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The Histopathology of Splenic Lymphoma With Villous Lymphocytes
By Peter G. Isaacson, Estella Matutes, Margaret Burke, and Daniel Catovsky
Whereas the hematologic, immunophenotypic, and molecu- neoplastic cells varies froma resemblance to small mantlelarcharacteristicsofspleniclymphoma
with villouslymzone-like lymphocytes to that of marginal-zone cells and
phocytes (SLVL) have been
well documented, the histologic
there are scattered blast forms. In involved lymph nodes,
features of the spleen and lymph nodes remain uncharacter- the infiltrate again centers on the fdlickr that are usually
ized. We have reviewed
the histopathology ofthe spleen in
replaced, but occasionally show preservation of follicle cen37 cases of SLVL and of involved splenic hilar lymph nodes ters; sinuses are often
prmewed. The tissue immunophenoin 6 cases. Tissue immunophenotyping was performed
in 24
type is similar to that of marginal-zone B cells. Membrane
cases, 6 of which had frozen tissue available, and
the results
immunophenotypingmaygive
difhrent results in some
were compared with the membrane immunophenotype of
cases and may vary depending on the compartment from
the circulating villous lymphocytes and cells extracted from which the cells are obtained. SLVL in the peripheral blood
spleen and lymph nodes.
In thesploen,SLVL is characterized is a histologically homogeneous
entity identicalto the condiby involvement of the white pulp follicles, which may be
tion previously characterised by histopathologists
as splenic
surrounded or replaced by the lymphoma cells. In the red
marginal-zone lymphoma.
pulp, the cellsformsmallnodulesand
infiltrate diffusely
0 1994 by The American Society of Hematology.
with sinusoidal invasion. The cytologic appearance of the
N 1987, MELO ET AL’ described a group of patients
presenting with splenomegaly in all of whom there were
abnormal circulating lymphocytes resulting in a moderate
lymphocytosis. These lymphocytes, which comprised a
monoclonal B-cell population, were distinguished by the
presence of thin and short unevenly distributed villi. The
term “splenic lymphoma with villous lymphocytes”
(SLVL) was coined for this condition. The same group have
gone on to characterize the clinical features: cytogenetic^,^
immunophenotype? and molecular genetic? of an ever-expanding number of cases.
The histopathologic features of the spleen and lymph
nodes in SLVL have not been fully characterized. In the
initial paper, Melo et al described infiltration of both red and
white pulp, resulting in an appearance indistinguishable from
chronic lymphocytic leukemia andor immunocytoma. They
commented on a bi-zonal appearance of the white pulp and
referred to several previous studies of cases with similar
clinical and hematologic featuresG8These studies contained
more histopathologic information including descriptions of
the appearances of involved lymph nodes. However, they
neither individually nor collectively conveyed any sense of
a uniform histologic entity, and none provided any immunohistochemical data. SLVL was discussed in depth at the
second workshop of The Society for Hematopathology held
I
From the Department of Histopathology, UCL Medical School,
University St, London; the Academic Department of Haematology
and Cytogenetics, The Royal Marsden Hospital (London and Surrey), London; and the Department of Histopathology, Mount Vernon
Hospital, Northwood, Middlesex, UK.
Submitted May 23, 1994; accepted August 9, 1994.
Supported by The Leukaemia Research Fund and The Cancer
Research Campaign.
Address reprint requests to P.G.Isaacson, Department of Histopathology, UCL Medical School, University Street, London, WClE
6JJ.
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.
8 1994 by The American Society of Hematology.
0006-4971/94/8411-0018$3.00/0
3828
in August 1993 in Toronto, Canada. The emphasis of this
discussion was on the histopathology of the disorder, the
consensus being that it was a histopathologically heterogeneous condition.
MATERIALS AND METHODS
Patients. The presenting clinical featuresof the 37 patients from
whomsplenic tissue or sections were available werebrieflyreviewed. Peripheral blood (PB) films from 32 of these patients were
still available and were reexamined.
Histopathology. Fresh (n = 6) or formalin-fixed (n = 5 ) whole
11 patients with SLVL were submitted
spleens or splenic tissue from
to the Department of Histopathology, University College London
(UCL) Medical School. Splenic hilar lymph nodes were available
in six cases.
Haematoxylin and eosin-stained paraffin sectionsof spleen were
obtained from a further 26 patients with SLVL. One to five additional
unstained paraffin sections were available in 13 of these cases.
Routine haematoxylin and eosin-stained sections were prepared
fromsplenictissue(11cases)andsplenichilarlymphnodes(6
cases). The histologyof these cases was reviewed together with that
ofthe26casesofSLVLinwhichonlylimitedparaffin
sections
were available.
Immunohistochemistry. Frozen (6 cases) and paraffin (1 1 cases)
sections from the splenic tissue and paraffin sections
of lymph nodes
(6 cases) were immunostained with the panel of antibodies listed in
Table 1. Limitedimmunohistochemistrywasperformedonthose
cases in which only spare paraffin sections were available using an
assortment of the antibodieslisted in Table 1. The alkaline phosphatase anti-alkaline phosphatase method was used for frozen sections
and the streptavidin-biotin peroxidase method for paraffin sections,
with prior heating or trypsin digestion
of the sectionsas appropriate.
Membrane immunophenotyping. Immunophenotypingwasperformed on isolated PB lymphocytes (PBLs) from 25 cases. In 2 of
these, immunophenotyping had been performedon both frozen and
paraffin sections of spleen. Spleencells were available from a further
5 cases, 3 of which yielded splenic hilar lymph node cells. Cells
were stained using an indirect immunofluorescence technique and
the results analyzed in a FACScanflow cytometer (Becton Dickinson, Mountain View, CA)as previously described! The monoclonal
antibodiesused arelisted in Table 2. Surface Igs(SmIg) were investigatedby a direct immunofluorescence technique with fluorescein
isothiocyanate (€WC)-conjugated goat anti-^ and anti-X plyclonal
antibodies (Cappel Laboratories, Cochranville, PA) and €WC rabbit
anti-Ig heavy-chain antibodies (Dakopatts, Glostrup, Denmark).
Blood, Vol 84, No 1 1 (December l), 1994 pp 3828-3834
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3829
SPLENIC
LYMPHOCYTES
LYMPHOMA WITH VILLOUS
Tabk l. Antfbodk. U d for Immunohlstochomi.try
CD No.
Antibodv
Source
P/F
Major Lymphoid Specificity
CD3
CD3
CD5
CD10
CD1l c
CD20
CD2 1
CD23
CD25
CD35
CD43
UCH-TI
CD3 poly
UCH-T2
Anti-CALM
Leu M5
L26
IF8
MHM6
Anti-IL-2
Ell
MTI
P. Beverley (Imperial Cancer Research Fund, London, UK)
DAKO (High Wycombe, UK)
P. Beverley
DAKO
Becton Dickinson
DAKO
DAKO
DAKO
Becton Dickinson
N. Hogg (Imperial Cancer Research Fund)
Biotest (Solihull, UK)
F
P
F
F
F
P
PiF
F
F
Pff
P
LNI
-
anti-lgM
anti-lgD
anti-K
anti-A
anti-bcl-2
MIB-l
MT2
UCL 4D12
Biotest
DAKO
DAKO
DAKO
DAKO
D.Y. Mason (Oxford University, Oxford, UK)
Binding site (Birmingham, UK)
Biotest
our labs
P
Pff
Pff
Pff
Pff
-
UCL 3D3
our lab'
F
T cells
T cells
T cells, some B cells
Follicle center B cells
Monocytes, some 8 cells
B cells
FDC, some B cells
FDC, some B cells
IL-2 receptor
FDC, some B aells
T cells, granulocytes,
some B cells
Follicle center B calls
p heavy chain
6 heavy chain
K light chain
A light chain
bcl-2 protein
Proliferating cells
T cells, some B cells
Marginal-zoneB cells,
some follicle center cells
Mantle-zone B cells, FDC
CDw75
-
P
P
P
F
Abbreviation: IL-2, interleukin-2.
all cases (Fig 1F). Typically, there was a scattering
of small
nodules of cells with the cytologic features
of marginal-zone
cells similar to those at the periphery of the follicles in the
white pulp (Fig 1G). These cells also infiltrated red
the pulp
diffuselywithoutformingnodulessometimesinlarge
loosely arranged sheets. Infiltrationof sinuses was a prominent feature in most, but not all cases (Fig 1H).
In two cases,
red pulp infiltration wasso dense as to obscure the nodular
white pulp component that was only apparent after immunostaining (see below).
The features described above were best seen in ideally
W
fixed
cases.Poorfixationrenderedthemmuchharderto
Histopathology. All cases were characterized by a nodular lymphoid infiltrateof the white pulp centered on preex- appreciate becauseof loss of tinctorial and cytologic features
isting follicles (Fig1B). In a minorityof cases, most follicle and blurring of the distinction between red and white pulp.
Inpoorlyfixedspecimens,thelargermarginal-zone-like
centers were well preserved and surrounded concentrically
cells tended to take on a plasmacytoid appearance because
by a broad zone of small lymphocytes with the appearance
of the cytoplasm.
of mantle-zone B-cells around which was a broader concen-of nuclear shrinkage and increased density
The histologic appearance
of the lymph nodes was equally
tric zoneof medium-sized lymphocytes similar to marginalzone cells. (Fig le).However, in most cases follicles were characteristic. The nodal architecture was partially effaced
enlarged to twice or more their normal
size. Clearly identifi- by a nodular infiltrate of lymphocytes similar to those in the
able follicle centerswere rare and most were either reduced spleen. However sinuses were usually preserved (Fig 2A).
Occasionalpreservedfolliclecenterswerepresentinthe
to a hyalinizecl nodule or completely or partly replaced by
center of the nodules, suggesting that, as in the spleen, they
small lymphocytes with darkly staining nuclei, similar to
were the basis for the nodular pattern (Fig 2A). The cytologic
mantle zone cells (Fig 1D). These small lymphocytes were
appearances of the infiltrate were the same as that in the
the predominant cell towardsthe center of the follicles.Toward the periphery, the small lymphocytes gave way to me- spleen (Fig 2B).
Immunohistochemistry. Theresultsaresummarizedin
dium-sized cells that resembled splenic marginal-zone
Bcells (Fig l , C through E). They were characterized by a
Table 3. In allcasesstainedeitherinfrozenorparaffin
moderate amount of palely eosinophilic cytoplasm and nusections, there was Ig light-chain restriction of the lymphoid
clei with a slightly irregular outline. Occasional nucleolated infiltrate, whereas residual follicle centers, where present,
blast forms were interspersed among them.
were polytypic. In cryostat sections, the immunophenotype
Red pulp infiltration was present to a varying degree in
of the neoplastic B-cell infiltrate was IgM+, IgD', CD20+,
RESULTS
Patients. The series included 18 men and 19 women
(Mi
F ratio 1:l) with a median age of 66 years (range,37 to 80).
All but one presented with splenomegaly and
this patient
developed an enlarged spleen during the course of the disease. The spleen was moderately to markedly enlarged with
a median of 10 cm below the costal margin (range,
5 to 22).
The median white blood cell count was 18 X 109L(range,
2 to 180). Reviewofall 32 PB films available showed a
lymphocytosis with characteristic villous lymphocytes (Fig
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Fig 1. (A) shows PBLs from patient with SLVL showing typical uneven distribution of thin and short villi with polar concentration. (B)
shows a section of spleen showing prominent nodular involvement of the whitepulp together with focal infiltration of red pulp. (C) shows a
white pulp nodule showing tumor infiltratesurrounding a reactive follicle center. Small dark-staining lymphocytes immediately abutting the
follicle center give way to larger cellsat the periphery. (D)In this white
pulp nodule, the follicle center has been replaced
by small lymphocytes.
(E) shows a high magnification of white pulptumor nodule showing small lymphocytesin the lower right giving way to larger cells with pale
staining cytoplasm, some of which show blast transformation. (F) shows nodular and diffuse involvement of red pulp. ( G ) shows high
magnification of red pulp nodule showing cells similar to those in the outer zone of the white pulp nodule. (H) Diffuse area of red pulp
involvement showing sinusoidal invasion.
Antibody
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3831
SPLENIC LYMPHOMA WITH VILLOUSLYMPHOCYTES
CDY, CD10-, CD23-, CD21’,CD35’,
CD43-, CD25-,
CDllc-, UCL3D3-, and UCUD12+.
In paraffin sections of spleen, immunohistochemistry
served to accentuate the histologic features andthiswas
especially helpful in cases which had been poorly fixed and
in those with an extremely dense red pulp infiltrate. Both
the small lymphocytes in the central area of the white pulp
follicles and the larger cells at the margin were CD20+,
MT2+, and CD43- (Fig 2C), and showed light-chain restriction (Fig 2D). The red pulp infiltration and intrasinusoidal
invasion by the lymphoma cells was highlighted in sections
stained with CD20 (Fig 2C). In preparations stained with
MT2 and with anti-bcl-2 protein, the unstained residual
reactive follicle centers stood out against the positively staining tumor cells; the reverse effect wasseenin
sections
stained withCDw75 (Fig 2E). Staining with theproliferation
marker MIB-1 (Fig 2F) served a similar purpose, contrasting
the high-proliferation fraction of even quite small follicle
centers against the low fraction in the tumor. There was a
decidedly higher proliferation fraction at the periphery of
the white pulp nodules. Both CD3 and CD43 showed a concentration of T-cells in the center of the white pulp nodules,
whether or not a follicle center was present, and a paucity
of T-cells in the white pulp tumour as opposed to the red
pulp. Staining with CD21 showed a moderately dense meshwork of follicular dendritic cells (FDC) in the center of the
white pulp nodules whether or not a follicle center could be
identified (Fig 2G). These cells were either sparse or absent
at the margins of the nodules with considerable variation in
the width of this FDC free zone. Each nodular aggregate of
Table 2. Antibodies Used for Flow Analysis
Major
Lymphoid
Specificity
CD
No.
CD2
RFTll
UCHT2
CD5
CO70
J5
CD1IC Leu-M5
CD19
CD22
CD23
C024
RFBS
OKB22
MHMG
L30
CD25
CD37
Anti 11-2
WR17
CD36
-
OKTlO
GRBl
-
FMC7
B-ly-7
-
HC2
-
Anti-lgM
Anti-lgD
Anti-K
chain
Anti-A
chain
-
G. Janossy (Royal Free Hospital,
London)
P. Beverley
Coulter (Hialeah.FL1
Becton Dickinson
T cells
T cells,
some B calls
Follicle center
B cells
Monocytes,
some B cells
B cells
B cells
Some B cells
B cells
G. Janosay
Ortho (Raitan, NJ)
DAKO (High Wycombe. UKJ
K. Kikuchi (Sapporo Medical
College, Sapporo, Japan)
Becton Dickinson
J.L. Smith (Southampton
University, Southampton, UKJ
Ortho
F. Garrido Torres (Universityof
Granada, Granada, Spain)
Sera-Lab
S. Poppema (Cross Cancer
Institute, Edmonton, Alberta,
Canada)
D. Possnett (Cornell University
Medical College, New York, NY)
DAKO
DAKO
OAK0
p heavy chain
6 heavy chain
K light chain
DAKO
A light chain
Abbreviation: IL-2, interleukin-2.
IL-2 receptors
B cells
Plasma cells
HLA-Or
B cells
Hairy cells
Hairy cells
tumor cells in the red pulp, even when verysmall, contained
FDC in the center.
The immunohistochemic features of lymph nodes were
essentially similar to those of the spleen. Each of the nodular
aggregates of tumor cells was centered on a CD21’ FDC
meshwork (Fig 2H).
Cellular immunophenotyping. The results of flow analysis of PBLs and cells teased from splenic tissue and lymph
nodes are given in Table 4. Those cases inwhich there
were immunophenotypic discrepancies between cells from
different sites or between flow analysis and immunohistochemistry are summarized in Table 5.
DISCUSSION
In 1979,Neiman et a16 reported 10 cases of splenic
lymphoma that mimicked hairy cell leukemia. The PB cells
were clearly identical to those later characterized as the villous lymphocytes of SLVL. The spleens were described as
showing nodular involvement of the white pulp bysmall- to
medium-sized lymphocytes that sometimes extended into the
red pulp. Partially nodular lymph node infiltration was also
noted. An identical case was reported by Palutke et a1in
1981: and in 1985, Spriano et alB reported a further eight
cases. However, these authors stressed the plasmacytic features of the cells and suggested the term “splenomegalic
immunocytoma withcirculating hairy cells”. Melo et al concentrated on the PB findings in 22 cases of SLVL and only
briefly referred to the histologic features, as did Rousselet
et al,” in describing a single case of this condition.
Both follicular (centroblastidcentrwytic)lymphoma and
mantle cell lymphoma may result in a follicular infiltrate in
the
spleen
that
closely resembles
SLVL.
Follicular
lymphoma may sometimes show a marginal-zone-like pattern. We have seentwosuch cases involving the spleen
(unpublished, March 1994). However, in both, the cytology
and immunophenotype of the cells in the center of the follicles was entirely characteristic of follicular lymphoma. Clear
light-chain restriction and strong expression of bcl-2 protein
by the follicle center cells were especially helpful differentiating features. Preservation of lymph node sinuses, a feature
of SLVL, is not characteristic of follicular lymphoma.
Mantle cell lymphoma
rarely
presents with splenic
involvement, but whenit does, involvement of the follicular
mantle zone and replacement of follicle centers occurs as it
does in lymph nodes. Furthermore, lymphoma
cells are often
present in the PB. The difficulty in distinguishing mantle
cell lymphoma is compounded by the fact that a proportion
of SLVL cases may cany the t( 1;14)(q
1
13;q32) translocation
andshow bcl-l(prad-l) gene rearrangement:which
are
findings characteristic of mantle cell lymphoma. In optimally
fixed tissue, the cytologic appearances of SLVL are quite
distinctive from those of mantle cell lymphoma, but in less
well-fixed preparations, the characteristic abundant pale
staining cytoplasm and presence of moderate numbers of
blast cells may be obscured, and distinction from mantle cell
lymphoma may be impossible without tissue immunophenotyping. By contrast with SLVL, most mantle cell lymphomas
express both CD5 and CD43. Preservation of lymph node
sinuses in SLVL is also a useful distinguishing feature. In
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.
Fig 2.
.-
(A) shows low magnification of involved lymph node showing overall nodular architecturewith preservation of somefollicle canter+.
The sinuses are open. (B) shows high magnification of lymph node infiltrate showing medium-sized lymphocytes with pale cytoplasm and
scattered transformed blasts. (C) Section of spleen stained
with CD20 showing extensive involvement of both whiteand red pulp. Sinusoidal
invasion is highlighted (arrow). (D) Whkepulp nodule stained (left)for K light chain and(right) for A light chain. The neoplastic infiltrate shows
K light-chain restriction. whereas the small residual follicle center is polytypic. (E) shows splenic white pulp nodule stained with anti bcl-2
protein (left)and with CDw75 (right). Reactive follicle center cells do not express bcl-2 protein and are CDw75positive. Tumor cells express
bcl-2 protein. (F) shows spleenstained with MIB-l toshow Ki-67 antigen. At low magnification (left),a concentrationof proliferating cells at
the margin of the white pulp nodules is evident. Higher magnification of a white pulp nodule (right) shows high-proliferation fraction in a
small residual reactivefollicle center and increased numbers proliferating
of
cells at margin of the nodule. (GISpleen stainedwith CD21 shows
a diffuse FDC meshwork in white pulp nodules fading towards the periphery. Each small nodule of lymphoma in the red pulp is defined by a
central FDC meshwork. (H) Splenichilar lymph node stainedwith CD21 (same sectionas Fig 2 A ) shows that each nodule is defined by aFDC
meshwork. (C to H, paraffin sections immunoperoxidase)
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3833
SPLENIC LYMPHOMA WITH VILLOUSLYMPHOCYTES
Table 5. Dwepanciw in Immunophennotyping R e s u b
Table 3. Immunohistochemical Reactivity of Tumor Cells
~~
Antibcdv
CD3
CD5
CDlO
CD1IC
CD20
CD2 1
CD23
CD35
CD43
CDW5
Anti-lgM
Anti-lgD
Anti-tr
Anti-A
Anti-bcl-2
MT2
UCL4D12
UCL3D3
No. Cases Studied
+
11
6
6
6
20
6 (F)
6
6 (F)
22
11
6 (F)
6 (F)
11
11
11
13
6
6
0
0
0
0
20
3
0
3
0
O*
6
2
7
4
11
13
6
0
0
0
0
CD5
0
CD5
100
CDlO
50
CD25
0
CD25
50
0
0
100
33
64
36
100
l00
100
0
Abbreviation: F, frozen sections (results forparaffin sections not
given).
Tumor cells in some cases showed dot-like staining.
the PB, the cells derived from mantle cell lymphoma lack
the characteristic villous projections of SLVL.
The tissue immunophenotype of SLVL is close to that of
splenic marginal-zone B-cells” except for the expression of
IgD as well as IgM in some cases and some variation in
expression of CD21 and CD35 The reasons for the discrepancies obtained when cases of SLVL are immunophenotyped
using flow analysis are unclear. Possible explanations are
that the sensitivity of the two methods differs so that low
expression of CD5, eg, is not detectable in tissue, or that the
cells adopt a different phenotype according to their microen-
Table 4. Results of Flow Analysis
No. cases
Marker
Positive
anti-lgM
anti-lgD
anti-rc
anti-A
CD22
CD24
FMC7
CD38
CD25
CD23
CDlO
CD5
CDllc
HC2
B-ly-7
%
Positive
Cases
Tested
11
10
25
25
20
12
19
13
la
24
la
23
16
16
16
9
2
15
10
20
11
16
5
6
7
5
6
3
1
1
Calls‘
% Positive
a0
20
60
40
100
92
a4
3a
33
29
28
26
19
6
6
All cases were CD19+, CD37+ HLA-Dl+, and CD2-. A marker was
considered positive when stained>30% circulating B cells except for
CD5, which had to stain 20% of cells above the proportion of CD2’
lymphocytes.
Case
Antibody
1
2
3
4
5
6
Anti-lgD
Tissue Lymph
(spleen)’
Blood Node Spleen
-
+
+
+
ND
ND
-
ND
ND
ND
+
-
+
-
ND
ND
-k
-
-
ND
+
-
ND
ND
Abbreviation: ND, not determined.
All showed light-chain restriction.
vironment. The latter is suggested by the slight differences
in phenotype, as determined by flow analysis, observed in
cells of the same case derived from different sites (Table 5).
It is important to be aware of these variables when investigating cases of SLVL.
In 1992, Schmid et a l l ’ reported four cases of primary
splenic lymphoma that shared distinctive histologic, immunophenotypic, and molecular genetic characteristics. No reference was made to the PB in any of the cases. The neoplastic
cells in these cases closely resembled splenic marginal-zone
cells and the term “splenic marginal-zone cell lymphoma”
was coined accordingly. In a subsequent case of this entity
(unpublished, January 1994), examination of the PB film
showed villous lymphocytes suggesting a link between
SLVL and splenic marginal-zone lymphoma. On review by
one of the authors (P.G.I.), the cases described by Schmid
et a1 in 1992,” and designated as splenic marginal-zone cell
lymphoma are histologically and immunophenotypically
identical to the cases of SLVL described in this report.
Schmid et al described the white pulp and lymph node
changes in detail, but failed to observe the nodular and diffuse red pulp infiltration and the cells within the sinusoids.
They also failed to note the wide range of cytologic appearances, including small- to medium-sized lymphocytes and
blast forms, which characterized the neoplastic component.
Therefore, one can state with some confidence that SLVL
and splenic marginal-zone cell lymphoma, as described by
Schmid et al, are one and the same entity. This has been
tentatively recognized in the proposed Revised European
and American Lymphoma classification” where splenic marginal-zone lymphoma (? villous lymphocytes) has been included as a provisional entity. However, in view of the wide
cytologic variation of the neoplastic cells, the appropriateness of the term “marginal zone” awaits confirmation.
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1994 84: 3828-3834
The histopathology of splenic lymphoma with villous lymphocytes
PG Isaacson, E Matutes, M Burke and D Catovsky
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