Chapter LXIII: Part 63

[Footnote 117: _Virchow-Hirsch's Jahresber._, 1874.]

[Footnote 118: _Deutsches Archiv f. klin. Med._, Bd. xxvi.]

Cafavy states[119] that the colorless corpuscles of leukæmia do not display active amoeboid changes, indicating thereby a diseased and enfeebled condition of protoplasm. I find a note made in Sanderson's laboratory in 1873 on the very sluggish and imperfect movements of the colorless corpuscles in a case of leukæmia in University College Hospital. In Case V. the note on one day is, "Active amoeboid changes," and in two other cases since Cafavy's paper I have seen the protoplasmic movements tolerably active, but not in all equally. Possibly the leucocytes from the marrow do not move so freely as the others; normal marrow-cells have very feeble amoeboid powers. Ehrlich[120] has observed that the number of leucocytes in leukæmic blood which contain granules reacting with eosin is very great, whereas in normal blood very few occur.

[Footnote 119: _Lancet_, ii., 1880.]

[Footnote 120: _Zeitschrift f. klin. Med._, Bd. i.]

Nucleated red blood-corpuscles, such as occur in the blood of the foetus and in the red marrow of the adult, have been found in leukæmic blood by Klebs, Mosler, and others. I have observed them in four cases. They are scanty, usually isolated, rarely more than one or two in a field; often, indeed, many fields must be searched before finding one. On two occasions (Case IX.) they might be called numerous--three or four in each field of the No. 9 immersion lens.

Schultze's granule-masses, the aggregations of the discoid hæmatoblasts, are {913} present in variable numbers, sometimes very numerous. I have examined slides in which they were absent. A curious mistake was made by a writer in the _Lancet_ (1878, ii.) when he described these as a hitherto unnoticed feature of the blood in leukæmia.

The fibrin network which separates between the corpuscles is usually very thick and dense.

Peculiar crystals, elongated octahedra or spindles, of variable size and bright-white appearance, separate very commonly on a slide of leukæmic blood, particularly if kept surrounded with oil or paraffin for twenty-four hours. They are known as Charcot's crystals, and are identical with those which occur in the bone-marrow, in semen, and in sputum in some cases of bronchitic asthma. White of Boston described them well in 1859,[121] and believed they were produced by the separation of a neutral principle which he named leukosin. I can confirm Zenker's observation,[122] that they form sometimes in the colorless cells.

[Footnote 121: _Boston Medical and Surg. Journal_.]

[Footnote 122: _Deutsches Archiv f. klin. Med._, xviii.]

Leukæmic differs from ordinary blood, and from that of other anæmic or cachectic states, by the readiness with which the hæmoglobin crystallizes. Often if a slide is kept and prevented from evaporating by a rim of paraffin, beautiful plates of hæmoglobin will crystallize.

The pulse is always quickened--80 to 100, and in the final stages 110-130--usually soft and compressible, and not always small in volume. The heart's action is readily excited. A systolic murmur is not infrequent at the apex; basic hæmic murmurs are not so often heard as in anæmia, but a venous hum in the neck is generally present. The apex-beat of the heart may be pushed up an interspace by the enlarged spleen. Oedema of the ankles and feet from the feeble circulation is constantly met with, particularly toward the close, and there may be general anasarca. Effusion into the pleural cavities is not common.

Hemorrhages are among the most constant features of the disease, and may occur at any time, early or late, in the course. The tendency to bleeding is greater in this than in any of the allied affections. Epistaxis is the most frequent form, and may precede the development of the disease for months or years. Hæmatemesis may carry off a patient early (Case II.), or even before the nature of the trouble is suspected (Case VI.). Hemorrhage from the bowel is common. Hæmoptysis and hæmaturia are rare. Bleeding from the gums may be present (Cases V. and VII.). In women there may be profuse menstruation. Petechiæ on the skin are frequent; occasionally there are large extravasations beneath the skin or between the muscles. Hemorrhage into the brain may prove quickly fatal (Case X.), and the extravasations into the retinæ may impair vision.

The respiratory system offers few special symptoms. The shortness of breath on exertion is due in great part to the anæmia, and progressively increases with the advance of the disease. The free action of the diaphragm is hampered by the enlarged spleen. There may be cough from bronchitis, and toward the end signs of oedema at the bases of the lungs. Pneumonia is not uncommon as a final complication.

The temperature in the early stages presents very slight variations, but when the disease is advanced there is always fever of the remittent or of the continuous type. There is usually a morning remission, and an evening exacerbation which reaches 101° or 103°. Periods of pyrexia may alternate with prolonged intervals of freedom from fever. In some cases the febrile movement is very slight throughout the entire course.

Genito-urinary System.--The urine is usually normal in amount, pale, strongly acid, and its specific gravity above the normal. Considerable variations occur in individual cases. Sediments of lithates are very common. {914} The urea presents no constant changes; sometimes it is increased, at others diminished, the quantity depending probably on the food and the presence or absence of fever. The quantity of uric acid excreted seems always to be increased, due either to a lessening of the oxidation processes in consequence of the reduced number of red corpuscles, or, as Salkowski suggests, it stands in relation to the existing splenic tumor; but observers have not found the amount proportionately increased in other forms of splenic enlargement, and the cause of the constant increase is still doubtful. Hypoxanthine, lactic, formic, acetic, and hippuric acids have been found, but their presence is neither constant nor apparently of special import. Albumen may be present. Sugar is rare. Hæmaturia, as before observed, very seldom occurs. Cystitis may arise and be troublesome (Case XI.).

A curious symptom in connection with the generative system is priapism, of which a number of cases have been recorded. Edes[123] narrates the case of a boy of fifteen in whom obstinate priapism was the first symptom. Longuet[124] reports a case of six weeks' duration. Saltzer[125] mentions five cases, in one of which the condition persisted for seven weeks, and Peabody[126] gives a case in which it lasted six weeks. It is not definitely settled whether the priapism is due to thrombosis in the corpora cavernosa or to irritation of the nervi errigentes.

[Footnote 123: _Boston Med. and Surg. Journ._, 1871.]

[Footnote 124: _Progrès méd._, 1875.]

[Footnote 125: _Berliner klin. Wochenschrift_, 1879.]

[Footnote 126: _New York Med. Journ._, 1880, xxi.]

In women there are the usual menstrual irregularities consequent upon a grave constitutional disease. Occasionally the flow is excessive; more commonly it is interrupted altogether.

Blood-glandular System.--Slow increase in the volume of the spleen, causing a sense of weight in the left hypochondrium, is an early symptom in many cases. Patients do not usually come under observation until the enlargement is established and the organ can be felt below the costal border. Pain and tenderness over the organ are very common, though sometimes it is painless throughout. Palpation often elicits a creaking fremitus due to the rubbing together of the adhesions. The gradual enlargement causes an evident increase of girth in the lower thoracic and upper abdominal zones, and marked prominence of the left hypochondrium. The tumor extends to the right and downward, and may occupy a large portion of the abdomen, extending even to the pelvis. When there is no ascites the edge can be easily felt with the anterior notch or notches. The pressure of a large spleen causes distress after a full meal, and by its mechanical effect may even compress the bowels and produce fatal obstruction.[127] The effect upon the heart and respiration has already been noticed. The adhesions may interfere with the depression of the organ during a deep inspiration. The size varies in an inexplicable way, considering the indurated fibroid nature of the enlargement. It may be perceptibly larger after a meal.[128] A hemorrhage or free diarrhoea may reduce the size very much, as in Morrill's case.[129] A murmur may occasionally be heard, and an enlarged spleen has been known to pulsate.[130]

[Footnote 127: Collins, _Brit. Med. Journ._, 1882, i.]

[Footnote 128: Johnson, _Lancet_, 1870, Jan.]

[Footnote 129: _Bost. Med. Journ._, 1877.]

[Footnote 130: Gerhardt, _Zeitschrift f. klin. Medicin_, Berlin, Bd. iv.]

Lymphatic Glands.--In the great majority of cases the lymph-glands are but slightly if at all involved. Even when they are affected it is rare to see such large bunches as in Hodgkin's disease. When they are growing there may be pain and tenderness, and if large they may be a source of inconvenience, but severe pressure symptoms are not often witnessed. Enlargement of the glands in the superficial groups is readily detected, but the deep-seated collections in the mesentery and retro-peritoneum can rarely be palpated unless of considerable size. Mediastinal lymph-tumors in leukæmia are exceptional. In none of the cases I have seen were the lymph-glands {915} greatly enlarged. It is stated that in children the lymphatic variety is more common than in adults.

There may be tenderness over the bones, and in rare instances swelling, but unless the tenderness is marked and accompanied by some local expansion or softening, we cannot determine positively the existence of the myelogenous variety. The sternum, ribs, and flat bones are most often affected, and there may be great irregularity and deformities, as in a case I saw with Riess of Berlin. It is well to bear in mind that in perhaps the majority of persons there is a tender spot upon the sternum which may cause marked wincing when touched firmly. No reliance should be placed upon tenderness without swelling or softening. Such tenderness may exist, and post-mortem the marrow be found normal;[131] and, on the other hand, there may be extensive changes in the bone-marrow without any tenderness (Litten).

[Footnote 131: _Deutsches Archiv f. klin. Med._, xxvi.]

MORBID ANATOMY.--There may be extreme wasting. Dropsy of the feet is common, and ascites may be present.

A noteworthy feature is the full amount of blood in the heart and blood-vessels, usually in the form of large coagula. In one case (XI.) the weight of clots alone in the heart-chambers, not including what came from the veins, was 620 grammes. The portal, cerebral, pulmonary, and subcutaneous vessels were also greatly distended with clots. The portal vein just above the union of the branches measured eleven centimeters in circumference.

The blood is usually clotted in the heart and vessels, and the aggregation of the colorless corpuscles densely infiltrating the fibrinous clots and the serum gives a pus-like appearance, so that it has not infrequently happened, as in Virchow's memorable case, that the observer on opening the right auricle believed for the moment that he had cut into an abscess. The leukæmic clots often have a peculiar greenish color, and resemble somewhat the fat of the turtle. Similar coagula may fill the veins of the brain and abdominal viscera. The tendency of the white corpuscles to aggregate together, and the subsidence of the red to the lower part of the heart-chambers and vessels, may give an appearance of more intense leukæmia than actually exists. The reaction of the blood is usually acid. The chemical constitution has been carefully studied, but with no very satisfactory results. Hypoxanthine, lactic acid, leucin, tyrosin, a mucin-like body, and a gelatinous substance have been described, but none of them may be regarded as characteristic of the disease. The octahedral crystals are thought by some to be tyrosin,[132] but Schreiner[133] says they consist of the phosphate of an organic base, the composition of which is not yet settled.

[Footnote 132: Huber, _Archiv der Heilkunde_, Bd. xviii.]

[Footnote 133: _Liebig's Annalen_, cxciv.]

The specific gravity of the blood is lowered, 1036 to 1049. The water is increased. The fibrin in many observations has also been found increased; 4.8 per 1000 was the average of ten observations by Bennett. The albumen and the salts have not often been estimated. The former is stated to be diminished. The fatty bodies have been found in excess of the normal quantities.

The heart is often pushed up by the large spleen; the pericardium, more rarely the endocardium, may present ecchymoses, and the fluid may be in excess. In a few instances leukæmic growths have been met with. The chambers are usually distended, the walls soft, and a moderate grade of fatty change is very common. No special alteration has been met with in the blood-vessels. I have seen extensive fatty degeneration of the intima and small arteries.

In the great majority of cases the spleen is increased in size, but the shape is retained. It is usually of a deep violet-red color, and strong adhesions may unite it to the abdominal wall, diaphragm, or stomach. The capsule {916} may be greatly thickened, forming a firm fibro-cartilaginous investment. The vessels are enlarged, particularly the veins at the hilus. The weight may vary from two to eighteen pounds. The largest on record is given by Langley Browne[134]--18½ pounds. Six or seven pounds is an average weight. The length may vary from seven to twenty inches, and the breadth eight to twelve. The organ is in a condition of chronic hyperplasia--hard, firm, cuts with resistance, and displays a uniform reddish-brown surface on which the trabeculæ are more or less prominent. There may be hemorrhages or infarcts, and it is not uncommon to see regions of yellow or rusty-brown staining, indicating where an extravasation had occurred. As a rule, no trace of the Malpighian bodies can be seen. Grayish-white, circumscribed lymphoid tumors may occur throughout the organ, contrasting strongly with the reddish-brown matrix. The process of gradual enlargement is a simple hyperplasia. In the early stage, not often seen, there is swelling of the pulp, increase in the cell-elements, without the firmness and induration of the fully-developed leukæmic organ. Rupture may occur at this period from the intense hyperæmia. The Malpighian bodies are enlarged and prominent by their grayish-white color. A gradual and progressive induration results from the increase in the adenoid network and the fibrous trabeculæ. A section shows the enormous development of the fibrous elements. The cells may be scanty, only two or three in meshes, or, indeed, the reticulum may be so close that only a single cell is enclosed. As a rule, the hyperplasia extends over the whole organ, and the Malpighian bodies become involved and lose their distinctness. In only one of the cases which I have examined were they at all prominent. Leukæmic new growths in the spleen are rare.

[Footnote 134: _Lancet_, 1877, ii.]

Uncomplicated cases of the lymphatic form are very uncommon: usually they enlarge with the spleen, and in the majority of instances the hypertrophy is not extensive, scarcely ever reaching the high grade seen in Hodgkin's disease. The groups of cervical, axillary, mesenteric, and inguinal are most frequently affected; the bronchial and mediastinal but rarely. The bunches of glands are not usually larger than walnuts, moderately soft, isolated, movable; large matted groups do not often occur. They may vary a good deal in size during the course of the disease, often diminishing notably before death. In chronic cases they may become very indurated. The leukæmic lymphadenitis is a simple hyperplasia, and the soft glands may look, on section, of a normal gray color or may have a deep gray-red appearance. Hemorrhages may occur, and twice I have seen the enlarged glands deeply hyperæmic. Histologically, the appearance is very like a normal gland, only the lymph-spaces are more closely packed. In the harder glands the fibrous reticulum is much increased, the capsule thickened, and the section more grayish in color. Caseation or suppuration rarely occurs, and invasion of contiguous parts is most exceptional.

The tonsils and the lymph-follicles of the tongue, pharynx, and mouth have been found much enlarged.

The bone-marrow is usually the seat of important changes, which in some cases appear early and persist as very prominent features of the disease. The most constant alteration is a uniform substitution of a grayish-red or gray-green puriform-looking tissue for the normal red and fatty marrow of the long and short bones. The entire medulla may resemble the consistent matter which forms the core of an abscess, and the term pyoid applied to this condition by German authors well expresses the general characters. More rarely the marrow has a reddish-brown hue. The difference depends largely on the number of colorless corpuscles, which in the pyoid form are enormously increased, and there are but few red cells. Ponfick has met with dark-red, dense hemorrhagic infarctions in leukæmic marrow. The condition of the {917} bones is variable; usually, the compact and cancellated tissues appear normal, but the hard shell may be much thinned and expanded, the cancellæ widened, and the whole substance rendered spongy. In marked cases there may be localized swellings which are tender, and even yield, on firm pressure. The sternum and ribs are most frequently affected in this way. There are instances in which the bone-marrow has not been involved, and in one case there was osteo-sclerosis.[135] Histologically, the chief change is hyperplasia of the colorless marrow-cells, which in the pyoid variety compose the chief part of the tissue. They vary much in size and appearance. Three forms can usually be recognized: large granular cells with distinct nuclei; medium-sized cells, like colorless blood-corpuscles; and smaller forms, like lymph-cells, with large nuclei and a narrow zone of investing protoplasm. The red corpuscles and microcytes are in variable numbers. In one case the latter were very abundant. Nucleated red corpuscles are very constant elements. Corpuscles containing red blood-corpuscles are not so numerous as in ordinary red marrow, nor, as a rule, are the myeloplaques abundant. Charcot's crystals are always to be found--if not at first, when the marrow is quite fresh, certainly later, when decomposition has begun.

[Footnote 135: Heuck, _Virchow's Archiv_, lxxviii.]

The thymus is rarely affected, and even in children is not often swollen. A few cases of enlargement have been recorded.

The thyroid is even less frequently involved.

In one case the suprarenal capsules were large and swollen,[136] and in addition to the leukæmia there was bronzed skin. Hemorrhage, caseous degeneration, and in one instance rupture,[137] have been noted.

[Footnote 136: Barclay, _Lancet_, 1863, i.]

[Footnote 137: Fleischer and Penzoldt, _loc. cit._]

In the digestive system the stomach rarely presents any changes other than catarrhal. Even when death has occurred from hæmatemesis the mucous membrane may be pale, without erosion, hemorrhage, or ulceration (Cases II. and VI.). In a few instances lymphatic growths have been described. In many cases the intestines have been the seat of leukæmic tumors which have originated in the solitary and agminated glands of Peyer. Occasionally the lymphoid infiltration is diffuse in the mucosa and not confined to the follicles. Ulceration may occur in the patches, and in a few cases the bowel lesions have been so pronounced that the term intestinal leukæmia seemed justifiable.[138] The cæcum and colon may also present these new growths, and in a few cases dysenteric processes have been observed (Case II.). The peritoneum has been found covered with small lymphoid growths. In Willcocks' case of lymphatic leukæmia[139] there were growths on the surface of the stomach and gastro-splenic omentum. Blood may be found in the cavity from rupture of the spleen. Ascitic fluid is common. Fibroid thickening, induration, and adhesions are very often met with, particularly in the neighborhood of the spleen.

[Footnote 138: Behier, _loc. cit._]

[Footnote 139: _Loc. cit._]

The liver is very commonly enlarged, pale, smooth, and retains the normal shape. It may be greatly increased in size, as in case of Walshe's, where it weighed 13½ pounds. The substance is usually firm, of a grayish-brown color, or even marbled. Two chief changes have been met with--a diffuse leukæmic infiltration and numerous small leukæmic tumors. The infiltration may be very slight, and not noticeable with the naked eye, or it may be in the form of irregular scattered areas of a yellowish-white appearance, not distinctly isolated, but merging into the hepatic tissue. When moderate, a section shows the columns of liver-cells to be separated by wide spaces occupied by leucocytes, which are partly within and partly outside of the capillaries. The accumulation of these elements produces atrophy of the liver-cells, and their aggregation and increase in certain regions produce the grayish-white areas, in the midst of which traces of liver-tissue may be found. {918} The defined leukæmic growths are small, not often attaining a large size, and may resemble tubercles. They are usually situated in the interlobular tissue, and consist of lymphoid cells in a well-defined reticulum, and they possibly have a different origin from the diffuse infiltrations.

Fatty degeneration of the liver-cells is a very common change.

The respiratory system is not often the seat of important lesions. Lymphoid growths have been found in the mucous membrane of the trachea and bronchi, and occasionally in the lungs, in which situation they may closely resemble tubercles, but differ from them in not tending to caseate or soften. Oedema of the bases of the lung is almost always found. Many patients are carried off by a low pneumonia. The greenish leukæmic clots projecting from the cut ends of the vessels may give a very curious appearance to the section of the lung. The pleural surfaces may be the seat of lymphoid growths.

The kidneys are usually pale, often enlarged, and show signs of parenchymatous swelling. The capillaries, like those of the liver, may be distended with leucocytes, and leukæmic tumors may occur, generally situated in the cortex and ranging in size from a pea to a cherry. In none of the cases I have examined were there any special changes in these organs beyond slight enlargement and filling of the capillaries with leucocytes.

The generative organs are usually normal. No changes have been found to account for the persistent priapism met with in certain cases.

The meninges of the brain, the veins, and sinuses, are often filled with grayish clots. Occasionally meningitis has been found, with exudation of lymph. The small vessels of the brain may be plugged with leucocytes, forming thrombi, from which softening results. Cerebral hemorrhage may prove rapidly fatal. In Case X. of the Montreal series the patient died suddenly, and without any premonition, with a huge apoplexy of the ventricles and posterior part of the hemispheres.

Leukæmic growths in the skin have been described.

The leukæmic tumors demand further consideration. They are not common. In 10 of the 11 Montreal cases careful post-mortem examinations were made, and in not one were there definite new growths. In Case I. there was diffuse leukæmic infiltration of the liver, the histological characters of which were carefully studied. In the 157 cases collected by Gowers[140] there were only 13 instances of leukæmic nodules in the liver, and 10 in the kidneys. They are still more uncommon in the lungs. In the spleen--unlike this organ in Hodgkin's disease--they are very rarely seen. The nodules consist of leucocytes in a meshwork of delicate reticular tissue. Their mode of origin has been much discussed. There can be no doubt, I think, that they are new growths of lymphoid tissue of local origin. Possibly they start from accumulations of colorless corpuscles which pass out of the capillaries. In the infiltration of the liver one sees diffuse collections which resemble new growths, but which have evidently resulted from the aggregation in and outside of the capillaries of enormous numbers of leucocytes, which cause the atrophy of the cells of the organ. Doubtless, they multiply in loco by a process of fission, and these aggregations may themselves be foci for the origin and development of colorless cells which pass into the blood-current and augment the number.[141] Quite recently Bizzozero has studied the development of these leukæmic new growths, and has shown clearly that the cells which compose them are in process of active fission.

[Footnote 140: _Loc. cit._]

[Footnote 141: "On the Histology of Leucocythæmia," _Canada Medical and Surgical Journal_, 1876.]

The COURSE OF THE DISEASE is slow and chronic, a matter of months and years. There are exceptional instances in which the disease has proved fatal in a few weeks; this occurs sometimes in children,[142] but acute leukæmia is {919} very rare. In a table of 63 cases collected by Gowers, in which the date of the first symptoms was fixed with tolerable accuracy, the duration was less than one year in 13 cases; from one to two years in 16; from two to three years in 19; from three to four years in 9; from 4 to 5 years in 3; and five years and upward in 3 cases. The course is rarely uniform, but periods of improvement occur in which the fever subsides, the painful sensations in the abdomen diminish, the appetite improves, and the spleen reduces in volume. Such intervals, corresponding to the administration of certain drugs, are apt to lead to therapeutic errors. A patient may sometimes get about for months, and even attend to a light business, with an enormous spleen and a ratio of white to red corpuscles of 1 to 6 (Case VIII.). Hemorrhages, high fever, profuse diarrhoea, and the occurrence of dropsy shorten the course. Toward the close there is great muscular debility, and usually a wandering delirium.

[Footnote 142: Golitzinsky, _Jahrb. f. Kinderheilkunde_, 1860-61.]

In the majority of cases death is by asthenia--a gradually progressive weakness and ultimate failure of the heart. Diarrhoea and hemorrhage hasten the fatal result. A profuse hemorrhage may cut off a patient early or after the disease is well established. Cerebral hemorrhage was noticed in 6 of 60 cases in which Gowers was able to ascertain accurately the cause of death. A few are carried off by pleurisy or pneumonia or peritonitis after tapping.

Pyæmia and rupture of the spleen are mentioned as causes of death in some cases.

The DIAGNOSIS of leukæmia rests upon the determination of a great and persistent increase in the colorless elements of the blood. Cases of Hodgkin's disease and of splenic anæmia, almost identical in general features, can only be distinguished by an examination of the blood. I should say that in any case we can speak of the blood as leukæmia when the ratio of white to red cells falls below 1 to 50. Some writers hold that to determine leukæmia the ratio should be at least 1 to 20, but when the study of the variations in the proportion of the corpuscles in any case extends over weeks or months, we not uncommonly find that the ratio, which, at one observation may be 1 to 8, or 1 to 10, a week later may be 1 to 60 or 80, or even 150. Indeed, the state of the blood is a variable factor, and too close attention to it has diverted our minds from the broad features which this disease has in common with others. For practical clinical purposes we have to distinguish ordinary lieno-lymphatic leukæmia from--(1st) chronic malarial infection with splenic hypertrophy; (2d) from cases of non-malarial splenic enlargements with anæmia; (3d) from general lymphadenoma or Hodgkin's disease. The history in malarial cachexia, the absence of lymphatic enlargement, and the blood-condition will usually be sufficient for purposes of a diagnosis. Great increase in the white blood-corpuscles is not often seen in the chronic splenic tumor of malaria; indeed they may be much diminished in number. Toward the end in very chronic cases the clinical picture may be very similar: the large abdomen, possibly ascites, dropsy of the feet, and irregular fever may resemble closely splenic leukæmia, and the absence of an increase in the colorless corpuscles may be the only marked difference. From anæmia splenica there is still greater difficulty, and I have seen instances in which the absence of an excess of the colorless corpuscles in the blood formed the sole criterion: the hemorrhages, the dropsy of feet and abdomen, retinal extravasations, the general cachexia, and the fever were identical with those of leukæmia. Still greater may be the difficulty of separating certain cases of lymphatic leukæmia from general lymphadenoma or Hodgkin's disease; but in the latter affection the glandular enlargement is usually greater and altogether a more prominent feature, and the spleen is not so often increased in size. There may, however, be a considerable increase in the number of the white corpuscles, 1 to 150 or 1 to 100 red, and cases do occur which appear intermediate {920} or transitional in character, and upon which judgment must be reserved until the progress of the case decides the question.

Pure cases of myelogenous leukæmia are almost unknown; if the osseous symptoms are not marked the course is very like that of pernicious anæmia. Indeed, there are two interesting cases on record in which the progressive anæmia seemed to pass into leukæmia. In Litten's case[143] the patient presented the symptoms of profound anæmia, and five days before death the blood became markedly leukæmic. There was no enlargement of spleen or lymph-glands, but the bone-marrow was intensely leukæmic--_i.e._ of the pyoid form. In the case reported by Leube and Fleischer[144] the patient, aged thirty, four months after her confinement became anæmic and the left leg was swollen. Though at first only anæmic, subsequently the ratio of white to red corpuscles rose to 1 in 10. Gangrene of the leg supervened, necessitating amputation, from the effects of which she died. There was no affection of spleen or lymph-glands, but the marrow was of the red lymphoid variety. A gastric ulcer was also present. This was no doubt a case of post-partum anæmia aggravated by the presence of ulcer of the stomach, and the great interest of the case lies in the transition of the anæmia into leukæmia.

[Footnote 143: _Berliner klin. Wochenschrift_, 1877.]

[Footnote 144: _Virchow's Archiv_, lxxxiii.]

There are certain general conditions, accompanied by an increase in the colorless corpuscles, which must be distinguished from leukæmia. In suppuration there may be marked leucocytosis; so also in cancer and protracted cachectic states, as phthisis. In cases with large cancerous masses about the stomach and omentum, or where, as occasionally happens in chronic phthisis, there is a greatly enlarged amyloid spleen, if the white blood-corpuscles are much increased, care may be necessary to escape a mistake in diagnosis. In diphtheria the colorless elements may be much increased. Bouchat says that in some instances there may be an acute leukæmia.[145] In puerperal fever also the condition of leucocytosis is not uncommon.

[Footnote 145: _Gazette des Hôpitaux_, 1877.]

The PROGNOSIS is in the highest degree unfavorable, and in those cases, few, indeed, in number, in which there were symptoms like leukæmia and which disappeared under treatment, the doubt remains whether they were true examples of the disease. When once established, the spleen and glands enlarged, the hemorrhages and dropsies present, and the blood condition marked, death is the only termination to be expected. Specially unfavorable signs are a tendency to hemorrhage, persistent diarrhoea, early dropsy, rapid increase in the splenic tumor, great excess of colorless corpuscles, and high fever. Temporary improvement may occur for weeks or even months, and the white blood-corpuscles reduce in number, but such breaks are usually transient.

TREATMENT.--If, as some writers hold, chronic malarial poisoning is an important factor in the induction of leukæmia, we should take special pains with patients so affected, and endeavor by the use of quinine and arsenic to free the system and reduce the volume of the spleen. There certainly may be danger of the development of leukæmia in any case of chronic splenic tumor, though my own experience has been that in these cases the production of anæmia of high grade, without increase in the white blood-corpuscles, is more common. It is a mistake to suppose that anæmia always accompanies chronic splenic enlargement: it may persist for years with a percentage of red corpuscles little if at all below normal, but grave anæmia or leukæmia are probabilities to be dreaded.

In an early stage, when the spleen is moderately enlarged, the lymph-glands scarcely swollen, and the leucocytosis not intense, there is a hope that by the persistent use of quinine, iron, and arsenic a cure may be effected; but when the disease is fully established and the leukæmia marked, a recovery {921} is rarely if ever witnessed, and the treatment is largely palliative and symptomatic. To reduce the volume of the spleen various remedies are recommended, and so long as the organ is only moderately enlarged and hardened some of them may be beneficial. Quinine should be given a full and prolonged trial, as undoubtedly under its use the organ may reduce in size. As anæmia is almost always present, iron may be administered at the same time. That the quinine has any special influence over the production of the white corpuscles, as some think, I have not been able to satisfy myself. To be of use, it must be employed early and in large doses. Ergotin internally and by injection into the spleen has been recommended. I have not seen any permanent benefit from its use. Local measures, such as inunction of biniodide of mercury ointment over the spleen, the interrupted voltaic current, the application of cold, either ice or the cold douche, may be employed. Moderate reduction in the volume may be effected by these means--most effectually by the electricity and mercurial inunction.

Arsenic should always be given a trial, and pushed for several months in increasing doses. Several cases are reported in which the improvement lasted for many months. Direct injections into the spleen are also of service. Phosphorus, from which much was expected after the favorable reports of Broadbent and Wilson Fox, has not proved of much value. There are very curious remissions in the course of the disease which render therapeutical deductions somewhat fallacious. I have seen the most marked improvement occur without any special treatment: ascites and dyspnoea disappear, the white corpuscles decrease in number, and the patient from a bed-ridden, wretched condition get up, attend to light duties, and walk half a mile to hospital (Case IX.). In Case VIII. there were also during eighteen months remarkable variations, depending more on the state of the gastro-intestinal canal than the blood condition.

Transfusion has proved useless. Leukæmic blood to the amount of several ounces has been withdrawn and other healthy blood substituted.

Excision of the spleen has been frequently practised in leukæmia. Collier[146] gives a résumé of 16 cases, and concludes that it is a useless and unjustifiable operation, as all of them proved fatal. A successful case, however, is reported from Italy. If performed early, there is a possibility of success, but when the organ is enormously enlarged and the blood intensely leukæmic, the conditions are most unfavorable.

[Footnote 146: _Lancet_, 1882, i.]

Gastric symptoms and diarrhoea call for careful treatment, as the comfort of the patient depends largely on the condition of the primæ viæ. Hemorrhage is frequent, and is a dangerous symptom, particularly when it depends upon engorgement of the portal system, and calls for appropriate remedies. Purgatives are to be employed with caution. The dragging pain in the left hypochondrium, and the sense of weight and distension after eating, are very distressing, and the splenic pain may require sedatives. Inhalations of oxygen relieve the dyspnoea and have been found to check the progress of the disease.

HODGKIN'S DISEASE.

DEFINITION.--A disease characterized by progressive hyperplasia of the lymph-glands, sometimes also of the spleen, with anæmia and the development of secondary lymphatic growths in various parts of the body.

SYNONYMS.--Pseudo-leukæmia; General lymphadenoma; Malignant {922} lymphoma (Billroth); Lympho-sarcoma (Virchow); Adénie (Trousseau); Desmoid carcinoma (Wagner); Anæmia lymphatica (Wilks); Lymphatic cachexia (Mursick); Adenoid disease (Southey).

HISTORY.--Morgagni and other writers mention cases of enlargement of the lymph-glands proving fatal, but Hodgkin of Guy's Hospital first called special attention to the subject in a paper before the Medico-chirurgical Society of London,[147] entitled "On Some Morbid Appearances of the Absorbent Glands and Spleen." Some of the cases then described were undoubtedly examples of scrofulous glands, but four at least were instances of the disease which now bears his name; and at the meeting of the London Pathological Society in 1878, when a discussion on lymphatic disease took place, Wilks exhibited the original specimens collected by Hodgkin. Other cases were recorded in England by several observers, and in 1856, Wilks[148] reported several examples of enlarged lymph-glands with growths in the spleen associated with anæmia, but without any leukæmia; and again in 1865 this observer published additional cases,[149] and gave the name of Hodgkin's disease to the affection characterized by enlargement of the lymph-glands, growths in the spleen and other organs, and anæmia. The cases and discussions contained in the _Transactions_ of the Pathological Society of London and Gowers' exhaustive article in _Reynolds's System of Medicine_ embrace the most valuable of the English contributions. In Germany, Virchow described the cases under the term lympho-sarcoma, and in his work on tumors gave a full account of the histology. Billroth gave the term malignant lymphoma to these growths to distinguish them from local non-infective lympho-sarcomas. Cohnheim and Wunderlich used the term pseudo-leukæmia to express the distinction between these cases and leukæmic enlargements.

[Footnote 147: _Transactions_, vol. xvii., 1832.]

[Footnote 148: _Guy's Hospital Reports_, 3d Series, vol. ii.]

[Footnote 149: _Ibid._, vol. ix.]

In France, Trousseau described it under the term adénie, and Ranvier used the term lymph-adénie. In America many cases have been described, and one of the first and fullest analyses of recorded observations is by J. H. Hutchinson in the _Transactions_ of the College of Physicians of Philadelphia, Series 3, vol. i.

ETIOLOGY.--No satisfactory etiological relations have been determined in the disease.

Age has an important predisposing influence. The majority of the cases are young persons. In Gowers' table of 100 cases, 30 were under twenty years, 34 between twenty and forty, and 36 above forty. Most of the cases I have seen have been in young adults.

Sex has a still more marked influence; at least three-fourths of all cases are in males, the proportion being considerably higher than in leukæmia--75 per cent. in Gowers' tables, and 40 out of 58 in Hutchinson's tables.[150]

[Footnote 150: _Loc. cit._]

Heredity has in a few instances been adduced as a possible cause, but not, I think, on very reliable grounds. In two cases (II. and III.[151]) the patients were each a twin. It might be supposed that members of tuberculous families, or those who had suffered from scrofulous enlargements when young, would be more liable to the disease, but the cases in which such connection can be traced are very few in number.

[Footnote 151: These figures refer to cases of which I have notes.]

Antecedent syphilis has been noted in a few instances.

Exposure, intemperance, bad food, etc. are possible predisposing causes.

Local irritation, which so often produces lymphatic swellings, appears to stand occasionally in causal connection with the development of general lymphadenoma. Trousseau lays particular stress upon this, and gives instances in which chronic irritation of the skin, otorrhoea, chronic nasal or pharyngeal catarrh, irritation of a decayed tooth, gave rise to local gland swelling which preceded the general development of the disease. But this {923} is a comparatively rare affection, and think of the hundreds of instances met with of local lymphatic irritation!

SYMPTOMS.--Enlargement of the lymphatic glands in the neck, axillæ, or groins is the earliest symptom noticeable in the great majority of cases. This may be quite painless at first, and the patient seeks advice on account of the disfigurement or the inconvenience felt in adjusting the collar. Occasionally the anæmic and constitutional symptoms first attract attention. When the trouble begins in the deeper groups--bronchial, mesenteric, or retro-peritoneal--pressure effects are the first complaint, and there may be great obscurity and uncertainty about the nature of the case. Thus, the first symptom may be dyspnoea, with pain in the chest, or pain in the abdomen with swelling of the legs and shooting pains in the course of the nerves; or in rare cases symptoms of a totally different nature may be among the first to attract attention. Thus in J. H. Hutchinson's case there was paraplegia from pressure of a secondary growth, and the same was observed in a case which I dissected at the Montreal General Hospital (Case VI.). But such are very exceptional, and in the great majority swelling of the superficial glands is the earliest phenomenon. In rare instances the tonsils and pharyngeal adenoid tissue have been first affected.

Hemorrhage is not an early symptom. Epistaxis has been noted, but not with the frequency with which it occurs in leukæmia.

With the progressive enlargement of the glands the patient becomes anæmic, and finally cachexia is developed.

The Lymphatic System.--In an early stage it is difficult or impossible to distinguish the affection from syphilitic or scrofulous adenitis. The gradual increase in the size and the involvement of other groups, and the oncoming anæmia, will alone in certain cases render a decision possible. In the cervical group, in which the trouble usually begins, the chain of glands on one side becomes enlarged--perhaps only those just above the clavicle, or in some instances the posterior ones are also affected. They are isolated, movable, and not, as a rule, tender. Months, or even years (three years, Case VII.), may elapse before the enlargement becomes general or affects the other side. With their increase in size and number the separation between the glands, at first evident, disappears, and they form distinct groups or bunches. Thus the submaxillary set, those of the anterior triangle, and those of the posterior may form irregular aggregations of various sizes. Ultimately, huge tumors may develop which obliterate the neck, extending upon the shoulders and over the clavicles and sternum. When these grow inward, toward the trachea, great dyspnoea may be produced, and the pressure may be so extreme that tracheotomy must be performed.

The skin becomes involved, and ulcerates. Usually it is freely movable over the masses. The pharynx and oesophagus may be compressed, and occasionally the carotids. The submaxillary tumors may limit the movement of the jaws.

Next to the cervical, the axillary glands are most frequently involved. If small, no inconvenience is felt, but when large bunches occur there is great pain in moving the arms, and pressure upon the brachial or axillary veins may cause swelling of the limbs. The tumors may pass far out, almost to the nipple.

The inguinal glands are not so often involved. In only one of the ten cases which I have seen were they affected, but they may form large and even pendulous tumors, as well shown in the cases of Surgeon-Major Porter.[152]

[Footnote 152: Figured in _Path. Soc. Trans._, xxix.]

Of the internal glands, those of the thoracic cavity are most often attacked. The chain in the posterior mediastinum may be involved and surround the aorta or compress the gullet; or they may pass up the trachea to the {924} neck, and involve the thyroid (Case V.). When the bronchial group is enlarged there are signs of pressure on the tubes, dyspnoeal attacks, and serious implication of the lung (Case VI.) In the mediastinum there may be large masses covering the aorta, extending over the pericardium, and producing bulging of the sternum and ribs, perhaps pulsation, and ultimately erosion of the bones and outward projection of the tumors (Cases II. and III.). There may be considerable pressure upon the veins and obstruction to the flow in the superior cava and jugulars.

In the abdomen the mesenteric glands are often affected, and if the belly-walls are thin can be readily felt. The continuous chain of retro-peritoneal glands may be greatly enlarged, and extend from the diaphragm into the pelvis, surrounding the aorta, cava, and nerves. When the patient is thin there may be no difficulty in detecting these, but when there is an enormously thick panniculus the diagnosis may be impossible, as in Case I., in which intense lumbar and sacral pain and swelling of the legs were the only symptoms. The matting of organs in the pelvis caused by these growths may be a source of great difficulty in the diagnosis, as in a case in which I saw an eminent and careful surgeon open the abdomen to extirpate a uterus for fibroids, and found general lympho-sarcoma of the retro-peritoneal and pelvic glands.

It is probably in connection with affection of the abdominal glands that the bronzing of the skin occurs which is mentioned in a few instances. It was well marked in Case IV. of my series.

The glands present great variations in the rate of growth and there may be fluctuations from month to month. They may diminish rapidly, and almost disappear from a region to develop again in a few weeks. The enlargements may diminish very much before death.

The spleen does not present the almost constant enlargement of leukæmia, and in the majority of cases cannot be felt below the ribs. Moderate hyperplasia is common, but I have never seen the large splenic tumor. In some instances it has been found extending into the umbilical region, and if there are secondary lymphoid growths the surface may be very irregular.

The thyroid may be enlarged; it was so in Cases II. and IV., and in Case V. the growth in the glands of the neck involved the right lobe.

The thymus has also been found affected; indeed, the disease may, according to Virchow, sometimes begin in the gland.

Blood and Circulation.--The blood presents the characters of anæmia, and as a rule the more advanced the glandular trouble the greater the impoverishment. The red corpuscles are reduced in numbers one-half or even three-fourths, but never, in my experience, to the extent in pernicious anæmia. The lowest number per cubic millimeter which I have counted was in Case II., when on one occasion the numbers sank to 2,100,000 per c.m. There may be most advanced disease without great anæmia. In one case (IV.) with enormous enlargement of the cervical and axillary gland there were 4,250,000 to the c.m., and during his three weeks' stay in the hospital the numbers were never much reduced. So also in Case III. there was not profound anæmia to within two months of the patient's death.

The red corpuscles are usually uniform in size. I have never seen extreme poikilocytosis, though occasionally the microcytes have been numerous. The colorless corpuscles are not greatly increased, although there may be moderate leucocytosis, as in Case IV., in which the ratio of white to red kept about 1:150. A condition of actual leukæmia may be induced. The corpuscles may be smaller than usual, and present the characters of the blood in lymphatic leukæmia. I have not met with nucleated red corpuscles in any of the cases which I have examined.

The granule-masses of Schultze are in variable numbers.

{925} Cardiac weakness and palpitation are common, due chiefly to the anæmia. The mediastinal growths in some cases cause great embarrassment from pressure. Fatty heart-muscle is an almost constant sequence of the anæmia. The pulse is quickened--80-110, or, if much fever, 120-130. Hæmic murmurs may be heard at the base of the heart, and the venous hum at the root of the neck is often very distinct. Pressure of the tumors upon the nerves may influence the heart's action, and in one case in which sudden death took place it may have been due to interference with the innervation of the heart by pressure on the nerve-trunks.

Respiratory System.--Shortness of breath from the anæmia is common, particularly on exertion. When the tracheal and bronchial glands are affected urgent attacks of dyspnoea may occur and suffocation be induced. Pressure on the pneumogastric or recurrent laryngeal may cause hoarseness or aphonia. The gland-tumors may invade the lung, or there may be secondary growths. These are not usually large enough to induce symptoms. The shortness of breath may be caused by pleuritic effusion, which may be an early symptom and the one for which the patient is sent to hospital (Case X.). It is due to pressure on the azygos and intercostal veins.

Fever is observed in nearly all cases; even in the early stages slight elevation of temperature may be noted. When the disease is firmly established the fever is a marked feature. It may be of an irregular hectic type, with morning remissions--this is, I think, the most common--or it may be continuous, with an evening exacerbation. More rarely there are ague-like paroxysms, with rigor, hot and sweating stage (Case I.), and during these the fever may rise to 104° and glands may become more swollen. The range is never very great, rarely exceeding 103°.

Digestive System.--Difficulty in swallowing may result from the enlargement of the lymph-follicles at the base of the lungs and of the tonsils and pharyngeal adenoid tissue. This may be so great as to necessitate feeding with a tube. There may be early gastric trouble when the mesenteric and abdominal glands are first affected--dyspepsia, nausea, and vomiting. Secondary tumors of the stomach are not common. The loss of appetite and feeble digestion, prominent symptoms in so many cases, are largely due to the anæmia.

Diarrhoea is not met with so frequently as in leukæmia; it may come on toward the close and carry off the patient. New growths in the intestine may produce severe attacks and sometimes hemorrhage. Obstinate constipation may be the result of pressure.

The liver is rarely enlarged, and there are not often hepatic symptoms. The new growths do not produce irregularity in the enlargement. Pressure of enlarged glands at the hilus may cause jaundice and ascites.

Genito-urinary System.--The urine is usually clear and presents no striking changes. Reaction acid; albumen may be present. The testicles may be the seat of secondary growths.

Nervous System.--Headache, giddiness, and noises in the ear are common, and are dependent upon the anæmic state. Southey[153] has noticed delirium and coma in some cases.

[Footnote 153: _Barth. Hospital Reports_, vol. ix.]

Special Senses.--Deafness is not uncommon, caused by pressure of the large glands in the neck or by the growth of adenoid tissue about the pharynx, closing the Eustachian tube. Inequality of the pupils has been noted, from pressure of a gland on the sympathetic. Retinal hemorrhages are uncommon.

Skin.--There may be definite secondary lymphatic tumors apart from direct infiltration by continuity.[154] Bronzing may occur (Case IV.). Papular rashes may be very troublesome. Subcutaneous oedema of feet and eyelids may occur when the anæmia is very profound.

[Footnote 154: Greenfield, _Path. Soc._, xxvii.]

{926} MORBID ANATOMY.--The Lymph-glands.--Virchow made the division into the hard and soft varieties, the difference depending on the proportion between the cells and the adenoid reticulum. Where the cells predominate the growth is soft--may be semi-fluctuating--but when the stroma is much hypertrophied the glands are hard, firm, and feel like organs in a state of chronic induration. The great majority of the cases are of the soft variety. When first affected the glands may be hard, and as the development proceeds become less consistent; but there are cases in which they maintain their firmness and solidity throughout.

When examined in the early stage the individual glands are more or less isolated, perhaps not larger than almonds or walnuts, adherent by their capsules, but readily separated and movable. Even when death has been caused, some groups may generally be found in this state, as it is rare for all to be equally developed. When advanced, the glands fuse together, distinction is lost between them, and the bunch may form a large tumor the size of an orange or even a cocoanut. When of moderate size the section may show normal-looking gland-substance, and the distinction between cortical and medullary portions may be well preserved. When much enlarged the section has usually a grayish-white appearance, smooth, and of variable consistence, either firm and dry or soft and juicy. The vascularity is not often marked, and extravasation and areas of congestion are not seen so frequently as in some actively-growing neoplasms of the lymph-glands.

The capsules are thinned, and may disappear in the fusion of contiguous glands, traces being seen on the section as strands of connective tissue. About large groups the capsular tissues may be much condensed, forming a very firm investment. The growth may perforate the capsule and invade contiguous parts--muscle, skin, or the solid organs.

The chief changes which the tumors may undergo are fibroid induration, suppuration, and caseation. The gradual increase of the stroma may give a high degree of density, and the gland on section may present a smooth, glistening appearance. Suppuration is most frequently seen when the growth reaches the skin; it may point and an abscess discharge. In the deep glands the formation of pus is not often met with. Caseation is extremely rare. Hemorrhages may take place from rupture of the thin-walled vessels.