malakoplakia of the bladder and kidneys
TRANSCRIPT
MALAKOPLAKIA OF THE BLADDER AND KIDNEYS.'
By STUART MCDONALD and W. T. SEWELL. iS.ro?n the Pathological Departments of ti le Lhiversify o f Durham CoMegc of Mediciiie and
the Xoyal Yictm-ia hjrvzary, NewcastZe-on-Tyne.
(PLATES XXV.-XXVII.)
AT the meeting of the Pathological Society of Great Britain and Ireland held in Newcastle-on-Tyne, in July 191 2, we demonstrated the case we are about to describe, and a preliminary note appears in the Proceedings of the Society (1 912-13 I). The extreme rarity of the condition, and the fact tliat we have now studied it in more detail, justify, we hope, a further illustrated communication on the subject. We wish, in the first place, to acknowledge our indebtedness to Professor L. Aschoff of Freiburg in Breisgau, who, a t the International Medical Congress in London (1913) was good enough to examine some of OUY preparations and refer us to the few similar cases which are on record.
The clinical history and morbid anatomy were published in the preliminary note already referred to, but we may briefly recapitulate the main facts.
CLINICAL HIsTonY.-The patient was a young married woman, aet. 24. She had been confined five months previously, and had been in bed ever since. Three months later an abscess formed in the right flank. This was not opened, but seems to have disappeared. There had been pain in the right flank since that date. More recently there had been severe pain in the right flank and in the vulva at the end of micturition. There was increased frequency of micturition. There was no history of hmakxria or of the passage of calculi. There was rapid emaciation. Tho patient had a severe rigor a few days before admission. On admission to the Royal Victoria Infirmary, Newcastle-on-Tyne, under Mr. Richardson, a fluctuating swelling was found in the left ileocostal space. There was pyuria. The temperature was 99" Fahr. The abscess was opened and 15 ounces of foul pus evacuated, containing B. coZi. On Ihe sixth day after the operation the temperature rose to 1 0 1 O . 4 Fahr. and reached 103O.6 Fahr. on the eighth day, when she died.
SECTIO (Post-mortem Records, R. V.I., 315/1911).-At the post-mortem exaniination there was found recent acute pericarditis and a right pleural empyema containing about a pint of thin greenish pus. There were patches of broncho-pneumonia in the lower lobe of the right lung. A recent operation wound in the left flank led down to a perinephric collection of pus. There were dense inflsmniatory adhesions between the capsule of the kidney and
Received October 1, 1913.
MALAKOPLAKIA OF THE BLADDER AND KIBNEYS. 307
surrounding structures. Throughout the kidney substance numerous yellowish white deposits were found (Plate XXVI. Fig. 2). These varied in size from a pin-head to a third of an inch in diameter. The deposits were firm and elastic. Some had hyperaemic centres, and some showed points of suppurative soften- ing. I n one large deposit the greater part was greyish in colour, and strongly resembled the " wash-leather " centre of a gunima. The nodules were largest near the surface of the kidney. They almost entirely replaced the kidney substance in the lower pole. The renal tissue was bright pink in colour, and even the parts free from the larger deposits showed minute points and streaks of infiltration through the medulla into the cortex. The apices of the papillae showed nodular infiltration with hyperaemia on the surface. The pelvis of the kidney showed slight granularity of the mucosa. The right kidney showed a similar condition, but the deposits were not so numerous or so large. One mass of fused nodules contained irregular cavities filled with pus, and the surface of the kidney appeared to have been infected from this. The arrange- ment of the lesions on this side was more suggestive of an ascending infection. There was superficial erosion of the papilla with whitish infiltration running in lines into the cortex. The ureters were slightly dilated and thickened. The bladder (Plate XXVI. Fig. 2) was slightly dilated; at the trigone and surrounding the openings of both ureters were numerous small rounded nodnles raised above the mucosa, averaging about one-eighth of an inch in diameter. The nodules were closely set, and extended up the posterior wall almost t o the fundus. The individual nodules were semi-transparent and greyish in colour with a more opaque white centre, and were surrounded by a hgperaemic zone. In places they coalesced so that the mucosa was covered with yellowish-white shects of deposit in areas up to an inch in diameter. The other pelvic viscera showed no abnormality.
BACTERIOLOGY.-A culture from one of the softening nodules in the kidney yielded a pure growth of B. col i communis.
HISTOLOGY.-Portions of both kidneys, both ureters, and the bladder, were examined microscopically, by means of frozen and paraffin sections. The other organs were examined microscopically, but showed no special change. Attention is therefore confined to the urinary tract.
We may briefly state that the lesions in the bladder and kidney are identical-a point of importance, seeing that, so far as we can find, the lesions observed in this condition have never before been described in the substance of the kidney. The impression conveyed by micro- scopical study is that we are dealing with a new formation, essentially consisting of a peculiar type o€ cell, and that there are secondary changes present, partly degenerative and partly the result of an in- flammatory condition associated with the presence of B. coli communis. The relation of these processes to one another will be afterwards discussed. As we have just stated, the lesions in the bladder and kidney are practically identical, and the clearest conception of the process will probably be gained by considering in detail the cellular elements present.
I n places they occurred in clusters and tended to fuse together.
These elements may be classified as follows :-
1. The large, peculiar and characteristic cells hereinafter referred to as the large cells (malakoplakia cells of V. Hansemann).
308 STUART McDONALD AND PK T. SEWELL.
2. Certain free and intracellular bodies which have been seen in the other recorded cases, and which will be spoken of as the Michaelis- Gutniann bodies, after the authors who first described them.
3. Leucocytes, cells of lymphocyte series and fixed cells. 4. The stroma and vessels. 5. Bacteria.
1. The large ee7ls.--In all of the lesions examined large niasscs of these cells are :L characteristic feature. I n the bladder they are found in the snb- mucosa (Plate XXVlI. Pig. 3), the epithelial lining of the viscus being raised above the level of the niucoiis membrane by these formations. The individual cells are quite uiililie any we have seen in odinary inHamniatory reactions. Healthy looking unaltei ad cells present the following appearaiices. They peniiiid one of liver cells or rather of cc~lls of the supiarcnal cortex. ]\'liere lyiiig loosely they are round or oval, but in the denser portions they are tlistinctly polygonal in shape. They arc fairly uniform in ,cize, on an svc*rage measuring about 20 p i n diameter. They linvc a well-defined cell membrane, anti for the most part are niononucleated. Tlierc are numerous chromatic granules scattered through the nucleus in an irreLgnlar manner. Mitotic figures are wanting. Degenerative changes are frequent. Chromatolysis, pyknosis, and liaryonliexis are coininon. The cytoplasm alio varies much in appearance; a special feature is its granularity and highly refractile character. At first sight the protoplasm appears to be vacuolated, but on closer examination the appearance is that of a homogeneous highly refractile substance, in small masses of irregnlar size and shape, scattered through the cell protoplasm. In many places these large cells are markedly degenerated ; some are homogeneous and necrotic looking, and some arc coarsely granular, the granules having a marked acidophil reaction with eosin. Often the nucleus has disappeared, or its appearance and the structure of the cell is masked by the cell inclusions to be described presently. The cells are not always arranged irregularly; in many places there is a distinct tendency to their formation in columns or rows, suggesting again a resemblance to the suprarenal cortex.
2. The Michaelis- Gzitinann bodies (Plate xxv. Fig. 1). - Scattered throughout the deposits of large eelis, numerous bodies of very peculiar and characteristic nature are to be found. They aremost numerous inside the large cells, biit they are also found between them, and large numbers are present towards the periphery of the deposits. We will take first the intracellular bodies. The largey forms attract attention at once by their staining reactions. They have a strong affinity for hsmatosylin dyes, which stain them a purplish colonr. By this reaction alone they are readily distinpishable from the nuclei of the cells. They are for the most part homogeneous and highly refractile, but the larger forms at least show a certain structure. Thus many of them show a definite concentric lamination suggestive of corpora amylacea. They arc round or oval in shape, and their peripheries often stain specially intensely, giving a double contour or capsulated appearance. The contour of the large forms often shows fine crenations or irregularities. Some present little bud-like projections from their edges, and at first sight the appearances arc suggestive of blastomycetes. The smallest forms giving this reaction may not be more than 1 or 2 p in diameter. The smallest forms appear to us to be definitely intracellular. All gradations in size occur, up to bodies occupying practically a whole cell. Numerous small and medium-sized forins may be present in a single cell. As they accumulate they obscure the nuclei, but srnall forms a t least may be found in cells whose nuclei show no striking alteration or signs of degeneration. The smaller forms are often surrounded by a distinct clear halo in the cell protoplasm. In some the central
The nucleus varies in size.
The? vary much in size.
MALAKOPLAKIA OF THE BLADDER AND KIDLVBYS. 309
portion stains more intensely, but there is nothing to suggest that these are of nuclear nature. Their homogeneity and whole appearance, indeed, suggests that they are degeneration products rather than of true cellular nature. They do not stain with the ordinary aniline dyes.
The reaction of these bodies to haematoxylin suggested the presence of lime salts. Sections were treated with weak acids and examined directly under the microscope, when free bubbles of gas arising from the bodies were readily observed. They also gave characteristic calcium reaction. Andrewes’ (2) modification of Kossa’s test, as described in his recent report to the Local Government Board on arterio-sclerosis, gave good results. It may therefore be taken that whatever be the composition of these bodies they certainly contain lime salts. I n addition to the intracellular bodies above described, free bodies of similar constitution are found present between the cells, and, as has been said above, are specially numerous and large towards the edges of deposits, in this latter situation lying in spaces in a fibrous matrix. They appear to us, however, in those situations to be almost certainly derived from the disintegration of the large cells, or from the breaking down of other phagocytic cells concerned, in an attempt to remove them. It may be mentioned here that, though their usual intracellular site is the large cells, similar bodies may occasionally be observed in what appear to be definite fibroblastic cells in the zone of inflammatory reaction at the periphery of the nodules.
Microscopical examination of the large cells shows, without difficulty, the presence of certain other bodies which may be referred to as cell inclusions. For instance, in sections stained by methylene-blue and eosin and by the triacid stain, comparatively unaltered red blood corpuscles may be observed both in and between the large cells. I t is evident, therefore, that the large cells are active phagocytes ; and, in addition to red blood corpuscles, masses of chromatin, evidently derived from the nuclei of ingested polymorphs, may also be observed. Smaller masses of chromatin are sometimes seen, whose exact nature it is impossible to determine. Some of these may be derived from extruded portions of the nuclei of the large cells, and in rare instances little bud-like projections of the nucleus have been seen, apparently in the process of separation. This appearance, however, is quite exceptional, and the majority of those little masses we regard as of the nature of cell inclusions, undergoing a process of intracellular digestion. By the use of ferrocyanide of potassium and hydrochloric acid, a somewhat faint but characteristic iron reaction can be demonst,rated in the Michaelis-Gutniann bodies. The impression is con- veyed that the iron is still somewhat firmly combined with some other body. I n addition to the comparatively unaltered red blood cells, other erythrocytes in various stages of decolorisation can be seen. Some appear as practically colourless globules; but, as other clear refractile bodies of similar size are present in and between the cells, it is sometimes very difficult to differentiate between them.
3. Leucocytes, cells of t h e lyniphocgte series and $xed cells.-Scattered throughout the lesions are numerous polymorpho-nuclear leucocytes, some well preserved but many obviously degenerating. They are most numerous in the zone of inflammatory reaction a t the periphery of the nodules and in the central degenerating parts of the deposits of the large cells. I n addition, many lymphocyte-like cells are present. These also are most numerous at the margins of the deposits. I n the case of the bladder they are found mainly in the snbmucosa. Elsewhere theg tend t o occur in small groups. Among them some typical plasma cells may occasionally be seen, but they are not numerous. A few larger lymphocytes are present, and occasional cells with rather more abundant clear protoplasm. Some of these suggest endo- thelial cells, but they never even approximate in size to the large cells described above. At the margins of the deposits an entirely different type of
310 S T U A R T McBONALD AND ?I? T SEWELL.
cell is found. These are elongated spindle-shaped cells, and correspond in all respects with typical fibroblasts. I n some of them, as in the large cells in the vicinity, numerous rounded bodies with intense acidophil reaction are present. Some of the cells are crowded with them, and at first sight the appearances are suggestive of sonie form of protozoal infection. Clear round globules may also be observed in and between those cells, and, as has already been said, the Michaelis-Gutmann bodies may also be present in the fibroblasts. The impression conveyed is that these fibroblastic cells are merely acting as phagocy tes.
4. The sdronaa awl vessels.-In the deposits of large cells the stroma is very scanty, only fine fibrils of connective tissue being present, while in many places there is no intercellular material at all. I n other places thin-walled blood channels are present, sometimes they are irregularly shaped and of sinusoidal character. They are lined by flattened endothelial cells, which occasionally are swollen up, rounded, and more prominent. Free red blood corpuscles may be occasionally seen in their vicinity ; these l~lood vessels do not quite correspond in character to the newly-formed blood channels which are about to be described, and which are obviously the result of an inflammatory reaction. At the margins of the nodules a definite fibrous matrix is present between the fibroblasts, and is evidently being formed from them. I n this neigh- bourhootl typical newly-formed blood vessels can be seen passing in towards the nodules from the surrounding tissues. Lying in this fibrous matrix are numerous large Michaelis-Gutmann bodies. They are often of considerable size; some are evidently occupying practically a whole cell, others are quite free.
5. Bacteria.-Sections have been stained for acid-fast bacilli by Gram’s method and simple aniline dyes. Spirochzetes have also been sought for. N o organisms have been discovered, however, other than short Grani-negative bacilli, corresponding morphologically to B. coli. These arc very numerous and we widely distributed throughout the lesions. They are found sometimes in masses towards the centres of the nodules of large cells. I n the kidney they are widely distributed between the nodules, and they are also seen in large numbers in the renal tubules.
I t is unnecessary to describe in detail the histology of the lesions in the bladder and kidneys. It is evident that in the bladder the priniarg formation of these large cells has occurred in the submucosa, quite independent of the superficial epithelium. I n most cases the epithelium of the mucosa is entirely lost. Tlie nodules may be seen impinging on the superficial layers and iiltiinately leading to their entire destruction. Sections have been made of both ureters, but nowhere, so far, have the characteristic lesions been found. The walls are thickened; there is a superficial catarrh of the niucosa with marked hyperamia of the submucons tissue. In the muscular coat there is a perivascular infiltration with lymphocyte-like cells, the appearances suggesting an ascending lymphatic infection.
In the kidneys it is obvious that we have to deal with an ascending suppurative pyelo-nephritis, and beyond the nodules of the characteristic large cells and cell inclusions there is nothing specially to note.
Pi.cIiio1uly Xeco7”dcd chses.
That the condition is extremely rare is apparent from the fact that we have only been able to find twenty-one cases of this kind in medical literature, twenty of which have occurred on the Continent and one in America. W e can find no reference to the condition in the Xnglisli surgical text-boolts or journals, though it is quite possible
MALAKOPLAKIA 03 THE BLADDER AND KIDNEYS. 311
that cases have been observed in this country, and that specimens may exist in some of the pathological museums. It was first described in any detail by v. Hansemann, though Michaelis and Gutmann had previously observed two cases. The best accounts we have found, so far, are those by Loele in 1 9 1 0 arid Hedren in 1 9 11. The list we annex is taken from Loele’s paper, his own case and that of Hedren being added. Both Loele’s and Hedren’s papers are accompanied by full bibliographies. I n many of the cases the condition has only been recognised at the sectio, but in three instances a t least the condition has been diagnosed clinically by the use of the cystoscope, and by micro- scopical examination of portions of tissue removed. A new aspect of the disease was presented by Kimla (1 9 0 6 3), who suggested that the condition was of tuberculous nature. Subsequent observers, however, have pronounced strongly against this view, though tuberculosis in some other part of the body has been frequently noted in the malako- plakic cases. A full study of the cases diagnosed clinically has been of course impossible, and even in some of the cases observed post- mortem the data are too scanty to be of any value. The following table (pp. 3 12-3 14) shows clearly the obscurity surrounding the etiology of the condition and the diveisity of opinion concerning the nature and origin of the characteristic malakoplakic cells and inclusions. A special feature in the recorded cases is the frequency of the disease in feinales and the advanced age of the patients in most instances. I n many cases there has been an entire absence of urinary symptoms. Our own case in point of age (24), in the prominence of the urinary symptoms, and in the wide distribution of the lesions throughout the urinary tract, is in striking contrast to the others observed.
DISCUSSION.
In discussing the present case we will follow the headings in the list of previously published cases.
1. With regard to the clinical aspect of the case, it may be noted that in several respects the case before us differs from those previously recorded. Thus, while the patient was a female, as is apparently so frequently the case in this disease, she was only 24 years of age. A glance a t the bibliography shows how eeldom the disease has been observed in one so young. Next, the prominence of the urinary symptoms is in marked contrast with what has been observed so often in these cases. The broncho-pneumonia, empyenia and pericarditis which were present point to a general pyEmic condition as the immediate cause of death, though the extensive acute lesions in the kidney must have played a part. I t is noteworthy that in our case there was no trace of tuberculosis in any part of the body.
2. I n regard to the nature of the large cells we think it is obvious that their possible origin, from the superficial epithelial cells of the
Num
ber.
Aut
hor.
L.
Mic
hael
is a
nd G
ut-
nian
n, ‘‘
Incl
usio
ns i
n B
ladd
er
Tnni
ours
, ”
Zttsc
hr. f.
klin
. ,!
fed.
, B
erlin
, 19
02,
Bd.
xl
vii.
S. 2
08.
V.
Han
sem
ann,
“ O
n M
alak
opla
kia
of
the
Uri
nary
B
ladd
er, ”
Virc
liow
’s
A r
ehiv
, B
erli
n,
1903
, B
d.
clxx
iii. S
. 302
.
R.
Lan
dste
iner
and
0.
Stoe
rk,
“On
a Pe
- cu
liar F
orm
of C
hrou
ic
Cys
titis
(V
. H
anse
- m
aim
’s
Mal
akop
la-
kia)
,”
Bci
tr. i. pa
tk.
Am
t. tc
. z.
allg
. Pat
h.,
.Jcn
a, 1
904,
Bd.
xxs
vi.
S. 1
31.
Gie
rkc,
“ O
n M
alak
o-
plak
ia o
f th
e U
rina
ry
Bla
dder
, ”
Niii
ache
ia.
me
d.
Wch
nseh
r..
Miin
chen
, 1905,
NO
: 29
, S.
1388
.
TA
BL
E.
Pati
ent.
1. F
erna
le, c
t, 42
yea
rs;
pyel
oncp
hriti
s.
2. F
erna
le, c
t. 46
yea
rs ;
hydr
onep
hros
is.
1. M
ale,
ct.
66
year
s;
lung
tube
rcnl
osis
. 2.
Fem
ale,
set.
70 g
ears
; ca
rcin
oma
of‘
gall
bl
adde
r.
1. F
eina
le, ;
ct. 6
7 ye
ars ;
neph
ritis
. 2.
Fem
ale,
ret.
40ye
ars;
tu
berc
ulos
is o
f nt
e-
rus
and
tube
s.
3. M
ale,
m
iddl
e ag
e;
phth
isis
pih
iona
le.
1. F
emal
e, c
t. 4
3yea
rs;
tube
rcul
osis
of t
uhes
. 2.
Fem
ale,
wt.
54ye
ars ;
neph
ritis
.
Pu’a
ture
of
Lar
ge C
ells
.
Prol
ifer
ated
epi
thel
ium
of
th
e m
ucou
s m
em-
bran
e.
Not
set
tled
; no
si
ini-
la
rity
to p
lasm
a ce
lls ;
endo
thel
ium
of
th
e ly
mph
ch
anne
ls
(no
tran
sit i
o 11
fo
rms)
. Pa
rasi
tic ?
Den
ied
by
Scha
udin
n.
Lar
ge
ph
ago
cyte
s;
M a
x im
o TT
~ ’s
p o
1 y-
blas
ts ; s
imil
arit
y to
la
rge
cells
not
iced
in
scle
rom
a o
f th
e
muc
ous
mem
bran
e of
resp
irat
ory
trac
t.
Des
cend
ants
of
fixed
or
mig
rato
ry ti
ssue
cel
ls,
swol
len
wit
h ur
ine.
Incl
usio
ns.
Org
auic
gr
ound
su
b-
stan
ce w
ith i
ron-
con-
ta
inin
g su
bsta
nce
in
com
b i 1
1 a t
i o n
. R
e-
sem
ble
L
eyde
n’s
“ b
ird
’ s
eye ”
- li
ke
bodi
es.
Am
orph
ous
subs
trat
um
wit
h ir
oii
reac
tion
; no
co
nnec
tion
wit
h re
d bl
ood
corp
uscl
es ;
not
para
site
s.
raki
ng u
p of
th
e re
d ce
lls
into
th
e ce
lls
and
man
nfac
ture
int
o th
e in
clus
ions
.
Tiss
ue
rem
ains
an
d el
emen
ts
take
n up
fr
om u
rine
.
Bac
teri
a.
~ No
men
tion
Bac
illi o
f co
lifor
m ty
pe,
prob
ably
w
ithou
t re
- la
tion
to th
e af
fect
ion.
Bac
illi
of
coli
form
(G
ram
-neg
ativ
e) ty
pe,
prob
ably
in
re
latio
n to
the
infe
ctio
n.
B.
coli
culti
vate
d in
on
e ca
se.
[ean
ing
of P
roce
ss.
sopl
astic
;
usua
lly
xnig
n pr
oces
s.
ther
inf
lam
mat
ory
Ir ne
w g
row
th.
;stit
is i
n pa
tche
s.
1 af
fect
ion
prod
uced
)y
th
e ur
ine
of Ly
stitis
.
Von
E
llenr
iede
r,
On
Mal
akop
laki
a of
th
e U
riu
ary
B
ladd
er,”
‘I
Dis
sert
atio
n,”
Frei
- bu
rg
in
Bre
isga
n,
1906
.
Bot
h ca
ses
K. H
art,
“O
n M
alak
o- 1 M
ale,
rc
t. 41
year
s ;
canc
er
of
plak
ia o
f th
e U
rina
ry 1
blee
ding
B
ladd
er,”
Zt
sehr
. f. 1
rect
um.
Kre
bsfn
rsch
unq,
B
er-
lin,
190
6, B
d.
iv.
S.
380.
Illin
elli,
Sp.
, “O
n M
al-
1 Old
w
oman
; cy
stiti
s ak
op
lak
ia
of
th;
cyst
ica;
h
yd
ro-
Uri
nar
y
Bla
dder
, ,
neph
rosi
s.
Yir
c h ow’s
Arc
hiv,
B
erlin
, 19
06,
Bd.
’ cl
xxxi
v. S
. 15
7.
11.
M.
Papp
enhe
imeT
, “ M
alak
opla
kia
of t
he
Uri
nar
y
Bla
dder
,”
Prnc
. N. Y
. Pat
h. S
ne.,
New
Yor
k, 1
906,
N.S
. vo
l. vi
.
1. F
emal
e, ie
t. 64
yea
rs.
2. F
emal
e, ie
t. 53
yea
rs ~
adva
nced
tu
herc
n.
losi
s.
of G
ierk
e.
Tra
nsiti
onal
fo
rms
be-
twee
n fix
ed c
ells
and
la
rge
phag
ocyt
ic n
an-
deri
rig
cells
and
lar
ge
lym
phoc
j tes
.
Dev
elop
men
t Fro
m p
oly-
ni
orph
an
d sp
indl
e-
cell
form
s (f
ixed
and
m
obile
cel
ls
of
con-
ne
ctiv
e tis
sue)
in
con-
se
quen
ce
of
soak
ing
wit
h nr
ine.
Epi
thel
yoid
cel
ls; e
ndo-
th
clia
l ce
lls e
nlar
ged
hy ta
king
up
wat
er.
Of
sim
ilar
orig
in
to
the
infl
amm
ator
y ce
lls
seen
in
othe
r in
flam
- m
ator
y pr
oces
ses.
Prod
uced
from
red
Moo
d co
rpus
cles
an
d po
r-
tion
s of
cel
ls.
Elab
orat
ion
of t
he n
rine
es
sent
ially
b
y
the
la
rge
cell
s; i
ron
pig-
m
ent
esse
ntia
l.
3atu
ratio
n of
tho
cel
ls
with
iro
n - c
onta
inin
g so
lutio
n an
d w
orki
ug
up o
f th
e sa
me
to th
e in
clus
ion ; n
o di
rect
co
nnec
tion
wit
h th
e re
d hl
ood
corp
uscl
es.
[n th
e fi
rst
case
, G
ram
- ne
gativ
e bac
illi
; in
the
seco
nd,
noth
ing.
$ram
~ po
sitiv
e ba
cilli
of
col
iforn
i typ
e w
itli-
ou
t co
nnec
tion
with
th
e af
fect
ion.
:ran
i-ne
gativ
e co
lifor
m
rods
.
‘nfl
amm
ator
y pr
o-
cess
; ch
roni
c cy
s-
titis
.
? h r
o n i c
in
flam
ma-
to
ry
hypc
rpla
sia,
pr
obab
ly
not
of
spec
ific
orig
in.
V-o
n-sp
ecifi
c gr
anu-
lo
ma
(hgp
erpl
asia
of
th
e en
doth
elia
l tis
sue
of t
he ly
mph
ch
anne
ls).
Che
fina
l w
ord
has
not b
een
said
.
TA
BL
E-c
onf
inue
d.
B.
coli
foun
d ;
no
tn-
berc
le.
B.
coli h
as a
re
latio
nshi
p w
ith
the
affe
ctio
n.
Kiii
itber
.
A c
hron
ic i
nfla
min
a-
tory
pro
cess
. Po
s-
sibl
y so
me
gene
ral
low
erin
g of
re
sist
- an
ce
or
incr
ease
d pe
rnie
abili
ty o
f th
e
10
11
12
berc
le b
acill
i.
Aut
hor.
diti
on o
f in
fect
ions
or
in
fect
ive
- toxi
c 1
1 na
ture
. B
. cnz
imay
be
the
spec
ific e
xcit-
in
g ca
use,
th
ough
pr
obab
ly q
uite
spe
- ci
al,
pred
ispo
sing
,
E.
F1~i
nlcc
.1, Y
whr
mdl
. d.
k
zt.
I’
erei
ns
211,
H
amhi
crg,
1
90
6 ;
De
11, t
s e
11 e
91
1. c d
. lV
cf~
?~sc
Izr.
, Eerl
in,
1906
; Af ii
n c
h, e 1
1.
nte
d.
Wch
nsc
hr.
, bl
iincl
ren,
19o
ti.
Lode
: “ E
in
Bei
trap
. z.
so
g.
Mal
akop
laki
a rle
r H
arnb
lase
,” L
’eitr
. 5
path
. A
xat.
tk.
z.
a2Zg
. Pat
h., J
ena,
191
0,
BI1
xlvi
ii. S
. 205
.
Hac
!ren,
“ U
eber
Mal
s-
kopl
altin
ve
sira
e m
i-
iiari
ae,”
N
ard.
X
ed.
Arc
hiv
Afd
. 1
(Kir
- it
ryi)
E’e
st. f. J.
Ber
g.,
Stoc
lrho
lin,
1911
, KO.
3.
Pati
ent.
Two
case
s,
one
in
an
11-y
ear-
old
girl
.
Fem
ale,
zt
. 76
yea
rs:
iir te
rio-
scle
rosi
s.
Fem
ale,
st.
45
year
s ;
chro
nic
neph
riti
s an
d ur
emia
;
no
bl
adde
r sy
mpt
oms ;
tnm
our-
li
ke m
asse
s in
blad
der.
Nat
ure
of L
arge
Cel
ls.
No
suffi
c
Gen
esis
not
abs
olut
ely
dete
rmin
ed.
In p
art
seen
to
co
me
from
g
ran
ii 1 a
tio
11 tis
sue
cells
.
The
larg
e ce
lls
are
slia
rply
dif
fere
ntia
ted
from
the
snr
all
1 oun
d ce
lls ;
no
tran
siti
ou
forn
is ;
very
di
tfic
ult
to d
eny
that
sonr
e may
ar
ise
from
fib
robl
astic
ce
lls;
th
ey
do
no
t su
gges
t en
doth
elia
l ce
lls.
Iucl
ueio
ns.
nt a
ccou
nt.
rli e
Mic
liael
is-G
utm
ann
bodi
es c
an a
rise
fio
m
acti
on
of
cyst
itic
ur
ine;
a
larg
e pa
rt,
how
ever
, due
toal
tere
d nu
clei
an
d ce
ll pr
o-
duct
s ;
calc
inm
an
d ir
on.
Lar
ge c
ells
can
pl
ay
a p
art
in
this
, bn
t no
t i~
otew
ortl
iy.
C‘o
iisid
ers
that
w
hile
fa
ctor
s pu
t fo
rwar
d Iiy
Lo
ele
are
impo
rtan
t,
ther
e iii
nst
be
hom
e sp
ecifi
c ce
llula
r ac
- ti
vity
of
the
reds
at
wor
k,
perh
aps
usin
g ot
her
ma
t er i
a1
to
man
it fa
ct n P
e t 1
1 e
bodi
es.
MALAKOPLAKIA OR THE BLADDER AND XIDNEYS. 315
bladder mucosa, can be absolutely excluded, from the fact that exactly similar cells are found in the substance of the kidney. Besides, they show no resemblance to surface epithelial cells. I t will be noticed from the abstracts of the papers published above that there is no uniformity of opinion with regard to their real nature and origin. So peculiar did they appear to v. Hansemann that the idea occurred to him that they themselves might be parasites, and specimens were submitted to Schaudinn for an opinion on the point. Schaudinn could find no evidence in support of this view, and it has not been suggested again apparently by any subsequent observer. The most popular view as to their origin is that they are directly derived either from endothelial cells lining the lymph spaces in the tissues or from connective-tissue or granulation-tissue cells. We can find no evidence in favour of this view. Indeed, most observers state definitely that transition forms between them and endothelial cells, plasma cells, or some other fixed connective-tissue cells cannot be demonstrated. This is our own opinion. There is always, so far as we can see, a striking difference between the largest of those fixed or wandering tissue cells and the characteristic large cells. Hedren only goes so far as to state that it is very difficult to deny that some may arise from fibroblasts.
The idea that the cells have in some way acquired their special characters from soaking with urine may, we also think, be definitely excluded from their occurrence in the substance of the kidney. We are left with a firm impression that these cells are in a class by themselves, and we consider that it is possible they may be pre-existing cells of the nature of suprarenal rests. The appearance of the cells lends some support to this view. Their arrangement, too, in columns or rows also favours this idea. Von Hansemann considers thie appearance an artefact, but Loele mentions it, and others have noted the same appearance. The clear refructile substance described in the cells may be of myelinic nature, for by means of crossed Nicol prisms we have found that a doubly refractile material sometimes occurs in the cyto- plasm. It may be mentioned that this clear refractile substance does not react to ordinary fatty stains.
3. The ,%?iehaelis-Gutmann inclusions.--Extraordinary diversity of opinion has also been expressed as regards the nature of these bodies. Michaelis and Gutrnann saw in them a distinct resemblance to Leyden's " bird's eye "-like bodies, but v. Hansemann could see no such resem- blance, and after careful examination was quite convinced that they were different and were lather of the nature of degeneration products. He is likewise convinced that they are not parasites-a view with which we agree. As to their nature, we consider that they probably arise primarily in connectioii with the droplets of clear refractile substance which we have mentioned, but i t is evident that iiiany factors are concerned in their production. We are inclined to agree with V.
Hansemann and Minelli that they have no direct connection with red
316 STUART McDONALD AND W. 3: SEWELL.
blood corpuscles. Loele, on the other hand, considers apparently that they may be derived directly froni the red cells, and has published certain experimental observations where he was able to demonstrate the formation of somewhat similar bodies by the direct action of coli- infected urine on red blood corpuscles in vitro without the agency of other cells. Hedreii, however, who has repeated these experiments, finds considerable difference between the bodies produced and true Michaelis-Gutmann bodies. We consider that whatever their origin and whatever be the composition of their ground substance, they are added to by the products of cell inclusions and degenerated cell products, saturation with blood pigment soaked out of the ingested red cells, and calcium salts occurring a t a later date.
4. Bacteria.-In our own case 6’. coli was isolated from the lesions in pure culture. Tubercle bacilli and other organisms were not found. That the B. coli has a certain relation to this disease appears fairly certain, but our present view is that i t is not a primary factor in the process, and only acts secondarily on a pre-existing, predisposing, and necessary factor.
Our conception of the nature a d meaning of the whole process will be found in our conclusions.
CONCLUSIONS.
Though our observations do not a t present permit of an absolutely definite opinion as to the nature of this rare affection, the fact, that we have found the lesions widespread in the kidney enables us to exclude some of the hypotheses as to its etiology which have been advanced. It is apparent, we think, that the influence of cystitic urine in producing these large cells, as many have held, is of no importance. In our case everything points against the theory that the process is tuberculous in nature. With reference to the relation- ship of the B. coli corninunis to the condition, it is evident that, as the organism or organisms resembling it have been fouiid in eleven out of fourteen recorded cases, there is a t least presumptive evidence of an etiological relationship. It niust be remembered, however, that this organism is the commonest pathogenic form found in the urinary tract, and it is remarkable that while coli infections are common this Condition is extremely rare ; besides, the lesions producecl by E. coli are very unlike those we meet with in malakoplakia. I t would appear, therefore, that for this condition to occur another factor is necessary. Loele’s suggestion that we may have to deal with some state of lowered general resistance, or an increased permeability of the bladder niucosa, does not appear to carry us niuch further in the elucidation of the disease. The B. coli may after all only act by paving the way for the entrance of the specific causal germ, if there is one, or i t may merely appear as a secondai y infective agent after the nialalioplakic process
MALAKOPLAKIA O F THE BLADDER AND KIDNEYS. 317
has reached the surface of the bladder mucosa. The B. coli then, though so often found, may be of merely secondary importance. We are left with the impression that the real cause must be sought for in a specific infective agent, or in some local predisposing factor on which some other exciting cause acts. Like other observers, we have entirely failed to demonstrate any such specific agent, protozoal, bacterial, or blastomycetic. While we cannot positively exclude this causal agent, the fact remains that the most striking histological feature of lesions is the presence of these large cells and the inclusions,unlike, so far as we know, anything that is found in such infections.
This suggests still more strongly that the essential cause lies in the presence of certain cell rests of developmental origin, which are stimulated to activity with associated specific degenerative changes by some other factor which may possibly be the B. coli itself. The necessity for both factors being present would afford a possible explanation of the extreme rarity of the condition. As regards possible cell rests, the well-known distribution of adrenal rests along the genito-urinary tract, and the distinct resemblance of the mala- koplakic cells to suprarenal cells, induces US to advance this hypothesis as a possible explanation of the etiology of the condition. It is apparent that there are many difficulties in accepting it. We inust presume either a very widespread distribution of such rests or an actual proliferation of the component cells of a neoplastic nature. Neither, however, appears to be inherently impossible, and we submit that, in the absence of any other satisfactory explanation, we may regard it a t least a8 a working hypothesis. One of us is a t present engaged in an experimental and chemical investigation to establish a more definite relationship, but the research is neither sufficiently advanced nor controlled to allow of a definite statement as yet. The in- flammatory changes appear to us to be readily explained by the action of such an organism as the B. coli, and we believe that much of the confusion that has occurred has been due to the fact that we have in this condition two separate processes working side by side. In conclusion, we should like to draw attention to the uusatjsfactory nomenclature of this disease. It was named malakoplakia by v. Hamemanu, who, admitting that the etiology was quite obscure, chose a purely descriptive title from the usual appearance of the lesion in the bladder, from pahacov (‘I soft ”) and rrhaf,plapues, thus suggesting a relationship with leucoplakia, etc. The fact that we have found the lesions in the substance of the kidney, renders the name inadvisable ; and practically all are agreed that wherever these large cells come from, they are not the derivatives of the superficial cells of the mucosa ; this affords a further contra-indication for the term. We have noticed, in going over the literature of the subject, that confusion has already arisen from the use of the word malakoplakia, for the well-known metaplasia which occurs in the pelvis of the kidney as a
318 MALAROPLAKIA OF THE BLADDER AND KIDNEYS.
result of long-standing inflammatory processes has been actually described as malakoplakia. As the cases up to this time have been recorded under the title of malakoplabia of the urinary bladder we have followed the eustom in this paper, but it is apparent, we think, that the time is ripe for a more scientific nomenclature.
We desire to thank Mr. Richardson for the clinical notes and permission to publish the case, and Mr. S. A. Sewell and Mr. Rcl. Muir for the drawings and photo-micrographs illustrating this paper.
REFERENCES.
1. STUART JICDONALD ASD Journ. Path. arul Uacteriol., Cambridge, 1912-13, vol. xvii. p. 115.
2. ANDREWEB . . . . . . Loeal Government Board Report, Ens. Suppl. 1911-12, London, 1912, p. 218.
3. RIMLA . . . . . . v. Hansemann’s ‘‘ Malakoplakin v e s i c s urin- a r i a und ihrc Heziehung zur plaquefbrmigen Tuberculase der Haniblase,” ViiircAozo’s Archiv, 1906, Hd. clxxxiv. S. 469.
SEWELL
DESCRIPTION OF PLATES XXV.-XXVlI.
PLATE XXV.
FIG. 1 .--I)rawing of section stained with alcoholic eosin, thionin l~lue, and polychrome blue, a t the periphery of a malakoplakic nodule in the kidney, showing characteristic malakoplakic cells with numerous Gl)roblasts between. The Michaclis-Gntmaun bodies are seen coloured blue. The larger fornis show distinct concentric markings. The nuclei of the cells show distinct nucleoli, and numerous spherical granules are present in the protoplasm. ( x 1200.)
PLATE XXVI. FIG. 2.-Drawing of the lesions in the Idadder and kidneys (4 of original size). The
bladder has been everted. The grouping of the lesions in the kidney vuggests an ascending infection and the sol‘tening occurring in the larger nodules in the kidney is apparent.
PLATE XXVII.
FIG. &--Photograph of low power of bladder, showing the abraded surface of the mucosa I n the subniucosa a zone of lymphocytic
~~ichaelis-Gutniann inclusions are scanty in this partic-
FIG. 4.--Section of a nodule from the kidney showing nnmerous highly grannlar malako- plakic cells, some polygonal, mostly ovoid or ronnded. A few leiicocytes may be seen between these cells, some of which are degenerating.
FIG. 5.--Section of siniilar nodnle in the kidney showing the characteristic Michaelis- Gntmann bodies. ( x 400.)
FIG. 6.-Section of similar nodule in the kidney showing the characteristic concclitric markings on the larger Michaelis-Gutmann bodies.
with a characteristic nodule. infiltration is seen. ular nodule. Note the tendency of the cells to run in rows. ( x 60.)
( x 250.)
( x 1000.)
JOURNAL OF PATHOLOGY.-VoL. XVIII.
F I G . 1.
JOURNAL OF PATHOLOGY.--VOL. XVIII. PLATE XXVI.
JOURNAL OF PATHOLOGY.-VOL. XVIII.
FIG. 3.
F I G . 5.
PLAm XXVII.
F I G . 4.
FIG. 6.