Part 24

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 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.

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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. 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.

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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 amoeboid 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.=

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