322 I R I S H J O U R N A L O F M E D I C A L S C I E N C E

A CASE OF ACUTE LYMPHATIC LEUK/EMIA.

B y HENRY MOORE a n d W. R. O'FARRELL.

T H E fo l lowing case of acu te l y m p h a t i c leuk~emia p resen ted such i n t e r e s t i ng f ea tu r e s t h a t i t appea r s to be w o r t h y of record :

A man of 44 years of age was admitted to the Mater Misericordim Hospital, Dublin, on November 19th, 1930. There was a purpuric rash on the front of the chest, on both forearms and on the right shin; on the dorsum of the right foot there was a subcutaneous ecchymesis, which was evidently, from the coleur changes, some days old. The patient did not feel or look ill, appeared only slightly aneemic, and came simply because of the purpura which had first appeared five days before admission. His previous history was unimportant, except for typhoid fever in 1911.

General physical examination revealed nothing abnormal, except one abscess (x-ray) at the root of the upper left second molar tooth. The heart, lungs, abdomen and urine were normal, the blood-pressure 150-80, the pulse rate 72 and regular, and the spleen and liver were apparently not enlarged. The erythrocyte count was 3,940,000 and the leucocyte count 8,600 per c.m. ; the hmmoglobin wa~ 90% (Sahli), the colour index 1.15 and the platelet count 100,000 per c.m. The differential leucocyte count showed 43% small lymphocytes, 26% lymphoblast-like cells, 16% large lymphccytes, 12% polymorphonuclear neutrophile leucocytes, and 3% large mononuclear cells. (See table.) Reticulocytes were 0.8%, and there was less than 0.1 rag. bilirubin per 100 c.c. ~ blood. The blood calcium was 9.4 mg. per cent., the clotting time 4 minutes, the bleeding time (prick) 2�89 minutes, and the clot retraction was poor. The Wasser- mann reaction was negative. A fractional test-meal analysis, done because of flatulence and glossitis, after the patient had been about three weeks in hospital, showed achlorhydria.

For the first two weeks of observation purpura was a prominent feature, crops of purpuric spots appearing in some areas of skin while they were fading in others, and there were occasional subcutaneous extravasations of blood of moderate size; later the purpura became less prominent, and in the last two weeks showed itself only as odd spots. A few days after admission oozing of blood from the gums became troublesome, and remained so throughout, except when it disappeared for 4 or 5 days after transfusion of blood. There were occasional h~emorrhages from the gastro-intestinal tract (metsena), occasional attacks of h~ematuria and epistaxis, and submucous hsemorrhagic spots frequently appeared on the buceal mucous membrane and soft palate. Blood culture was negative,

�9 and at no time was there pharyngitis or stomatitis. On December 14th the patient complained of dimness of vision, and ophthalmoscopic examin- ation showed rather extensive retinal h~emorrhages which were pronounced subhya]oid by Dr. D. O'Donoghue; later, retinal, vitreous and sub-con- junctival h~emorrhages occurred. The abscessed tooth was removed by Dr. Ryan a few days after admission, and the resulting steady oozing of blood from the alveolus gave some trouble before it was controlled.

In the latter half of the illness the temperature sometimes rose to about 100 o or 101 o F. for a few consecutive days; as time went on the respi- ratory rate gradually rose to 38, the heart rate to 140, and as the anaemia progressed " h~emic " murmurs became audible over the precordial area.

The progress was downward, the patient becoming gradually weaker and more anaemic, with temporary partial improvement for some days after transfusion of blood. The spleen was never palpable, and the liver edge was for the first time just felt below the costal margin two d a ~ " before death. The patient died 67 days after admission; a partial autopsy was permitted. The results of the chief laboratory examinations are recorded in the table, and the post-mortem findings are discussed below.

The main treatment consisted of transfusion of whole (uncitrated) blood; five such transfusions were given of 320 to 1,000 s.c. each on Nov. 16th, Nov. 23rd, Nov. 24th, Dec. 6th, and Dec. 18th. Adrephine and

ACUTE L Y M P H A T I C LEUK2EMIA 323

adrenalin were used for local treatment of the gums, and h~emoplastic �9 Oruln for local treatment and by in~ection; adrenalin wa~ also adminis- tered subcutaneously by mouth and per rectum, and attention was directed to oral hygiene. Whipple's new liver extract with iron for secondary anaemia, liver extract for pernicious anaemia and whole liver were tried. Radiostoleum was given by mouth, calcium was given intra- venously and by mouth, and iron and hydrochloric acid by mouth. These and other drugs were given often in desperation, and not necessarily because of any scientific basis for their use. The diagnosis of acute (" aleuk~emie ") lymphatic leuksemia was made after the first blood count and, we believe, w~s verified by the subsequent events Leukopoenia appeared after some weeks, and was replaced towards the end by a leucocytosis of considerable degree with almost complete agranulocytosis.

On doing the first total leucocyte count, one was immedi- ately impressed by the size of the white blood corpuscles. On examination of the stained films this feature was again prominent, as was also the immature type of many of the white cells. The cells which at once focussed at tention in the stained smear were of the large lymphocyte type, but these cells bore characteristics which placed them in a category of priori ty in h~ematopoietic origin to the mature large lymphocyte of the peripheral blood.

Apar t from the relatively large size of the cells In quest ion-- about 18 microns in d iameter- -even more striking and undoubtedly more cytologically important was their nuclear structure. The nuclei of these cells showed a coarse basi-chromatin stippling which at the nuclear edge was collected into a fa i r ly dense nuclear membrane. A varying number of nucleoli were present- -2 to 3 per cell. The nuclei measured about 16 microns in diameter and showed a graceful, sinuous, but comparatively rounded, outline. The cytoplasm showed a clear non-granular r im of varying depth, at the widest about 2 microns in diameter. These characteristics enabled the cells to be classified as lymphoblasts. In contra- distinction, the nucleus of the myeloblast presents a fine stippled s t ructure and no nuclear membrane, while the nucleus of the p r o monocyte has a fine thread-like basi-chromatin ar rangement ; no such cells were seen in this pat ient ' s blood.

The oxidase reaction has fallen somewhat into disrepute of recent years, owing to its inability to distinguish between the early myeloblast and the early lymphoblast; however, its application failed to demonstrate any granules in the cells under examination. We are inclined, for various reasons, to lay special stress on the morphological characters of the lymphoblasts; they appeared in the blood at an early stage of the disease, they indicated a grave hmmatopoietic lesion and they increased in numbers through the

illness. The number o f lymphoblasts in the blood was considerable on

the first examination, comprising 26% of the differential leucocyte count. The remainder of the differential count showed 43% of small lymphocytes, 16% of large ]ymphocytes, 3% of large mono- nuclears and 12% of polymorphonuclear neutrophiles. The total leucocyte count only numbered 8,600 per c.m. In order to avoid a tedious repetition of figures the table has been constructed to show the various important laboratory findings during life.

324 IRISH JOURNAL OF MEDICAL SCIENCE

DATE

~ ) �9

3~ "~d

2ot11/'3o

2 4 1 1 1 f 3 o

1 / 1 2 / ' 3 o

4 1 1 2 / ' 3 o

3 , 9 4 0 , 0 0 0 9 0 I . 15 8,600 i o o , o o o + -- SI. --

L

. . . . . . 1 6 5 , o o o + - - __ - -

3 , 2 8 o , o o o 7 ~ 1 . o 7 8 , 4 0 0 I 4 5 , o o o + - - R a r e - -

2 , 6 2 o , o o o 6 0 1 . 1 5 8 , 2 0 0 1 4 5 , o o o + S1. -- -- --

9/12/'3o

11/12/'3o

15/12/'3o

1 8 / 1 2 / ' 3 o

2 2 / 1 2 / ' 3 o

2 3 1 1 2 f 3 o

z 9 / I 2 f 3 o

2/1/'31

9111'31

1 , 6 8 o , o o o 45 1 . 3 6 6 , 6 0 0 1 2 5 , o o o + S1. R a r e -- --

1 , 9 o o , o o o 35 0 . 9 2 5 , 1 o o 1 5 o , o o o + S1. S1. -- --

1,44o, ~ 35 1 . 2 5 5 , o o o 7 5 , 0 0 0 + S1. S1. -- --

1 , 3 4 o , o o o 3 ~ 1 . I 5 3 , 7 0 0 9 0 , 0 0 0 + S1. S1. S I . [ - -

I,OlO,OOO 2 0 I .OO 2 , 7 0 0 8 0 , 0 0 0 + S1. -- S1. 5 i n 2 f i l m s

1 , 4 5 ~ 1 7 6 1 7 6 34 1 . I

1 , 5 2 o , o o o 3 ~ I . o

J

M I - ~ - - ~

2 , 8 0 0 + S1. S1. - - - -

3 , o 0 o 1 5 o , o o o + �9 - - �9 SI. SI . - -

2 , 0 0 0 + S1. S1. S1. - -

17/1/'31

2op/'31

2 4 / I / ' 3 1

1,125,ooo 20 0.9 11,35o 29,000 + SI. SI. -- --

. . . . 23,ooo Sl. Sl. Sl. Sl. x in

i f i l m

- - - - 3 1 , 8 o o S1. S1. S1. - - - -

S1. = S l i g h t o r f ew. + = m a r k e d .

ACUTE LYMPHATIC LEUK2EMIA 325

OTHER FINDINGS

43 16 3

J

- - 2 7 6 2

t

- - 2 3 I I - -

t

I in I7 9 - -

I film.

x in 16 9 - - I film.

i

- - 28 12 I

t

x in 36 I4 2 i film.

x m 45 3 I 2 films.

i in I film.

I in I film.

27 5 --

1

38 5 --

31 6

2 3 I I 2

t

8 3~

1 2 26 Clotting t ime 4 m i n u t e s ; bleeding t ime 2�89 m i n u t e s ; clot re t ract ion no t good. Calcium, 9.37 rag. pet IOO c.c. Serum. Urine. No Albumen.

1 3

Stools: occult blood s t rong positive.

52 Tendency of whi te blood corpuscles to break down and form shadow cells. Rieder cells present .

IO I - - 55 Rieder cells present .

7 ~ Urine : heavy cloud of a lbumen blood.

7 ~ Megalocytic tendency.

12 I - - 46 Ur ine : trace of a lbumen. Stools : occult blood s t rong positive.

io 38 Ret iculocytes : 0.8 per cent. Test meal : achlorhydria.

9 42 Dist inct megalocytic tendency. Reti- culocytes : 1.2 per cent. van den Bergh : less t han o. i mg. of Bilirubin per ioo c.c. of plasina.

Ur ine : Trace of a l b u m e n ; a few red blood corpuscles.

Blood cul ture : negative.

7 I , - - . 60 Numerous free particles of cell cytoplasm.

18 39

15 I. - - . 47 Megalocytic tendency.

13 I - - 5 ~ Megalocytic tendency.

3 - - - - 86

I 87 A few Rieder cells; numerous free particles of cell cytoplasm.

326 I R I S H JOURNAL OF M E D I C A L S CIEN CE

Through the whole series of observations there was a rapidly progressive anaemia which very soon assumed a " pernicious " type. There was no leucocytosis until near the end; iudeed, although there was soon a leucopenia, it must be noted that the fall in leucocytie numbers ran almost parallel on its own level with the decreasing numbers of red blood corpuscles, unti l in the later examinations a leucocytosis became manifest. The relative lymphocytosis at first sight might be taken to be the result of an overactivity of a compensatory nature of a normal lymphocytic system. The lymphocytic system showed, however, grave departure f rom the normal, as evidenced by the occurrence, persistence and increase of immature elements, the lymphoblastie cells. I t would seem as if the disease of the lymphocytic system was the basic lesion and the myeloid disturbance, as evidenced by the decrease of granulocytes and blood platelets, and the megalo- blastic anaemia were of secondary nature. The disease was there- fore considered to be a leucosis of the acute lymphatic type, but ex- hibiting unusual characters. I t was now considered necessary to correlate our findings with the known atypical leuk~emias. To quote f rom Pineyl :

It has long been recognised (Conheim) that all the anatomical changes characteristic of " leuk~emia " might occur without any increase in the number of circulating leucocytes, although there were grave alterations in the qualitative composition, as evidenbed by the presence of immature cells of a character not found in the normal circulation; this is the " pseudo-leuk~emia " of Conheim and the " aleuksemic leukmmia " of many authors. The essential changes in the h~ematopoetie tissue in these diseases are great cellular overgrowths together with alteration in the structure of the newly-formed cells.

Reed 2 has described a case of acute lymphatic leuk~emia without enlargement of lymphatic glands.

In our case, in the early stages, the colour index of 1.15 may, we think, fair ly be taken as at an extreme maximal normal point. On one occasion (9/12/30) it rose to 1.36, but in two days ' time re turned to 0.92; on 15/12/30 it rose to 1.25, but in three days ' t ime it fell to 1.15, to reach uni ty four days later. I t is here interesting to cite a case of " aleukmm]c " leuk~emia reported by Brodribb and Lazarus-Barlow s with an erythrocyte count of 2,200,000 per c.cm., a total leucocyte count of 6,600 per c.m. and a eolour index of 1.4.

Divergent views exist as to the significance of megaloblasts in the peripheral blood. N~egeli and his followers contend that their presence is pathognomonic of pernicious anaemia. Their occurrence in other conditions has, however, been noted by various authorities. P iney 1 states that Ullman and Weiss recorded a case which in its early stages had all the characters of pernicious anaemia, but later became converted into an equally typical ease of acute leuk~emie lymphadenosis.

Achlorhydria does not appear to have been recorded in the s tudy of previous published cases of acute lymphatic leukmmia.

A C U T E L Y M P H A T I C L E U ~ A g ~ M I A 327

The blood films showed an abno rma l f r a n g i b i l i t y of the lympho- blast ic cells, cha rac te r i sed by the presence of n u m e r o u s so-called basket, shadow or smudged cel ls ; there were also p re sen t numerous R i e d e r cells or b inuc lea te lymphoblas ts .

POST-MORTEM EXAMINATION.

Only a partial post-mortem examination was permitted. This was per- formed on Jan. 25th, 1931, about three hours after death. ~t tent ion was directed to what were considered to be the most important organs.

The abdomen was opened, and it was noted that the liver was slightly enlarged, pale in colour, firm in consistency, with sharp edges, and that i t bled freely on incision; the whole liver was not removed, but a small slice was taken for examination. No enlarged lymphatic glands were felt on palpation in the abdominal cavity.

The spleen was removed entire and was slightly enlarged, weighing 276 gms. The substance of the spleen was moderately soft, showing bright red points on a pinkish background.

The left kidney was removed, was ot~ about normal size, and was embedded in a large quantity of peri-renal fat of a dead white colour. I t was smooth, showed slight persistence of festal lobulations, and was of a uniformly pale colour.

The thoracic cavity was not opened. The only palpable superficial gland, a small, oval one about the size of

a haricot bean, was removed from the left inguinal region. The head of the tibia was trephined, and an at tempt was made to

obtain a sample of the bone-marrow; this marrow was completely fluid, of a pale colour showing a few red streaks, and was of about the consis- tency of cream. Even scraping with a Volkmann's spoon produced only a greasy fluid which immediately spread out, forming a scum, on the sur- face of the fixing fluid.

~A portion of a rib was excised; its marrow appeared normal to the naked eye. Smears were made from the splenic pulp, from the tibial anal rib marrow.

EXAMINATION OF FILM PREPARATIONS OF ORGANS.

Bone-marrow o] Tibia.mFilms stained with the greatest difficulty owing to their greasy nature. After t reatment with ether and alcohol only a few scattered patches with cellular content could be made out. These areas consisted partly of normal and megalocytic red blood corpuscles (one megaloblast was seen), and partly of cells closely resembling the lympho- blastic cells found in the peripheral blood; only one myelocyte was noted, and no polymorphonuclear cells.

Bone-marrow of Rib.raThe cells closely resembled lymphoblasts. No polymorphonuelear cells were seen.

Spleen Smears.--Besides showing a number of red blood corpuscles and a few large pigment-containing cells, the bulk of the cells seen were of lymphoblastic type.

In all the film preparations other than those of the blood, the cells were almost devoid of cytoplasm, were distorted, stained indifferently, and were unsuitable for careful cytological study.

EXAMINATION OF SECTIONS.

Lymphatic Gland.--The architecture of. the gland was moderately well preserved. The lymph follicles were intact, and, regarded as a whole, there was no germinal-centre proliferation. The sinuses and the pulp of the gland contain a greater number than normal of large cells of lympho- cyte type. The impression conveyed was that the gland, acting as it were as a net, had caught up in its meshes numerous lymphoblastic cells.

Spleen.--Malpighian corpuscles were in evidence, but were not unduly prominent, nor were they increased in size. Their small cells stood out rather clearly in contrast to the larger cells packing the splenic pulp. Careful examination of the cells contained in the trabecular vessels, and of those in the pulp, showed them to be identical in appearance and of lymphoblastic type.

328 I R I S H J O U R N A L OF M E D I C A L S C I E N C E

Kidney.--No collection of lymphoblasts were seen in the kidney. A few were present in the renal capillaries.

Boue-marrow of Rib . - -The cells contained in the marrow spaces were almost entirely of the large lymphocyte type.

Liver.--The hver cells in general showed a slight fatty infiltration and a considerable deposit of pigment. The most striking features were col- lections around the poltal areas of lymphoblastic cells and a subcapsular zone of considerable depth containing many of the same cells. These cells in the portal areas and subcapsular zone were identical with the cells con- tained in the portal vessels, and were morphologically lymphoblasts. Numbers of these lymphoblasts in the portal areas showed mitotic figures. This particular distribution of lymphocytic cells is very characteristic of lymphatic leuk~emia (lymphadenosls).

Leishman and Giemsa stains were used in the s tudy of the blood films and h~ematoxalin and eosin for the paraffin sections. The oxydase reaction was done with benzidine and hydrogen peroxide and basic fuchsin. We are, of fcourse, aware that it is by many considered impossible to distinguish between the lympho- blast and the early myeloblast in the circulating blood, but we believed that we were dealing with a case of acute lymphatic leukvemia for the reasons already stated.

_As only a partial post-mortem examination was possible in this case it is useless to speculate as to the site of origin of the over- production of the lymphoblasts, but in this connection it is interesting to note the mitoses in the periportal lymphoblastic cellular collections.

We are indebted to Mr. P. J. Smyth for his surgical assistance with the transfusions of blood, and to Dr. L. Doyle for referr ing the case to us.

References.

(1) Piney, A. " Recent Advances in Hvematology," 1931, London: J. and A. Churchill.

(2) Reed, D. M. : Amer. Jour. Med. Sci., 1902, cxxiv, p. 653. (3) Brodribb, A. W., and Lazarus-Barlow, P , Lancet, 1931, ccxx, p. 347.

ST. ULTAN'S INFANT HOSPITAL.

A Postgraduate Course in Diseases and Feeding of Infants will be held in St. Ultan's Infant Hospital, September 7th-13th, 1931. For further particulars, please apply to the I-Ion. Sec., St. Ultan's Hospital, 37 Char- lemont Street, Dublin.

APPOINTMENTS BY LOCAL AUTHORITIES.

Through the courtesy of the Minister for Local Government and Publio Health we are enabled to publish the following n~mes of Medical Candi~ dates appointed to offices under Local Authorities on the recommendation of the Local Appointments Commissioners:--

Dr. Jeremiah Murphy, 4 Anglesea Terrace, Cork, to be Medical Officer, Rooskey Dispensary District. Co. Roscommon. (May, 1931.)

Dr. Denis Finn, Templemore, Co. Tipperary, to be Medical Officer, Moyne Dispensary District, Co. Tipperary. (May, 1931.)