leukemic reticuloendotheliosis. a clinicopathologic study with review of the literature

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 accepted October 4, 1973.

The salient clinical and pathologic features of leukemic reticuloendotheliosis 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 related 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 reported 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, probably had other hematologic malignancies [4-81. Confusion in se- mantics and lack of pathologic criteria have hampered a wider recognition of leukemic reticuloendotheliosis as a distinct clinicopathologic entity.

In the past 3 years, we studied 13 patients with leukemic reticuloendotheliosis. 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 suspected of having the disease [ 9-1 I]. Our purpose here is to report the clinical, hematologic and pathologic findings in these 13 patients 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 biopsy specimens, 4 lymph nodes and 6 liver biopsy specimens) 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 reticulum 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, embedded 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 particular 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 descriptions 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


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

t 19

70

[171

1 4 +

+

+

+

+

+

v/1

2 pa

tient

s)

2,00

0 87

0

- -

. .

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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-lamella complexes (arrows). Electron mi- crograph; original magnification X 10,000, reduced by 12 per cent. Inset,

an LRE cell. Wright-Giemsa stain; original 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-


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 configuration, occasional prominent nucleoli, and hairy cytoplasmic 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; original magnification X 800, reduced by 25 per cent.

tion was marked, and focal hemorrhage was frequent. 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 histiocytes scattered among LRE cells. These histiocytes 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 infiltration with LRE cells. The normal architecture is hardly recognizable except for an attenuated trabecula. Hema- toxylin and eosin stain; original magnification X 73, reduced 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 infiltration surrounded by normal marrow. The early small focus of LRE cell infiltration was made evident


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 magnification 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 infiltration. 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; original magnification X 880, reduced by 25 per cent.

with reticulum stain, which revealed an increase of fine reticular meshwork (Figure 7). In the more advanced stages (Figure 8), the bone marrow was ex- tensively replaced by proliferating LRE cells. The cells were usually less densely packed than in infiltrates in lymphosarcoma or chronic lymphatic leukemia. 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 aspiration, the biopsy usually revealed a hypercellular marrow 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 diameter 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 portal 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 described [ 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 lymphosarcoma very closely. Of the two autopsies, enlargement 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 architecture) 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.


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 reticuloendotheliosis 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 defined 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 moderate 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 histopathologic observation.

The term “leukemic reticuloendotheliosis” was



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 appearance 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 reticuloendotheliosis,” 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 functional [ 18,4 11, histochemical [ 12,231 and ultrastructural [40,64] studies. We suspect that the bone marrow 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 observations 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 little 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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leukemic reticuloendotheliosis. a clinicopathologic study with review of the literature

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