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CD7 " and CD56 " Myeloid/Natural Killer Cell Precursor Acute Leukemia:
A Distinct Hematolymphoid Disease Entity
By Ritsuro Suzuki, Kazuhito Yamamoto, Masao Seto, Yoshitoyo Kagami, Michinori Ogura, Yasushi Yatabe,
Taizan Suchi, Yoshihisa Kodera, Yasuo Morishima, Toshitada Takahashi, Hidehiko Saito,
Ryuzo Ueda, and Shigeo Nakamura
The disease spectrum of natural killer (NK) cell leukemias
and lymphomas has recently been expanding with the continuing evolution in diagnostic concepts. We describe here
seven cases of acute leukemia of conceivable myeloid and
NK cell precursor phenotype in six men and one woman
varying from 19 to 59 years of age (median, 46 years). Striking extramedullary involvement was evident at initial presentation, with peripheral lymphadenopathy and/or mediastinal masses. Two lacked any leukemic cells in the bone
marrow at diagnosis. Using cytochemical myeloperoxidase
staining, less than 3% of the leukemic cells showed positive
reactivity. However, expression of CD7, CD33, CD34, CD56,
and frequently HLA-DR, but not other NK, T-cell, and B-cell
markers was observed. Cytoplasmic CD3 was detected in
three of the cases by flow cytometry and in six by Northern
blotting, suggesting an origin from common progenitors between the NK cell and myeloid lineages. All but one presented germline configurations of the T-cell receptor b and
g chain genes and Ig heavy chain gene. With regard to morphology, the cells were generally L2-shaped, with variation
in cell size, round to moderately irregular nuclei and promi-
nent nucleoli, pale cytoplasm, and a lack of azurophilic granules. Histopathologic examination of biopsied specimens of
extramedullary tumors showed a lymphoblast-like morphology, implying the differential diagnostic problem from
lymphoblastic lymphomas, especially in cases lacking bone
marrow involvement. Three patients were successfully
treated with chemotherapy for acute myeloid leukemia
(AML), whereas three other patients proved refractory to
chemotherapeutic regimens for lymphoid malignancies, although two responded to subsequent AML chemotherapy.
However, despite intensive chemotherapy, including allogeneic bone marrow transplantation, most persued fatal
courses within 41 months. These data suggested that the
CD7" and CD56" myeloid/NK cell precursor acute leukemia
might constitute a distinct biologic and clinical disease entity. Its recognition appears to be particularly important for
the clinicopathologic evaluation of CD56" hematolymphoid
malignancies and the development of therapeutic approaches to such disease.
q 1997 by The American Society of Hematology.
C
leukemia of conceivable myeloid/NK cell precursor phenotype (ie, CD7/, CD33/, CD34/, CD56/, and frequently
HLA-DR/ type) suggested to be immature in terms of morphology, phenotype, and genotype compared with those described by Scott et al.14 These seven cases were all characterized by extramedullary disease, represented by peripheral
lymphadenopathy and/or mediastinal bulky masses, with a
lymphoblastoid appearance and a lack of azurophilic granules in the cytoplasm. Clinically, most of them responded
to chemotherapeutic regimens for AML. However, in all,
except for one case that died of graft-versus-host disease,
D56 IS A 200- TO 220-kD glycoprotein expressed predominantly on human natural killer (NK) cells and a
minor subset of T cells mediating major histocompatability
complex (MHC)-nonrestricted cytotoxicity.1-4 Its expression
in leukemias and lymphomas has been extensively investigated over the past decade, and our knowledge of the CD56/
hematolymphoid malignancies has expanded dramatically.
The expression of CD56 is a rare phenomenon in
lymphoid malignancies, mostly confined to those of T/NK
cell origin,5-8 generally characterized by unique extranodal
involvement, with lesions in the nasal-paranasal region, skin,
lung, and stomach, and often display the angiocentric growth
pattern. Because the CD56 antigen has been found to correspond to a neural cell adhesion molecule with homophilic
binding characteristics,9,10 its expression in leukemia and
lymphoma cells is thought to play an important role in their
extranodal localization and behavior.5,11,12
In acute myeloid leukemia (AML), CD56 expression has
been identified in approximately 20% of the cases examined,
generally in association with a monocytic morphology and
cytogenetic abnormalities t(8;21) or trisomy 8.13 Because
the incidence of extramedullary tumor formation is identical
in both CD56/ and CD560 cases, the clinical significance
of CD56 expression remains to be elucidated. Recently, Scott
et al14 proposed a myeloid/NK cell acute leukemia disease
entity presenting the HLA-DR0, CD33/, CD56/, and CD160
phenotype, although CD7 was not covered in their series. A
mature myeloid morphology was manifested with deeply
invaginated nuclear membrane, scant cytoplasm with fine
azurophilic granules, and finely granular Sudan black B and/
or myeloperoxidase (MPO) cytochemical reactivity. In their
series, extramedullary disease was noted in only 5 (25%) of
the 20 cases.
We have identified seven cases of a unique form of acute
From the Department of Hematology and Chemotherapy, Department of Pathology and Clinical Laboratories, Aichi Cancer Center
Hospital, Nagoya, Japan; the Laboratory of Chemotherapy and Laboratory of Immunology, Aichi Cancer Center Research Institute,
Nagoya, Japan; the Department of Internal Medicine, Japanese Red
Cross Nagoya First Hospital, Nagoya, Japan; and the Department of
Internal Medicine, Nagoya University School of Medicine, Nagoya,
Japan.
Submitted February 6, 1997; accepted May 5, 1997.
Supported in part by a Grant-in-aid for the 2nd-Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health
and Welfare; a Grant-in-aid for Science on Primary Areas (Cancer
Research) from the Ministry of Education, Science and Culture,
Japan; and Bristol-Myers Squibb Unrestricted Biomedical Research
Grants Program.
Address reprint requests to Ritsuro Suzuki, MD, Department of
Hematology and Chemotherapy, Aichi Cancer Center Hospital, Kanokoden 1-1, Chikusa-ku, Nagoya, Japan 464.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
‘‘advertisement’’ in accordance with 18 U.S.C. section 1734 solely to
indicate this fact.
q 1997 by The American Society of Hematology.
0006-4971/97/9006-0009$3.00/0
Blood, Vol 90, No 6 (September 15), 1997: pp 2417-2428
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2418
SUZUKI ET AL
recurrence of leukemia occurred and they persued fatal clinical courses within 41 months, thus appearing to be more
aggressive than those of Scott et al.14 We believe that the
present cases provide fundamental data for understanding
the disease spectrum of myeloid/NK cell hematolymphoid
malignancies.
MATERIALS AND METHODS
Patients. During the 8-year period between 1988 and 1995,
seven cases of CD7/ and CD56/ myeloid/NK cell precursor acute
leukemias were encountered in the Aichi Cancer Center Hospital
(Nagoya, Japan). These cases were identified from more than 600
cases of fully immunophenotyped acute leukemias or malignant
lymphomas. The clinical records and pathologic materials of these
seven cases were reviewed.
Morphology. Patients’ bone marrow or peripheral blood cells
underwent May-Grünwald-Giemsa (MG), MPO, a naphthol AS-D
chloroacetate esterase, a naphthyl butyrate (NB) esterase, and periodic acid-Schiff (PAS) staining. Biopsied tissues were fixed in 10%
formaldehyde and embedded in paraffin. Sections were cut at 5 mm
and stained with hematoxylin and eosin, Elastica-van Gieson, silver
impregnation, PAS, MG, and methyl green-pyronin. Imprint smears
of the surgically resected specimen were stained with MG stain.
Immunophenotyping. Surface immunophenotyping of the tumor
cells was performed by flow cytometry using a broad panel of monoclonal antibodies (MoAbs). Mononuclear cells were separated from
heparinized bone marrow samples using Ficoll-Hypaque centrifugation. Fresh biopsied specimens were also made into single-cell suspensions, and the tumor cells were analyzed on FACStar and FACScan analyzers (Becton Dickinson, Mountain View, CA) for
fluorescent intensity using fluorescein isothiocyanate (FITC)- or phycoerythin (PE)-conjugated antibodies or unconjugated antibodies followed by fluorescein-conjugated antimouse second antibodies. The
MoAbs used were OKT6 (CD1), OKT11 (CD2), OKM1 (CD11b),
OKB7 (CD21), OKB22 (CD22), OKM5 (CD36), OKT10 (CD38),
and OKT9 (CD71) (Ortho Diagnostics, Rarian, NJ); Leu4 (CD3),
Leu3a (CD4), Leu1 (CD5), Leu2 (CD8), LeuM5 (CD11c), LeuM1
(CD15), Leu11 (CD16), Leu12 (CD19), Leu16 (CD20), HPCA-1
(CD34), HPCA-2 (CD34), Leu7 (CD57), TCR1 (TCRab), and antiTCRgd (Becton Dickinson); Tp120 (CD6) and Tp40 (CD7) (established in our laboratory15); TP82 (CD9), MCS-2 (CD13), KOLT2
(CD28), (CD41b), and Mik-b1 (CD122; Nichirei, Tokyo, Japan); J5
(CD10), My4 (CD14), My9 (CD33), and NKH-1 (CD56; Coulter,
Hialeah, FL); Tac (CD25; kindly provided by Dr T. Uchiyama,
Kyoto, Japan); and anti-CD11a, anti–HLA-DR, anti-IgA, anti-IgG,
anti-IgM, anti-IgD, anti-k, anti-l, anti-MPO, and anti-terminal
deoxynucleotidyl transferase (TdT; DAKO, Carpenteria, CA). Cytoplasmic antigens and TdT were analyzed as described elsewhere,16
with a modification on fixation from 0.5% methanol-free formaldehyde to 50% ethanol with 1% paraformaldehyde. Multiparameter
analysis of gated cell populations on cell suspension studies was
used to provide more definitive immunophenotyping information
(Consort 30 and Lysis II computer softwares; Becton Dickinson).
Cytogenetic analysis. Cytogenetic analysis was performed as described previously.17 In brief, pretreatment bone marrow leukemic
cells or single-suspended lymph node cells were cultured in
RPMI1640 supplemented with 20% fetal calf serum without mitogens for 72 hours and incubated with colcemid at a final concentration of 0.02 mg/mL for 1.5 hours at 377C. Cells were then exposed
to 50 mmol/L KCl solution for 20 minutes at room temperature and
fixed with methanol-acetic acid (3:1). Chromosomes were banded
using the trypsin-Giemsa method.
Southern blot analysis. High molecular weight DNA was extracted from fresh or frozen stored leukemic cells or lymph nodes
and digested with the restriction enzymes (BamHI, EcoRI, and Xba
I), and genotypic blot hybridization was performed as described
previously17 using the human T-cell receptor (TCR) b chain gene
probes, CTb and Jb2 (provided by Dr T.W. Mak [Ontario Cancer
Institute, Toronto, Canada] and Dr Y. Kurosawa [Institute for Comprehensive Medical Science, Fujita Health University School of
Medicine, Aichi, Japan], respectively); the TCR g chain gene probe,
Jg1 (provided by Dr T.H. Rabbitts, Medical Research Council Laboratory of Molecular Biology, Cambridge, UK); and the human Ig
heavy chain (IgH) gene joining region probe JH (provided by Dr
J.V. Ravetch, Laboratory of Molecular Genetics, National Institutes
of Health, Bethesda, MD).
Northern blot analysis. Total RNA was extracted from mononuclear cells or frozen tumors, and Northern blot hybridization was
performed as described previously.17 Probes used were the human
MPO probe (provided by Dr K. Morishita, National Cancer Center
Research Institute, Tokyo, Japan) and CD3d and CD3e chain probes
(provided by Dr T.H. Rabbitts).
Epstein-Barr virus (EBV) study. Detection of EBV-encoded
small RNAs (EBERs) by in situ hybridization (ISH) using EBER
oligonucleotides was performed on formalin-fixed paraffin-embedded sections, according to the method previously described.8 Presence of the EBV genome was also assessed by Southern blotting
analysis using an EBV terminal sequence-specific Eco I probe (provided by Dr K. Takada, Cancer Institute, Hokkaido University
School of Medicine, Sapporo, Japan).
RESULTS
Clinical features. The clinical features of the seven patients are summarized in Table 1. Six were men and one
was a woman; their ages ranged from 19 to 59 years, with
a median of 46 years. At the time of initial presentation,
Table 1. Pretreatment Clinical Characteristics of Myeloid/NK Cell Precursor Acute Leukemia Cases
BM Involvement
Case
No.
Age
(yr)/
Sex
WBC
(1109/L)
%
Blasts
Hb
(g/dL)
PLT
(1109/L)
Diagnosis
(relapse)
Site of Involvement
LN
Liver
Spleen
Mediastinum
1
2
3
4
5
6
7
34/M
46/M
54/M
29/F
48/M
19/M
59/M
8.8
51.0
2.1
1.1
5.9
1.3
2.7
0%
87%
29%
5%
0%
11%
5%
17.0
14.4
15.2
12.6
15.7
14.0
13.0
381
39
86
76
217
258
199
0% (81.0%)
86.5%
89.5%
91.5%
0% (56.0%)
78.0%
19.5% (84.0%)
Neck, axillary, inguinal
Neck
Neck, axillary, tonsil
Submandible, neck
—
Neck, inguinal
Neck, axillary, inguinal
0
/
0
0
0
0
0
0
/
0
0
0
0
0
0
/
0
0
/
0
0
Abbreviations: LN, lymph node; BM, bone marrow; WBC, white blood cell count; Hb, hemoglobin level; PLT, platelet count.
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MYELOID/NK CELL PRECURSOR ACUTE LEUKEMIA
2419
circulating leukemic cells were detected in five patients (nos.
2, 3, 4, 6, and 7), and thrombocytopenia was observed in
three (nos. 2, 3, and 4). No patients were anemic. Initial
bone marrow involvement was detected in five cases (nos.
2, 3, 4, 6, and 7) to various degrees, whereas two (nos. 1
and 5) showed bone marrow involvement at relapse. Although patient no. 7 presented with 19.5% of leukemic blasts
in bone marrow, a rather low percentage for the diagnosis
of acute leukemia, his bone marrow examination at relapse
showed hypercellular marrow with 84.0% leukemic blasts.
Peripheral lymphadenopathy and/or mediastinal bulky
masses were common findings, although none presented B
symptoms. Four patients (nos. 3, 4, 6, and 7) initially presented with localized lymphadenopathy, occurring mainly in
the cervical region, and bone marrow involvement. Two
patients (nos. 2 and 5) clinically manifested a mediastinal
bulky mass associated superior vena cava syndrome, further
accompanied in one case (no. 2) by cervical lymphadenopathy, hepatosplenomegaly, and bone marrow involvement.
Testicular and meningeal involvement was encountered at
relapse in patients nos. 5 and 7, respectively. Serum obtained
from all patients did not show antibodies to human T-cell
leukemia/lymphoma virus type 1 or human immunodeficiency virus using an enzyme-linked immunosorbent assay.
Morphology. The bone marrow and peripheral blood
smears of all patients (nos. 1 and 5 at relapse) showed L2shaped leukemic cells of various sizes, with moderately irregular nuclei, prominent nucleoli, and pale cytoplasm (Fig
1). Cytoplasmic granules or Auer’s rods were not recognized
in bone marrow smears and in touch imprints of biopsied
specimens. Less than 3% of leukemic cells showed cytochemical MPO reactivity in all cases. The leukemic cells
were histochemically negative for a-naphthol AS-D chloroacetate esterase, a-NB esterase, and PAS. Lymph node biopsies was obtained from six patients (nos. 1 through 4, 6, and
7) and needle biopsy specimen of a mediastinal tumor was
available for patient no. 5. All these biopsied specimens
morphologically showed diffuse infiltration by monotonous
proliferation of immature mononuclear cells (Fig 2). In most
of the affected lymph nodes, such infiltrates showed a Tzone distribution with sparing of follicles. The component
cells had a similar blastic morphology to those seen in bone
marrow or peripheral blood. These findings seriously pose
the differential diagnostic problem from lymphoblastic
lymphoma (LBL); indeed, a diagnosis of LBL was tentatively made for four of the patients (nos. 1, 2, 5, and 6).
Immunophenotyping. The immunophenotypes of all
seven cases are listed in Table 2. All cases expressed the
NK cell-associated CD56 antigen, but neither CD16 nor
CD57. All cases also expressed CD7, CD33, and CD34,
together with the other myeloid/monocyte-associated antigens, CD11b or CD13, to varying degrees. HLA-DR–related
(Ia) antigen was positive in five (nos. 1 through 4 and 7) of
the seven cases. One case (no. 3) was CD2/, and three (nos.
2, 3, and 6) of six cases examined exhibited faint cytoplasmic
CD3 (cyCD3; Fig 3), in contrast to high expression of
cyCD33 or cyMPO, although all were negative for other
B- or T-cell antigens. TdT was negative in all six cases
examined.
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Fig 1. Morphologic and cytochemical features of myeloid/NK cell
precursor acute leukemia. MG-stained bone marrow smear of patients
no. 4 (A) and no. 3 (B). (A) The leukemic cells show a L2-shaped morphology, with varying cell size, irregular nuclei with prominent nucleoli, and
pale cytoplasm. Azurophilic granules are not apparent in the cytoplasm
(original magnification Ì 1,200). (B) The leukemic cells present with
unremarkable nucleoli and some with deeply invaginated nuclear membrane (original magnification Ì 1,200). (C) MPO-stained bone marrow
smear of patient no. 3. Less than 3% of leukemic cells are positive for
MPO staining (original magnification Ì 1,200).
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2420
SUZUKI ET AL
Fig 2. Lymph node biopsies
of patients no. 1 (A and B), no.
3 (C), and no. 4 (D). (A) Diffuse
infiltration of tumor cells is
noted in a T-zone area with sparing of follicles (original magnification Ì 100). (B and C) The component cells show blastic
morphology with round to moderately irregular nuclei, small to
intermediate-sized nucleoli, and
scant cytoplasm (original magnification Ì 600). (D) The tumor
cells show irregular nuclei with
inconspicuous nucleoli.
Genotypic analysis. The results are listed in Table 3. In
all but one case (no. 4), no clonal rearrangement of the TCR
b and g chain genes or the IgH gene was detected with all
three restriction enzymes used. Case no. 4 exhibited clonal
rearrangement of all these genes.
Of six cases examined by Northern blot analysis, four
(nos. 1, 4, 5, and 7) expressed the MPO gene, two (nos. 3
and 4) the CD3d chain gene, and six (nos. 1 through 5 and
7) the CD3e chain gene.
Cytogenetic analysis. The results are listed in Table 4.
One case (no. 3) presented a normal karyotype, 46,XY, but
the other six cases had various chromosomal abnormalities.
Although these varied from case to case, four showed chro-
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mosome 7 translocation. No t(9;22) or 11q23 abnormalities
were detected.
EBV study. ISH did not detect EBV transcripts in paraffin sections of any of the six cases examined (nos. 1 through
5 and 7). Southern blot analysis showed all seven cases to
be negative for EBV genome in leukemic cells.
Therapy and clinical course. The initial therapies, responses, and clinical course of myeloid/NK cell precursor
leukemias are summarized in Table 5. Three patients (nos.
3, 4, and 7) were treated with chemotherapy including daunorubicin and cytosine arabinoside on diagnosis of AML and
three with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) -based regimens because of initial
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MYELOID/NK CELL PRECURSOR ACUTE LEUKEMIA
2421
Fig 2 (cont’d).
diagnosis of LBL/acute lymphoblastic leukemia (ALL). One
patient (no. 5) with a sole mediastinal bulky mass underwent
thoracic irradiation and subsequent chemotherapy for LBL.
All those who received the initial regimens for AML
achieved complete remission (CR), although patient no. 4
required three courses of induction chemotherapy. None of
the patients treated with CHOP-based chemotherapy
achieved CR; one (no. 6) showed a partial response (PR)
and two (nos. 1 and 2) proved refractory. Two (nos. 1 and
6) of them attained CR with subsequent AML chemotherapy.
Patient no. 5 also achieved CR after irradiation. Patient no.
4 underwent allogeneic bone marrow transplantation (BMT)
from a human leukocyte antigen (HLA) genotypically identi-
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cal sibling, but died of chronic graft-versus-host disease 12
months after BMT without evidence of relapse. Patient no.
6 received allogeneic BMT from the HLA phenotypically
identical father, but relapsed 9 months after BMT. Four patients treated with consolidation and maintenance chemotherapy relapsed 3, 6, 23, and 27 months after remission,
respectively. All but one patient (no. 4) had died of leukemia
and/or related complications within 41 months. The median
survival was 19 months.
DISCUSSION
In the present study, we have described seven cases of
acute leukemia characterized by distinct morphologic, im-
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2422
SUZUKI ET AL
Table 2. Phenotypic Analysis of Myeloid/NK Cell Precursor Acute
Leukemia Cases
Case No.
CD1
CD2
CD3
CD4
CD5
CD6
CD7
CD8
CD9
CD10
CD11a
CD11b
CD11c
CD13
CD14
CD15
CD16
CD19
CD20
CD21
CD25
CD28
CD33
CD34
CD36
CD38
CD41b
CD56
CD57
CD71
CD122
HLA-DR
TCRab
TCRgd
cyCD3
cyCD22
cyCD33
cyIgM
cyMPO
TdT
1
LN
2
PB
3
BM
4
BM
5*
BM
6
BM
7
BM
10
17
13
12
14
44
89
5
90
1
ND
72
ND
19
5
10
1
2
2
1
4
8
80
74
3
42
4
78
1
64
ND
86
14
ND
ND
ND
ND
ND
ND
ND
1
7
5
5
6
12
94
7
87
1
34
82
26
4
3
5
5
11
3
2
7
3
49
67
4
81
3
86
3
88
2
86
4
1
18†
3
12
ND
35
2
1
28
4
2
13
8
96
4
21
1
98
56
40
5
1
2
0
3
3
2
1
25
76
30
9
96
3
77
3
66
2
61
2
2
12†
1
37
10
65
1
0
6
5
3
9
60
89
2
42
0
91
24
10
65
0
5
1
1
2
1
1
4
43
60
3
81
0
77
2
89
1
92
4
0
5
1
41
2
28
2
0
6
5
2
19
6
94
3
26
0
55
88
4
0
0
1
1
0
0
1
0
3
74
78
4
93
1
46
3
64
1
9
4
1
4
ND
22
ND
19
12
0
9
4
3
6
24
84
4
10
4
78
74
27
13
3
10
2
8
6
1
2
4
63
50
6
88
3
41
1
36
3
19
3
ND
15†
3
70
ND
1
4
1
7
5
19
23
29
64
4
37
3
74
85
37
21
17
22
8
9
2
2
26
3
92
43
17
94
1
66
2
59
28
66
5
1
6
0
57
4
82
5
Values are expressed as percentages of cells positive for each
marker. Leukemic cells considered to be positive for each marker are
underlined.
Abbreviation: ND, not determined.
* Patient no. 5 was immunophenotyped at the time of relapse.
† Dimly positive, as described in Fig 3.
munophenotypic, genotypic, and clinical features. Leukemic
cells showed immature morphologic appearance without
MPO reactivity and coexpression of CD7, CD33, CD34,
CD56, and frequently HLA-DR. Although one case expressed CD2, the present cases exclusively lacked the other
T- or B-cell–specific antigens and, of note, the genotypical
germline configurations of TCR b and g chain genes and
IgH gene except for only one case. Although case no. 4
showed gene rearrangements in the TCR b, TCR g, and IgH
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genes, this does not necessarily mean commitment to T- or
B-cell lineages, as shown previously for AML cases.18,19
These data suggested that the leukemic cells of the present
series might be phenotypically those of myeloid/NK cell
precursors. One of the clinical characteristics of this myeloid/
NK cell precursor acute leukemia was the presence of extramedullary involvement, superficial lymphadenopathy, and/
or mediastinal mass. Two cases lacked the bone marrow
involvement at diagnosis, which provided some difficulties
in differential diagnosis from LBL. Etiologically, EBV was
not detected in myeloid/NK cell precursor acute leukemia
using Southern blot analysis and ISH. These findings of the
present cases showed that they appeared to constitute a distinct clinicopathologic entity of myeloid/NK cell precursor
acute leukemia, hitherto undescribed in the literature.
NK cells differentiate from immature thymocytes under
appropriate conditions in vitro and in vivo and share cytotoxic activity and some surface antigens with T cells, all of
which suggest a thymocyte origin.20-24 On the other hand,
they arise in athymic mice25 and are present in severe combined immunodeficient (SCID) mice26 and human SCID patients.27 Recently, NK cells were proven to develop from a
population of CD34/, CD33/, CD560 cells in vitro, which
indicates a close relationship with the myeloid lineage.24,28
NK cell progenitors are now considered to have a CD34/,
CD33/, CD7/, CD2//0, CD560, cyCD3/ phenotype,
whereas mature NK cells exhibit CD340, CD330, CD7/,
CD2//0, CD56/. Our series of seven leukemias (CD34/,
CD33/, CD7/, CD20//, CD56/, cyCD3dim), therefore
showed a phenotype midway between these two. NK cells
contain truncated CD3e mRNA, which is expressed as
cyCD3, causing some confusion with the surface CD3
(sCD3) that distinguishes NK cells from NK-like T cells.29,30
In the present series, although sCD3 was negative in all
cases, the fact that cyCD3 was dimly detected in three cases
by flow cytometry and in six cases by Northern blotting
showed their NK cell lineage, although the clinical behavior
and therapeutic response were rather more indicative of immature myeloid leukemia than lymphoblastic leukemia/
lymphoma. In our study, all cases were CD160, using Leu11
MoAb. However, because some cases of chronic LGL leukemia have been reported to be negative with Leu11 but positive with other anti-CD16 MoAbs,31 we cannot be certain
from the present study whether these myeloid/NK cell precursor acute leukemias expressed IgG Fc receptors.
Recently, Scott et al14 also proposed a myeloid/NK cell
acute leukemia entity characterized by mature myeloid morphology, scant cytoplasm with fine azurophilic granules, and
MPO cytochemical reactivity. Their cases were described to
be exclusively negative for HLA-DR, and less commonly
for CD34, indicating a more mature state than found for
our series. CD7, which is expressed in immature NK cell
progenitors, was a feature of our myeloid/NK cell precursor
acute leukemia, not described in the Scott’s type. There were
also some morphologic differences between the two series,
presumably reflecting the different developmental stage of
leukemic cells. Although the therapeutic schedules were not
uniform, the prognosis differed considerably, with their myeloid/NK cell acute leukemias, mainly treated according to
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MYELOID/NK CELL PRECURSOR ACUTE LEUKEMIA
2423
Fig 3. (A) Flow cytometric
analysis of cyCD3 in myeloid/NK
cell precursor leukemia cases.
The x-axis represents fluorescence intensity (4-decade log
scale) and the y-axis the relative
cell number. The thick line indicates the histogram for leukemic
cells stained with cyCD3 and the
thin line indicates the histogram
for leukemic cells stained with
cyCD22 (negative control). The
right shift of the histogram wave
observed in patients nos. 2, 3,
and 6 indicates that the leukemic
cells are cyCD3 dimly positive. In
patient no. 2, the fluorescence
intensity of 18% of the leukemic
cells was calculated to exceed
the cut-off level (maximum intensity of negative control), but
most (approximately more than
80% to 90%) of them are dimly
positive. In patient no. 5, the
cyCD22 analysis was not available. (B) CD3e expression by
Northern blotting analysis. HL60 was used as a negative control and Jurkat was used as a
positive control. All six cases expressed CD3e mRNA to varying
extents.
SWOG protocol, showing a relatively fair prognosis (9 of
20 alive after a median of 30 months). In our series of seven
myeloid/NK cell precursor acute leukemias, although six
attained CR with chemotherapy including daunorubicin and
cytosine arabinoside, the remission duration was relatively
short with a fatal outcome, despite multiagent intensive chemotherapy including BMT.
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Leukemia of NK cell origin has historically been considered to fall within the large granular lymphocyte (LGL)
leukemia category, now divided into two main groups, TLGL leukemia and NK-LGL leukemia.32 The first presents
an indolent and chronic clinical course, an sCD3/ phenotype,
and rearrangement of the TCR gene, suggesting a T-cell
origin.33-35 The seven cases of myeloid/NK cell precursor
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2424
SUZUKI ET AL
Table 3. Genotypic Features of Myeloid/NK Cell Precursor Acute
Leukemia Cases
Case No.
1
2
Southern blot analysis
IgH
G/G
G/G
TCR b
G/G
G/G
TCR g
G/G
G/G
Northern blot analysis
MPO
/
0
CD3d
0
0
CD3e*
/
/
3
4
5
6
7
G/G
G/G
G/G
R/G
R/G
R/R
G/G
G/G
G/G
G/G
G/G
G/G
G/G
G/G
G/G
0
/
/
/
/
/
/
ND
/
ND
ND
ND
/
ND
/
Abbreviations: IgH, Ig heavy chain; G, germline; R, rearranged; ND,
not determined.
* The result of Northern blot analysis is shown in Fig 3B.
acute leukemias in the present study were found to be quite
different from T-LGL leukemias in their clinical, morphologic, phenotypical, and genotypic characteristics. An aggressive variant of CD3/ CD56/ T-LGL leukemia,36 which
is now considered to be the leukemic form of NK-like Tcell lymphoma,37,38 has also been reported, with the TCR
gene analysis confirming its T-cell origin. NK-LGL leukemia exhibits an aggressive clinical course, a lack of sCD3
but a cyCD3e/ phenotype, and a germline configuration of
TCR genes, indicative of a true NK cell origin.39-44 Although
the expression of myeloid and stem cell-associated antigens
has not been described for most of these LGL malignancies,
CD56/ aggressive NK cell leukemias reported by Imamura
et al43 were CD130 and CD330. Patients with aggressive NK
cell leukemia have a tendency to present B symptoms and
marked splenomegaly, although lymphadenopathy is not
common (3 of 11 cases [27%]).32 Some investigators have
also emphasized the EBV integration seen in NK-LGL leukemia.42,44 The morphologic, phenotypical, clinical, and virologic differences between myeloid/NK cell precursor acute
leukemia and NK-LGL leukemia thus suggest that they were
distinct disease entities, despite sharing NK cell characteristics and an aggressive clinical course.
Malignant lymphomas of conceivable NK cell phenotype
were first described as angiocentric immunoproliferative lesions45 and are known to predominantly show an extranodal
presentation with a broad morphologic spectrum.5-7,11,46-50
Such CD56/ lymphomas are prevalent in Asian populations,
and an increasing number of reports have described nasal
and nasal-type T/NK cell lymphomas, with pleomorphic/
polymorphous morphology, a frequent mucosal presentation
(most commonly nasopharyngeal region), and EBV positivity.51 The tumor cells of both nasal and nasal-type lymphomas also often show an LGL appearance and a CD2/,
sCD30, cyCD3/, CD50, CD7/, CD56/, and myeloid marker
negative phenotype, suggesting a mature NK cell nature,
distinct from the present myeloid/NK cell precursor acute
leukemia. Recently, we also described a distinct entity designated the blastic NK cell lymphoma, characterized by a
lymphoblastoid appearance often with azurophilic granules;
a proclivity to involve the skin, lymph nodes, and bone
marrow; and EBV negativity.8 The lymphoma cells of this
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entity were usually CD20, sCD30, cyCD3//0, CD50, CD7//0,
CD330, CD340, CD56/, and TdT//0 (data unpublished).
Some of these features were shared by the present myeloid/
NK cell precursor acute leukemias, and only one exceptional
case of CD33/ and CD34/ phenotype in our previous reports
giving this case no. 4 was recategorized into myeloid/NK
cell precursor acute leukemia as case no. 2 in the present
study. Although these two entities might lie on a continuous
spectrum with overlapping and borderline cases, the clinicopathologic profile of the blastic NK cell lymphoma appeared
to correspond to an intermediate position between myeloid/
NK cell precursor acute leukemia and nasal and nasal-type
T/NK cell lymphoma. Other types of malignant lymphoma,
such as NK-like T-cell lymphoma,11,37 hepatosplenic gd Tcell lymphoma52,53 and S-100/ T-cell lymphoproliferative
disorder54 have also been described to be CD56/. NK-like
T-cell lymphoma, which is considered to be lymphomatous
form of aggressive CD3/, CD56/ LGL leukemia,36 shows
CD3 and TCR expression, rearrangement of TCR genes,
and an LGL-like morphology. The hepatosplenic gd T-cell
lymphoma and S-100/ T-cell lymphoproliferative disorder
are characteristically also positive for CD3 and TCR and
for TCR gene rearrangement. With this background, these
CD56/ lymphomas are suggested to have T-cell nature and
thus to be distinct from myeloid/NK cell precursor acute
leukemias.
Because the biopsied specimens of myeloid/NK cell precursor acute leukemias were characterized by diffuse proliferation of lymphoblasts and negative esterase staining, with
phenotypic and genotypic studies confirming their non–Tand non–B-cell lineage. These finding pose a differential
diagnostic problem between myeloid/NK cell precursor
acute leukemia and LBLs unless flowcytometric analysis is
performed. However, LBLs virtually all express TdT, and
the majority occur in children or young adults. Although
there are some reports of LBL cases with NK cell marker
expression,55,56 these were positive for CD57 (Leu7) and Tcell markers (CD2, CD5, or CD8), but no information was
available for the expression of CD56 or myeloid antigens.
T-ALL with the same phenotype have also been reported.57,58
CD57/ T-LBL/ALL may thus constitute a definite disease
entity, but again this is different from the myeloid/NK cell
precursor acute leukemia. Very recently, Ichinohasama et
al59 reported a case of LBL with note of the CD56, myeloid
antigen, CD7 and cyCD3 expression, and germline configurations of TCR and Ig genes. The mediastinal mass without
Table 4. Cytogenetic Characteristics of Myeloid/NK Cell Precursor
Acute Leukemia Cases
Case
No.
Karyotype
1
2
3
4
5
6
7
45,XY,/del(3)(p21),04,t(7;?)(p21;?),010,020,/mar
45,XY,07,t(7;11)(q11;p11)
46,XY
46,XX,t(1;3)(p36;p21),016,017,022,/3mar
46,XY,add(1)(q44),t(7;14)(p15;q32),del(9)(p13)
46,XY,del(6)(q23),012,t(12;17)(q11;p13)
46,XY,t(3;7)(p25;p15)
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MYELOID/NK CELL PRECURSOR ACUTE LEUKEMIA
2425
Table 5. Therapeutic Responses and Clinical Courses of Myeloid/NK Cell Precursor Acute Leukemia Cases
Case
No.
Age
(yr)/
Sex
Initial Therapy
Response
Subsequent Therapy and Clinical Course
Received DCVP and attained CR. Relapsed in BM 6 mo
after CR, and DOD.
Received DCVP but no response. DOD.
Relapsed in BM 27 mo after CR, no response to
DCMP. DOD.
Received allo BMT from HLA identical sibling, and
died of GVHD in CR.
Received chemotherapy for LBL. Relapsed in BM and
testis 23 mo after CR. Attained short 2nd CR by AraC / ACR. DOD.
Received DCVP and attained CR. Received allo BMT
from phenotypically identical father in 1st CR.
Relapsed in BM at 13 mo after CR. DOD.
Relapsed in CNS 6 mo after CR, with subsequent BM
relapse. No response to high-dose Ara-C and DOD.
1
34/M
CHOP-B
PD
2
3
46/M
54/M
Radiation, CHOP-B
DCMP
NR
CR
4
29/F
DCMP
CR
5
48/M
Radiation
CR
6
19/M
CHOP-L
PR
7
59/M
LDCA, DCVP
CR
Survival
(mo)
17
4
30
19
41
19
11
Abbreviations: CHOP-B, cyclophosphamide, doxorubicin, vincristine, prednisolone, and bleomycin; DCMP, daunorubicin, cytosine arabinoside,
6-mercaptopurine, and prednisolone; CHOP-L, CHOP and L-asparaginase; LDCA, low-dose cytosine arbinoside; DCVP, daunorubicin, cytosine
arabinoside, vindesine, and prednisolone; CR, complete remission; PR, partial response; NR, no response; PD, progressive disease; DOD, died of
disease; allo BMT, allogeneic bone marrow transplantation; HLA, human leukocyte antigen; GVHD, graft-versus-host disease; LBL, lymphoblastic
lymphoma; ACR, aclarubicin.
bone marrow involvement found at the initial diagnosis and
the leukemic conversion at relapse were similar to the clinical course of our patient no. 5. An LBL diagnosis was made
on the basis of histopathologic features of biopsied specimens, but it could be included in a single nosological entity
of myeloid/NK cell precursor acute leukemia.
The particular morphologic, phenotypic, genotypic, and
clinical characteristics of the present cases included features
of AML M060 or minimally differentiated AML.61 The AML
M0 is characterized by an immature lymphoblastoid morphology without cytochemical MPO reactivity, expression
of myeloid antigens, lack of T- or B-cell antigens, a complex
karyotype, and a poor prognosis.60-65 CD7 was found to be
expressed in 31 of 73 (42%) cases,62,65,66 whereas CD56 expression has not been described in the literature. By definition, M0 is cyCD30, whereas some of our myeloid/NK cell
precursor acute leukemias were dimly positive. The possibility that some M0 cases might be classifiable as myeloid/
NK cell precursor acute leukemias on the basis of CD56
expression needs further investigation.
CD7/, CD40, CD80 acute leukemias67 or CD7/ stem cell
leukemias68-70 also share some clinical, morphologic, and
phenotypic features with myeloid/NK cell precursor acute
leukemias. Kurtzberg et al67 described acute leukemia cases
with frequent extramedullary involvement, MPO and TdT
nonreactivities, CD7 expression, and a poor prognosis. Although they did not mention expression of myeloid antigens,
other investigators have identified myeloid antigen-positive
cases.68-70 Because CD56 expression was not investigated,
the possibility of overlap between CD7/ stem cell leukemia
and myeloid/NK cell precursor acute leukemia remains open.
Because the expression of CD7 and cyCD3 observed in
our series of leukemias has historically been considered as a
characteristic of T cells, some cases of the literarily described
mixed lineage leukemia of myeloid and T-cell might be
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reclassifiable into the myeloid/NK cell precursor acute leukemia category. However, mixed-lineage leukemias sometimes
present Philadelphia chromosome or 11q23 abnormalities,71-76
whereas none of our cases had such aberrations. In our seven
cases, four cases showed abnormality of chromosome 7 (3
for 7p and 1 for 7q) and three showed abnormality of chromosome 3p. Although the T-cell receptor g chain gene is
located in 7p15 locus, none of the present cases carrying 7p
abnormality exhibited the rearrangement of TCR g gene.
Further investigation is required for the understanding the
mechanism of neoplastic transformation of myeloid/NK cell
precursor acute leukemia.
These seven myeloid/NK cell precursor acute leukemia
cases exhibited extramedullary presentation, including two
of them with mediastinal mass, and some of them lacked
bone marrow involvement at initial presentation. Because
the CD56 antigen is a cell adhesion molecule, its expression
on tumor cells is believed to play an important role in their
localization and CD56/ lymphomas5,8,77 or leukemias12,78
with unusual sites of involvement have been reported. In a
recent review of extramedullary myeloid cell tumors, CD56
was described as a possible risk factor in extramedullary
leukemia.79 On the other hand, studies of large populations
for AML showed no correlation between CD56 expression
and an extramedullary localization,13,80,81 suggesting that cell
adhesion molecules other than CD56 might determine the
sites of involvement. Further exploration of this area is
needed to interpret the contradictory results.
In this series, three cases proved to be refractory to CHOPbased chemotherapeutic regimens for lymphoid malignancies; in contrast, five of six cases were successfully treated
with regimens for AML including daunorubicin and cytosine
arabinoside. These data also support the clinicopathologic
concept of a myeloid/NK cell precursor acute leukemia. Although the number of cases was limited, the fact that 5 of
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2426
SUZUKI ET AL
the 6 remission cases eventually relapsed within 3 years
after remission, despite intensive chemotherapy including
allogeneic BMT, suggests the need for more intensive therapeutic approaches.
ACKNOWLEDGMENT
The authors are grateful to K. Koike, Y. Okada, M. Andoh, and
T. Kobayashi for technical assistance.
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1997 90: 2417-2428
CD7+ and CD56+ Myeloid/Natural Killer Cell Precursor Acute Leukemia: A
Distinct Hematolymphoid Disease Entity
Ritsuro Suzuki, Kazuhito Yamamoto, Masao Seto, Yoshitoyo Kagami, Michinori Ogura, Yasushi Yatabe,
Taizan Suchi, Yoshihisa Kodera, Yasuo Morishima, Toshitada Takahashi, Hidehiko Saito, Ryuzo Ueda
and Shigeo Nakamura
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