LEUKEMIA (SUMMARY OF 100 CASES) AND LYMPHOSARCOMA
COMPLICATED BY PREGNANCY.
CELLULAR CHANGES PRODUCED IN GUINEA PIGS BY EXTRACTS OF
"LEUKEMIC"
PLACENTA
LOWELL A. E R F , M . D .
From the Charlotte Drake Cardeza Foundation, Jefferson
Philadelphia,
Pennsylvania
Medical College
Hospital,
The purpose of this paper is to report: (1) an additional case of chronic myeloid
leukemia complicated by pregnancy; (2) the completion of a case of myeloid
leukemia previously reported; 1 (3) an additional case of lymphosarcoma complicated by pregnancy; and (4) the cellular changes found in the organs of
guinea pigs injected with lipid extracts obtained from a normal placenta and
from the placenta of a patient with chronic myeloid leukemia.
REPORT OF CASES
Case 1. Myeloid leukemia complicated by pregnancy
Clinical data. A 25 year old white housewife was referred t o Jefferson Hospital b y D r .
Oscar Wood on September 20, 1944, because of splenomegaly, fatigue and bleeding from the
gums. T h e p a t i e n t h a d noted a mass in t h e region of t h e spleen a year previously, b u t because it was not associated with symptoms she had not consulted a physician. T h e patient
had two children, aged 2 and 4 years, respectively. T h e p a t i e n t ' s father had died a t the age
of 54 of pernicious anemia. T h e p a t i e n t was a slight, dark-haired, pale individual weighing
about 120 pounds. There were small clots of blood a t several points on t h e margins of the
gums. There was slight generalized lymphadenopathy. The inferior hepatic edge could
be felt 1 inch, and t h e splenic edge 2 inches, below their respective costal margins.
Laboratory findings were as follows: hemoglobin, 60 per cent ( K l e t t ) ; erythrocytes,
3,100,000 per cu. mm.; platelets, 200,000; leukocytes, 190,000; differential count in per cent:
polymorphonuclears, 55; metamyelocytes, 32; myelocytes, 7; basophils, 3; lymphocytes, 3;
prothrombin time 35 per cent of normal; basal metabolic rate, plus 17 per cent; blood uric
acid, 4.8 mg. per 100 cc. X-ray therapy was directed to the adrenal glands. From October
6, t o October 14, 1944, she received a total of 400 r.
Course. Menstruation did not occur during the month of J a n u a r y 1945. In March 1945,
a positive Friedman test was obtained. It was believed t h a t the patient should have been
aborted, but she refused. By March 1945, the white blood cell count had dropped to 20,000
but in May 1945, it had risen to 80,000. Fowler's solution was started then because of the
danger of exposing the fetus to x-ray irradiation. The leukocytic level remained below
100,000 until September 1945, when it rose to 172,000 and was associated with 20 per cent
myeloblasts in the differential count. During October 1945, the ninth month of pregnancy,
the white blood cell count rose to about 400,000 despite the continuous use of Fowler's
solution. During the first twenty-eight days of October t h e patient received fifteen blood
transfusions (500 cc. each). On October 29, the patient was delivered by D r . J. E . Lynch of
a 6 pound, 6 ounce normal boy. A differential leukocyte count of the cord blood revealed
the following percentages of cells: polymorphonuclears, 55; eosinophils, 5; lymphocytes, 38;
monocytes, 2 along with 28 per cent normoblasts. Blood count of t h e baby revealed the
following: hemoglobin, 105 per cent; erythrocytes, 4,500,000 per cu. mm.; leukocytes, 19,850
* Received for publication, J a n u a r y 4, 1947.
268
LEUKEMIA I N PREGNANCY
269
per cu. mm.; differential count in per cent: polymorphonuclears, 66; eosinophils, 3; basophils, 1; lymphocytes, 25; monocytes, 5; (normoblasts, 2). During the two weeks the baby
remained in the hospital, five complete blood counts were made and the findings in all of
FIG. 1. LEUKEMIC INFILTEATIONS OF SKIN, CASE 1.
them were within the limits of normal. The placenta weighed 550 gm. and, on section, was
histologically essentially normal except for some slight infiltration of the maternal lacunas
with myelocytes. The uterus was packed with gauze, soaked in thromboplastin, fibrinogen
and adrenalin and the cervix sewed because of profuse uterine bleeding. During the first
seven hours following delivery, the patient received intravenously seven pints of blood.
Despite the transfusions and the cessation of bleeding, the blood findings on the next morning were as follows: hemoglobin, 39 per cent; erythrocytes, 1,700,000 per cu. mm.; leuko-
270
ERF
cytes, 169,000 per cu. mm.; differential count in per cent: polymorphonuclears, 27; metamyelocytes, 17; myelocytes, 19; blasts, 26; lymphocytes, 5; monocytes, 6. The uterine pack was
removed November 1, 1945 and no bleeding followed. The white blood cell count rose to
400,000 by November 12, when 5 millicuries of radiophosphorus was injected intravenously.
The leukocyte count gradually decreased to 70,000 by December 5, 1945. The patient
developed some uterine bleeding (platelets 130,000) and radium (2400 mg. hr.) was applied
to the uterine cavity and several transfusions were administered. On December 22, 1945,
the patient developed leukemids over the entire body and the breasts became stony hard
(Fig. 1). The leukemids were purplish in color, were elevated and many of them each
measured about 1 cm. in diameter.
The patient was readmitted to hospital January 14, 1946 complaining of bleeding gums,
tender,hard breasts,"purple spots"in the skin, and partial blindness of the left eye. Physical examination revealed large retinal hemorrhages in both eyes, bilateral subconjunctival
hemorrhages, generalized lymphadenopathy, leukemids in most of the skin of the body,
and the spleen was palpable 4 | inches below the left costal margin.
Laboratory findings were as follows: hemoglobin, 37 per pent; erythrocytes, 1,680,000 per
cu. mm.; platelets, 170,000; leukocytes, 284,000 per cu. mm.; differential counts in per cent:
polymorphonuclears, 26; metamyelocytes, 19; myelocytes, 21; blasts, 25; lymphocytes, 7;
and monocytes, 2; urea clearance, 42 per cent of normal; blood proteins, albumin 4.2 gm.
and globulin, 1.3 gm. per 100 cc.
Course. The daily peak of temperature ranged from 102 P. to 104 F. Transfusions were
given three times a week. The white blood cell count rose to nearly 600,000 per cu. mm.
before the patient expired on March 5, 1946. During the last year of her life, she had received fifty-two transfusions.
Post mortem. The autopsy findings were typical of myeloid leukemia. Hemorrhages
were observed in the sclera and in the skin of the chest and abdomen. The left pleural
cavity contained 2000 cc. of straw-colored fluid. All organs appeared infiltrated. The
spleen weighed 950 gm. and the liver 2460 gm. The uterus was normal in shape and size.
The lungs were congested and edematous. The histologic findings follow: myeloid cell
infiltration of nearly all organs and tissues; extensive and marked infiltration of the skin;
fibrosis and infiltration of the breast; considerable infiltration of ovaries and uterus; pulmonary congestion and edema.
CELLULAR CHANGES IN GUINEA PIGS FOLLOWING INJECTION OF EXTRACT OF
" L E U K E M I C " PLACENTA
As stated above, the placenta of Case 1 was delivered October 29, 1945'
weighed 550 gm. and, histologically, was essentially normal except for slight
leukemic infiltration and for a few myelocytes in the maternal lacunas. It
was ground up and mixed with 3 liters of methyl alcohol acidified by hydrochloric acid and allowed to stand overnight. A normal placenta (Mom),
which weighed 850 gm., was obtained the following day and it, too, was extracted
identically with acidified wood alcohol. The alcoholic extract of the normal
placenta and that of the placenta of Case 1 were treated identically as follows.
The alcoholic extract was filtered and then extracted with petroleum ether.
The ether extract was extracted by an alcoholic solution of potassium hydroxide
(300 gm. potassium hydroxide in 1000 cc. methanol). To this extract was
added hydrochloric acid until acid to congo red paper. The solution was then
extracted with ethyl ether. The ether was evaporated and 0.4 gm. of a dark
ttrown oily highly odorous material was thereby ultimately obtained from the
LEUKEMIA I N PREGNANCY
271
placenta of Case 1 and 0.3 gm. of a similar appearing substance was obtained
after the normal placenta was so treated. 38
One-tenth gm. of the extract of the leukemic placenta was injected subcutaneously into each of two guinea pigs27 and the injections were repeated a
week later. The extract of the normal placenta was likewise similarly injected.
All four guinea pigs were sacrificed three weeks after the second injections
were administered and all organs were studied histologically.10 The organs
of both guinea pigs receiving the extract of the normal placenta were normal;
but of the two animals receiving the extract of the leukemic placenta, one had
slight myeloid infiltrations in the liver and kidneys, while the other had signifi-
F I G . 2. M Y E L O I D C E L L I N F I L T R A T I O N OP L I V E K OF G U I N E A P I G T H A T R E C E I V E D
INJECTIONS OF L I P I D 'EXTRACTS OF THE PLACENTA OP P A T I E N T W I T H
CHRONIC M Y E L O I D L E U K E M I A , C A S E 1.
cant myeloid cell infiltrations in the liver (Fig. 2), the kidneys and spleen, and
the marrow was hyperplastic. These findings indicate that although the placenta
of Case 1 was histologically not markedly leukemic the potentialities of experimentally producing a "myeloid reaction" 28 were still present.
In October 1946, the male child born of Case 1, on October 29,1945, was alive
and well.
Case 2. Myeloid leukemia complicated by two pregnancies
Clinical data. This case was first reported 1 in 1944 after t h e leukemic patient delivered
her first child, b u t is mentioned again to relate the fatal outcome of the p a t i e n t and her t w o
offspring. The p a t i e n t , 22 years old, was first seen b y D r . H . M . Angelucci, in December
272
ERF
1942, a t which time she had been pregnant for two m o n t h s . I n J u n e 1943, when the white
blood cell count was 126,000, the p a t i e n t received x-ray therapy directed to the anterior
and posterior aspects of the thighs and chest. In July, a 7 pound, 2 ounce hydrocephalic
male infant was delivered. I n J u l y and August of 1943, the patient received x-ray therapy
directed towards the spleen and femurs. The patient became pregnant the second time in
J a n u a r y 1944. During t h e pregnancy the leukocytes rose t o 400,000 per cu. mm. and the
patient received additional x-ray therapy directed to the spleen and long bones. Dr.
Angelucci delivered the second baby in September 1944. The p o s t p a r t u m course was complicated by much bleeding and by poor healing of the perineum. The patient was sterilized
by ten x-ray treatments to the ovaries in December 1944. On March 28, 1945, the patient
was admitted to Jefferson Hospital complaining of weakness, nausea and vomiting, loss of
50 pounds of weight during the preceding ninety days and nonproductive cough of t h i r t y
days' duration. On physical examination, the patient was pale, slightly jaundiced, emaciated and dark complexioned. Cold beads of perspiration were present on her forehead and
she coughed i n t e r m i t t e n t l y and nonproductively. The temperature was 103 P . , the pulse
rate 120 and the respiratory rate 26. A soft blowing systolic murmur was heard over the
mitral area. The spleen was hard and extremely large, the inferior tip extending into the
pelvis. The liver was palpable 2 inches below the right costal margin. There were small
hemorrhoids present. Laboratory findings were as follows: hemoglobin, 26 per cent;
erythrocytes, 1,320,000 per cu. m m . ; platelets, 38,000 per cu. m m . ; leukocytes, 116,000 per
cu. mm.; differential count in per cent: polymorphonuclears, 11; metamyelocytes, 20;
myelocytes, 23; blasts, 16; basophils, 15; basophilic myelocytes, 12; and lymphocytes, 3; bilirubin, 4.3 mg. per 100 cc.
Course. In spite of transfusions, liver extract and penicillin for inflamed pharynx, the
fever persisted, t h e blood findings changed little and t h e patient died M a y 26, 1945.
Post mortem. T h e anatomic findings were typical of leukemia. The spleen weighed
3940 gm. and had many infarcts and perisplenic adhesions. The liver weighed 4600 gm.
T h e gallbladder was distended and contained several stones. There were also bilateral
hydrothorax, atelectasis of the lungs and an infarct of the right upper lobe. The histologic
findings were: myeloid cell infiltration of nearly all t h e organs; extramedullary myelopoietic
foci in sinusoids of the liver; bronchopneumonia; and venous congestion in the lungs.
Offspring
of Case 2
T h e first child, born J u l y 21, 1943, was a d m i t t e d to Jefferson Hospital, J u l y 15, 1945,
with the complaint of irregular continuous fever since b i r t h . The fever seemed to be related to the room temperature according to caretakers, who also informed us t h a t the
parents had been first cousins. On physical examination, the boy had a large hydrocephalic
head, but otherwise seemed fairly well developed. A bruit was heard over the left carotid
artery.
Laboratory findings. Hemoglobin was 61 per cent; erythrocytes, 4,080,000 per cu. mm.;
platelets, 160,000 per cu. mm.; leukocytes, 7,900 per cu. mm.; differential count in per cent:
polymorphonuclears, 33; eosinophils, 1; lymphocytes, 60; and monocytes, 6. The sternal
marrow findings were essentially normal. The cerebrospinal fluid was clear and under
75 mm. of water pressure. Tests revealed chlorides, 781 mg.; proteins, 120 mg.; Wassermann,
negative. There were 6 leukocytes per cu. mm. X-ray studies of the long bones were normal. The p a t i e n t ' s mental age was much below normal.
Course. There was a spiking fever t h a t reached 102 F . daily. There was a definite correlation between the room temperature and the p a t i e n t ' s body temperature. An a t t e m p t
was made to obtain an arteriogram of the internal carotid tree. The patient died two days
later, on September 5, 1945.
Post mortem. The anatomic diagnoses were hydrocephalus, pulmonary edema and congestion. The brain weighed 1300 gm. The convolutions were flattened and the sulci obliterated. T h e spleen weighed 60 gm. and the liver 440 gm. T h e histologic diagnoses were:
LEUKEMIA IN PREGNANCY
273
immature development of the cortex of the brain and congestion of the brain, lungs, kidneys
and spleen.
The second child, as noted above, was born in September 1944 in Women's Hospital.
Five days after birth, the child's temperature rose to 107 F. and on the sixth day to 110 F.
An autopsy was performed by Dr. B. Meine who felt that the child might have had toxoplasmosis.
Both of the offspring of the patient in Case 2 apparently had some disturbance of their
thermal centers. Were these disturbances due to the x-irradiation received by the mother?
The placentas were unfortunately not examined histologically.
Case 3.
Lymphosarcoma complicated by pregnancy
Clinical data. A 34 year old colored housewife was referred to the Elizabeth Storck
Kraemer Foundation, Jefferson Medical Hospital, April 22, 1942, as an out-patient because
of an enlarged left cervical lymph node of two months' duration, which on biopsy was reported as typical of Hodgkin's disease. The patient also complained of generalized itching.
Physical examination was essentially negative except for the enlarged left cervical node
which measured about 3 cm. in diameter. All of the laboratory findings were negative except for x-ray evidence of enlarged mediastinal nodes.
Course. The patient received a total of 4000 r. of x-radiation directed to neck and chest
during the months of May, August and December 1942; in April and August of 1943, she
received an additional 3000 r. Dr. W. H. Kraemer examined the patient in August 1943
and found evidence that she was pregnant. A positive Friedman test was obtained in September. On November 24, during the fifth month of pregnancy, a hysterotomy was performed on the patient in the Philadelphia Lying-in Hospital. Neither the fetus nor placenta were studied histologically. On January 14, 1944, the patient entered Pennsylvania
Hospital in a moribund state. Physical examination revealed an extremely emaciated
dyspneic 36 year old Negress with a blood pressure of 70/50. The spleen extended 2 inches
and the liver 4 inches below the costal margin. Laboratory findings were: hemoglobin, 71
per cent; erythrocytes, 3,200,000 per cu. mm.; leukocytes, 13,000 per cu. mm.; differential,
normal. The patient died on the third day after admission.
Post mortem. The anatomic findings were: extensive lymphosarcoma of mediastinum
which involved the periaortic lymph nodes and extended into the right lower lobe of the
lung, and by following the portal vein, into the liver and pancreas. The spleen was enlarged
and the bone marrow hypoplastic. Histologically, the tumor was a "collection of atypical
whorls of spindle-shaped cells with bizarre-shaped and hyperchromatic nuclei which were
associated with much reticulum."
The case began as Hodgkin's disease but ended as lymphosarcoma. This change or shift
from Hodgkin's disease to lymphosarcoma, or vice versa, has been fully discussed elsewhere.18
DISCUSSION
Many hematologic dyscrasias have been complicated by pregnancy,40 polycythemia, 8 aplastic anemia, 2 ' 20 purpura 11,33 and sickle cell anemia.36 One
hundred cases of leukemia complicated by pregnancy12 • 13 • 16 • 25 • 4 1 have been
reported (Table 1). By slightly modifying the interpretations and data of
some of the authors one may reach some rather practical, although rough,
conclusions. There were 87 cases of myeloid leukemia (24 acute and 63 chronic)
and 13 cases of lymphoid leukemia (10 acute and 3 chronic). Of the 34 acute
cases, all died either before delivery or within less than three months after
delivery; while of the 66 chronic cases, 43 survived more than one year after
delivery. The chronic types of leukemia complicated by pregnancy are more
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* T h e two cases listed in reference " were 21 a n d 38 years of age, respectively. T h e diagnosis of chronic myeloid leukemia was made i n
b o t h during t h e l a t t e r months of pregnancy. Both patients delivered normal children. T h e former was given orally 41 millicuries of radiophosphorus and t h e l a t t e r 60 millicuries before d e a t h . T h e postmortem findings of t h e former were typical of myeloid leukemia (the bone
marrow had m a n y megakaryocytes), while those of t h e l a t t e r were myeloblastic.
t A personal letter from D r . G. C. Bates, Independence, Kansas, dated August 20, 1946, indicated t h a t a normal healthy boy was d e livered from his p a t i e n t with chronic myeloid leukemia b y cesarian section on J a n u a r y 10, 1942. T h e p a t i e n t died J u n e 6, 1942, b u t t h e
child a t 4 j years of age was in perfect health.
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frequently of the myeloid type. (It has been stated that the ovaries are not
as intensely infiltrated in myeloid leukemia as in lymphoid leukemia.) Excluding abortions and maternal deaths before delivery, less than 50 per cent
of the babies will be normal in cases of acute leukemia, but nearly 75 per cent
of the babies will be normal in cases of chronic leukemia (Table 2). The evidence
indicates that the course of leukemia is not altered by pregnancy; that in acute
leukemia, abortions are not indicated because of the acute course of the leukemic
process; that in chronic leukemia, abortions are not indicated because of the
high percentage of normal offspring. There has been no report of a leukemic
newborn delivered of a leukemic mother, although there have been reports 6, 17,22,30 of leukemic newborns delivered of hematologically normal
mothers. The placentas are normal30 in the latter. Pregnant leukemic mice
deliver normal young.3 There is no consistent evidence that pregnancy increases
the activity of leukemia, lymphosarcoma or Hodgkih's disease, or that, in these
diseases, it hastens the death of the mother.
TABLE 2
A N A L Y S I S OF B I R T H S FROM M O T H E R S W I T H A C U T E AND CHRONIC T Y P E S OF L E U K E M I A
ABORTIONS (BOTH
INDUCED AND
SPONTANEOUS) AND
FETAL DEATH DUE
TO MATERNAL
DEATH
Mothers with acute leukemia...
Mothers with chronic leukemia..
STILLBIRTHS
BABIES THAT
LIVED LESS THAN
2 YEARS
NORMAL BABIES
12
17
12
7
5
9
37
29
19
5
46
The cause of leukemia is unknown. The theoretical mechanism that seems
most logical at present is that proposed by F. R. Miller.28-29 He implies that
acute leukemia is due to a lack of a specific maturation factor. Cooke has a
similar theory. 4 Viruses and bacteria have frequently been implicated as
causes, but as yet leukemia has never been transmitted in human beings.37
It is possible, however, that intestinal bacteria could supply the maturation
factor needed. Except for the lymphemic aspects of some malignant processes,
as lymphosarcoma, leukemia is not cancerous. And although there is a rare
familial instance, 6 , 1 2 , 1 9 , 2 6 leukemia is not inherited. Some of the other causes
of leukemia that have been presented are abnormal hormones (adrenal hypoactivity increases lymphopoiesis7 • 31 ), cosmic rays, hypofunction of the spleen
and emotional excesses.
Because the causes of leukemia are unknown, there are many types of treatment. Fowler's solution, which contains arsenic, is probably an enzyme inhibitor and has been used in cases of leukemia complicated by pregnancy because
of the rather large margin of safety offered the fetus. There is much evidence
that x-radiation directed toward the pelvis can be harmful to the fetus; possibly
LEUKEMIA IN PREGNANCY
277
the two offspring of Case 2 were injured by x-radiation. X-radiation directed
towards areas other than the pelvis and abdomen, probably would not harm the
fetus. In Case 1, before pregnancy occurred, x-radiation was directed toward
the adrenal glands in an endeavor to reduce their function so that more lymphocytes might be released.31 So far, radiophosphorus41' has been used twice* in
leukemia complicated by pregnancy. Because it emits beta rays it probably
is less dangerous to the fetus than x-ray. It does not alter ovulation because
a patient with polycythemia, 9 who desired pregnancy greatly, became pregnant
about two months after the intravenous administration of 5 millicuries of radiophosphorus (P32). The administration of large amounts of yeast seems to have
a place in the treatment of leukemia because yeast neutralizes, or aids in the
conjugation of, the substances stimulating the white cells to abnormal growth.
Urethane16 -32 and nitrogen mustards 34 have not been used extensively enough
in leukemia to draw definite conclusions.
The histologic findings in placentas from mothers with leukemia and from
mothers with leukemic newborn babies are rarely discussed. In instances
of the former, the placentas examined have rarely been infiltrated with leukemic
cells but some immature cells have been observed in the maternal lacunas.411
Apparently in instances of congenital leukemia, the placentas are normal.30
It would seem, therefore, that the placenta is a distinct barrier to leukemia,
and without regard to the side of the placenta on which the leukemia exists.
There are several reports of cases of Hodgkin's disease complicated by pregnancy 14 • 23 •24 •40 but few reports of lymphosarcoma.21 •36 The biopsy of the
cervical node of the patient of Case 3, in April 1942, was typical of Hodgkin's
disease, but at death, in January 1944, the lesions were typical of lymphosarcoma.
Herbut, Miller and Erf18 have seen such changes frequently and believe that
the changes are due to varying amounts of lymphokentric and myelokentric
acids circulating in the body.39
SUMMARY
An additional case of chronic myeloid leukemia complicated by pregnancy
is reported. The patient had received 52 transfusions during the last year of
her life. A photograph of leukemids and the autopsy findings are presented.
A second case of chronic myeloid leukemia, previously reported, is completed. The autopsy findings of the mother and two offspring are discussed.
The parents had been first cousins. Both children died apparently of disturbances of the thermal center, possibly brought on by x-radiation of the mother
during pregnancy.
A brief analysis of 100 cases of leukemia complicated by pregnancy is presented. There were 87 cases of myeloid leukemia (24 acute, 63 chronic) and 13
cases of lymphoid leukemia (10 acute, 3 chronic). Less than 50 per cent of
babies of mothers with acute leukemia are normal, while 75 per cent of babies
whose mothers have chronic leukemia are normal.
* See first footnote to Table 1.
278
ERF
An additional instance is reported of lymphosarcoma complicated by pregnancy. In this case, the findings at biopsy were those of Hodgkin's disease and
at autopsy, those of lymphosarcoma.
Lipid extracts of a normal placenta and of one obtained from a patient with
chronic myeloid leukemia were injected into two guinea pigs. A photograph
is presented which shows myeloid cell infiltration of the liver of a guinea pig
which had been injected with the extract of the "leukemic" placenta.
CONCLUSIONS
The course of leukemia is not altered by pregnancy. Fowler's solution, transfusions and brewer's yeast are still probably the best therapeutic agents in
leukemia complicated by pregnancy. X-radiation directed even close to the
abdomen is probably dangerous to the fetus.
The placenta from a patient with chronic myeloid leukemia showed slight
infiltration with myeloid cells. A lipid extract of this placenta, injected into
two guinea pigs, produced myeloid cell infiltrations in the organs, while
injection of a similar extract of a normal placenta produced no abnormal
celjular infiltrations in the organs of two control animals.
The placenta is a complete barrier to leukemia, whether the leukemia is
in the mother or in the fetus.
Acknowledgments.
valuable assistance.
I wish t o t h a n k D r . Franklin R . Miller and D r . Daniel L. Turner for
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