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Counting a large number of fields one makes out the following proportion among the white corpuscles :Large lymphocytes,
94:6 per cent. Small lymphocytes,
1.4 Polynuclear cells, .
2:7 Eosinophile cells (?),
1:3 It is difficut to place these eosinophile cells, as most have their granules too large for marrow cells and too small for the ordinary eosinophile cell. The size of the granules, too, varies a good deal in the different cells. They seem to occupy an intermediate position between the marrow and the eosinophile cells. One "mast" cell is found in a careful examination of many films.
Microscopic examination of the nervous system.---The tissues were fised, parts in formol (10 per cent) and parts in Müller's fluid. The sections were cut in celloidin and stained by the methods of (a) Nissl, (b) Marchi, (c) Weigert, and with (d) hæmatoxylin and cosin.
The most striking abnormality to be seen in these sections was the great dilatation of the vessels with lymphocytes. This was almost equally marked throughout the pons, medulla, and cord. The lymphocytes seemed closely packed inside the vessels, and only in a few sections were any red blood corpuscles to be found associated with them. Hæmorrhages were rare, and except for that into the posterior limb of the left internal capsule, which was about the size of a horse-bean, they were very small in size. So that the collections of lymphocytes were almost entirely confined within the vessel, and only in a few sections was there evidence of rupture of its wall. The vessels seemed fairly healthy, but in places there was seen to be commencing colloid degeneration. There was no apparent increase of the connective tissue elements throughout the sections. The hæmorrhage into the internal capsule was made up almost entirely of lymphocytes, the proportion of red corpuscles being small.
The ganglion cells throughout the pons, medulla, and cord stained rather faintly, corresponding in that respect to the ganglion cells in cases of diabetes. Almost 50 per cent of the cells contained a certain amount of light yellow-coloured pigment, but very few (not one in fifty) had their plasma entirely filled with it. This pigment was diffused through the cell rather than limited to any definite part of its plasma. The pigmentation was perhaps most marked in the lumbosacral region of the cord, but it was also well seen in the
dorsal and cervical regions, and in the nuclei of the third, fifth (motor), sixth, and seventh nerves. The ganglion cells in the twelfth nuclei were free of pigment, at least at the level examined. The ganglion cells otherwise throughout the cord, medulla, and pons were practically normal, i.., they showed no definite signs of fragmentation of the Nissl granules, and almost no ghost-cells were to be seen. Still, the cells in this respect were not quite normal, for they showed a slight deficiency in Nissi granules, and sometimes a slight breaking up of these granules, though no definite fragmentation. Possibly the pigment in the cells would account for this deficiency in their Nissl bodies.
The sections stained with Marchi's and Weigert's stain showed no abnormality, no degenerated nerve fibres, and no ascending or descending degenerations.
The median and posterior tibial nerves were also normal ; they gave no reaction with the Marchi stain, and showed no increase in their internodal nuclei.
STATEMENT OF RESULTS OF MICROSCOPICAL EXAMINATION
BY DR. ALEC R. FERGUSON.
The hæmatopoietic organs and tissues have been carefully examined, as well as the different viscera. The results of this examination are embodied in the following statement, the blood-forming organs being first dealt with :
Blood-clot.— Extensive pale greenish “pus-like” coagula were found in the heart chambers and in many of the great vessels. Portions of such examined in microscopical sections present a very striking appearance. The clot consists almost entirely of mononuclear non-granular cells, lying in a delicate fibrinous reticulum. Red corpuscles are almost absent, except at the periphery of the clots. The nucleated elements are inainly of the lymphocyte class, but a considerable proportion are of rather larger size than that of the ordinary lymphocyte. They are rounded in form, and non-granular. In addition, a certain small proportion of mononuclear cells with neutrophile granules are observed throughout the coagulum. These, which must have entered the blood from the bone-marrow, are present throughout the various organs; their proportion is everywhere insignificant, and they are seldom found outside the vessels. It is surmised that they may have entered the blood stream shortly before death.
Nucleated red corpuscles of the normoblast type are occasionally met with in sections of blood-clot. Evidences of
nuclear division are but rarely observed in the cells of the coagulum ; on the other hand, evidences of nuclear fragmentation and degeneration are fairly common.
Lymphatic glands. Both the superficial and deep sets of the lymph glands were found moderately enlarged. They were everywhere of a pallid greenish appearance in section. Microscopically the entire adenoid reticulum is overrun with lymphocytes, which are also present in large numbers in the cortical and deep sinuses of the gland. The “germ-centres” of the lymphoid tissues are for this reason almost indistinguishable, being apparent only as denser cellular collections grouped round the periphery of the gland.
Evidences of cellular activity in these situations are found. The capsule and periglandular connective tissues are densely infiltrated with lymphocytes.
It should be added that the endothelium of the sinuses generally is in a proliferative state, and in many places these cells are observed to be desquamating.
Spleen.—The condition of this organ closely resembles that of the lymph glands. Its pulp is similarly overrun with mononuclears, especially lymphocytes. The Malpighian bodies are fairly distinct, and only show a slight relative enlargement. Evidences of cell-destruction are common, fragments of both red blood corpuscles and lymphocytes being seen enclosed in the large mononuclear phagocytes of the organ.
Scattered throughout the vessels of the pulp are a fair number of neutrophile granular cells with simple rounded nucleus, probably the result of emigration from the marrow.
Bone-marrou.—That of the rib and femur was examined. In both situations the same changes are exhibited. These consist, broadly speaking, in a replacement of the elements proper to the marrow by mononuclear cells. The latter are everywhere abundant, forming frequently coherent masses of considerable size. Both the neutrophile and eosinophile cells characteristic of the marrow are greatly diminished, especially the cells of the latter category. There are no signs of nuclear activity in the granular cells of the marrow. The marrow does not contain much blood, and nucleated red corpuscles are comparatively rare. Giant cells with multiple nuclei are also reduced in numbers, but large cells with single contorted nuclei, and containing cellular fragments or blood pigment, are fairly numerous.
Thymus. It is noteworthy, in view of the age of the patient, that the thymus was not only persistent, but enlarged.
It is so infiltrated with lymphocytes as to closely resemble a lymphatic gland in appearance; this infiltration extends for a considerable distance throughout the fatty connective tissue surrounding the thymus gland. The minute appearances inet with suggest that lymphocytes have been actively formed here.
The thyroid presents a closely similar appearance.
Liver. The capillaries throughout the organ are uniformly dilated, and contain an excessive number of lymphocytes, and thus are unusually prominent under a low power. In addition, there are more distinct nodular collections of lymphocytes in the portal areas.
The kidney presents similar appearances, but no actual lymphocytic nodules are distinguished. The renal epithelium, especially of the cortex, is swollen, highly granular, and exhibits feebleness or entire loss of nuclear staining—the result of profound catarrhal change.
Stomach and intestine.—The lymphoid tissue normally present in the alimentary tract is considerably increased in amount. In addition, there is a marked and general infiltration of the mucous membrane with this class of cell—the infiltration often being of such density as to obscure the glandular elements. (Submucous hæmorrhages are also met with.)
Skin nodules.-Numerous rounded or oval masses—the larger of which measured 15 cm. in circumference---were present beneath the skin of the trunk. These, which appeared to the naked eye in section as homogeneous nodules of a greenish yellow colour, were found to be composed of dense collections of mononuclear cells, while elsewhere the connective tissue fibres of the subcutaneous tissue were separated by a diffuse lymphocyte infiltration. In the case of the smaller of these tumours they may be related to thrombi of mononuclear leucocytes locally formed in the vessels, with subsequent emigration. In other cases, however, they are not merely lymphocyte collections, but exhibit a delicate reticulum with new formed vessels—a true lymphoid tissue formation.
The facts revealed by the microscopic examination are therefore those met with in a severe case of lymphatic leukæmia.
It is doubtless very difficult to make a definite statement with regard to the sites of origin of the mononuclear cells which are so excessive in proportion, but the cellular activity found in the germ-centres of the lymphatic glands and in
association with other abnormal sites of active lymphoid tissue in the adult (e.g., thymus and thyroid) must, in considering this point, receive close attention.
CONCLUDING REMARKS. In all respects the case just described may be regarded as a characteristic case of acute lymphatic leukæmia, satisfying all the requirements of even the older conception of the essential nature of the disease. The older conception of leukæmia was that there should be an enormous excess of white blood corpuscles in the blood--as many as 1 in 20, or even 1 in 2. Moderate increase in the number of white cells was called a leucocytosis, to distinguish the condition from the disease called leukæmia. Recent researches in the histology of the blood, however, have enabled us to approach the study of leukæmia from another standpoint, viz., from that of the morphological character of the white blood corpuscles. As regards lymphatic leukæmia, we are now, according to some authors, able to apply the name to conditions in which there may be no great increase in the actual number of white blood cells, provided it can be established by the examination of the blood film that there is a great excess of lymphocytes, large or small, in the proportion, at least, of from 95 to 98 per cent of the other white cells. If this be true, then we have made a notable step in advance, and the researches of Dock, Gulland, Melville Dunlop, and Byrom Bramwell certainly lend probability to this view. Hitherto all my cases of leukæmia, whether published or recorded in my ward journals, have fulfilled the older requirements for the diagnosis of the disease, but I shall certainly in the future be prepared to investigate clinical cases from the morphological standpoint as well as from the merely numerical, particularly as such a method of investigation may enable us to diagnose the disease in its very earliest stages.
While the present case illustrates very well the main clinical and histological facts of this interesting disease, it may be doubted whether it throws much light upon the exciting cause of the disorder. The clinical history shows that privation and exposure were important elements in the development of the patient's illness, but it may well be questioned whether these alone were likely to bring about the extraordinary disease with which we are dealing Clinically, at least, there was no obvious source of infection, if we except the boil on his leg from which he suffered about