leukemic reticuloendotheliosis. a clinicopathologic study with review of the literature
TRANSCRIPT
REVIEW
Leukemic Reticuloendotheliosis. A Clinicopathologic
Study with Review of the Literature
ISA0 KATAYAMA, M.D.
HARVEY E. FINKEL, M.D
Boston. Massachusetts
From the Departments of Pathology and Medi- cine, Boston University Medical Center, Boston, Massachusetts; and Department of Pathology, St. Vincent Hospital, Worcester, Massachu- setts, and the Greater Lawrence Community Cancer Program, Lawrence, Massachusetts. Requests for reprints should be addressed to Dr. I. Katayama, Department of Pathology, St. Vincent Hospital, 25 Winthrop Street, Worces- ter, Massachusetts 01610. Manuscript accept- ed October 4, 1973.
The salient clinical and pathologic features of leukemic reticu- loendotheliosis are evaluated in our 13 patients and in 98 patients described in the literature. Leukemic reticuloendotheliosis affects mainly male adults whose chief clinical manifestations are relat- ed to pancytopenia and splenomegaly. Splenomegaly is nearly constant and frequently massive, whereas lymphadenopathy is infrequent and skin involvement rare. Characteristic pathologic changes are present in the bone marrow, spleen and liver. Sple- nectomy often leads to remission; chemotherapy is not beneficial in most cases and is probably to be discouraged. The entity de- serves recognition because the optimal clinical management is different from that of other forms of leukemia and lymphoma.
Bouroncle, Wiseman and Doan published in 1958 [l] a classic paper on leukemic reticuloendotheliosis in which 26 patients with a strikingly uniform disease picture were described. Subsequently, two additional series of leukemic reticuloendotheliosis were re- ported under the terms “reticulum cell leukemia” and “hairy cell leukemia” [2,3]. Some workers, however, made a diagnosis of leukemic reticuloendotheliosis in patients who, in our view, proba- bly had other hematologic malignancies [4-81. Confusion in se- mantics and lack of pathologic criteria have hampered a wider rec- ognition of leukemic reticuloendotheliosis as a distinct clinicopatho- logic entity.
In the past 3 years, we studied 13 patients with leukemic reticu- loendotheliosis. In general, the diagnosis in our patients was made earlier than in most reported series, partly due to the utilization of the sensitive histochemical test for the demonstration of tartrate- resistant acid phosphatase activity in tumor cells of those sus- pected of having the disease [ 9-1 I]. Our purpose here is to report the clinical, hematologic and pathologic findings in these 13 pa- tients and to review the literature for acceptable cases of leukemic reticuloendotheliosis, and thus to try to define the clinicopathologic features of leukemic reticuloendotheliosis.
MATERIALS AND METHODS
Our series was comprised of 13 patients, most of whom were referred to us from neighboring hospitals. The diagnosis of leukemic reticuloendo-
theliosis was based on the demonstration of the pathognomonic neOPlaS-
tic lymphoid reticulum cell in blood or bone marrow 1121 which is hereaft-
er referred to as “LRE cell.” The patients were examined, clinical records
reviewed, follow-up data obtained, and hematologic and histopathologic materials reviewed.
July 1974 The American Journal of Medicine Volume 57 115
LEUKEMIC RETICULOENDOTHELIOSIS-KATAYAMA. FINKEL
The surgical specimens (11 spleens, 7 bone marrow bi- opsy specimens, 4 lymph nodes and 6 liver biopsy speci- mens) and autopsy material (Cases 2 and 7) were fixed in formalin, embedded in paraffin and cut at 8 p. Sections were stained with hematoxylin and eosin, Gomori’s reticu- lum or Masson’s trichrome stains. The tartrate-resistant acid phosphatase reaction was performed on at least one specimen from each patient (method in reference [IS]). Specimens (most biopsy specimens mentioned plus 2 bone marrow aspirates, 5 peripheral blood buffy coats and autopsy material) were also fixed in glutaraldehyde, em- bedded in Epon, cut at 1 to 2 p and stained with toluidine blue for light microscopy [ 141.
We reviewed the reports of other investigators with par- ticular reference to the descriptions of their case records regarding clinical, hematologic and pathologic findings. Cases were accepted as leukemic reticuloendotheliosis primarily on the basis of adequate morphologic descrip- tions of the diagnostic LRE cells, although in the cases thus selected from the literature clinical and pathologic features were remarkably homogeneous.
CLINICAL PICTURE OF OUR 13 PATIENTS (TABLE I).
The patients in our series were predominantly middle-
aged and included 10 men and 3 women. Four
sought medical attention for unrelated problems,
leading to the discovery of asymptomatic spleno-
megaly or abnormal blood counts. In three additional
patients, the symptoms were minimal. Presenting
symptoms of anemia or thrombocytopenia related to hypersplenism occurred in six and four patients, re-
spectively. Massive splenomegaly probably produced
symptoms in two patients, a sense of abdominal full-
ness in one and a left inguinal hernia in the other. In-
fections were present at the time of presentation in
four patients; disseminated aspergillosis in one, a
rectal fistula in another, a draining pilonidal cyst and
superficial herpes simplex in a third, and superficial
herpes simplex in a fourth. Aside from the signs of
the complications just described, abnormal physical
findings were virtually limited to splenomegaly which was massive in seven patients and moderate in five.
Notable by its absence was lymphadenopathy. Signif- icant laboratory findings not listed in Table I included
tartrate-resistant acid phosphatase isoenzyme 5 [ 91
in all patients, abnormal platelet function in the seven
patients appropriately tested, markedly increased
leukocyte alkaline phosphatase in three, an acceler- ated erythrocyte sedimentation rate in five, normal
karyotypes in four and folate deficiency in one. There was no particular abnormality of serum proteins.
Treatment consisted of chemotherapy only (Cases 4 and 7), splenectomy only (Cases 8, 9, 11 and 12) chemotherapy and splenectomy (Cases 1, 3, 5, IO and 13) and splenic radiation, chemotherapy and splenectomy (Cases 2 and 6). In cases with com-
bined therapies, chemotherapy preceded splenecto-
my in three (Cases 2, 6, and 13), splenectomy pre-
ceded chemotherapy in three (Cases 3, 5 and lo),
and chemotherapy was given before and after sple-
nectomy in one (Case 1). Chemotherapy and/or
splenic radiation were administered to some patients
(Cases 2, 3, 5 and 13) because of initial misdiag-
nosis, e.g., lymphosarcoma for Case 3 in 1954,
which was later revised to leukemic reticuloendothe-
liosis. In more recent cases the patients were treated
only by splenectomy. Improvement occurred after
splenectomy in 9 of 11 patients in whom this opera-
tion was performed. The two who did not show im-
provement died 5 (Case 1) and 9 months (Case 10)
after splenectomy. No long-term benefit resulted
from chemotherapy in the nine patients who received it, except for a temporary improvement in one (Case
4). Of the total 13 patients, 4 patients were dead at
the time of study and 1 patient was being considered
for splenectomy because of continuing transfusion
requirement. The remaining eight patients were in
symptomatic remission as long as 19 years (Case 3).
Apparently remission followed splenectomy in all
eight cases.
CLINICAL PICTURE OF 98 PREVIOUSLY REPORTED CASES (TABLE II)
There were 79 males and 14 females (sex was not
described in 5 patients), with a male to female ratio of approximately 6 to 1. Age of the patients ranged
from 30 to 83 years, with an average of 53 years.
Physical examination revealed splenomegaly, hepa- tomegaly and lymphadenopathy, respectively, in 90
(92 per cent), 31 (31 per cent) and 24 (24 per cent)
patients. Hematologically, most patients showed pan-
cytopenia. In 63 patients from the three largest se-
ries combined [l-3], 50 patients were anemic, 37
leukopenic and 59 thrombocytopenic. Thus the inci-
dence and degree of cytopenia were highest in plate-
lets and lowest in leukocytes. The white cell count
actually varied considerably: of 92 patients with doc-
umented white cell counts, 55 had counts below 5,000/mm3, 28 between 5,000 and 15,000/mm3 and
9 over 15,000/mm3. The four highest counts record-
ed were 38,000 [2], 43,100 [3], 127,000 [15] and
134,000/mm3 [ 11. The ratio of LRE cells in the differ-
ential cell count varied between 0 to 99 per cent at
different times for a given patient as well as among the different patients.
Of 85 patients with known follow-up, 49 had died
and 36 were still alive. Of the 49 deaths, 17 occurred
in less than a year, 23 between 1 and 5 years and 9 after 5 years with 5 deaths occurring more than 13
years after onset [ l-3,15]. Of the 27 documented causes of death, 17 were related to infection and 3 resulted from massive hemorrhage. Transition from leukemic reticuloendotheliosis to other forms of leu-
116 July 1974 The American Journal of Medicine Volume 57
TAB
LE
I D
ata
on
Ou
r 13
Pat
ien
ts
wit
h
Leu
kem
ic
Ret
icu
toen
cbth
etio
sis
Age
(y
r>
Cas
e an
d P
rese
ntin
g N
o.
Sex
S
ympt
oms
_.._
____
1 47
,M
Ano
rexi
a,
wei
ght
loss
, sw
eats
, ch
ills
2 42
,M
Fat
igue
, M
assi
ve
abdo
min
al
sple
no-
fulln
ess
meg
aly
3 32
,F
Mas
sive
sp
leno
-
meg
aly
foun
d af
ter
child
bi
rth
4 56
,M
Con
gest
ive
Pal
lor,
w
ide
AA
he
art
med
ias-
failu
re
due
tinum
by
to
an
emia
x-
ray
Spl
enom
egal
y,
LRE
he
pato
- m
egal
y
Pac
ked
Cel
l R
etic
- In
itial
V
ol-
UIO
-
Initi
al
Phy
sica
l D
iag-
um
e cy
tes
FIn
ding
s no
sis*
(%)
(%)
Blo
od C
ount
s B
efor
e S
plen
ecto
my
(Afte
r S
plen
ecto
my)
(Z) (E
) Whi
te
Blo
od
Neu
- P
late
r C
ells
tr
o-
LRE
le
ts
Bon
e M
arro
w
(x
lo”/
ph
ils
Cel
ls (
i< 1
0X:
(% r
epla
ced
mm
3)
(%)
(%)
mm
‘)
by L
RE
cel
l)
2.6
34
35
122
(80)
(1.7
) (4
8)
(37)
(1
50)
CLL
Mas
sive
sp
leno
-
meg
aly,
pe
riora
l
herp
es
sim
plex
LSA
28
1.4
(40)
(0
.8)
28
9.0
(37)
(0
.8)
3.0
18
? 87
D
ry?,
(7
.0)
(40)
(4
0)
(197
) ne
arly
co
m-
plet
e re
- pl
acem
ent
by
LRE
ce
lls
12
0.2
48
1.4
46
30
Dry
(4
0)
~_~
~ ~
____
__
2-28
40
47
51
(8
2)
(9.8
) (2
5)
(75)
(2
50)
Wei
ght o
f
Spl
een
(8)
Spe
cific
The
rapy
975
Chl
oram
buci
l,
vinc
ristin
e,
ster
oids
3,45
0 S
tero
ids,
sp
leni
c
radi
atio
n
3,38
0 C
hlor
ambu
cil
. V
incr
istin
e,
ster
oids
,
andr
ogen
Cou
rse
Sys
tem
ic
sym
ptom
s
and
abno
rmal
bl
ood
coun
ts
con-
tinue
d de
spite
th
erap
y;
died
w
ith
diss
emin
ated
as
perg
illos
is
and
LRE
Afte
r 5
year
s w
ell
bein
g po
st-
sple
nect
omy,
pa
tient
be
cam
e an
emic
an
d re
quire
d tr
ans-
fusi
on;
seru
m
hepa
titis
deve
lope
d an
d pa
tient
di
ed
of
liver
fa
ilure
Sin
ce
sple
nect
omy
patie
nt
has
re-
mai
ned
wel
l ex
cept
fo
r on
e
epis
ode
of
pneu
mon
ia
with
hem
olys
is
and
one
of
alm
ost
com
plet
e m
arro
w
supp
ress
ion
by
chlo
ram
buci
l
Che
mot
hera
py
resu
lted
in
tran
sien
t be
nefit
an
d se
vera
l co
m-
plic
atio
ns;
seve
re
anem
ia
requ
ires
tran
sfus
ions
:
Fol
low
-up
(sur
viva
l)
Dea
d (1
3 m
o)
Dea
d (1
26 m
o)
Aliv
e (2
10 m
o)
Aliv
e (13
mo)
TAB
LE
I (c
on
t’d
) D
ata
on
Ou
r 13
Pat
ien
ts
wit
h
Leu
kem
ic
Ret
icu
loen
do
thel
iosi
s
Blo
od C
ount
s Be
fore
Sp
lene
ctom
y (A
fter
Sple
nect
omy)
Age
(yr)
Case
an
d N
o.
Sex
Pres
entin
g Sy
mpt
oms
Pack
ed
Whi
te
Cell
Retie
- B
lood
Ne
u-
Plat
e-
Initi
al
Vol-
ulo-
Ce
lls
tro-
LR
E le
ts
Bon
e M
arro
w
Initi
al
Phys
ical
Di
ag-
ume
cyte
s (x
lOt/
phils
Ce
lls
(xlO
a/
(%
repl
aced
Fi
ndin
gs
nosi
s’
(%)
(%)
mm
3)
(%)
(%)
mm
,‘)
by L
RE
cell)
5 38
,F
Fatig
ue,
dysp
nea,
an
kle
edem
a,
brui
sing
, ep
ista
xis
Mas
sive
sp
leno
- m
egal
y
RCS
13
2.8
1.7
24
60
23
Dry
near
ly
(43)
(0
.8)
(5.6
) (4
2)
(40)
(4
65)
com
plet
e re
plac
emen
t by
LR
E ce
lls
Wei
ght
of
Sple
en
(g)
2,92
0 Vi
ncris
tine,
cy
clop
hos-
ph
amid
e,
ster
oids
6 54
, M
Sp
leno
meg
aly
Mas
sive
di
scov
ered
sp
leno
- du
ring
meg
aly
phys
ical
ex
amin
atio
n
LRE
-~
- 7
40,M
W
eakn
ess
Sple
nom
egal
y,
LSA
pa
llor,
herp
es
sim
plex
on
no
se,
pilo
nida
l si
nus
8 41
,M
Fatig
ue,
dysp
nea,
pe
rinea
l pa
in,
diar
rhea
Sple
nom
egal
y,
LRE
ecch
ymos
es,
rect
al
fistu
la
(Z) (Z
) (i
i)
19
2.5
3.5
1.2
,::,
(0.8
) (1
6’::)
Spec
ific
Ther
apy
19
79
16
(65)
1,
175
(54)
(2
2)
(211
)
12
40
33
Near
ly
com
- 1,
110
plet
e re
- (a
u-
plac
emen
t to
psy)
by
LR
E ce
lls
16
83
25
Dry,
ne
arly
52
0
(3)
(36)
(1
20)
com
plet
e re
plac
emen
t by
LR
E ce
lls
Ster
oids
, sp
leni
c ra
diat
ion
Vinc
ristin
e,
ster
oids
Non
e
Cour
se
Follo
w-u
p 2 6
(sur
viva
l) 3
Panc
ytop
enia
im
- Al
ive
m
prov
ed
afte
r (7
8 m
o)
2
sple
nect
omy;
m
mild
m
edia
stin
al
F an
d ce
rvic
al
2 ly
mph
aden
opat
hy
2 w
as
unre
spon
sive
to
ch
emot
hera
py;
.z
patie
nt
has
re-
a $ m
aine
d w
ell
P
Initi
al
ther
apy
with
Al
ive
ster
oids
an
d (9
6 m
o)
sple
nic
radi
atio
n w
as
of
no
help
; pu
rpur
a de
velo
ped;
sp
lene
ctom
y re
lieve
d sy
mpt
oms
and
patie
nt
has
re-
mai
ned
wel
l si
nce
Ther
apy
was
of
no
De
ad
subs
tant
ial
bene
- (2
m
o)
fit,
but
mig
ht
have
in
tens
ified
le
ukop
enia
; di
ed
of
pulm
onar
y as
perg
illos
is
Pneu
mon
ia,
Aliv
e ur
inar
y tra
ct
in-
(15
mo)
fe
ctio
n an
d se
psis
de
velo
ped;
sp
lene
ctom
y re
sulte
d in
im
prov
emen
t; ac
tive
and
wor
k-
ing
sinc
e
LEUKEMIC RETlCULOENDOTHELlOSlS-KATAYAMA. FINKEL
0 z
I
!a 'a I
3
ID
July 1974 The American Journal of Medicine Volume 57 119
TAB
LE
II D
ata
on
98
Pat
ien
ts
wit
h
Leu
kem
ic
Ret
icu
loen
do
thel
iosi
s D
escr
ibed
in
th
e L
iter
atu
re
6
Refe
renc
e
No.
of
Pa-
Age
(yr)
Hem
oglo
bin
tient
s an
d S
ex
(g/1
00 m
f)
Blo
od C
ount
s (X
10
”/m
ms)
Whi
te B
lood
Cel
ls
Pla
tele
ts
Leuk
open
ic
Thr
ombo
cyto
- (1
5/26
pe
nic
patie
nts)
(2
6/26
patie
nts)
Wei
ght o
f Ly
mph
ad-
Ski
n F
ollo
w-u
p S
plee
n S
plen
omeg
aly
Hep
atom
egal
y en
opat
hy
Invo
lvem
ent
(sur
viva
l) (g
)
+
(25/
26
+
(512
6 +
(9
/26
+
(3/2
6 9
aliv
e 50
0-3.
800
patie
nts)
pa
tient
s)
patie
nts)
pa
tient
s)
(<12
-84
mol
),
(6 s
ple
ens)
16
dea
d
(i
12-1
90 m
o),
I lo
st
(?)
+
(5/5
. .
. . .
. . .
. . .
. pa
tient
s)
+
+
- . .
. de
ad
(3 m
o)
+
+
- .
dead
(8
mo)
+
- . .
. .
. de
ad
(156
mo)
2,
450
+
- . .
al
ive
(72
mo)
+
- . .
. al
ive
(48
mo)
+
- . .
. .
. al
ive
(36
mo)
+
- . .
. .
aliv
e (2
4 m
o)
+
+
. . .
+
(100
1 +
(3
/11
- (1
1/U
~
(ll/l
l al
ive
(16
mo)
75
0
1 al
ive
(36
mo)
pa
tient
s)
patie
nts)
pa
tient
s)
patie
nts)
5
dead
(6
-45
mo)
3.2-
18.8
2.9
. .
2.6
. 12
7.0
. . .
7.8
97.0
7.1
53.0
4.7
62.0
1.3
120.
0
4.2
48.0
2.5
8.0
(ave
rage
) (a
vera
ge)
3.6
51.0
. .
Leuk
open
ic
Thr
ombo
-
(15/
25
cyto
peni
c
patie
nts)
(2
2125
patie
nts)
6.0
30.0
2.3
60.0
0.9
67.0
1.6
60.0
5.1
60.0
-120
.0
1.1-
43.1
T
hrom
bo-
cyto
peni
c
(11/
12
patie
nts)
12.4
80
.0
1.9
70.0
11.0
-13.
0 . .
0.2-
0.5
. . .
Bou
ronc
le
et
al.
1958
[II
26
31-7
6 A
nem
ic
(21M
,5F
) (2
0/26
pa
tient
s)
Mitu
s et
al
. 19
61
IQ1
Rab
inow
itz,
Sch
rek
1962
(65
1 M
atsu
i 19
63 (
151
Jam
es,
Goo
dwin
19
64 [
19]
Sch
rek,
D
onne
lly
1966
[18
] B
oiro
n et
al
. 19
68
1161
Yam
et
al
. 19
68 (
231
Bea
chey
et
al
. 19
69
(421
Le
e et
al
. 19
69 [
2]
83,M
5.
1
54,M
5.
0
52,M
.
55,F
10
.5
55,F
9.
6
42,F
10
.5
68,M
10
.0
46,M
10
.0
30-6
4 8.
0 (lO
M,lF
) (a
vera
ge)
+
+
+ . . .
5 lo
st
(660
m
o)
2,94
0 1 1 25
48,M
9.
9
51,M
. .
.
- . .
. . .
. +
+
(912
5 . .
.
patie
nts)
. .
34-8
3 A
nem
ic
(21M
,4F
) (1
9/25
patie
nts)
64,M
41
,M
55,M
35,M
47,M
37
-78
(12M
)
8.0
11.9
7.
1
11.3
7.0
Ane
mic
(11/
12
patie
nts)
+
(abo
ut
l/2
patie
nts)
+
(211
25
patie
nts)
9 al
ive
(<
12-2
04
mo)
, 16
dea
d
(<12
-180
m
o)
dead
(3
6 m
o)
aliv
e (3
mo)
aliv
e (8
mo)
al
ive
(12
mo)
al
ive
(36
mo)
5
aliv
e (1
2-15
6
mo)
7
dead
(l-
156
mo)
al
ive
(24
mo)
1,10
0-l,
600
(6 s
plee
ns)
Rub
in
et
al.
1969
[41
] B
erg,
B
rand
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kemia or lymphoma was not recorded except for one
instance in which reticulum cell sarcoma developed
terminally [ 121. The survival time in the 36 survivors
ranged from 3 months to 17 years, with 3 patients
surviving over 13 years [2,3].
The modes of treatment included blood transfu-
sion, radioactive phosphorus-32, steroids, alkylating
agents, vinca alkaloids and splenectomy. Long-term
or temporary improvement followed splenic radiation
[ 16- 191, vincristine [ 2,191, cyclophosphamide [ 201,
steroids [ 16,171 and splenectomy [ 16,18,2 l-231.
Because of possible spontaneous remission in some
cases [2], as well as the extreme variability in the
severity of disease among the patients, it is difficult
to evaluate the relative merits of different therapies,
and probably more studies are necessary for the final
analysis. However, in recent reviews on this subject,
splenectomy rather than chemotherapy is recom-
mended for hypersplenism [3,11]. Data on many other cases reported in the litera-
ture were not included in Table II because sufficient cytologic descriptions of the leukemic cells were
lacking. However, the clinical and pathologic features
in many of them were highly suggestive of leukemic
reticuloendotheliosis [24-3 11. Although diagnosed as
leukemic reticuloendotheliosis by the investigators,
some patients were so young [4-6,32,33], the
course of disease so acutely fatal [8,34] or so atypi-
cal in other clinical or histochemical aspects [7,35- 371 that the diagnosis of leukemic reticuloendothe-
liosis would seem to be most unlikely.
PATHOLOGY OF LEUKEMIC RETICULOENDOTHELIOSIS
LRE Cells. In Romanovsky stained preparations
(Inset, Figure l), LRE cells were of medium size, usu-
Figure 1. An LRE cell with long cy-to- plasmic villi and multiple ribosome-la- mella complexes (arrows). Electron mi- crograph; original magnification X 10,000, reduced by 12 per cent. Inset,
an LRE cell. Wright-Giemsa stain; origi- nal magnification X 1,300O reduced by 12 per cent. From Katayama et al. 1391, reproduced by permission of the American Journal of Pathology.
LEUKEMIC AETlCULOENDOTHELlOSlS-KATAYAMA, FINKEL
ally measuring 10 to 18 p in diameter. Nuclei tended
to be eccentric in location. The nuclear configuration
was markedly variable ranging from the most fre-
quently observed oval form to dumbbell, horseshoe
and clover-leaf shapes. The nuclear membrane was
heavy and distinct, and the chromatin pattern was
more open than in mature lymphocytes and less so
than in blast forms. Nucleolar features were variable,
being prominent in about half of the LRE cells but
quite inconspicuous in others. The cell border was characteristically serrated in all LRE cells, with the
pathognomonic long cytoplasmic villi recognizable in
occasional cells. In the cytoplasm of some of the
LRE cells, azurophilic granules were present; and, in
addition, intracytoplasmic inclusions [38] were dem-
onstrated occasionally in preparations from a few
patients. Phase contrast microscopy readily revealed
the pathognomonic lace-like projections and also nu-
merous mitochondria [ 121. Histologic sections (Fig-
ure 2) showed LRE cells with cytology essentially
similar to that in Romanovsky stained preparations.
Electron microscopy (Figure 1) demonstrated multiple mitochondria, lamellate ergastoplasm, Golgi appara-
tus, centrioles, numerous vesicles (lysosomes), ribo-
some-lamella complexes and cytoplasmic villi mea-
suring up to 4 p in length [39].
Spleen. The weight of our 11 splenectomy speci-
mens ranged from 335 to 4,000 g, with 4 spleens
weighing more than 2,000 g. The weight of the 24
spleens detailed in Table II ranged from 500 to 3,800
g, with 12 spleens (50 per cent) weighing more than
2,000 g. Healed or recent infarcts were frequently
observed: otherwise the cut surface was homoge-
neously dark red and meaty. Definite tumor nodules
were not seen. Microscopic examination disclosed
diffuse proliferation of LRE cells (Figure 3). Conges-
July 1974 The American Journal of Medicine Volume 57 121
LEUKEMIC RETlCULOENDOTHELlOSlS-KATAYAMA. FINKEL
Figure 2. Epoxy section from huffy coat of peripheral blood (Case 11). All nucleated cells in this field are LRE cells, which are characterized by variable nuclear configu- ration, occasional prominent nucleoli, and hairy cytoplas- mic borders. Toluidine blue stain; original magnification X 1,400, reduced by 25 per cent.
Figure 4. Epoxy section of spleen (Case 1) shows LRE cells, erythrocytes and a few histiocytes with phagocytized debris in the cytoplasm (arrows). Toluidine blue stain; origi- nal magnification X 800, reduced by 25 per cent.
tion was marked, and focal hemorrhage was fre- quent. The Malpighian follicles were atrophic or ab-
sent. The trabeculas were slender and sparse, and E >me were infiltrated by LRE cells. The sinusoids
\rl .re difficult to recognize, as they were masked by
the heavy infiltration of LRE cells. Study of epoxy em-
bedded sections (Figure 4) revealed phagocytic his- tiocytes scattered among LRE cells. These histio- cytes differed cytologically from LRE cells, and the possibility of their being altered LRE cells during ac-
tive phagocytosis could be excluded by morphologic criteria. Erythrophagocytosis by LRE cells was not
observed. Of particular importance was the rarity of mitoses and the lack of cytologic atypicality, points also stressed by other investigators [ 16,171, al-
Figure 3. Section- of spleen (Case ii) shows diffuse infil- tration with LRE cells. The normal architecture is hardly recognizable except for an attenuated trabecula. Hema- toxylin and eosin stain; original magnification X 73, re- duced by 25 per cent.
Figure 5. Section of bone marrow (Case 4). In otherwise normal marrow, there is a focus of LRE cell infiltration which is indicated between large and small arrows. The same lesion is marked likewise by two arrows in Figures 6 and 7. Hematoxylin and eosin stain; original magnification X 140, reduced by 25 per cent.
though mitoses were relatively frequent in one in-
stance (Case 8). Most investigators [2,3,15,
18,21,40] did not elaborate on the splenic histopa-
thology beyond noting leukemic infiltration. Some
workers made a diagnosis of lymphosarcoma or
equivalent descriptions [ 1,17,19,22]. Malpighian folli-
cles were generally atrophic [ 1,231; hypertrophy of Malpighian follicles would probably favor an alterna-
tive diagnosis of lymphosarcoma. Extramedullary he-
matopoiesis may be present [2,17] or absent [ 161. Bone Marrow. The bone marrow was always infil-
trated by LRE cells. In the early stage (Figures 5 and
6) there was only an occasional area of LRE cell in- filtration surrounded by normal marrow. The early small focus of LRE cell infiltration was made evident
122 July 1974 The American Journal of Medicine Volume 57
LEUKEMIC RETICULOENDOTHELIOSIS-KATAYAMA, FINKEL
Figure 6. A magnified view of the same section as Fig- ure 5 shows presence of LRE cells mixed with lymphocytic infiltration. Hematoxylin and eosin stain; original magnifica- tion X 550, reduced by 25 per cent.
Figure 7. The same field shown in Figures 5 and 6 re- veals increase of reticulin fibers in the area of LRE cell in- filtration. Gomori’s reticulum stain; original magnification X 3 70, reduced by 25 per cent.
Figure 6. Section of bone marrow (Case 9) with more advanced involvement than in Figures 5, 6 and 7. Almost all nucleated cells here are LRE cells, which are loosely packed and show no mitoses. A persisting megakaryocyte is visible in one corner. Hematoxylin and eosin stain; origi- nal magnification X 880, reduced by 25 per cent.
with reticulum stain, which revealed an increase of fine reticular meshwork (Figure 7). In the more ad- vanced stages (Figure 8), the bone marrow was ex- tensively replaced by proliferating LRE cells. The cells were usually less densely packed than in infil- trates in lymphosarcoma or chronic lymphatic leuke- mia. Mitosis of LRE cells was rare. Many authors [i-3,16,18,40,41] emphasized the importance of bone marrow biopsy as opposed to aspiration since, after repeated unsuccessful or hypocellular aspira- tion, the biopsy usually revealed a hypercellular mar- row with numerous LRE cells and dense reticulin fi- brosis. Liver. The liver was often slightly to moderately en- larged. No circumscribed tumor was seen at the time
of splenectomy. At autopsy, however, nodular areas of leukemic infiltration were present, ranging in diam- eter from 0.3 to 2.5 cm in Case 2, and up to 0.2 cm in Case 7. On microscopic examinations of the liver biopsy specimen isolated cells or clusters of LRE cells were present diffusely in the sinusoids and por- tal tracts, and occasional foci of densely packed LRE cells were noted in the dilated space of Disse. In the later stage as observed at autopsy, nests of LRE cells invaded the hepatic parenchyma and were grossly recognizable as circumscribed tumor. Both portal and sinusoidal infiltration by LRE cells were de- scribed [ 1,3,22], but circumscribed tumor had not been previously recorded.
Lymph Nodes. No lymph node biopsy as such was performed in our series. All the perisplenic lymph nodes obtained from the splenectomy specimens (Cases 1, 5, 10 and 13) were of normal size, but they showed leukemic infiltration ranging from focal aggregation of LRE cells to almost complete oblitera- tion of normal architecture, thus simulating lympho- sarcoma very closely. Of the two autopsies, enlarge- ment of para-aortic lymph nodes up to 3 by 1.5 by 0.5 cm with leukemic infiltration was found in Case 2 and no enlargement of lymph nodes was found in Case 7. A biopsy diagnosis of lymphosarcoma or an equivalent description (complete loss of normal ar- chitecture) was made by some workers [ 1,201, whereas only minimal lymph node enlargement was noted at autopsy by others [ 15,401. Skin. None of the patients in our series had skin manifestations, and skin biopsy was not performed. In only 5 of 98 previously reported cases were skin lesions documented. In two instances the presence of LRE cells in the skin lesions was proved by phase microscopy [20,42]. In the remaining three cases skin lesions were described as being infiltrative [ 11.
July 1974 The American Journal of Medicine Volume 57 123
LEUKEMIC RETlCULOENDOTHELlOSS--KATAYAMA, FINKEL
DIFFERENTIAL DIAGNOSIS Malignant Lymphoma. The fact that a pathologic di-
agnosis of lymphosarcoma or reticulum cell sarcoma was made on biopsies from patients with LRE
[ 19,20,22] is more indicative of the pathologist’s un-
familiarity with the entity than of diagnostic difficul-
ties. In contrast to other lymphomas, leukemic reticu-
loendotheliosis as a rule shows very little mitotic ac-
tivity, cytologic atypia, necrosis or phagocytosis. Fur-
thermore, in the spleen and lymph nodes the basic architecture remains unaltered until very late, despite
heavy LRE cell infiltration. In the bone marrow, cellu-
lar infiltrates are often less densely packed than in
lymphosarcoma or chronic lymphocytic leukemia. Histiocytic Medullary Reticulosis (Malignant Histio- cytosis). This is a rapidly fatal disease, with death occurring within 6 months after onset in most pa-
tients. The clinical picture is characterized by pro-
found systemic symptoms including fever, wasting
and jaundice. Generalized lymphadenopathy and
hepatosplenomegaly are present. Histopathologic
studies reveal diffuse proliferation of morphologically atypical histiocytes with prominent erythrophagocy-
tosis and frequent mitosis in the lymph nodes, liver,
spleen and bone marrow [43,44]. Areas of necrosis,
hemorrhage and fibrin deposition are present [45].
Abnormal histiocytes may circulate in the blood
[43,46]. By contrast, leukemic reticuloendotheliosis
is a chronic disease with insidious onset and vague
symptoms. The patients are often able to perform
their normal functions. Lymphadenopathy is uncom- mon. Microscopic studies rarely show erythrophago-
cytosis, mitosis or necrosis.
Under the heading of “malignant histiocytosis,”
Rappaport [47] included both histiocytic medullary
reticulosis and leukemic reticuloendotheliosis, and he
described a wide spectrum of possible histopatholog-
ic alterations in order to accommodate several het-
erologous disorders. Hence, the four cases of malig-
nant histiocytosis reported by Liao et al. [48] were
neither typical histiocytic medullary reticulosis nor by any means typical leukemic reticuloendotheliosis. On the contrary, two cases considered to be histiocytic
medullary reticulosis by Scamps et al. [27] were in- stead suggestive of leukemic reticuloendotheliosis.
Schilling’s Monocytic Leukemia (Histiocytic Leuke- mia). The classic Schilling type of monocytic leuke-
mia can be readily distinguished from leukemic reti- culoendotheliosis by its fulminating course, overtly
leukemic blood picture, and the cytologic character-
istics of the abnormal cells [49,50]. In contrast, chronic monocytic leukemia, a rare and poorly de- fined variant of Schilling’s leukemia, may simulate leukemic reticuloendotheliosis very closely; both dis-
eases are characterized by a chronic course, leuko-
penia, anemia, minimal lymphadenopathy and mod- erate to marked splenomegaly [49,51,52]. Differen-
tial diagnosis, therefore, rests on identification of the abnormal cells in the blood or bone marrow. A nega- tive muramidase [ 171 and positive tartrate-resistant
acid phosphatase reaction [ 1 l] may help in exclud-
ing monocytic leukemia.
Reticulum Cell Sarcoma Terminating in Acute Leu- kemia. Leukemic transformation is a relatively rare
complication in the course of reticulum cell sarcoma.
It occurred in 6 of 113 [53] and 2 of 40 cases [54]
of reticulum cell sarcoma. Leukemic reticulum cell
sarcoma and leukemic reticuloendotheliosis can be
differentiated not only by the clinical picture, but also
by the pathologic mononuclear cells present in the
blood. In a tabulation of cases from the literature,
Lowenbraun et al. [55] excluded two of six cases in Zeffren’s series [53] with an interpretation that they
represented leukemic reticuloendotheliosis, but in our
view the two cases were indeed leukemic reticulum
cell sarcoma and not leukemic reticuloendotheliosis.
Sbzary’s Syndrome. A few workers [7,56] have
postulated that Sezary’s syndrome is no more than a clinical variant of leukemic reticuloendotheliosis. The
presence of reticuloendothelial cells in the blood, in-
volvement of skin and lymph nodes, and the chronic
course were the basis for this hypothesis. However,
involvement of the bone marrow is exceptional in Se-
zary’s syndrome [57] and constant in leukemic reti-
culoendotheliosis, whereas involvement of skin and
lymph node is constant in Sezary’s syndrome and un- common in leukemic reticuloendotheliosis. Moreover, Sezary cells and LRE cells are distinctively different
cytologically.
COMMENTS
We have reviewed the literature and have been able
to find 98 well documented cases of leukemic reticu-
loendotheliosis. To these, 13 cases of our own are
added. It is clear that leukemic reticuloendotheliosis
is a distinct clinicopathologic entity to be distin-
guished from other lymphomas and leukemias. The pathognomonic LRE cell is characterized by the hairy
appearance and tartrate-resistant acid phosphatase activity. The role of the LRE cell in the diagnosis of
leukemic reticuloendotheliosis appears analogous to
that of Reed-Sternberg cells in Hodgkin’s disease in that the cell is essential for diagnosis but a proper clinicopathologic background is also necessary [ 581. The clinical picture is so characteristic that the dis-
ease can be suspected on this basis alone. The pathologic features are likewise very characteristic, and the diagnosis can be ascertained by histopatho- logic observation.
The term “leukemic reticuloendotheliosis” was
124 July 1974 The American Journal of Medicine Volume 57
LEUKEMIC RETICULOENDOTHELIOSIS-KATAYAMA. FINKEL
first coined in 1923 by Ewald [59] when he de-
scribed a case of acute leukemia. This case was later interpreted by many reviewers [49,50,60] to be
an example of Schilling’s monocytic leukemia. Sub- sequently the term became synonymous with Schil- ling’s monocytic leukemia [61,62] until 1958, when Bouroncle and her associates [l] published their classic paper on leukemic reticuloendotheliosis in which they defined the disease as we understand it today. Since then most investigators have used the term leukemic reticuloendotheliosis in the same con- text as Bouroncle et al. After Schrek et al. [ 181 intro- duced the term “hairy cell” for the spectacular ap- pearance of the LRE cell under the phase micro- scope, leukemic reticuloendotheliosis gained wider recognition [ 631, and a few workers started to call it “hairy cell leukemia” [3,40]. However, in the opinion of Trubowitz et al. [21], with which we concur, it seems practical to adhere to the term “leukemic re- ticuloendotheliosis,” for most students of the disease prefer it. Moreover, the recent literature does not use leukemic reticuloendotheliosis as a synonym for Schilling’s leukemia, and, above all, a new name [41] would merely add to the semantic confusion.
The histogenesis of the LRE cell is controversial. Arguments have been made for both lymphocyte and reticulum cell origin of LRE cells on the basis of func- tional [ 18,4 11, histochemical [ 12,231 and ultrastruc- tural [40,64] studies. We suspect that the bone mar- row plays a major role in producing the LRE cells,
2
8
9
10
and that the spleen and liver play a secondary role of filtering the cells from the circulating blood and stor-
ing them. This hypothesis is based on the observa- tions of early multicentric involvement of the bone marrow, and retention of the normal architecture of the spleen until later stages of the disease, despite massive infiltration by LRE cells. There is relatively lit- tle involvement of lymph nodes. Thus, although the question of the site of origin of the LRE cells cannot
be considered to be settled, it seems to us that the
bone marrow has first claim. Based on this assump-
tion one might wish to add leukemic reticuloendothe-
liosis to the already established group of myeloprolif-
erative disorders. In this regard, the abnormalities of
platelet function and leukocyte alkaline phosphatase
are particularly intriguing.
ACKNOWLEDGMENT
We are indebted to Drs. L. T. Yam and L. Weintraub
for their generous collaboration during the progress
of this study and to Drs. W. J. Mitus, T. Shirahama
and R. A. DeLellis for reviewing the manuscript. We
are grateful to Drs. W. H. Crosby, I-l. Fanger, D.
Fitzpatrick, A. Gagnon, J. Grassi, J. Hiebel, P. H. Le-
vine, J. Lipkind, W. Murray, R. S. Schwartz, E. Sharp,
M. Tavassoli, R. Wenk, P. Wheat and L. Wolsky for
allowing us to study their patients and providing us
with follow-up data. We thank Mr. Gerald Ribicki for
photography and Mrs. Evelyn Teague for secretarial
assistance.
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126 July 1974 The American Journal of Medicine Volume 57