2. Adolph Schmidt has urged the converse argument. He shewed that in the sputum of patients with myelogenic leukæmia no more eosinophil cells were present than are commonly to be found in the bronchial secretion, although the blood was unusually rich in eosinophil cells. In our opinion however this observation does not support the hypothesis of local origin, but on the contrary is clear evidence that not the larger or smaller number of eosinophil cells in the blood decides their emigration, but the presence of specifically active chemical stimuli. For we know from our observations on leucocytosis in infectious diseases that the bacterial stimulating substances act on the eosinophil cells rather in a negative than in a positive sense. And if ordinary sputum is not rich in eosinophils in spite of a marked eosinophilia of the blood, this only corresponds to our experience in general. Indeed, this phenomenon is quite similar to Neusser's pemphigus experiment, where the specific foci of disease shewed an eosinophilia, whilst abscesses produced artificially, on the contrary, only neutrophil cells. Finally we may employ, to support our view, another analogous experiment of Schmidt himself. He found numerous eosinophil cells in the sputum of an asthmatic patient, but only neutrophil cells in an artificially produced suppuration of the skin.

Thus we see that the chief reasons brought forward by the supporters of the theory of local origin are not proof against the most obvious objections that can be raised from the chemiotactic standpoint. Moreover, neither histological nor experimental proof has been given for this theory in spite of numerous investigations in this direction. All the same, it should not be out of place to explain the possibilities that are given for a local origin of the eosinophil cells. First, the eosinophil cells might be the result of a progressive metamorphosis of the normal tissue cells. That such a process is possible, is proved by the local origin of the mast cells. These may arise, as Ehrlich and his school have always assumed, by transformation of pre-existing connective tissue cells[29]; but that the same holds good for the eosinophil cells as well, has nowise as yet been proved. Secondly, it is conceivable, that isolated eosinophil cells, pre-existing in the tissues, should rapidly multiply, and so produce the local accumulation only. Numerous mitoses could be considered an adequate proof of this process. But so far no figures of nuclear division have been observed; indeed A. Schmidt, who has directed special experiments thereto from the standpoint of his theory, has found them entirely absent.

As a third possibility for the local origin of the eosinophil cells, their direct descent from neutrophil cells is conceivable, and is by many regarded as a kind of ripening. This assumption nevertheless must be described as unsound, since the necessary condition of its foundation, namely the observation of corresponding transitional stages, has not so far been fulfilled.

By the inductive method then we conclude that a local origin of the eosinophil cells can hardly come under discussion. And this conclusion is strengthened by comparison with the behaviour of the mast cells, which are related to the eosinophils in many points, and only differ from them essentially in the nature of their granulation. The mast cells too, like the eosinophils, form a normal constituent of the bone-marrow, and occur regularly besides in normal blood, though in very small number—according to Canon they amount to 0.28% of the leucocytes. We know that the mast cells are produced in large quantities locally, wherever an over-nutrition of the connective tissue occurs, for instance in chronic diseases of the skin, elephantiasis, brown induration of the lungs. In the case of the mast cells, then, we see the conditions actually realised, which the supporters of the theory of the local origin of the eosinophil cells only assume. We should therefore expect that an increase of mast cells in the blood or in certain inflammatory exudations would be by no means seldom. With this point in mind Ehrlich has subjected the sputum in emphysema and brown induration of the lungs to exact examination for 20 years. Nevertheless he has obtained entirely negative results. The special blood investigations of Canon have likewise proved to be practically negative. In 22 healthy persons Canon entirely failed to find the mast cells on nine occasions, in the others he found on the average 0.47%; the highest percentage number obtained was 0.89%. Only in a few cases of skin disease was a slight increase indicated. The average amounted to 0.58%, a number, therefore, which is often to be found in healthy individuals. A leucocytosis of mast cells, comparable with the eosinophil or neutrophil forms of leucocytosis, has not been demonstrated in the cases of Canon or other observers. On the other hand, the mast cells undergo a considerable increase in myelogenic leukæmia, in many cases equalling or even exceeding that of the eosinophils. We shall not err in deriving the mast cells of the blood solely from the bone-marrow, on the grounds of this fact; or in conjecturing that their origin is not from the connective tissue, even when they are there excessively increased[30].

We think we have shewn in the preceding paragraphs that the evidence, so far brought forward for a local origin of the eosinophil cells, does not withstand the objections that have been raised. The task now lies before us, to produce positive proof that the accumulations of eosinophil cells in the organs and secretions must be explained by emigration from the blood.

This proof offers great difficulties in as much as we normally find eosinophil cells in many places. Here then we cannot trace a process step by step, but we have to deal with final conditions. Could we observe the genesis of eosinophil cells in organs usually free from them, it would be easier to clear up this question. Up to the present but a single observation on this point is available. Michælis established the interesting fact, that on interrupting lactation in suckling guinea-pigs, in the course of a few days numerous eosinophil cells collect in the mammary glands, but not in the lumen of the canaliculi. The eosinophil cells are further polynuclear, exactly corresponding to those of the blood, and therefore to be regarded as immigrants. We may explain this condition according to modern views as follows. Under certain conditions the mammary gland is capable of an internal secretion, by means of which substances are produced that are specifically chemiotactic for the eosinophil cells. When the external secretion of milk is disturbed, the internal secretion is abnormally increased. The fact too that in Michælis' researches no eosinophil cells passed into the true secretion of the gland may be thus explained[31].

Exactly similar observations have been made on pathological material, first recorded in the brilliant and fundamental work of Goldmann. In a case of malignant lymphoma Goldmann found a considerable accumulation of eosinophil cells within the tumour, and demonstrated anatomically, that it was brought about by an emigration of the cells from the vascular system. Hence Goldmann concluded that the eosinophil cells pass over into the tissue in question, at the call of certain chemiotactic products. Goldmann, and later Kauter, shewed that these eosinophil cells were not merely due to an ordinary inflammation; for in a large number of other diseases of the lymph glands—particularly the tuberculous, they were entirely absent. Similarly Leredde and Perrin have shewn in their investigations of Dühring's disease, that the eosinophil cells, which are also present in the cutaneous tissue in large numbers, apart from the contents of the bullæ, are due to an emigration from the blood-stream.

Thus it is evident from a number of various facts, that the eosinophil cells found in the tissues are not formed there, but have immigrated from the blood-stream. It naturally often happens that this appearance is not preserved equally distinctly in all cases. For, as has been seen in the ordinary polynuclear leucocytes, the immigrated polynuclear eosinophils may similarly change to mononuclear cells; they may perhaps settle down, and approximate to the character of fixed connective tissue cells. Such appearances may readily give rise to the view that in this case the reverse nuclear metamorphosis has occurred; that is a progressive development from mononuclear eosinophil to polynuclear cells.

In agreement with Goldmann, Jadassohn and H. F. Müller, we believe that the only admissible explanation for the facts mentioned above is that the eosinophil cells obey specific chemiotactic stimuli. By this hypothesis we can easily understand eosinophil leucocytosis, the presence of eosinophil cells in exudations and secretions, and the local accumulation of this kind of cell.

As to the nature of these chemiotactically active substances, we can so far only surmise. From amongst the clinical phenomena capable of throwing light on this subject we mention once more the fact, that the metabolic products of bacteria repel the eosinophil cells.

The question, what cells produce on their destruction actively chemiotactic substances, is of very great importance; but cannot be answered with the material at present available. The breaking up of ordinary pus cells or lymphocytes does not appear to give rise to any such substances; but there is much evidence that the decomposition products of epithelial and epithelioid cells act chemiotactically. Thus we can explain the frequent occurrence of eosinophilia in all kinds of skin-diseases. Again, in all atrophic conditions of the gastric, intestinal and bronchial mucous membrane there occurs a local accumulation of eosinophil cells; further, this kind of cell is increased in the neighbourhood of carcinoma. Additional support for this view is seen in the fact that in bronchitis and asthma the less the suppurative element of the secretion is developed, the more numerous are the eosinophil cells. An observation of Jadassohn is worthy of mention in this connection. He observed abundant eosinophil cells in foci of lupus after injection of tuberculin. In these foci then, by the destruction of the epithelioid cells brought about by the tuberculin, substances must have been produced which act chemiotactically on the eosinophil cells.

The specific substances are absorbed and reach the blood, and impart to it also the chemiotactic power. The direct cause then of most forms of eosinophilia seems actually to lie in a destruction of tissue, and in the products thus produced.

On the other hand, it cannot be doubted that substances foreign to the organism, circulating in the body, may act chemiotactically on the eosinophil cells[32]. The observations quoted above, of the well-marked eosinophilia in the different forms of Helminthiasis, may here be specially mentioned. The action of the Helminthides was formerly regarded as purely local, but the indications that they act also by the production of poisonous substances continue to increase. Thus Linstow has pointed out that the general typhoid state, and the fatty degeneration of liver and kidneys, that is of organs which the Trichina does not reach, necessitate the assumption of a poisonous substance. And in several varieties of Ankylostoma as well, there is distinct evidence of the production of a poison. We gather from Husemann's article on "animal poisons" (Eulenberg's Realenencyclopœdie 1867) that just as Ankylostomum in man produces the well-known severe anæmia, so Ankylostomum trigonocephalum in the dog, and Ankylostomum perniciosum in the tiger, causes analogous general effects.

Bothriocephalus latus too is now generally accredited with the production of a definite toxic substance; and the common tapeworm even, by no means infrequently brings about injuries to the body which are to be referred to the action of a poison.

So much follows from these observations, that the tapeworms can not only absorb but also can give out substances that are absorbed from the intestine of the host, and are able to bring about distant effects. One expression of these distant actions is, as Leichtenstern insists, the eosinophilia of the blood. We do not think we should assume on the evidence before us, that the substance which attracts the eosinophil cells is identical with the cause of the anæmia. Many observations, the absence, for example, of eosinophilia in Bothriocephalus anæmia (Schauman), render probable the existence of two different functions. In any case the substance causing the eosinophilia is more widely distributed than that to which the anæmic condition is due.

Leukæmia.

("Mixed leucocytosis.")

In spite of the enormous extent of the hæmatological observations of the last decennia, of which a very considerable portion deals with the problem of leukæmia, the literature shews many obscurities and misconceptions, even on important fundamental ideas. This is especially the case with the weighty question of the distinction between various forms of leukæmia.

From the purely clinical standpoint it is usual to describe a lienal, a lienomedullary, and a pure medullary (myelogenic) form of leukæmia. But the distinguishing characteristics in this classification are crude and purely external, and they find no place in hæmatology.

Neumann first shewed that the lymphoid proliferation in lymphatic anæmia 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 leukæmia, or the condition of the blood. In spite of the splenic tumour we have to deal then with a pure lymphatic leukæmia. In customary clinical language, a case of this kind would be described as lieno-lymphatic leukæmia. The unreliability and incorrectness of this terminology is best illustrated by another form of leukæmic metastasis. In lymphatic leukæmia the liver may swell by lymphomatous growth, to a large tumour, and we ought then to speak of a "hepato-lymphatic" form of leukæmia. 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 leukæmia is totally unwarranted from hæmatological investigations. The possibility of a specific blood change, depending solely upon disease of the spleen, appears à 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 leukæmia 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" leukæmia must also be described as illogical and misleading.

We distinguish then, from the histological standpoint, but two forms of leukæmia:

1. leukæmic processes with proliferation of lymphoid tissue:

"lymphatic leukæmia";

2. leukæmic processes with proliferation of myeloid tissue:

"myelogenic leukæmia."

The accompanying clinical phenomena may be indicated by simple unequivocal amplifications, for instance, "lymphatic leukæmia with enlargement of the spleen or of the liver"; "myelogenic leukæmia 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 leukæmia have quite a different ætiology. The recent discovery of Löwit should be decisive on this point, for he demonstrated in myelogenic leukæmia the presence of forms like plasmodia within the white blood corpuscles, but was unable to find them in lymphatic leukæmia.

The necessity of separating lymphatic from myelogenic leukæmia is further shewn by the fundamental clinical differences between them.

Lymphatic leukæmia falls clinically into two readily distinguishable forms. In the first place acute lymphatic leukæmia, characterised by its rapid course, the small splenic tumour, the tendency to petechiæ and to the general hæmorrhagic diathesis. By its startling course this disease has given all observers the impression of an acute infectious process.

The second form of lymphatic leukæmia 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 leukæmia represents a single disease, or should be etiologically subdivided. Hæmatologically, all lymphatic leukæmias 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 leukæmia, 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 leukæmia, 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 leukæmia presents a picture that is different in every particular. In former years the distinction between myelogenic leukæmia 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 leukæmia 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 leukæmia brings elements into the blood that are abnormal. The cells here introduced are so characteristic as to render the diagnosis of leukæmia 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 leukæmia 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 leukæmia 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 leukæmic 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 hæmorrhage.

From these considerations it is obviously necessary to derive the description of leukæmic 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 leukæmia; and that the diagnosis of leukæmia 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 hæmatologist will have had to diagnose a leukæmic 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 leukæmic 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 leukæmia, and whether it belongs to the lymphatic or myelogenic variety.

The microscopic picture of myelogenic leukæmia, 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 leukæmia 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 leukæmia, 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 Türk's investigations, in the critical period of pneumonia as parts of a general leucocytosis, the danger of confusion with leukæmic 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 leukæmic 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 Türk'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 leukæmia, 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 leukæmia. These are to be regarded as for the most part identical with the mononuclear eosinophil cells, noticed by Müller 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 leukæmia, 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 leukæmia 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 leukæmia, Ehrlich stated that the absolute number of polynuclear eosinophils is always much increased in myelogenic leukæmia. 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 Müller 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 leukæmia only the normal percentage number of eosinophils is found, it indicates, all the same, a great absolute increase; and Müller 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:

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 Müller 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:

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 leukæmia 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 leukæmia 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 leukæmia, constitutes no exception to the law that the eosinophil cells are increased in myelogenic leukæmia. In this connexion the self-evident principle must be observed, that only analogous conditions are comparable. The standard of comparison for a leukæmic 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 leukæmia described by Rieder and Müller, 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 leukæmia 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 leukæmic blood.

At the time when Ehrlich formulated his proposition on the diagnostic importance of the eosinophil cells in leukæmia, the simple eosinophil leucocytosis (see p. 148), first discovered later by the investigation of asthma etc., was unknown. For no confusion can arise between leukæmia, 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 leukæmia; (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 leukæmia, 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 anæmic constitution of the blood (nearly always present it may be mentioned in leukæmia), there was found a marked increase of the white blood corpuscles, numerous neutrophil myelocytes and nucleated red corpuscles. Anyone holding, as Müller and Rieder do, that the number of eosinophil cells need not be considered in the diagnosis, must in this case have diagnosed myelogenic leukæmia. 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 leukæmia.

4. The absolute increase of the mast cells. The mast cells are always increased in myelogenic leukæmia. They may be counted in leukæmic 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 leukæmia 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 leukæmia 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 Löwit.

A large number of authors (H. F. Müller, Wertheim, Rieder) have demonstrated mitoses, particularly of the myelocytes, in the circulating blood in leukæmia. No diagnostic importance of any kind can however be ascribed to them. They are found in all cases only in very small numbers. Thus Müller 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 leukæmia they are valueless.

6. Nucleated red corpuscles form a constant constituent of leukæmic 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 leukæmia may be either a specific phenomenon, or merely the expression of an anæmia accompanying the leukæmia. We are inclined to the first supposition, since the occurrence in such numbers of nucleated red cells is hardly ever observed in other anæmias of the same severity.

So much for the characteristics of leukæmic blood, upon which the diagnosis of the disease is made. We must add that although in any case of medullary leukæmia 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 leukæmia. 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 myelæmic 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.

We will here mention a few rare cases, demanding special attention, shewing the alterations leukæmic blood may undergo, and occasionally presenting almost insuperable difficulties in diagnosis. We find but a single case of this kind mentioned in the literature. Zappert reported a patient, who in February, 1892, had shewn the typical signs of myelogenic leukæmia. Amongst others the relation of white to red cells was found to be 1:4.92, and 1400 eosinophil cells per mm.³ (3.4%) were counted. At the end of September of the same year the patient was brought in a miserable condition to the hospital, where she soon died with gradually failing strength. During this period of observation the proportion of white to red was 1:1.5; the percentage of eosinophils, 0.43; the mononuclears, most of which had no neutrophil granulation, amounted to 70% of the leucocytes. Zappert expressly mentions that these mononuclear cells were in no way similar to the lymphocytes in general appearance. At the autopsy Zappert found the bone-marrow studded with non-granulated mononuclear cells, and the eosinophil cells were much more scanty than is usually the case in leukæmic bone-marrow. Blachstein, under Ehrlich's direction, investigated a second case of this kind. This patient had also been the subject of exact clinical investigations for some time on account of a myelogenic leukæmia. During the time he was last in hospital the blood could only be examined a day before the fatal termination, the direct consequence of a septic complication. With a markedly leukæmic constitution of the blood there were found 62% polynuclear cells, 17.5% mononuclear about the size of the ordinary myelocyte, 0.75% eosinophil cells, nucleated red blood corpuscles in moderate amount. The preponderance of polynuclear and the small number of eosinophil cells is readily explainable from the septic infection; on the other hand the absence of granules in the mononuclear cells is most surprising.

These two observations can only be interpreted by assuming a loss, in certain terminal stages, on the part of the organism, of its power of forming neutrophil substances. Similar conditions occur in non-leukæmic conditions; for example in a striking case of posthæmorrhagic anæmia described by Ehrlich. It is of great importance to direct attention to these cases, which up to the present have been practically disregarded—for ignorance of their occurrence may easily give rise to gross errors concerning the nature and origin of the mononuclear cells, and to the manufacture of a lienal form of leukæmia.

Finally we have to discuss the important question, how the origin of myelæmic blood is to be explained. According to our conceptions two possibilities come under consideration. Either we have to deal with a passive inflow of bone-marrow elements, or with an active emigration from the bone-marrow into the circulation. This important and difficult question is certainly not fully ripe for discussion. The most weighty objection to be raised against an active emigration of the bone-marrow cells is derived from the behaviour of the white blood corpuscles on the warm microscopic stage. These investigations have been performed by a number of authors of whom may be mentioned Biesiadecki, Neumann, Hayem, Löwit, Mayet, Gilbert, and particularly H. F. Müller on the ground of his summary of this subject. Concerning the behaviour of the forms of cell here involved, all authors are agreed that under no conditions do the lymphocytes shew the smallest spontaneous movement; whilst the polynuclear neutrophil cells always exhibit vigorous contractility. With regard to the forms most characteristic of leukæmic blood the statements are partially contradictory. Some authors deny all spontaneous movement of these cells; but most of them report observations from which it follows that a certain power of spontaneous movement is not to be gainsaid. It will be admitted that in questions of this kind, negative results are weakened by positive data. Thus Jolly recently described similar observations as follows: "C'étaient des changements de forme sur place, lents et peu considérables, formations de bosselures à grands rayons, passage d'une forme arrondie à une forme ovulaire ou bilobée etc. Ces mouvements étaient visibles dans les observations i et iv et appartenaient surtout à des globules de grande taille." It is naturally impossible to decide if these minute movements suffice for a spontaneous locomotion. But one cannot exclude off-hand the supposition that they do. It is indeed supported by a further observation of Jolly on the mononuclear eosinophil cells of the marrow. Hitherto it was taken for established that these cells are completely devoid of spontaneous movement. Jolly however was recently able to examine a specimen from a case of typical leukæmia, in which nearly all the eosinophil cells shewed active movement. He says: "Ces globules granuleux actifs présentaient des mouvements de progression et des changements de forme caractéristiques et rapides; cependant je n'ai pas vu ces globules présenter de pseudopodes effilés; de plus, leurs contours restaient presque toujours assez nettement arrêtés. Ces particularités correspondent exactement à la description, qu'a donnée depuis longtemps Max Schultze des mouvements des cellules granuleuses du sang normal." Examination of dry specimens from the same case shewed, as Jolly expressly mentioned, that the blood contained, as leukæmic blood always does, polynuclear and mononuclear eosinophil cells. In contrast then with all earlier observations, Jolly has demonstrated an active spontaneous movement of the mononuclear eosinophil cells. The amœboid movement of the mononuclear cells is so seldom seen, not because they lack this function, but obviously from defects in the methods of investigation, which as is manifest are rather rough and wholly unsuited for delicate biological processes. There are many instances in the literature of the failures of this method, even in the case of cells with undisputed mobility. Thus Rieder failed to observe any contractility in the majority of polynuclear leucocytes in a case of malignant lymphoma, whereas according to all other observations they possess this property without exception.

We think then we must draw the conclusion that the feeble mobility of the mononuclear cells, both eosinophilous and polynuclear, is only apparent, and is owing to the gross method of investigation. In reality they doubtless have mobility sufficient for emigration.

A further, but much less weighty objection to the view that myelogenic leukæmia is an active leucocytosis is, that pus artificially produced in leukæmic patients has nearly always the histological constitution of normal pus. But from our previous detailed remarks we should only expect a myelæmic constitution of the pus, if the specific morbid agent of leukæmia were present in a concentrated form at the place of inflammation. Just as we saw in pemphigus, Neusser's eosinophilous suppuration occurred only in the specific pemphigus bullæ, but not in the foci of suppuration that were artificially produced. We know that the myelocytes are in no way positively influenced by the chemiotactic stimuli of ordinary infectious agents. On the contrary, it clearly follows from the above-mentioned observations on the transformation of leukæmic blood under the influence of infectious diseases, that the common bacterial poisons act in a negatively chemiotactic sense, both on the eosinophil and on the neutrophil mononuclear cells. Under these circumstances we should indeed expect that artificially produced suppuration in leukæmic patients would have, not a myelæmic, but a polynuclear neutrophil character.

It will be the task of further investigations to examine accurately inflammatory products, e.g. pleuritic exudations, in leukæmic patients, with the object of elucidating the question, whether under special conditions of disease all the leucocytes characteristic for leukæmia may not be able to wander from the blood. Thus in a case of pleurisy in a leukæmic patient, Ehrlich received the impression from the preparations that a "myeloid" emigration had in fact occurred, carrying all the elements in the blood into the exudation. This observation does not prove the point, for numerical estimation of the proportion of white to red blood corpuscles in the exudation was not made. And these estimations are necessary in order to prove indisputably the active emigration of the white blood corpuscles into the exudation, and to exclude their purely mechanical passage, per rhexin, from the blood-stream.

The hypothesis of the active origin of myelæmia is considerably supported by a further train of argument. In leukæmia, besides the myelocytes, the polynuclear leucocytes are also enormously increased, and their active emigration is beyond doubt. And the view, that the mononuclear cells are washed into the blood, excludes that of a single mode of origin of the leukæmic blood condition; and commits us to a highly artificial explanation of its production.

The morphological changes of leukæmic blood under the influence of infectious diseases can only be explained from the standpoint of the emigration theory. For if the white blood corpuscles were mechanically carried out of the bone-marrow as a whole, it is incomprehensible that a bacterial infection should alter this process to a polynuclear leucocytosis. This change of character is easily explained on the other hand, as we have above shewn more in detail, by the assumption that ordinary bacterial poisons act positively chemiotactically only on the polynuclear neutrophil cells, but negatively on the other forms.

We explain the origin of leukæmic blood by the emigration into the blood under the influence of the specific leukæmic agent, not only of the formed polynuclear elements, but also of their mononuclear, eosinophil and neutrophil early stages; and to classify myelogenic leukæmia with the active leucocytoses.