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Relationship Between Carcinoma and Thrombosis

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Relationship Between Carcinoma and Thrombosis CARCINOMA AND VENOUS THROMBOSIS: THE FREQUENCY OF ASSOCIATION OF CARCINOMA IN THE BODY OR TAIL OF THE PANCREAS WITH MULTIPLE VENOUS THROMBOSIS E. E. SPROUL, M.D. (Frm the Deportment of Pathology, Cohgs of Phyddwu ad Surgeons, Colvrnbh Udvsrdty) RELATIONSHIPBETWEEN CARCINOMAAND THROMBOSIS Text-books of medicine and of pathology often refer to the coincidence of a malignant tumor of epithelial origin and venous thrombosis. One of the earliest observers to stress this relationship was Trousseau (1) in 1865. He was especially interested in the frequency with which thrombosis of one or more peripheral veins was the first indication of the presence of a malignant tumor. Since his series of patients included those with tumors arising in the stomach, uterus, and testis, he concluded that the tendency to thrombosis was a characteristic of carcinoma in general and not dependent upon its origin in any particular organ. Recently Thomson @) quoted extensively from Trous- seau's original article and added a description of three cases in which the presenting disability was thrombosis of the veins of the leg. Examination after death showed a carcinoma arising in the tail of the pancreas in one of the patients, and of uncertain origin in another, A tumor of the stomach wall was demonstrated by x-ray studies in the third. Again emphasis was placed on the absence of any sign of internal disorder when the venous thrombosis was first apparent. In citing somewhat similar cases, James and Matheson (3) regarded thrombosis as an incident of the advanced stages of'a variety of debilitating diseases such as chronic infections, anemias, and malignant. tumors. They describe two cases of carcinoma of the stomach in which there was occlusion of the basilic and saphenous veins respectively and a carcinoma of the lung associated with multiple thrombosis oL internal and peripheral veins. Such individual cases, while of value, give no indication of a significant relationship. It was of interest, therefore, to note that an analysis by Barker (4) of the non-infectious systemic diseases complicated by thrombosis at the Mayo Clinic revealed the presence- of a carcinoma in 27 of the 58 cases in- cluded in this group. This report was based on clinical observation alone, necessitating limitation of the study to thrombosis of the veins of the legs and occasionally of the upper extremities. A similar study, based on necropsy reports, of causative factors involved in intru vitum coagulation of the blood was presented by Haward (5). In a series of 2,903 necropsies, fatal throm- bosis had occurred in 81. A list of the underlying diseases in these cases placed cancer second in frequency, exceeded only by middle ear infection. Further indication that a relationship may exist between cancer and coagu- lation of the blood was found in the numerous reports of changes in bleeding and coagulation time in the presence of a carcinoma. Figurelli (6) reviewed 566 CARCINOMA AND VENOUS THRODOSIS 567 the literature on this subject and listed the coagulation time in 35 cases of cancer and 20 noncancerous conditions, including several sarcomata. While there was considerable variation, the average time was found to be several minutes lower in the cancer group. The findings of Antonioli (7) were simi- lar. Bock and Rausche (8) offered a method of testing the coagulative power of the blood as an aid in the diagnosis of cancer. The method entails the recording of the number of drops of a 2 per cent solution of magnesium sulphate required to prevent the coagulation of plasma. Normal blood can be kept liquid by 3 to 5 drops. In 18 cases of carcinoma, among which were several arising in the alimentary tract, the plasma clotted unless 7 or 8 drops of the salt solution were added. The opposite situation was encountered in diseases complicated by jaundice, where the blood remained fluid with the addition of as little as 1 to 3 drops. This test was examined by numerous workers. Perlmann and qodin (9) thought it unreliable for differentiation between carcinoma of the stomach and peptic ulcer because of the overlapping in the two groups. Abramson (lo), on the other hand, cited many others who found it more difficult to prevent coagulation when a carcinoma was present, and his own series indicated that more cases of cancer were associated with increased tendency to coagulation of the blood than cases of sarcoma, 'ulcer, or nondebilitating diseases. Little is found concerning such an association in animal experimentation. Mendelkff (11) first observed that the coagulation time of guinea-pig plasma was greatly reduced when the animal bore a tumor. By extraction of the tumor, precipitation at pH 4, and solution of the sediment in an alkaline mcdkun, she found that the agent responsible for transmission of the tumor, as well as the factor stimulating blood coagulation, was present in the sediment, w'bile an agent inhibiting both tumor growth and blood coagulation had been separated in the supernatant fluid. Her studies were continued by investi- gating the effect of the addition of leukocytes and red cells on the coagulation of plasma in Vitro. The red cells of a tumor-bearing animal greatly accel- erated clotting of the plasma in comparison with the effect of red cells of normal guinea-pigs (12). When a similar test was applied to three cases of human catdnoma, the results were comparable (13). Holf (14) followed the changes in coagulability of chicken plasma by a variety of concentrated salt solutions following inoculation of the Rous sarcoma No. 1. All showed an increasing speed of clotting up to the fourth day after injection. It could hardly be expected that all tumors would affect blood coagulation in the same way. Quite the opposite effect was reported by Van Allen (15), who studied the blood of rabbits bearing the Brown-Pearce carcinoma. The growth of the tumor paralleled a delay in clot initiation and retraction. Kopauewski (16) carried the investigation into the field of synthetic carcino- genic chemical agents. His findings that many of these substances had the ability to coagulate horse serum in vitro or to accelerate the action of other coagulating substances led him to -believe that this characteristic was of considerable importance in the production of tumors. This study was undertaken to ascertain the incidence of carcinoma in the cases &owing thrombosis at necropsy and to determine whether any one organ was more commonly involved than others in such a relationship. 568 E. E. SPROUL TABLEI: Systamic CaAssociated with Thrombosis of Vmns is Various &ghs - Aseociated Cerebral Neck 'ulmonary hdominal 'elvic UPF LOWV Condition -Extremitiee 2xtremities Infection 15 30 19 1 26 Arteriosclerotic heart disease 6 12 10 Rheumatic heart disease 1 6 2 2 Pregnancy 2 Carcinoma 6 50 29 4 48 Syphilitic heart dime 1 1 Peptic ulcer 2 1 Hyperthyroidism 1 2 Tuberculosis 1 3 Perniciousanemia 1 Cause unknown 2 2 1 3 Polycythemia 3 1 Trauma 1 1 Lead poisoning 1 Hernia 1 1 Varicosity 3 Cirrhosis of liver 5 Leukemia TOTAL 23 13 I 12 101 CONDITIONSASSOCIATED WITH THROMBOSIS A review was made of 4258 consecutive necropsies performed at the Pres- byterian Hospital, New York, and the presence of a thrombus in the heart, arteries, or veins was noted in 617 or 14.4 per cent. The findings were based on microscopic as well as gross examination of the body. The presence of 8 thrombus was therefore not necessarily of importance in causing the death of the patient. The highest incidence occurred in the sixth decade, which is in accordance with previous studies, but in contradistinction to most reported series, thrombosis was found to be somewhat more common in the male than the female, the proportion of cases being 355 to 262. In the total series of 4258 cases males constituted but 56.01 per cent. A thrombus in either auricle or ventricle was present in 279 cases. In recording the associated diseases a certain amount of arbitrary interpretation was necessary. When sclerosis of the coronary arteries and tuberculosis were present in the same patient, the former was regarded as the condition more likely responsible for thrombus formation in the heart. In the absence of such a local cayse, tuberculosis would have been recorded as the associated systemic disease. The study of cardiac thrombosis showed the following relationships: coronary sclerosis, 142 ; rheumatic heart disease, 85 ; carcinoma, 17; syphilitic heart disease, 16; general infection (Le., pneumonia, bacteremia, peritonitis, etc.) , 7 ; tuberculosis, 5 ; polycythemia Vera, 2 ; hyperthyroidism, 2; cause unknown, 2; cirrhosis of liver, 1. Thrombosis of the veins and arteries can best be summarized according CARCINOMA AND VENOUS THROMBOSIS 569 TABLE11: Sydemik Corrditions Ass& with Thvmbosis of Artcrics in Various Regions Lower Aeaocited Cerebral Neck Pulmonary Lbdominal Pelvic Upper Condition Extremities Extremities -- I Infection 4 1 12 1 Arteriosclerosis 'I 1 15 1 14 Carcinoma 4 1 23 1 1 Cirrhosis of liver Syphilis 2 Peptic ulcer Pol ycythemia 1 Hyperthyroidism 1 1 Lead poisoning 1 Rheumatic heart disease 13 3 Tuberculosis 1 2 Cause unknown 1 Arterial aneurysm 1 TOTAL I l7 to the regions involved. Table I indicates the number of cases with obstruc- tion of veins due to coagulation of the blood and the conditions thought to be of greatest significance in the development of the process. Despite the fre- quency of infection in the abdominal cavity, here, as well as in the lower extremities, the presence of a carcinoma accounted for almost half of the instances of venous thrombosis. The incidence is somewhat less striking in the series of pelvic vein thrombosis, while clotting in the cerebral veins was more often dependent upon a contiguous infectious process in the brain or meninges.
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