Fatal Pulmonary Leukostasis
Following Treatment
in Acute Myelogenous Leukemia
Jacob J. Lokich, MD, and
William C. Moloney, MD, Boston
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is
frequently associated
Leukemiapulmonary
with complications
which may be due to infection
or to infiltration with leukemic
cells either within the pulmonary
parenchyma or obstructing the pul-
monary vasculature.1 Vascular ob-
struction by emboli, as well as by leu-
kostasis, may develop during the
course of leukemia.2-7 The occurrence
of rapid and fatal leukostasis in
the pulmonary vasculature following
therapy in two patients with acute
myelogenous leukemia (AML) is de-
scribed in this paper.
Patient Summaries
Patient 1.\p=m-\A75-year-old man was in
excellent health until September 1970. At
that time he developed acute abdominal
pain and on admission to the hospital was
found to have a white blood cell count
(WBC) of 439,000/cu mm. The peripheral
smear revealed 62% myeloblasts, but seg-
mented neutrophils and metamyelocytes
were also noted. The only significant find-
ing on physical examination was moderate
hepatosplenomegaly. The clinical impres-
sion was that this represented a patient
with chronic myelogenous leukemia with
transformation to a blast cell crisis. Bone
marrow examination revealed substantial
replacement of normal marrow elements
Received for publication April 27, 1971;
cepted Sept 3.
From Harvard Medical School (Drs. Lokich
and Moloney), Peter Bent Brigham Hospital
(Drs. Lokich and Moloney), and Children's Can-
cer Research Foundation (Dr. Lokich), Boston.
Reprint requests to Peter Bent Brigham Hos-
pital, 721 Huntington Ave, Boston 02115 (Dr.
Lokich).
by myeloblasts. Chromosome studies were
not performed. Laboratory findings in¬
cluded the following values: blood urea ni¬
trogen (BUN), 65%; serum creatinine, 6.7
mg/100 ml; uric acid, 31.8 mg/100 ml; se¬
rum lactic dehydrogenase (LDH), 2,550 in¬
ternational units (IU); and an initial white
blood cell count (WBC), 575,000/cu mm,
with a hematocrit of 17.5% and a platelet
count of 125,000/cu mm. Serum murami-
dase level was 8(ig/ml, (normal 5µg to
^g/ml). Chest roentgenogram was nor¬
mal.
Course.—Diagnosis was chronic gran-
ulocytic leukemia transitioning into blast
cell crisis, and it was decided to cautiously
employ x-ray therapy to the spleen. An ini¬
tial course of 50 rads was applied and
within 12 hours the patient manifested
signs of rapidly progressive respiratory
failure. Blood gas determinations at the
time showed an arterial partial pressure of
oxygen of 40 mm Hg with a pH of 7.12.
Ventricular fibrillation developed and the
patient died 24 hours following x-ray ther¬
apy.
On postmortem examination the pulmo¬
nary vessels were filled with plugs of my¬
eloblasts (Fig 1 and 2). The parenchyma,
interstitial spaces, and alveoli were free of
infiltrates. The lungs weighed approxi¬
mately 1,000 gm and demonstrated severe
bilateral hemorrhagic bronchopneumonia
in addition to the vascular obstruction
noted microscopically. The spleen weighed
1,500 gm and showed marked leukemic in¬
filtration and foci of extramedullary he-
ac-
matopoiesis. The kidneys contained uric
acid crystals within the tubules. In addi¬
tion, leukemic infiltrates were noted in the
liver, kidney, lymph nodes, and adrenal
glands. Vascular engorgement with leuke¬
mic cells was noted in the cerebral and
coronary vessels as well. Postmortem cui-

Fig 1.—Pulmonary arteriole with
x450) (patient 1).
Fig 2.—Pulmonary arteriole with myeloblasts
eosin stain, 1,000) (patient 1).
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tures of the lung yielded Staphytococcus
aureus and Escherichia coli.
Patient 2.—A 58-year-old man developed
diffuse nodular skin lesions of the scalp in
November 1969. These lesions did not re¬
spond to antibiotics, and when he became
febrile and had night sweats, further eval¬
uation was undertaken. Findings of physi¬
cal examination were unremarkable except
for hepatomegaly and diffuse nontender
nodules in the scalp. Laboratory values ob¬
tained included hematocrit, 47.5%; plate¬
lets, 45,000/cu mm; and WBC, 99,500/cu
mm with a differential cell count that in¬
cluded 76% monomyeloblastic cells and 7%
neutrophils. Other values obtained in¬
cluded LDH, 1,710 IU; serum glutamic ox-
aloacetic transaminase (SGOT), 225 IU; se¬
rum bilirubin, 2.1 mg/100 ml; alkaline
phosphatase, 115 IU; BUN, 21 mg/100 ml;
serum creatinine, 2.1 mg/100 ml; and se¬
rum muramidase, 15 mg/ml (normal less
than 10 mg/ml). Bone marrow exam¬
ination revealed replacement with micro-
a "plug" of myeloblasts (hematoxylin-eosin stain, myeloblasts and monomyeloid cells which
were peroxidase positive.
Course.—The patient was treated with
combined therapy consisting of vincristine
sulfate and methotrexate intravenously
along with mercaptopurine and prednisone
orally. Twenty hours after initiation of
therapy, epistaxis developed and was fol¬
lowed four hours later by progressive
in a mesh of fibrin thrombus (hematoxylin- dyspnea with cyanosis and hyperpnea. In
the emergency ward, blood gas deter¬
minations revealed Po2, 110 mm Hg; Pco2,
15 mm Hg; and pH, 7.08. Cardiac ar¬
rhythmias developed with subsequent car¬
diac arrest and resuscitative efforts were
unsuccessful. Blood drawn just prior to
death revealed a hematocrit value of 44%,
platelet count of 48,000/cu mm, and a WBC
of 13,000/cu mm. Serum muramidase level
was 80 mg/ml and uric acid, 17.5 mg/100
ml.
At autopsy the most striking finding and
cause of death was the presence of plugs of
myeloblasts within the pulmonary vascula¬
ture, predominantly arterial (Fig 3 and 4).
Myeloblastic thrombi were not evident in
the blood vessels of other organs, but leu¬
kemic infiltrations were present in the
bone marrow, spleen, liver, adrenals,
testes, and myocardium.
Comment
Pulmonary complications in acute
leukemia are frequent and often pre¬
sent diagnostic and therapeutic diffi-
 culties for the physician. Pulmonary
infection, embolism, or infiltration
with leukemic cells may all develop in
the clinical course of the disease. In¬
fection is the most common pulmo¬
nary complication. The series re¬
ported by Bodey et al reported 31
major pulmonary infections in a
series of 50 patients.1 Leukemic infil¬
tration, on the other hand, was identi¬
fied in 64% of the postmortem speci¬
mens in this same series but was not
necessarily clinically significant. The
commonest pathological finding was a
leukemic peribronchial infiltrate. In
the series of Bodey et al, leukostasis
was noted in six patients; however,
clinical symptomatology related to
the leukostasis was not evident. Fur¬
thermore, leukemic involvement with¬
in the parenchyma of the lung or
within the pulmonary vasculature ap¬
peared to be related to the level of the Fig 3.—Multiple vascular channels filled with myeloblasts (hematoxylin-eosin stain, 25)
WBC. The most striking leukostasis (patient 2).
was associated with WBCs of more
than 100,000.
Pulmonary embolism in acute my-
elocytic leukemia is a rare cause of
death, and the apparent paradox of
thrombosis and embolism in the pres¬
ence of thrombocytopenia remains an arteriole with cellular thrombus
Fig 4.—Pulmonary a (hematoxylin-eosin stain, 450)
unsolved problem. Pulmonary embolie (patient 2).
disease has been reported in acute
leukemia by Wiernik and Serpick in
seven patients.2 They noted an overall
incidence of acute pulmonary embol¬
ism of 6.3% in patients with myelo¬
genous leukemia, although no pa¬
tients with lymphatic leukemia died
with pulmonary embolism. Clinical
symptomatology related to pulmo¬
nary embolism was not present in
these patients, nor was there patho¬
logical infiltration of the pulmonary
vasculature or parenchyma.
Leukostasis within pulmonary ves¬
sels has been reported infrequently.
Old et al7 described eight of 16 pa¬
tients with chronic myelogenous leu¬
kemia with WBCs ranging from 350
to 600,000, who had engorged vessels
on postmortem examination. They
proposed that the low pulmonary
hemodynamic pressure caused pool-

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 ing in the stagnant capillary system
of the lungs and that this resulted in
the sequestration of these relatively
large-sized leukemic cells. Turusov,6
reporting on the anatomic changes in
the lungs in acute leukemia, referred
to occasional cases in which infil¬
tration of the lung was associated
with thrombosed vessels, but details
of the cases were not available. Joa¬
chim and Lowe,8 however, did report
a case of migratory infiltrations of
the lung which at autopsy were at¬
tributed to pulmonary infarctions
secondary to vascular occlusion with
myeloid cells. Leukostasis in pulmo¬
nary vessels has generally been asso¬
ciated with extremely elevated WBCs
in chronic myelogenous leukemia.
This frequently results in intra-
pulmonary hemorrhage similar to
that developing in the brain as a con¬
sequence of vascular disruption by
leukostasis.9
Patient 1 is an example of the de¬
velopment of leukostasis in a blast
cell crisis of chronic myelogenous leu¬
kemia. This patient developed an
acute respiratory insufficiency syn¬
drome 12 hours after splenic irradia¬
tion. The relationship of x-ray ther¬
apy to the spleen to the occurrence of
pulmonary leukostasis is unclear.
However, it may be postulated that
either by direct effect of ionizing ra¬
diation on the leukemic cell mem¬
brane or as a consequence of humoral
factor released by damaged myeloid
or splenic cells, enormous numbers of
circulating myeloblasts were rapidly
sequested in the pulmonary vascula¬
ture.
The development of acute pulmo¬
nary sequestration of white blood
cells has been reported with hemo-
dialysis, in association with leuko-
agglutinin transfusion reactions, and
in the normal compartmentalization
of the life cycle of leukocytes.1012
Ward11 has reported that in the de¬
velopment of pulmonary infiltrates
associated with leuko-agglutinin
transfusion reactions, although the
histological varification of the pulmo¬
nary lesions was not available, ex¬
perimental evidence indicated that
intrapulmonary agglutination of leu¬
kocytes was a possible mechanism.
In patient 2 the syndrome of acute
pulmonary insufficiency was typical
for pulmonary embolism. Pathologi¬
cally, vascular obstruction by clots of
myeloblasts was demonstrated in the
lungs. This suggests that the pulmo¬
nary vasculature was the primary
sieve through which the white blood
cells were unable to pass. As in pa¬
tient 1, it is possible that aggressive
chemotherapy may have caused some
form of injury to the cellular surface
of the myeloblasts and resulted in a
rapid clumping of and sequestration
of myeloblasts in the pulmonary ves¬
sels. The chronological sequence of
events following chemotherapy and
the rapid fall in WBC from 100,000 to
13,000 in 24 hours is strongly sugges¬
tive of such a phenomenon.
Summary and Conclusions
Two cases of myelogenous leuke¬
mia with greatly elevated white blood
cell counts are reported in which, fol¬
lowing x-ray therapy to the spleen in
one case and combined chemotherapy
in the other, abrupt onset of pulmo¬
nary failure developed associated
with rapid and profound fall in the
leukocyte count in one case. At post¬
mortem examination both patients
showed marked sequestration of leu¬
kemic cells in the pulmonary vessels.
It is postulated that injury to the leu¬
kemic cell surface, by x-ray or by
chemotherapeutic agents, resulted in
massive sequestration of large popu¬
lations of circulating leukocytes in
the lung with resulting acute and
fatal pulmonary vascular obstruction.
This investigation was supported in part by
Public Health Service research grants 5-S01-FR-
05489-07 and 5-TI-HE-5274.
Arthur Skarin, MD, supplied the photographs;
and the House Staff, Peter Bent Brigham Hospi¬
tal, assisted in the management of these pa¬
tients.
Nonproprietary and
Trade Names of
Drug
Vincristine sulfate— Oncovin.

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