Part 23

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.

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:

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 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: