POSTGRAD. MED. J. (1 966), 42, 514.

Case Reports

MALIGNANT-THROMBOSIS SYNDROME:
PANCREATIC CARCINOMA PRESENTING WITH BILATERAL
CEREBRAL THROMBOSIS IN A YOUNG WOMAN
E. L. JoNEs, M.B., Ch.B.,

Medical Registrar,
Birmingham General Hospital

Department of Pathology,

The occurrence of venous thrombosis with
carcinoma is well recognised, as first described iby
Trousseau (1873). In recent years it has been
found that arterial occlusion can also occur in
patients with neoplasms (Oelbaum & Strich, 1953;
Williams, 1954; Figher & Baird, 1956) and that
arteriolar and capillary occlusion may involve the
brain (Smith, 1961, 1962).

Further investigations: Hb 65%, WBC 6,100/
cu. mm., polys 80%, ESR 16mm/hr. No LE cells.
Blood fibrinogen 63 mg/100 ml. Ham's acid serum
test negative. Direct Coombs' test negative. Serum
hilirubin 1.8 mg/100 ml. Haptoglcobin normal.
Alkaline phosphatase 23 K-A units/ 100 ml. SGOT
24 units/ ml., SGPT 413 units/ml., EGG normal, in
sinus rhythm.
Heparin was discontinued after 12 days. Phenindione therapy was recommenced, a rash then developed and ethyl biscoumacetate (Tromexan) was
subbstituted. Prothrombin levels were 2 to 21 times
normal controls, -but on 114th January, 1965, sudden
left cdhest pain with dyspnoea and haemoptysis
indicated further pulmonary infarction. Heparin
therapy was resumed.
On 18th January, 1965, she complained of upper
abdominal discomfort, the spleen was enlarged, and
the temperature 102'F. Three blood cultures were
negative. The bone marrow was normoblastic and
macronormoblastic with no evidence of secondary
carcinoma or reticulosis.
On 31st January, 1965, she was jaundiced and
began to vomit. A mass was noted in the epigastrium,
the liver was palpable and the ,spleen much larger.
Diplopia developed and she became unconscious.
Death occurred on 9th February, 1965, from hypostatic bronchopneumonia.
The diabetic glucose tolerance test, evidence of
widespread vascular occlusion and the terminal
epigastric mass strongly suggested a pancreatic
carcinoma.
Necropsy: The body (height 5' 6", weight 51.45 kg.)
was that of a young well-nourished female with
jaundice and minimal oedema of the left leg and arm.
Pancreas was of normal size, but there was an ill
defined, hard, greyish-white mass of tumour 5 cm. X
3 cm. in the middle third of the body. The distal
third of (thebody and tail showed dilatation of duets,
fat necrosis and parenchymal atrophy, indicating
chronic duct obstruction. Lymph nodes in the porta
hepatis and around the coeliac axis and pancreas
were firm, enlarged and replaced by metastases.
Spleen (435 g.) was enlarged and showed an extensive yellow-white-necrotic infarct (8 cm.) surrounded
by dark congested pulp. The splenic vein was
thrombosed. Liver (1570 g.) contained multiple
necrotic, umbilicated secondary deposits. Its cut
surface was mottled and displayed alternating pale
and dark congested areas. The portal vein was
completely occluded by firm organising antemortem
thrombus and the intrahepatic radicals contained
small strands of propagated thrombus. Kidneys
(340 g.)) were symmetrically enlarged, the left con-

Case Report
The patient was a previously healthy 39-year-old
housewife. She was not taking oral contraceptives.
On 29th October, 1964, she awoke with a right
hemiparesis and was admitted to hospital some hours
later.
On examination she showed weakness of the right
face, arn and leg, a right Babinski response, and
total right hemianaesthesia. (BP 150/80 mm. Hg.,
pulse rate 90, in sinus rhythm. There were no abnormal signs elsewhere in the body. Rectal and
vaginal examinations were negative.
Investigations: Hb 78%, WBC 5,600/cu. mm.,
normal differential count. ESR (Westergren) 10 mm/
hr. Serum Na 132, K 4.1, Cl 92 m.Eq/l. Blood
urea 32, cholesterol, 187 mg/100 ml., (DSF: normal
pressure with a free rise and fall, 41 lymphocyte/
cu. mm., protein 25 mg/ 100 ml. WR and Kahn
negative. Skull and chest X-rays normal. ECG
normal.
On 9th November, 1964, she developed a total left
hemiplegia with aphasia and increased involvement of
the right side, no pyrexia or cardiac murmurs.
Bilateral carotid angiograms (Fig. I) showed
occlusion of the right middle cerebral artery 1 cm.
beyond its origin, the left posterior parietal artery,
and the angular branches of the left middle cerebral
artery. There was an anastomotic supply from the
anterior cerebral arteries. No evidence of atherosclerosis. Phenindione therapy was commenced. A
glucose tolerance test showed a definite diabetic
curve: FBS [10, I hr., 190, 1 hr., 240, 11 hr., 230,
2 hr. 200 mg/'l00 ml.
On 26th November, 1964, she developed sudden
dvspnoea and right pleuritic pain. The left calf was
slightly tender. Chest X-ray showed bilateral diffuse
nodular shadowing coalescent in the midzones, probably due to multiple pulmonary infarcts. At this
time anticoagulant therapy was thought adequate
from estimations of rprothromrbin times.
On 3rd December, 11964, gross swelling of the left
thigh and leg developed suggesting extension of the
deep vein thrombosis. Intravenous heparin therapy
(40,000 units/day) was started.

University of Birmingham

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B. J. SEALEY, M.B., M.R.C.P.,

August 1966

T_

SEALEY AND JONES: Malignant-Thrombosis Syndrome

515

L

FIG. 1.-The right middle cerebral artery is absent beyond the first cm. (Arrow).
The posterior parietal and angular 'branches of the left middle cerebral are absent. (Arrow).

tained multiple white infarcts, the largest 6 cm. The
left renal vein was 'thrombosed and a mass of
propagated thrombus extended into the left suprarenal vein. The inferior vena cava contained several
unattached portions of ,antemortem thrombus. The
common and both internal and extemal iliac veins
corutained old and recen;t organising antemortem
thromnbi, which extenided into both superficial femoral
veins. Heart (275 'g.) showed no changes. In particular the endocardium and valves were unaffected.
The pulmonary artery was normal but several of
its 'terminal branches showed -thrombotic occlusion.
Lungs showed multiple small wedge-shaped infarcts.
Their bases were firm, nodular and congested.
Carotid Arteries and main branches, the circle of
Willis and the vertebral arteries did not show
atheroma. Brain. The right middle cerebral artery
was thrombosed over a small segment just proximal
to its trifurcation. The left nmiddle cerebral artery
also showed a smaller thrombosed area just beyond
its first division. These thromrbi were old and

consistent in age with the presenting cerebro-vascular
accidents. There was a recent thrombotic occlusion
of the right posterior cerebral artery. The brain was
swollen and oedenatous showing widespread softening in the right middle and posterior cerebral artery
distribution territory.
The remaining organs did not show macroscopical
changes.
Histology.-Pancreas. The tumour is a wellAdifferentiated large-dut-cell adenocarcinoma showing a
marked fibrous stromal reaction, scattered foci of
mucous secretion and infiltration of small nerves.
The tail shows diffuse fibrosis and atrophy. A
number of small vessels are thromnbosed. Liver shows
widespread areas of necrosis. The metastatic deposits
display a pronounced degree of differentiation with
ciliation of the large clls, a feature seldom seen in
pancreatic carcinoma. (Frantz, 1959). Lungs show
old organising haemorshagic infarcts, tumour emboli
in the peribrondial and perivasoular lynmphatics, and
areas of bronchopneumonia. Spleen and Kidneys are

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R.

516

POSTGRADUATE MEDICAL JOURNAL

major neurological complications i.e., hermiplegia,

first appeared within a week of death. In the
remaining 4 cases, 4 weeks, 6 weeks, 20 weeks
and 2 years 'before death respectively.
The relationship between thrombosis and
tumours 'has not been clarified (Aguayo 1964).
Toxic, metabolic, haemodynamic and immunological factors have been suggested as being
important in causing the thrombotic tendency,
particularly in non-bacterial endocarditis '(Angrist,
Oka, Nakao and Marquiss, 1960).
Trousseau (1873) first suggested that thrombosis resulted from hypercoagulaibility of the
blood 1but no alterations in cdotting factors bhve
been described.
Some authors considered thromiboses to be
particularly related to m'ucin-iproducing tumours
(Kenney, 1943; Jennings and Russell, 1948;

McKay, Mansell and Hertig, 1953). Jn pancreatic
neoplasms the amount of mucin produced is not
great except i'n the rare colloid tumours. In the
patient we describe there is little evidence of
mucin production. In contrast the syndrome may
occur in association with squamous carcinoma
of the lung. Tumour emboli may rarely be the
cause of thromiboses (Williams, 1954) but there
was no evidence of tumour emboli in the cerebral
vessels in our case.
Thromboplastins may be released from the primary tumour or metastases but confirmation of
this is lacking. McKay, ,Mansell and Hertig 1(1953)
described a case of carcinoma of the body of the
pancreas'with 'fibrin throsnbi and fibrinogenapenia
suggesting that the tumour had released thromboplastins causing the thrombosis. In 'our patient
the 'blood fibrinogen was reduced to 63 mg. /
1 00ml., we think ;probably as a result of the
massive clotting which had taken place.
Sproul i(1938) suggested that pancreatic neoplasms liberate pancreatic enzymes into the circulation, and that 'trypsin and lipases might thus
interfere with 'the clotting mechanism. There is
no evidence that all pancreatic neoplasms are
secretory and multiple thromboses have 'been
found in non-secretory pancreatic 'neoplasms.
Therefore this hypothesis is not valid.
Wright (1952) drew attention to 'the significance
of resistance to anticoagulant therapy in ithe malignant-thrombosis syndrome. He noted that
although artticoagulant therapy may be effective
in controlling phleibothrom'bosis in its early stage,
the thrombotic element may "break through"
an'd worsen as the malignant disease progresses,
despite anti-coagulants. This happened in our
patient. Her venous thrombosis extended and she
suffered multiple pulmonary emrboli despite
Tromexan therapy judged adequate by the Quick
one-stage prothrombin estimation. Treatment with
herapin on the other hand was thought clinically
to have 'brought about resolution of her femoral
vein 'thrombosis judged by -a reduction of nearly
7" in the circumference of the affected thigh and
the non-recurrence of clinically obvious pulmonary emboli.
Considering the widespread nature of the metastases in this patient and in view of the obseqrvations of O'Meara and O'Halloran (1963) on the
use of protamine in preventing the spread of the
neoplasm, it is interesting to speculate whether
heparin actually promoted more widespread
dissemination of the tumour. An interesting feature in our patient is that
though previously healthy she developed sudden
hemilplegia. Cerebrovascular incidents described
preiously usually ocrred in patients with wellmarked !symptoms or in an advanced stage of
the disease. The second factor is that though she
was too i'll for adequate barium studies of the
gagtrointestinal tract theof diabetic GTiT provided
'a pancreatic neoplasm.
a clue to the presence
There is a significant relationship between pan-

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congested and show pale necrotic infarcts. Brain
shows scattered areas of haemorrhage and extensive
colliquative necrosis. Tumour emnboli are not present
in the ithromxbosed arteries, and arteriolar microthrombi were not detected.
,Relevant histological changes were not found elsewhere.
Discussion
Widespread vascular thrombosis occurs most
commonly wilth pancreatic carcinoma, but 'also
occurs in association with bronchial, ovarian and
gastrointestinal carcinomas. There is a significantly higher incidence of multiple venous thromboses
in carcinoma of the body and tail of tbe pancreas,
31.3 per cent compared with carcinoma of the
lung, 2.5 per cent, and of stomach 1.3 per cent
(Sproul, 1938). It is interesting that in one series
comparing the incidence of multiple thromboses
in carcinoma of the head of t'he pancreas with
carcinoma of ithe body and tail of that organ no
multiple thromboses were seen in the former
group compared with 33 per cent in the latter
(Kenney, 1943).
Sproul (1938) described non-bacterial thrombotic vegetations on the heart valves in patients
who'had died with pancreatic neoplasms. Adams
(1955) subsequently described cerebral embolism
secondary to such vegetations which presented
as the first indication of 'a latent carcinoma.
These findings were confirmed and their clinical
significance discussed 'by McDonald and Robbins
(1957), Barron, Siqueria and Hirano (1960) and
Aguayo (1964).
Spontaneous thrombosis in cerebral arteries,
arterioles and veins without evidence of cardiac
vegetations was also reported (Smith, 1961). We
consider such spontaneous cerebral thromboses
to be uncommon and could find.few relcorded
cases.
Smith (1957, 1961) 'found neurological disorders
attributable to the malignant-thrombosis syndrome in 10 out of 993 consecutive fatal cases
of carcinoma. The primary 'tum-ours were as
follows: 4 pancreatic, 2 uterine, 2 gastric, one
mammary and one bronchial. In 6 of the cases,

August 1966

August 1966

SEALEY AND JONES: Malignant-Thrombosis Syndrome

creatic neoplasms and abnormal glucose tolerance
(Bell, 1957).
The persistence of clotting and pulmonary
emboli despite adequate oral anticoagulants is
significant and confirms Wright's (1952) opinion
that -the possibility of an occult neoplasm should
be considered when this phenomen occurs.
Finally the unusual finding of ciliated cells in
the metastatic deposits is noteworthy because of
its rarity.

We are indebted to Dr. P. H. Davison under
whose care this patient was admitted, for his permission to 'publish this case.
We also wish to thank Dr. D. B. Brewer and
Dr. W. T. Smith for their helpful advice and
criticism and Dr. P. 'B. Carpenter for the preparation
of the icarotid angiogram diagrams.
We would also like to thank Miss K. G. Ruud
for typing the manuscript.
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Cases. II. The Relation of Carcinoma of the
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Summary
A case of pancreatic carcinoma in a woman
cf 39 is described which presented with hemiplegia and hemianaesthesia which subsequently
became 'bilateral. Despite anticoagulant therapy
widespread venous and arterial thrombosis
occurred with recurrent 'pulmonary emboli.
The current theories concerning the association
between neoplasia and vascular thrombosis are
reviewed. Little is known of the exact cause of
this association.

517