transferase (TdT), CD2, and CD4 were

identified among 38 patients who were screened for

LBL. These tumors, as a group, were designated ‘‘NK-

LBL.’’16 Subsequently, CD56 has been recognized as a

sensitive marker for NK cells and has become popular

for identifying NK cell neoplasms. There are approxi-

mately 200 CD561 hematopoietic neoplasms with

immature features reported in the literature using an

array of names. However, CD56 is not a NK cell-speci-

fic marker and can be expressed by other neo-

plasms,33,34 and it has been difficult to determine

whether these tumors are of a true NK cell derivation.

Blastic NK cell lymphoma (CD41/CD561 hematodermic

neoplasm). Starting in 1994, several individual cases

or small series of lymphoblastoid-appearing tumors

that expressed CD4 and CD56 and involved the

skin, bone marrow, and lymph node were reported

that described such tumors as a distinct entity.22 An

NK cell origin was suggested for many of these

lesions based on CD56 expression in the absence of

markers of T-cell, B-cell, and myeloid lineage-specific

antigens.6,7,17–19,21,28–32 Consequently, these tumors

were classified provisionally as blastic NK cell lym-

phoma in the WHO classification scheme of hemato-

poietic tumors.11 However, CD56 is not a specific

marker for NK cells,33,34 CD4 expression is not typi-

cal of NK cell development,35 and previous attempts

to differentiate CD41/CD561 tumors into NK cells

were not successful.36,37 In searching for an alterna-

tive to an unlikely NK cell origin, an important dis-

covery of strong expression of surface CD123, a

molecule mainly expressed by dendritic cells (DCs)

and pDCs, by these CD41/CD561 tumors suggested

an origin from pDCs.14,38,39 Further progress came

with the immunophenotypic and functional evidence

that most CD41/CD561 tumors are related to the

pDC lineage.12–14 Immunophenotypically, they share

expression of CD4, CD43, CD68, CD123, human leu-

kocyte antigen-D related (HLA-DR), TCL-1, and the

cutaneous lymphocyte associated antigen (CLA).

They are negative for the major T-, B-, and myeloid

cell differentiation antigens (CD3, CD19, CD20, and

MPO).12,13 Functionally, Chaperot et al. demonstrated

that cultured CD41/CD561 tumor cells exhibited fea-

tures of pDCs like secreting interferon-a, undergoingdifferentiation to DCs with interleukin-3 stimulation,

and being able to stimulate naive T lymphocytes.14

More recently, it was demonstrated that a more spe-

cific DC marker, blood DC antigen 2 (BDCA-2), is

expressed in a subset of these CD41/CD561 tumors,

which further supports the pDC derivation of this

type of tumor.40 However, some issues remain unde-

termined, such as an association of this type of

CD41/CD561 tumor with precedent, concurrent, or

subsequent myelomonocytic tumors41 and lacking

expression of CD56 on nonneoplastic pDCs.42 More

investigation is required to establish the definitive

nature of this type of CD41/CD561 tumor.

The term agranular CD41/CD561 hematodermic

tumor originally proposed by Petrella et al.39 has the

virtues of describing a key diagnostic feature, the

most common pattern of clinical manifestation, and

the defining immunophenotype. Therefore, it seems

suitable as a provisional name to replace the misno-

mer blastic NK cell lymphoma. In the recent WHO-

European Organization of Research and Treatment of

Cancer classification of cutaneous lymphoma, the

term blastic NK cell lymphoma was replaced with

CD41/CD561 hematodermic neoplasm.43

CD42/CD561 immature NK cell tumors (provisional

precursor NK cell neoplasms). There are rare cases of

CD561 immature lymphoid tumors reported in the

literature that do not match the features of blastic

NK cell lymphoma (CD41/CD561 hematodermic

1426 CANCER April 1, 2008 / Volume 112 / Number 7

neoplasm). The cells in these tumors are character-

ized by a blastic appearance (Fig. 1) with a compos-

ite phenotype (CD42/CD561/CD132/CD332), and

they lack expression of CD3, CD19, CD20, and

MPO. Five well documented cases were identified in

the English literature (Table 1).44–48 It is noteworthy

that all of the patients in those reports were female

and were primarily of Asian and Hispanic descent

(4 of 5 patients; 80%). Those patients ranged in age

from 4 years to 57 years, and their median age was

14 years, which was much younger than the median

age for patients with blastic NK cell lymphoma

(CD41/CD561 hematodermic neoplasm) (age range,

8–96 years; median age, 63.5 years in 1 study).49

These findings were similar to the observations

reported by Sheibani et al.16 The patients frequently

presented with leukemia and lymphadenopathy

without skin involvement. These tumors were nega-

tive for EBV. TCR and/or Ig genes were in germline

configuration in all tumors in which the tests were

performed. Two patients with complete karyotype

results showed add(21)(p11). It is unclear whether

this karyotype represents a recurrent chromosome

aberration given the very small number of patients

and the limited cytogenetic data. The outcomes of

these patients were unfavorable, because only 2 of 5

patients (40%) were alive 3 years after diagnosis.

Although the characteristics of precursor NK cells

have not been defined fully, the immature morphol-

ogy with NK cell-associated phenotype and geno-

type suggest that these tumors likely represent true

precursor NK cell neoplasms.

Recent advances in the developmental biology of

T cells and NK cells indicate that both cell types are

derived from a common T/NK cell thymic precursor.

Interleukin 15 (IL-15) and transcription factor ID2

are essential for the NK cell lineage to diverge from

the T cell lineage.20 CD94 1A, a distal promoter of

the CD94 molecule (an NK cell receptor), is activated

only by IL-15.20,50,51 Lin et al. recently reported that

CD94 1A is the predominant form expressed in

immature NK cells20 and is expressed in TCR2 LBL

(NK-LBL) but not in TCR1 LBL (T-LBL). On the basis

of the expression of CD94 1A transcripts and nega-

tive TCR, those investigators identified 7 patients

with LBL of immature NK cell origin (CD94 1A1,

TCR2) by studying 21 patients with LBL. It is note-

worthy that those NK-LBLs occurred in younger

patients and had better outcomes compared with

patients who had T-LBL (CD94 1A2, TCR1), and

none of the tumors were positive for CD56. Because

CD56 is not lineage-specific, it is not surprising that

neither its presence nor its absence implies commit-

ment to NK cell lineage. Thus, the use of CD94 1A in

conjunction with TCR appears to be more precise for

identifying an immature NK cell neoplasm than

CD56 alone.

Myeloid/NK cell leukemia/lymphoma. In 1994, Scott

and colleagues described a distinct form of acute

leukemia that shared features of both myeloid and

NK cells and designated it myeloid/NK cell acute

leukemia.52 These tumors have the following charac-

teristics: 1) acute promyelocytic leukemia-like mor-

phology; 2) the presence of MPO1/Sudan Black1

cytoplasmic, fine, azurophilic granules; 3) lack of

t(15;17) and the resultant PML/RARa fusion tran-

script; 4) a unique immunophenotype (HLA-DR2/

CD331/CD561/CD162/CD32); and 5) functional NK

cell-mediated cytotoxicity in a subset of tumors.

Furthermore, those investigators also identified nor-

mal CD331/CD561/CD162 counterpart cells in pe-

ripheral blood from healthy individuals and

proposed that this type of acute leukemia may arise

from transformation of a precursor cell that is com-

mon to the myeloid and NK cell lineage.

Later, Suzuki et al. proposed another disease

entity, CD71 and CD561 myeloid/NK cell precursor

acute leukemia, based on its phenotypic similarity to

the myeloid antigen-positive NK cell precursors.53

This entity is characterized by extramedullary

involvement, blastic morphology without cytoplas-

mic granules and MPO reactivity, CD71/CD561/

CD331/CD341/CD32 phenotype, and poor progno-

sis.17,18 Several more patients with this type of leu-

kemia were reported in the literature after its initial

FIGURE 1. Morphologic features of a CD4-negative/CD56-positive imma-ture natural killer-cell tumor. The tumor cells show lymphoblastic features

with a high nuclear:cytoplasmic ratio, slightly dense chromatin, and indistinct

nucleolus.

Natural Killer Cell Tumors/Liang and Graham 1427

TABLE

1Clin

icop

atho

logicFe

atur

esof

CD4-ne

gative

/CD56

-pos

itiveIm

matur

eNatur

alKiller-cellTu

mor

s(Provision

alPr

ecur

sorNatur

alKiller-cellNeo

plasms)*

Patien

tReferen

ceAg

e,y

Rac

eOrgan

invo

lvem

ent

Immun

ophe

notype

EBVstatus

TCR/IgH

gene

sCy

toge

netics

Trea

tmen

tan

dou

tcom

e

1Lian

g20

0744

4Hispa

nic

BM,L

NCD32

CD42

CD13

2CD19

2CD20

2CD33

2CD56

1CD21

CD71

CD82

CD10

2CD16

2CD34

2CD57

2Td

T2MPO

2HLA

-DR1

GrazymeB2

Neg

ND

Loss

ofTE

L(12

p13)

byFISH

NHLtherap

y;alloge

neic

BMT;

aliveat

3y

2Dub

ois20

0245

9Cau

casian

BM,L

NCD32

CD42

CD13

2CD19

2CD20

2CD33

2CD56

1CD22

cCD32

CD52

CD71

CD82

CD10

2CD16

2CD34

2

CD57

2Td

T2MPO

2HLA

-DR1

GrazymeB

2

Neg

G/G

43,XX,de

l(2)(p2

3),a

dd(3)(p1

2),

del(6

)(q23

),29,211

,213

,

add(19

)(q1

3.3),2

20,a

dd(21)

(p11

.2),1

mar

ALLtherap

y;relaps

ed;D

OD

at35

mo

3Hya

kuna

2004

4614

Asian

BM,p

leura,

med

iastinum

,

perica

rdium

CD32

CD42

CD13

2CD33

2CD56

1CD21

cCD32

CD51

CD71

CD34

1HLA

-DR1

Neg

G/G

46,XX,ad

d(2)(q33

),ad

d(21

)(p1

1)AL

Ltherap

y;BM

Tfrom

aHLA

-

iden

tical

sibling;

aliveat

3y

4Matan

o19

9947

57As

ian

BM,L

N,liver,s

plee

n,

ascites

CD32

CD42

CD13

2CD19

2CD20

2CD33

2CD56

1CD21

CD52

CD71

CD82

CD10

2CD16

2CD57

2Td

T2

HLA

-DR1

GrazymeB

2TIA-

12

Neg

G/G

Threeco

ursesof

behe

noyl,a

ra-C

,

doxo

rubicin,

etop

oside,

and

pred

niso

lone

;relap

sed;

DOD

at25

mo

5Ta

mura19

9848

38As

ian

BM,L

N,lun

gs,p

ancrea

sCD32

CD42

CD13

2CD19

2CD20

2CD33

2CD56

1

CD22

cCD32

CD52

CD72

CD82

CD10

2

CD16

1CD34

2MPO

2HLA

-DR2

Neg

G/G

CHOP;

DOD

at6mo

EBVindica

tesEp

stein-

Barr

virus;

TCR,

T-ce

llrece

ptor;IgH

,immun

oglobu

linhe

avych

ain;

BM,b

onemarrow;L

N,lym

phno

des;

1,p

ositive

;2,n

egative;

TdT,

term

inal

deox

ynuc

leotidyl

tran

sferase;

MPO

,mye

lope

roxida

se;H

LA-D

R,hu

man

leuk

ocytean

tigen

D-related

;Neg

,neg

a-

tive;

ND,n

otdo

ne;T

EL,trans

loca

tionetsleuk

emia;F

ISH,fluoresce

ncein

situ

hybridization;

NHL,

non-

Hod

gkin

lymph

oma;

BMT,

bone

marrow

tran

splantation;

G,g

ermlin

e;de

l,de

letio

n;ad

d;ad

ditio

n;mar,m

arke

rch

romos

ome;

ALL,

acutelymph

oblastic

leuk

emia;D

OD,d

ied

ofdisease;

TIA-

1,T-ce

llintrac

ellularan

tigen

;ara-C

,cytos

inearab

inos

ide;

CHOP,

cyclop

hosp

hamide,

doxo

rubicin,

vinc

ristin

e,an

dpred

niso

ne.

*All5

patie

ntsrepresen

tedin

this

tableweregirls

orwom

en.


identification.54–58 However, because CD56 expres-

sion has been identified in approximately 20% of

patients with acute myeloid leukemia (AML),59 the

features of immature cytologic appearance and the

presence of myeloid antigen without light-micro-

scopic MPO reactivity in this type of leukemia over-

lap with those in AML with minimal differentiation

(French-American-British classification, AML-M0).

Because there were only a small number of patients

studied and the terminology of CD71 and CD561

myeloid/NK cell precursor acute leukemia has not

been recognized widely, currently, it is believed that

this subset of leukemia falls into the category of

AML-M0.60 Comparing CD71/CD561 M0 with other

M0 (CD72/CD562, CD72, or CD562), Suzuki et al.

observed a significantly younger age of onset, no 5q

abnormalities, more frequent extramedullary involve-

ment, and worse disease-free survival in the patients

with CD71/CD561 M0 disease. Multivariate analysis

demonstrated that the CD71/CD561 phenotype was

a significant and an independent poor prognostic

factor for patients with AML-M0.60 Additional clini-

copathologic studies are needed to elucidate whether

this subtype of acute leukemia represents a distinct

entity.

Mature NK cell neoplasmsThe distinct nature of NK cell tumors was acknowl-

edged formally at the Hong Kong workshop in

1996.15 Several clinicopathologic entities have been

recognized.

Extranodal NK cell lymphoma, nasal type. Both nasal

and nasal-type (extranasal) NK cell lymphomas are

more prevalent in Asia, Mexico, and Central and

South America10,61 and are characterized by extrano-

dal presentation and an aggressive clinical course.

Because nasal NK cell lymphoma and extranasal NK

cell lymphoma share the same histology, the WHO

classification groups both nasal NK cell lymphoma

and extranasal NK cell lymphoma in the same cate-

gory.10 However, nasal and extranasal NK cell lym-

phomas have different clinical manifestations,

treatment approaches, and prognoses.61

Nasal NK cell lymphomas refer to tumors that

occur in the nose and the upper aerodigestive

tract.62–67 They are the most common type among

primary lymphomas of the nasal cavity.8 Men are

affected more than women, and the median age at

diagnosis in the fifth decade. The location is primar-

ily in the midline and includes the nasal cavity, naso-

pharynx, paranasal sinuses, tonsils, hypopharynx,

and larynx. Common symptoms include nasal dis-

charge, nasal obstruction, purulent rhinorrhea, epis-

taxis, and local swelling of the nasal bridge. In

patients with more advanced disease, there may be

erythema, swelling of the face, proptosis, and impair-

ment of extraocular movement.8,62,67 The tumors

may be destructive, leading to the highly characteris-

tic midline perforation.

Extranasal NK cell lymphomas represent the

counterpart of nasal NK cell lymphomas and involve

any other part of the body. Men are affected predo-

minantly, and the median age of presentation is in

the fifth decade. Primary sites of involvement include

the skin, gastrointestinal tract, salivary glands,

spleen, and testis.7 The diagnosis of extranasal NK

cell lymphoma requires the exclusion of nasal invol-

vement at presentation. A nasal panendoscopy with

random biopsies should be performed to rule out

occult involvement.61 Patients with extranasal NK

cell lymphoma are more likely to exhibit a more

advanced stage of disease with significantly higher

International Prognostic Index and lactate dehydro-

genase levels and with significantly lower hemoglo-

bin and platelet levels compared with patients who

have nasal NK cell lymphoma.

The histologic features are similar regardless of

the involved sites. Mucosal sites often show ulcera-

tion. The lymphomatous infiltrate is diffuse (Fig. 2

[Top]). An angiocentric and angiodestructive growth

pattern with associated fibrinoid changes in the

blood vessels is observed frequently. Coagulative ne-

crosis and apoptosis are common. In most patients,

the tumor is composed of medium-sized cells or a

mixture of small and large lymphoid cells with mod-

erate amount of cytoplasm, irregular or elongated

nuclei, granular or vesicular chromatin, and incon-

spicuous, small nucleoli (Fig. 2 [Bottom]). Mitotic

figures are found easily. In Giemsa-stained touch pre-

parations, azurophilic cytoplasmic granules com-

monly are detected. There may be admixture of

inflammatory cells consisting of small lymphocytes,

plasma cells, histiocytes, and eosinophils in some

patients.10

Aggressive NK cell leukemia. Aggressive NK cell leu-

kemia was characterized first by Imamura et al.68,69

This is a catastrophic, systemic disease and also is

more prevalent in Asians than in Caucasians.9 It is

characterized by the presence of neoplastic NK cells

mainly in the peripheral blood and bone marrow

and by a rapidly progressive clinical course. There is

an equal sex incidence in men and women. The dis-

ease typically affects young to middle-aged adults

with a median age in the third decade. Patients usu-

ally are very ill at presentation with fever, systemic

symptoms, liver dysfunction, and hepatosplenome-


galy sometimes accompanied by systemic lymphade-

nopathy. In contrast to extranasal NK cell lymphoma,

skin lesions are uncommon. Some patients may have

disease that is complicated by a reactive hemophago-

cytic syndrome.8 Severe anemia and thrombocytope-

nia are common because of bone marrow

involvement or active hemophagocytosis.70 The clini-

cal progression is inexorable despite treatment, and

most patients survive for only days to weeks.

Morphologically, the leukemic cells in aggressive

NK cell leukemia are slightly larger than normal

LGLs. There is an ample amount of pale or slightly

basophilic cytoplasm that contains fine or coarse

azurophilic granules. Nuclei show slightly immature

chromatin pattern and inconspicuous or distinct

nucleoli (Fig. 3 [Top]). Hemophagocytosis is common

(Fig. 3 [Bottom]). In tissue sections, the neoplastic

infiltrate is diffuse, destructive, and permeative. The

lymphoid cell population often appears monomor-

phous.8 Necrosis, apoptosis, angioinvasion, and

angiodestruction are common findings.7–9,71–73

Chronic NK cell lymphocytosis. Chronic NK lympho-

cytosis is defined as chronic expansion of mature-

looking NK cells (�600/mL) in the peripheral blood

for �6 months.18,74,75 The median age of 16 patients

in 1 study was 60.5 years (range, 7–77 years).76 Most

patients present with a chronic, indolent course.18

Associated severe neutropenia, pure red cell aplasia,

FIGURE 2. Morphologic features of extranodal natural killer-cell lym-phoma, nasal type. (Top) Massive lymphoid infiltration in a biopsy of nasal

septum (hematoxylin and eosin [H&E] stain; original magnification, 3100).

(Bottom) Diffuse infiltration of small, medium-sized, and large neoplastic

lymphocytes in a biopsy of nasal septum (H&E; original magnification,

3400).

FIGURE 3. Morphologic features of aggressive natural killer-cell leukemia.(Top) In this peripheral blood smear, the neoplasm cell shows an ample

amount of cytoplasm that contains coarse, azurophilic granules and irregular

nuclei with a slightly immature chromatin pattern (Wright stain; original mag-

nification, 31000). (Bottom) Bone marrow aspirate smear shows hemopha-

gocytosis (arrow) (Wright stain; original magnification, 31000). Reproduced

with permission from Xiaoqin Wang, MD, PhD, Huashan Hospital, School of

Public Health, and Institutes of Biomedical Sciences, Fudan University,

Shanghai, China.


vasculitic syndromes, and fever with undetermined

origin are reported in some patients.76,77 Occasion-

ally, patients present with a slowly progressive

increase of peripheral blood NK cells and with organ

involvement. These cases may be labeled chronic NK

cell leukemia, but the clonality of the NK cells must

be proven. In rare cases, the disease transforms to

aggressive NK cell leukemia.18 Cytologically, the cir-

culating neoplastic cells show LGL morphology.

There is a moderate amount of pale cytoplasm that

contains �3 azurophilic granules (Fig. 4).76,77

All subtypes of mature NK cell neoplasms share

a typical immunophenotype of CD21/CD32/

cCD3e1/CD561/MPO2 and are cytotoxic molecule-

positive.9,10,76–79 The TCR gene typically is in germ-

line configuration. Another characteristic feature of

mature NK cell neoplasms, in contrast to immature

NK cell neoplasms, is the strong association with

EBV.79–81 Nasal NK cell lymphoma is associated

almost invariably with EBV infection (Fig. 5). Most

patients with aggressive NK cell leukemia, extranasal

NK cell lymphoma, and chronic NK cell lymphocyto-

sis also are positive for EBV. A large comprehensive

study of NK cell neoplasms in Japan by Oshimi et al.

indicated that EBV was detected in all patients with

nasal NK cell lymphoma (101 of 101 patients), in 22

of 25 patients with extranasal NK cell lymphoma, in

10 of 12 patients with aggressive NK cell leukemia,

and in 6 of 7 patients with chronic NK cell lympho-

cytosis.79 Analysis of the terminal repeat region of

the EBV genome indicated that the virus is in a clo-

nal episomal form. This finding, in addition to pro-

viding an indirect proof of the clonal nature of the

lymphoid proliferation, also implies that the EBV

may play an etiologic role in mature NK cell neo-

plasms rather than being a bystander.8,82,83

Conventional cytogenetic analysis of mature NK

cell neoplasms is difficult, partly because of necrosis

and the scarcity of specimens.8 A study by Wong

et al.84 demonstrated that 77% (23 of 30) of patients

with mature NK cell neoplasms had abnormal clonal

karyotypes. Most patients exhibited pseudodiploidy

(57%; 13 of 23 patients), hypodiploidy (<46 chromo-

somes) was identified in 3 of 23 patients (13%), and

7 patients (30%) were hyperdiploid (>46 chromo-

somes).84 Abnormalities of chromosome 6 were the

most frequent findings. A common deletion on 6q in

the target area 6q21-25 has been defined by fluores-

cence in situ hybridization and molecular genetic

methods.85,86 Comparative genomic hybridization

and loss of heterozygosity studies have indicated

that, in addition to deletion of 6q21-25, deletions in

chromosome 11q, 13q and 17p also were pres-

ent.8,87,88 The putative genes implicated in these

deletions have not been identified.

Diagnostic Criteria and Differential DiagnosisDiagnosis of NK cell neoplasms requires the integra-

tion of clinical presentation, morphology, immuno-

phenotype, and genotype. Expression of at least 1 NK

cell marker (CD56, CD16, or CD57); lack of expres-

sion of surface CD3, B-cell antigens (CD19 and

CD20), MPO, and other lineage markers; and/or TCR

and Ig genes in germline configuration in tumors are

FIGURE 4. Morphologic features of chronic natural killer-cell lymphocyto-sis. A peripheral blood smear shows a large granular lymphocyte (arrow)

with moderate amount of cytoplasm containing a few fine, azurophilic gran-

ules (Wright stain; original magnification, 31000).

FIGURE 5. Epstein-Barr virus (EBV) signal was detected in tumor cells byin situ hybridization for EBV-encoded small RNA in a patient with extranodal

natural killer-cell lymphoma, nasal type (original magnification, 3400).


essential. EBV status is supportive. It is important to

distinguish T-cell neoplasms, myelomonocytic neo-

plasms, and myeloid neoplasms with CD56 expres-

sion and CD41/CD561 hematodermatic neoplasm

from true NK cell neoplasms. The differential diag-

nostic features are proposed and summarized in

Table 2.

Treatment and PrognosisCD42/CD561 immature NK cell tumors (provisionalprecursor NK cell neoplasms)A standard treatment protocol for immature NK cell

neoplasms has not been established because of the

paucity of patients. Chemotherapy, non-Hodgkin

lymphoma, or acute lymphoblastic leukemia (ALL)

therapeutic strategies were the most common. How-

ever, the overall outcomes were dismal. Two pediatric

patients (Patients 1 and 3) (Table 1) who received

non-Hodgkin lymphoma therapy and ALL therapy,

respectively, followed by allogeneic hematopoietic

stem cell transplantation (HSCT) achieved complete

remission for 3 years. Three other patients (Patients

2, 4, and 5) who did not undergo bone marrow trans-

plantation died of disease between 6 months and 35

months. Further studies are necessary to determine

whether increased survival can be obtained with

aggressive chemotherapy followed by HSCT. It is pos-

sible that allogeneic HSCT could provide additional

graft versus leukemia/lymphoma benefit. The age of

disease onset also appears to be an important prog-

nostic factor. Two patients who were in remission

were pediatric patients (Patients 1 and 3). This obser-

vation is consistent with other studies.19 In the study

on CD561 blastic tumors by Suzuki et al., patients

aged >30 years had worse outcomes than patients

aged <30 years.19

Mature NK cell neoplasmsThe clinical outcome of patients with nasal NK cell

lymphoma is variable. Most observational studies

have demonstrated consistently that radiotherapy is

superior to chemotherapy alone in patients with

stage I/II disease.89–91 Some patients with early-stage

disease are cured by radiation therapy. It has been

demonstrated that radiotherapy, either as initial

treatment or as part of the chemotherapy regimen, is

the single most important key to a successful out-

come.66,90,93–96 However, some patients with early-

stage disease have early local or systemic recurrences

and die of disease. For patients with stage III/IV

disease, chemotherapy is the mainstay of treat-

ment.61 In several published series, the median sur-

vival of patients with advanced-stage disease was

approximately 12 months.62,70

Extranasal NK cell lymphomas are clinically

aggressive. Because the disease may be disseminated,

chemotherapy usually is the initial choice of treat-

ment.8 The response is poor, and most patients die

within 6 months after diagnosis.7,97 The long-term

remission rate with allogeneic HSCT reportedly is

<10%.67,92

Aggressive NK cell leukemia is a catastrophic dis-

ease with an almost uniform mortality. A few

patients have a clinical response with conventional

chemotherapy,61 although the response typically is

transient. Survival is measured in days to weeks.

Allogeneic HSCT reportedly results in short-term

remission in a few patients.98,99 To our knowledge,

no survival >1 year has been recorded.100

Patients with chronic NK cell lymphocytosis usu-

ally have an indolent clinical course and respond to

immunosuppressive therapy.77 Because of the poten-

tial long-term side effects of immunosuppressive

therapy, limiting specific therapy only to patients

with symptomatic disease is recommended.77

New therapeutic strategiesBecause of the inferior outcomes with current thera-

pies for NK cell neoplasms, novel approaches must

be considered to improve survival. Chemotherapeutic

agents currently being tested in cutaneous T-cell

lymphoma (CTCL) and peripheral T-cell lymphoma

(PTCL) provide possible new agents to consider for

NK cell treatment protocols. Examples of such agents

with efficacy in CTCL and/or PTCL include gemcita-

bine and liposomal doxorubicin as well as the purine

analogs, such as fludarabine and clardribine.101

Furthermore, the use of histone deacetylase inhibi-

tors (depsipeptide and vorinostat) is being tested in

CTCL.102,103 Monoclonal antibodies like alemtuzu-

mab have some activity in PTCL and are being inves-

tigated in combination with other therapy.101

Although no NK cell-specific antibodies are under

active development, the future availability of such

antibodies may offer novel treatment options. In

addition, a greater understanding of the signaling

pathways activated in NK cell neoplasms could make

other biologically targeted agents potential candi-

dates for inclusion in NK cell treatment protocols.

SummaryOverall, NK cell tumors are an uncommon, aggressive,

and heterogeneous group of disorders. Precursor NK

cell lymphoma/leukemia is an extremely rare clini-

copathologic entity that is characterized by blastic

morphology, CD32/CD42/CD561/CD132/CD332

immunophenotype with predominant CD94 1A

expression, TCR germline configuration, and lack of


TABLE

2Different

ialDiagn

osis

ofNatur

alKiller-cellNeo

plasms

Variab

lePr

ecur

sorNK

cell

neop

lasm

s(pro

vision

al)

CD41

CD56

1

hematod

ermic

neop

lasm

Mye

loid/N

Kce

llpr

ecur

sor

acut

eleuk

emia

(CD71

CD56

1M0)

Mye

lomon

ocytic/

mon

ocytic

tumor

sT-LB

L

Extran

odal

NK

cell

lymph

oma,

nasalt

ype

Aggressive

NK

cell

leuk

emia

Cello

rigin

ImmatureNKce

llPlasmac

ytoid

dend

ritic

cell

Mye

loid

prec

urso

rMye

loid

and/

ormon

ocytic

cell

ImmatureT-ce

llMatureNKce

llMatureNKce

ll

Major

orga

ninvo

lvem

ent

BM,L

NSk

inBM

,extramed

ullary

sites

BM,e

xtramed

ullary

sites

BM,m

ediastinum

,LN

Nasoc

avity

,extrana

soca

vity

Periph

eral

bloo

d,BM

Morph

olog

yBlastic

Blastoid

Blastic

Mye

loid/m

onoc

ytic

orblastic

Blastic

Pleo

morph

icce

llswith

angioinv

asion

andan

giod

estruc

tion

Maligna

ntlargegran

ular

lymph

ocytes

Cytop

lasm

icgran

ules

22

22/1

21

1Im

mun

ophe

notype

CD32

CD42

CD13

2

CD33

2CD56

1CD32

CD41

CD56

1CD32

CD71

CD13

/331

CD56

1CD32

CD41

CD13

/331

CD56

1CD31

CD56

�CD21

CD32

cCD3e

1CD56

1CD21

CD32

cCD32

1CD56

1

Other

marke

rs

MPO

22

<3%

1/2

22

2Ly

sozyme

22

21

22

2CD94

1A1

22

2CD94

1B2

21

1CD12

32

Strong

ly1

2Wea

kly1

22

2BD

CA-

22

1/2

22

22

2TC

L-1

21

22

1/2

22

TCRge

neGermlin

eGermlin

eGermlin

eGermlin

eRe

arrang

edGermlin

eGermlin

e

EBV

22

22

21

1

NKce

llindica

tesna

turalk

iller

cell;

T-LB

L,T-ce

lllymph

oblastic

lymph

oma/leuk

emia;B

M,b

onemarrow;L

N,lym

phno

de;2

,neg

ative;

1,p

ositive

;MPO

,mye

lope

roxida

se;B

DCA

-2,b

lood

dend

ritic

cellan

tigen

2;TC

R,T-ce

llrece

ptor;E

BV,E

pstein-B

arrvirus.


EBV positivity. Extranodal NK cell lymphoma, nasal

type; aggressive NK cell leukemia; and chronic NK cell

lymphocytosis originate from mature NK cells and

have distinct geographic distribution. A consistent

association with EBV infection suggests that the virus

may be of pathogenetic significance in these sub-

types. Further studies are needed to define the molec-

ular pathogenesis and biologic markers that aid in the

diagnosis of NK cell neoplasms. Furthermore, clinical

trials and/or multi-institutional cooperation are

necessary to define the optimal therapeutic strategies

that will lead to better outcomes in patients with this

uncommon group of disorders.

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Natural Killer Cell Neoplasms - University of Wisconsinâ€“Madison