is not confined to the lymph glands, but may extend to the spleen and
bone-marrow. These proliferative processes may give rise to a
considerable enlargement, for example, of the spleen, without any change
in the specific character of the leukaemia, or the condition of the
blood. In spite of the splenic tumour we have to deal then with a pure
lymphatic leukaemia. In customary clinical language, a case of this kind
would be described as lieno-lymphatic leukaemia. The unreliability and
incorrectness of this terminology is best illustrated by another form of
leukaemic metastasis. In lymphatic leukaemia the liver may swell by
lymphomatous growth, to a large tumour, and we ought then to speak of a
"hepato-lymphatic" form of leukaemia. This term is by no means so
misleading as lieno-lymphatic; for no one would conclude from the former
that any liver-cells passed into the blood, whilst the latter implies
the idea, that specific splenic cells take part in the blood changes.
Further, the assumption of a pure =lienal= variety of leukaemia is totally
unwarranted from haematological investigations. The possibility of a
specific blood change, depending solely upon disease of the spleen,
appears _a priori_ almost excluded, after what has been said on the
physiological participation of the spleen in the formation of the blood.
Pathological data completely confirm this view. Ehrlich at least, in an
enormous number of cases, has never once succeeded in confirming the
existence of a purely splenic form from the blood examination[33].
The conditions in myelogenic leukaemia are quite similar, for foci of
myeloid tissue may appear in the spleen or lymph glands according to the
kind of metastasis. As it is the proliferation of the myeloid tissue and
not the accompanying swelling of spleen or lymph glands that is specific
in the process, the nomenclature "lienomedullary or medullary-lymphatic"
leukaemia must also be described as illogical and misleading.
We distinguish then, from the histological standpoint, but two forms of
leukaemia:
1. =leukaemic processes with proliferation of lymphoid tissue=:
"~lymphatic leukaemia~";
2. =leukaemic processes with proliferation of myeloid tissue=:
"~myelogenic leukaemia~."
The accompanying clinical phenomena may be indicated by simple
unequivocal amplifications, for instance, "lymphatic leukaemia with
enlargement of the spleen or of the liver"; "myelogenic leukaemia with
enlargement of the lymph glands," &c.
From our present knowledge, which, it may be remarked, is still far from
full, we may assume that lymphatic and myelogenous leukaemia have quite
a different aetiology. The recent discovery of Loewit should be decisive
on this point, for he demonstrated in myelogenic leukaemia the presence
of forms like plasmodia within the white blood corpuscles, but was
unable to find them in lymphatic leukaemia.
The necessity of separating lymphatic from myelogenic leukaemia is
further shewn by the fundamental clinical differences between them.
~Lymphatic leukaemia~ falls clinically into two readily distinguishable
forms. In the first place acute lymphatic leukaemia, characterised by its
rapid course, the small splenic tumour, the tendency to petechiae and to
the general haemorrhagic diathesis. By its startling course this disease
has given all observers the impression of an acute infectious process.
The second form of lymphatic leukaemia is marked off from the preceding
by its chronic, and often very protracted course. The spleen shews its
participation in the disease, as a rule by very considerable
enlargement. We have at present no investigations adequate to decide
whether chronic lymphatic leukaemia represents a single disease, or
should be etiologically subdivided. Haematologically, all lymphatic
leukaemias are characterised by a great preponderance of lymph cells, in
particular of the larger varieties. It should here be expressly
mentioned, that richness of the blood in large lymph cells, is by no
means characteristic of the acute form of leukaemia, for chronic, very
slowly progressing cases shew the same condition. Thus in a case of this
kind under observation in Gerhardt's wards, all observers (Grawitz, v.
Noorden, Ehrlich) found the large cells during its whole course. In
agreement with our remarks elsewhere (see p. 104), we assume with
regard to the origin of lymphatic leukaemia, =that the increase of the
lymph cells is brought about by a passive inflow into the blood; and not
by an active emigration from chemical stimuli=.
~Myelogenic leukaemia~ presents a picture that is different in every
particular. In former years the distinction between myelogenic leukaemia
and simple leucocytosis offered great difficulties. These conditions
were regarded as different stages of one and the same pathological
process, and when the proportion of white to red corpuscles exceeded a
certain limit (1:50) it was said that leucocytosis ceased, and leukaemia
began. By the aid of the analytic colour methods the fundamental
difference between the two conditions was first disclosed. Leucocytosis
is now recognised to be chiefly an increase of the normal polynuclear
neutrophil leucocytes; whereas myelogenic leukaemia brings elements into
the blood that are abnormal. The cells here introduced are so
characteristic as to render the diagnosis of leukaemia possible, even in
the very rare cases where the total number of the white blood corpuscles
is not to any extent increased. The best example of which we are aware
is a case observed by v. Noorden, in which the proportion of white to
red was only 1:200.
Although the blood picture of myelogenic leukaemia has been so clearly
drawn by Ehrlich, misconceptions and obscurities still occur in the
literature. And they are due to great errors in observation. It has for
instance happened that unskilled observers have regarded and worked up
cases of lymphatic leukaemia as myelogenic. The apparent deviations
discovered in this manner are copied, as specially remarkable, from one
book to another. Through insufficient mastery of the staining method,
the characteristic and diagnostically decisive elements (neutrophil
myelocytes for example) are frequently mistaken. A further source
productive of misconceptions lies in the circumstance that the typical
leukaemic condition of the blood may essentially change under the
influences of intercurrent diseases. Thus the intrusion of a
leucocytosis, brought about by secondary infection, is able to
obliterate more or less the specific character of the blood. Such
conditions must naturally be considered apart, and should not be used to
overthrow the general characteristics of the picture. No one surely
would deny the diagnostic value of glycosuria for diabetes, because in
conditions of inanition, for instance, the sugar of a diabetic may
completely vanish, although the disease continues. And one does not deny
the diagnostic value of the splenic tumour in typhoid fever, because the
enlargement of the spleen may occasionally subside, under the influence
of an intestinal haemorrhage.
From these considerations it is obviously necessary to derive the
description of leukaemic blood from pure uncomplicated cases; and to
construct it with the aid of standard methods. In this manner a type is
obtained so characteristic, as to render diagnosis absolutely certain
from the blood alone.
It is needful here to emphasise this hundred-fold repeated experience
with special distinctness, for some recent authors do not even yet allow
the full diagnostic importance of the blood examination. v. Limbeck says
in the latest edition of his clinical _Pathology of the Blood_, "That
one should not regard the blood changes as an invariably reliable
diagnostic resource in myelogenic leukaemia; and that the diagnosis of
leukaemia should not rest on the presence or significance of one or more
cells. Not only the general features of the case, but the blood
condition as well should be considered." To these remarks the objection
must be made that up to the present no serious haematologist will have
had to diagnose a leukaemic disease principally "from the presence of one
or more cells." In the work of Ehrlich and his pupils at least, it has
always been shewn that the character of a leukaemic condition is only
settled by a concurrence of a large number of single symptoms, of which
each one is indispensable for the diagnosis, and which taken together
are absolutely conclusive. With these premises it is indisputable =that
the microscopic examination of the blood alone on dry preparations,
without the assistance of any other clinical method, can decide whether
a patient suffers from leukaemia, and whether it belongs to the lymphatic
or myelogenic variety=.
The microscopic picture of =myelogenic leukaemia=, disregarding the almost
constant increase of the white blood corpuscles, has a varied, highly
inconstant character. This arises from the co-operation of several
anomalies, namely:
A. =that in addition to the polynuclear cells, their early stages, the
mononuclear granulated corpuscles likewise circulate in the blood=;
B. =that all three types of granulated cells, the neutrophil, eosinophil,
and mast cells participate in the increase of the white blood
corpuscles=;
C. =that atypical cell-forms appear=, _e.g._ =dwarf forms of all the kinds
of white corpuscles; and further mitotic nuclear figures=;
D. =that the blood always contains nucleated red blood corpuscles, often
in great numbers=.
1. We begin with the discussion of the =mononuclear neutrophil cells=,
Ehrlich's "=myelocytes=." They are present so abundantly in the blood of
medullary leukaemia as to impart to the whole picture a predominantly
mononuclear character. As we have frequently mentioned, myelocytes occur
normally only in the bone-marrow, not in the circulating blood. Their
eminent importance for the diagnosis of myelogenic leukaemia, where they
have been regularly found by the best observers, is in no way diminished
by their transitory appearance in a few other conditions (see pages 77,
78). Though they have been occasionally found, according to Tuerk's
investigations, in the critical period of pneumonia as parts of a
general leucocytosis, the danger of confusion with leukaemic blood
changes is non-existent. This is guarded against by (1) the much smaller
increase of the white cells; (2) the diminution of the eosinophil and
mast cells; (3) the fact, that the myelocytes of leukaemic blood are
nearly always considerably larger; (4) the preponderating polynuclear
character of the leucocytosis, which is not effaced by the small
percentage amount of myelocytes (at most 12%): (5) the incomparably
smaller absolute number of myelocytes. In the most pronounced case of
Tuerk's, for example, in which the percentage number of myelocytes
amounted to 11.9, calculation of their absolute number gives at most
1000 myelocytes per mm.^{3} This is a figure which bears no comparison
with that obtaining in leukaemia, where 50,000-100,000 myelocytes per
mm.^{3} and over occur in cases that are in no way extreme.
2. =The mononuclear eosinophil cells.= Before the introduction of the
staining method, Mosler had described large, coarsely granulated cells,
"marrow cells," as characteristic for myelogenic leukaemia. These are to
be regarded as for the most part identical with the mononuclear
eosinophil cells, noticed by Mueller and Rieder as peculiar, and aptly
described by them as the eosinophil analogues of the preceding group.
They appear as large elements with oval, feebly staining nucleus.
Undeniably a valuable sign of leukaemia, they are not nearly so important
as the mononuclear neutrophil cells, as follows from the numerical
superiority of the latter. To regard the presence of "eosinophil
myelocytes" as absolute proof of the existence of a leukaemia is
inadmissible, since they are occasionally present in small numbers in
other diseases.
3. =The absolute increase of the eosinophil cells.= In his first paper on
leukaemia, Ehrlich stated that the absolute number of polynuclear
eosinophils is always much increased in myelogenic leukaemia. This
assertion of Ehrlich has been received under some protest; v. Limbeck in
his text-book even speaks of an "alleged" increase of the eosinophil
cells. The well-known work of Mueller and Rieder has more particularly
given rise to this opposition, and thrown doubt on the diagnostic
importance of the eosinophil cells. These authors however base their
contradiction on false premises.
For Ehrlich did not speak of a rise of the percentage of the eosinophil
cells, but only of an increase in their absolute number. If in a case of
leukaemia only the normal percentage number of eosinophils is found, it
indicates, all the same, a great absolute increase; and Mueller and
Rieder would themselves have fully confirmed Ehrlich's statement, had
they only calculated the absolute figures in a few of their cases.
Selecting from the seven cases in this paper, those where it is possible
from the given data to obtain the absolute number of the eosinophil
cells, we get the following results:
Case 29 3.5% eos. 14,000 per mm.^{3}
" 30 3.9% " 8,000 "
" 31 3.4% " 11,000 "
The figure given by Zappert as a high normal value is 250. In these
cases there is an average number of 11,000, that is 50 times as great.
The observations then of Mueller and Rieder themselves suffice fully to
confirm Ehrlich's statement.
The absolute number of eosinophil cells depends naturally to a certain
extent on the relative proportion of white to red corpuscles, and the
greater the relative number of leucocytes, the greater should be the
number of eosinophils. Zappert, for instance, found the following
figures in his cases:
Proportion of white Absolute number
to red corpuscles. of eosinophils.
1:24 3,000-4,560
1:18 3,300
1:15 7,000
1:13 8,700
1:11 6,000
1:7.6 8,300
1:7.0 7,600
1:7.0 29,000
1:5.0 14,000
1:3.8 34,000.
Apart from the approximate parallelism between the two rows of figures,
this abstract shews that the minimal value--3,000 eosinophils with a
proportion of white to red of 1:24--still amounts to 15 times the
normal. The maximal figure found by Zappert of 30,000 is moreover by no
means to be considered extreme. Cases of leukaemia are not infrequent in
which we find 100,000 eosinophils per mm.^{3} and over.
From these figures it must be admitted that the absolute increase of the
eosinophil cells in medullary leukaemia is not "alleged" (v. Limbeck) but
on the contrary is very real and considerable.
That the absolute and relative number of eosinophil cells may markedly
sink in certain complications of leukaemia, constitutes no exception to
the law that the eosinophil cells are increased in myelogenic leukaemia.
In this connexion the self-evident principle must be observed, that only
analogous conditions are comparable. The standard of comparison for a
leukaemic patient suffering from severe sepsis is not the blood of a
healthy person with normal numerical proportions, but that of a patient
similarly attacked by a severe sepsis. Now we know that in sepsis the
number of eosinophil cells is enormously diminished, so that Zappert, in
five cases of this nature, was unable to recognise any eosinophils in
the blood. In contrast to this stands a case of myelogenic leukaemia
described by Rieder and Mueller, complicated by a severe and lethally
ending suppurative process. In consequence of the acute neutrophil
leucocytosis brought about by the septic infection, the number of
eosinophils sank rapidly from 3.5% to 0.43% (4 hours before death). The
absolute number of eosinophil cells however in this terminal stage still
amounted to 1400-1500 per mm.^{3}, and was therefore, in comparison with
an uncomplicated sepsis, very much raised. Writers should not have
disputed the importance of the eosinophil cells for the diagnosis of
leukaemia from cases like these; on the contrary they should have seen in
them a decisive confirmation of the constancy of the absolute increase
of the eosinophils in leukaemic blood.
At the time when Ehrlich formulated his proposition on the diagnostic
importance of the eosinophil cells in leukaemia, the simple eosinophil
leucocytosis (see p. 148), first discovered later by the investigation
of asthma etc., was unknown. For no confusion can arise between
leukaemia, and conditions accompanied by eosinophilia, as they can be
distinguished on clinical grounds alone. The blood moreover provides
ample means for a differential diagnosis: (1) the total increase of the
white cells in this case seldom reaches degrees that remind one of
leukaemia; (2) the eosinophil cells are exclusively polynuclear; (3) mast
cells and neutrophil myelocytes are almost entirely absent.
In favour of the diagnostic value of the absolute increase of the
eosinophil cells are those cases too, where with a blood condition
closely recalling leukaemia, the absence of eosinophil cells excludes the
diagnosis of that disease. In a case of carcinoma of the bone-marrow,
described by Epstein, with an anaemic constitution of the blood (nearly
always present it may be mentioned in leukaemia), there was found a
marked increase of the white blood corpuscles, numerous neutrophil
myelocytes and nucleated red corpuscles. Anyone holding, as Mueller and
Rieder do, that the number of eosinophil cells need not be considered in
the diagnosis, must in this case have diagnosed myelogenic leukaemia.
This however was according to Ehrlich's system impossible owing to the
complete absence of eosinophil cells.
From all these observations it follows that an absolute increase of
eosinophil cells is indispensable for the diagnosis of leukaemia.
4. =The absolute increase of the mast cells.= The mast cells are always
increased in myelogenic leukaemia. They may be counted in leukaemic blood
with the aid of the triacid or eosine-methylene blue stain. As shewn by
the former they appear as polynuclear cells free from granules, since
their granulation takes on no dye of the triacid mixture.
In all cases of myelogenic leukaemia the increase of mast cells is
absolute and considerable. Generally they are equally or half as
numerous as the eosinophils, occasionally they may exceed the latter in
number. Hence it follows that the mast cells undergo an increase in
number relatively greater than the eosinophil cells, for they normally
amount only to some 0.28%. They are perhaps of greater diagnostic value
than the eosinophils, because up to the present time we know of no other
condition (in contradistinction to eosinophil leucocytosis) in which a
marked increase of the mast cells occurs.
5. =Atypical forms of the white corpuscles.= Amongst these are to be
mentioned: (_a_) dwarf forms of the polynuclear neutrophils and of the
eosinophil elements respectively. As a rule they resemble normal
polynuclear cells on a small scale. (_b_) Dwarf forms of the mononuclear
neutrophil and eosinophil leucocytes, which correspond to the
pseudo-lymphocytes described elsewhere (see p. 78). The importance of
these dwarf forms for leukaemia is as yet insufficiently explained; and
it is difficult to decide whether they are already small forms on
reaching the blood-stream, or whether they are there produced by
division of a large cell. (_c_) =Cells with mitoses=. Formerly particular
weight was laid on the observation of mitoses, for they were regarded as
evidence that the increase of white blood corpuscles was brought about
in the circulating blood itself, an assumption specially supported by
Loewit.
A large number of authors (H. F. Mueller, Wertheim, Rieder) have
demonstrated mitoses, particularly of the myelocytes, in the circulating
blood in leukaemia. No =diagnostic= importance of any kind can however be
ascribed to them. They are found in all cases only in very small
numbers. Thus Mueller says that he generally must look through many
thousands of white cells before meeting one mitosis. Only in one case
did he find the figures of nuclear division somewhat more abundant,
where there was one mitosis only to several hundreds of leucocytes.
These really negative observations shew that the mitoses play a
completely negligeable part in the increase of the cells in the blood
itself. For the diagnosis of leukaemia they are valueless.
6. =Nucleated red corpuscles= form a constant constituent of leukaemic
blood. In different cases their number is very varying; in one case they
occur extremely sparingly, in another every field contains very many.
The normoblastic type is found most frequently, but side by side with
it, megaloblasts and forms transitional between the two are occasionally
found. Mitoses within the red blood discs have been described by
different authors, but possess no theoretic or clinical importance. The
appearance of erythroblasts in leukaemia may be either a specific
phenomenon, or merely the expression of an anaemia accompanying the
leukaemia. We are inclined to the first supposition, since the occurrence
in such numbers of nucleated red cells is hardly ever observed in other
anaemias of the same severity.
So much for the characteristics of leukaemic blood, upon which the
diagnosis of the disease is made. We must add that although in any case
of medullary leukaemia each particular factor described is to be
recognised, yet the manner of its appearance, its numerical relation to
the others and to the total blood varies extremely. Apart from the
degree of increase of the leucocytes, no one case is the same as another
with regard to the other anomalies. In one case the blood bears a
large-celled, mononuclear neutrophil character; in another the increase
of the eosinophil cells predominates; in a third the nucleated red blood
corpuscles preponderate; in a fourth we see a flooding of the blood with
mast cells. And hence results a multiplicity of combinations, and each
single case has its own individual features[34].
* * * * *
It is of special importance to study the changes due to certain
intercurrent diseases in the blood picture of medullary leukaemia. This
point has recently been the object of detailed investigation, in
particular by A. Fraenkel, Lichtheim and others[35]. According to these
authors, under the influence of febrile diseases the total number of
leucocytes may be enormously decreased. The blood moreover is altered,
so that the myelaemic characteristics become less marked, and the
polynuclear neutrophil elements largely preponderate. The latter may
attain the percentage numbers of common leucocytosis up to 90% and
over.