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. The number of cases of thrombosis in neck, arm and pulmonary veins is too limited to be of significance, but again carcinoma was the most common associated condition except in the last named group, where it was exceeded by cardiac insufficiency. Table I1 was similarly prepared from an analysis of arterial thrombosis in various portions of the body. It will be seen that carcinoma plays a minor r61e in all but the pulmonary group. It may be that these were actually emboli and the source in the venous system went unnoticed. From such a study, then, it is apparent that one must qualify observations on coincidental lesions by specification of the region and type of vessel in- volved. Thrombus formation in the heart occurs most frequently when there has been myocardial and endocardial damage due to coronary occlusion. Thrombosis of the arteries, with the exception of those in the lung, most often seems to be dependent upon an underlying sclerosis. On the other hand, venous thrombosis shows a significant relationship to the presence of a car- cinoma, especially when the veins of the abdomen and lower extremities are involved.

RELATIONSHIPOF CARCINOMAOF VARIOUSORGANS TO THRO~OSIS The high incidence of cancer associated with venous thrombosis in this necropsy series stimulated our curiosity as to the types of tumor found. For 570 E. E. SPROUL TABLE111: Imidsncs of Thrombosis- in Garcinoma of Va*iour Organs Caaet~With &sea With Multiple Total Thrornbosii Thromboses Organ in which tumor arose No. cases cent 01 No. Cases 'er No. Cam 'er cent of - Total Total Anywhere in pancreaa 47 14 29.7 8 17 Head of pancreaa . 31 5 16.1 3 9.7 Body or tail of pancreas 16 9 56.2 5 31.3 4 Lung 81 12 14.8 2 2.5 5- Liva 22 6 27.2 0 Gallbladder 30 5 16.6 0 Stomach 147 32 21.8 2 1.3 Duodenum 16 3 18.7 0 Colon 94 15 15.9 0 Kidney 27 7 25.9 0 Prwtate 43 7 16.3 0 Uterus 27 6 22.2 0 -17 4 23.5 0 this purpose the cases of the more common carcinomata were examined and the presence of thrombosis noted. Since a single vessel might well be throm- bosed without relationship to the presence of a tumor in the body, the number of cases of each type of carcinoma accornpanied by multiple thromboses was thought to be of greater significance. See Table 111. It is immediately apparent that a carcinoma originating in the pancreas, and more especially if the body or tail alone were involved, was most frequently accompanied by thrombosis of numerous vessels. A more detailed study of each case was conducted in the hope of determining the causative factors. Carcinoma oj the Pancreus: The fact that a carcinoma of the pancreas may first manifest its presence by thrombosis of peripheral veins has been noted in several reports of individual cases. Umlauft (17) described three cases of multiple thrombosis of which two were associated with such a tumor, while in the third a carcinoma arising in the lung was found. In one 'instance the veins of all four'extremities were involve& Tumor cells were not present in the vessel walls. (In three cases reported by Thoenes ( 18) a carcinoma was found in the pancreas and many of the peripheral veins were thrombosed. Thoenes suggested that pancreatic ferment may have been responsible, without further elucidation of the mechanism. In tbe single case described by Winter ( 19) invasion of veins by the pancreatic tumor accompanied widespread throm- bosis of these vessels. Smith (20) found a carcinoma arising either in the pancreas or in the alimentary tract in a case predominantly one of thrombosis of the iliac veins and inferior vena cava. Gangrene of the intestine has been noted following thrombosis of the portal and mesenteric veins with pancreatic carcinoma (21). And, as would be expected, a pancreatic tumor has suffi- ciently invaded and obstructed the splenic artery and vein to cause infarction of the spleen, and in one case spontaneous rupture of necrotic tissue (22). In our series of 47 cases of carcinoma arising in any portion of the pan- creas, the ages ranged from thirty-two to eighty-two years, the majority oc- CARCINOMA AND VENOUS THR0116BOSIS 571 cumng in the sixth and seventh decades. Thirty-four of the patients were males, 13 females. Many races were represented, but the great majority of patients were white and born in America. In only 16 cases was the head of the pancreas well preserved, the remain- ing 31 having pronounced involvement of the head either primarily or as a result of extension of the process from the body of the organ. These tumors of the head, while somewhat more often accompanied by thromboses than those arising in other organs, did not show this association with the same frequency as did the tumors originating in the body or tail. The most obvious result of the difference in location is the effect upon the patency of the pan- creatic ducts and the activity of the remainder of the organ. As would be expected, almost all of the carcinomata in the head of the pancreas effected a complete closure of the excretory ducts, and in most instances a profound atrophy and fibrosis of the body and tail of the organ had taken place. The 3 cases of carcinoma of the head of the pancreas with multiple thromboses recorded in Table I11 presented various degrees of change. In one, the duct curved around the tumor and was patent throughout, leaving the distal parts of the pancreas well preserved. In another the head of the pancreas with the tumor had been resected in part and the remaining organ suffered little damage. The third case did show the customary extensive loss of secretory tissue and fibrosis. ( In all of the 16 cases of carcinoma confined to the body or tail of the pancreas well preserved parenchyma was found in the head of the organ and the communications with the duodenum were patent. 1 In 9 of 56.2 per cent of this group of 16 cases there was thrombosis of some vessel, and in 5 or 31.3 per cent many thrombosed vessels were found in various parts of the body. Obstruction of veins in the immediate neighborhood of a tumor, especially if the latter had a tendency to invade the vessels, could readily be explained on a mechanical basis alone. Since many of the vessels involved were at some distance from the primary tumor site, they were studied for any his- tologic changes which might account for the development of a thrombus. The pancreatic tumors were often disseminated by the blood stream and it is conceivable that the presence of tumor cells in vessel walls could have formed a nidus for thrombus formation. The 3 cases of carcinoma arising in the head of the pancreas showed somewhat less widely distributed throm- boses than those described later, but all were at a sufficient distance to exclude the possibility of direct invasion or obstruction by pressure. In one case the ovarian and iliac veins were distended with partly organized thrombus material and the patient died, presumably following pulmonary embolism. The thrombi in the second case were somewhat similarly located, the prostatic and iliac veins and the inferior vena cava being completely obstructed. In the third case thrombi were found not only in the prostatic, femoral, and iliac veins and the inferior vena cava, but in the right external jugular vein as well. Again emboli in the pulmonary arteries with infarction of the parenchyma had occurred. The thrombi and emboli were all undergoing organization. In no instance were tumor cells found in the thrombi or vessel walls, nor waa there any inflammatory process involving the vessels or the contiguous organs. The 5 cases of carcinoma of the pancreas arising in the body or tail of the 572 E. E. SPROUL organ, in which multiple venous thromboses were described, did not present a uniform picture. The first showed thrombi in the saphenous, femoral, iliac, hypogastric, renal, inferior mesenteric, superior mesenteric, portal, and cephalic veins and the inferior vena cava. The pulmonary arteries were distended by emboli and an infarct of the lung was present. Numerous microscopic sec- tions revealed the presence of tumor cells in the walls of several veins even in the lower extremities. Several thrombi were organized. In the second case there was thrombosis of the testicular, prostatic, sperm- atic, hepatic, and portal veins. Emboli were again found in the pulmonary arteries. The thrombi were quite old, often undergoing organization, but in none of the sections were tumor cells or an inflammatory process found to account for the occluded vessels. In the third case the veins involved were the saphenous, femoral, iliac, prostatic, hemorrhoidal, splenic, and portal, and the inferior vena &a. There were infarcts of the spleen and lung, the latter due to an embolus in the pulmonary artery. Microscopically tumor tissue was found in the portal vein alone. Those vessels at a distance from the site of origin of the tumor showed no invasion and no inflammatory changes in the walls. In general the thrombi were undergoing organization. In the fourth case fewer large vessels were involved, but since the thrombi were found in the femoral vein apart from the tumor and there were numerous small vessels in the brain, lungs, and heart occluded by thrombotic material, it was included in this group. The thrombus material in the leg was of more recent formation; that elsewhere was organized in good part. No tumor cells were found in the sections of any of these vessels. In the last case thrombi occluded the splenic, portal, pelvic, ovarian, and coronary veins, and there were numerous infarcts in the liver, spleen, kidneys, and heart. Tumor cells were found within the intrahepatic branches of the portal vein but not elsewhere. An interesting finding was the presence of non-bacterial vegetations on the heart valves, either the mitral, or both mitral and aortic, in 4 of the 5 cases just described. The vegetations were composed of masses of fibrin sufficiently large to have been interpreted as bacterial endocarditis on gross examination. Not only were cultures and smears of the vegetations negative, but sections showed no organisms or leukocytes and the only valvular change was the proliferation of endothelial cells and fibroblasts to invade the base of the fibrin mass. That they did not represent a mere terminal agglutination of platelets is attested by the degree of organization and by the positive fibrin stain with the Gram method. It seems probable that they were further evidence of the increased tendency to coagulation of the blood in the presence of a carcinoma in the tail of the pancreas. The benign epithelial tumors arising in the pancreas were also reviewed to see if the same association could be established. Although 9 of the 25 cases, or 36 per cent, had a single thrombus somewhere in the body, there were no instances of multiple thrombosis. It was also considered of interest to determine whether the presence of a tumor secondarily invading the pan- creas, but not originating from pancreatic cells, could in some way alter the function of the secreting cells and favor coaguiation of the blood. Among CARCINOMA AND VENOUS THROMBOSIS 573

83 cases of malignant disease with metastases in the pancreas, only 11 or 13.2 per cent had any thrombus in the body, and no examples of multiple thrombosis were noted. Since multiple venous thrombosis in cases of carcinoma of the pancreas could seldom be explained by the presence of tumor cells in the vessel walls, by inflammation or by mechanical obstruction from the growth of the primary tumor, further study of this group was directed toward the factors which might conceivably effect the coagulation of the blood. It is apparent from the few studies available that the amount of pancreatic secretion as measured by enzyme content of the duodenal juices varies greatly in cases of pancreatic tumor. Chiray and Bolgert (23) found little constancy in the volume of excretion following secretin injections when the head of the pancreas was occupied by a carcinoma, but the enzyme content, especially the amount of lipase recovered, was greatly reduced. Huguenin, Albot and Bolgert (24) also found a greater diminution of lipase than of trypsin in a Comparable case. Meerssemann, Blan and Perrot (25), on the other hand, arrived at somewhat different conclusions as a result of detailed studies of the enzymes in duodenal contents and fat and protein digestion as measured by stool analyses in a case of carcinoma of the head of the pancreas. The volume of pancreatic secretion was reduced after secretin (8 C.C. as compared with 100 to 150 C.C. in a normal individual), but the quality of the secretion as far as enzymes were concerned matched the normal juice. There was faulty metabolism, however, both of proteins and fatty foods. Bolgert and Audpy (26) described a case in which the tumor was situated in the body of the organ but microscopic examination of the head is said to have revealed no normal secreting tissue. Analysis of the duodenal contents following an in- jection of secretin showed a diminution in both lipase and tryptic activity. The clearest differentiation between the pancreatk ‘activity in cases in which the head is involved and those- where the body or tail alone is occupied by tumor was found in the report of MrClure et al (27). In the latter group the proteolytic activity of the duodenal juice was increased by about one- fourth over the normal; lipase activity was three times that in normal indi- viduals, and only the amylase was reduced. When the tumor was present in the head of the pancreas all enzymes were greatly diminished.) Additional information regarding the secretory activity of pancreatic tumds was found in the analytical studies of Sugiura, Pack, and Stewart (28). While their material was limited to one adenocarcinoma and three normal pancreases, the same rate of digestion of starch, degree of proteolysis, and hydrolysis of esters were present in the tumor extract as in that of the normal organs. It is prob- able that the lack of uniformity can well be explained by differences in degree of involvement of the ducts and the amount of unaltered pancreatic tissue remaining. Maceration juice obtained from the pancreas shortly following ligation of the ducts had no tryptic activity, although it retained the ability to activate juice from a normal pancreas (29). No estimations of the lipase or esterase activity were made. With these reports in mind, an attempt was made to establish the presence or absence of secretory activity of the pancreatic tumors by their histologic appearance. Such a study gave little support to the physiological evidence 574 E. E. SPROUL that the tumors were actively secreting. All but one of the 8 tumors asso- ciated with multiple thromboses showed gland formation of more or less ir- regular pattern, and there was usually an abundance of much within the cells and free in the lumen of the glands. But this was also true of the cases in which no thrombi were found. Occasionally the inner margin of the tumor cell, approximating the lumen, stained somewhat more deeply with eosin than the base of the cell but did not show distinct granule formation. When this was compared with the deep eosin stain of the zymogen granules in the normal acinar cells which were often present in the same section, the disparity was too great to permit interpretation of the tumor stain as representing secretion. The condition of the liver and the degree of obstruction of the biliary tract are also of interest where changes in coagulability of the blood are concerned. In reports describing carcinomata of the pancreas and the accompanying lesions, jaundice has been noted in the majority of those in which the tumor was in the head of the organ; tumors in the tail of the pancreas have rarely caused obstruction of the bile ducts. It has long been observed that a tend- ency to bleeding may be present in jaundiced individuals, and more recently this has been ascribed to a diminution in the blood prothrombin resulting from exclusion of bile from the intestinal tract (30). Though the secretory activity of the pancreatic tumors might tend to increase blood coagulation, any interference with the flow of bile into the duodenum would counteract such an effect, Extensive replacement of the liver by metastases, or con- siderable parenchymatous degeneration possibly following reduction of pan- creatic secretion into the intestinal tract, would also tend to neutralize the coagulative effect of excessive pancreatic secretion. Smith, Warner and Brinkhous (31) demonstrated that the bleeding tendency accompanying at least some liver degenerations is due to a deficiency in both plasma fibrinogen and plasma prothrombin. The condition of the liver and degree of jaundice werk therefore noted in all of the cases of pancreatic carcinomata to see whether these factors could be correlated with the extent of venous thrombosis. In the 39 cases in which no thrombi or a single thrombus appeared, jaundice was described in 27, or 68.9 per cent. Of the remaining 12 cases without obstructive jaundice, 6 had extensive involvement of the liver by tumor metastases, 3 showed either necrosis or fatty metamorphosis in the liver, and only 3 of the 39 cases had neither liver damage nor jaundice which might depress the prothrombin level in the blood and prevent the formation of thrombi. On the other hand, in the group of 8 patients with pancreatic carcinomata and multiple venous thromboses, only 2 were jaundiced and in both instances the cause of the jaundice lay in the degree of liver involvement and not in obstruction of the extrahepatic ducts. The latter as well as the duodehum were stained with bile. In all but one case, however, there were many tumor nodules in the liver, fully as many as in those unaccompanied by thrombosis, and in one instance infarcts of the liver were also conspicuous. The only other factor amenable to investigation which might alter the incidence of thrombosis, especially in the abdominal cavity, is the operative procedure. Pancreatic tumors, in particular those in the tail, where recog- nition is difficult, are less often subjected to surgical interference than. those CARCINOMA AND VENOUS THROMBOSIS 575

in the stomach or colon. Only 3 of the patients with multiple thrombi had been operated upon, and in all 3 the activity had centered about the upper abdomen, while the thrombi were present in the pelvis, lower extremities, or neck. Curcinomu of the Lung: If thrombi form in the veins of patients bearing carcinoma of the pancreas merely because of mechanical injury to the vessel by the disseminated tumor cells, it would be expected that tumors arising in other organs and especially prone to invade the veins would have a similar e#fect. The lung is frequently the site of origin of a widely distributed car- cinoma, presumably reaching remote parts of the body by way of the blood stream. Despite this there are few reported cases in which thrombosis has been a prominent feature of the disease. In a discussion of a case of thrombo- phlebitis migrans by Warner and Dauphinee (32) it is stated that the patient had a bronchogenic carcinoma as well. A careful histologic study of the peripheral veins involved failed to reveal any underlying change in the vessel wall. Except for the report of James and Matheson (3), previously men- tioned, this case seems to be unique, others showing only a more limited thrombosis which might well be a chance occurrence. Such a one is found in the description by Fielden (33) of a bronchogenic carcinoma with thrombo- phlebitis of the splenic and portal veins. In the present series only 12 or 14.8 per cent of the cases of bronchogenic carcinoma bad thrombosis of any part of the vascular system and but 2, or 2.5 per cent, were accompanied by multiple thrombosis (Table 111). The sections of these cases were reviewed for possible causes of thrombosis. It was found (see Table IV) that local invasion of the venae cavae with com- plete obstruction accounted for the formation of most of the thrombi. In- fectious processes involving the vessels were not encountered. It is also of interest that in many instances tumor tissue was present in the walls or lumina of the veins without thrombus formation, indicating no especial coagulating ability of this carcinoma. Examination of the liver and pancreas in the cases cited yielded no features in which they differed from the cases free of thrombi. In both, the liver frequently contained metastatic nodules. The pancreas was usually unaltered; it rarely showed secondary invasion by tumor. Curcinomu of the Liver: Tumors arising in this organ might reasonably be expected to affect the coagulability of the blood either by taking part in the pertinent functions of liver cells or by replacing normal active paren- chyma. The liver is thought to be in good part responsible for the production of fibrinogen, but it has been stated that the rate of clotting of the blood is little influenced by its fibrinogen content (34). The liver is also a source of the controversial anticoagulant heparin. Although many believe its action in duo to be inconsequential, Chargaff (35) points out that it requires such drastic procedures to detect its presence that its r61e in inhibiting the clotting of blood is not settled as yet. The variation of prothrombin content of the blood with liver damage, however, and the direct parallel with clotting time of the blood (31) remain at the present time the best established means of association of these two factors. Again an individual case report can be found suggesting a relationship between a particular tumor and thrombosis. In this instance the thrombus TABLEIV: TbromboJis in Cases of Carcinoma not Arising in Pancreas -

Location of ?lo. Primary. Location of Thrombi Factora Responsible for Thrombosis Tumor 18e8

- ~ ~ Lung 1 'ortal vein Many metastases in liver 1 'ulmonary vein Lobectomy 3 7enae cavae Local invasion by tumor 3 liac vein None 2 ugular vein 3batruction of superior vena cava 1 liac, portal, mesenteric, renal, Wide dimemination of tumor in vesecl spermatic, and splenic veins and walls inferior vena cava 1 iuperior vena cava, jugular, sub- Zomplete obstruction of vena cava by - clavian, and portal veins tumor Liver 3 'ortal vein rumor in vein 1 'ortal and mesenteric veins rumor in vein 1 'ortal vein and inferior vena cava rumor in vein 1 nferior vena cava rumor in vein

- -~ ~ ~ Gallbladdei 1 hart None 1 ;mall pulmonary artery None 1 liac vein None 1 'ulmonary artery None -1 ?ortal vein Comprewed by primary tumor Kidney 3 -Ieart Sclermis coronary arteries 1 hall pulmonary artery None 1 Prostatic veins Cardiac insufficiency -2 ienal veins and inferior vena cava Invaded by tumor Prostate 4 3eart Rheumatic carditis or coronary oc- clusion 1 Iliac artery Marked scleroeie 1 lliac vein None -1 Pampiniform plexus Invaded by tumor Uterus 2 Femoral vein Radiation-acar tissue 2 Iliac vein Compression by tumor 1 Inferior vena cava None -1 Pulmonary veins None Ovary 1 Iliac vein None 1 Iliac vein and inferior vena cava None 1 Femoral vein Compression iliac veins by fibroids. Tumor in vena cava -1 Iliac and femoral veins Tumor in perivaacular lymphatics Stomach 10 Femoral or iliac veins or inferioi One invaded by tumor. Others no vena cava change I Pulmonary artery Embolus (7) No tumor 4 Portal vein Two invaded by tumor. One sup- purative infection. One no change 3 Pulmonary vein None 3 Adrenal vein None 1 Renal vein None 1 Prostatic vein None 1 Hart None 1 Subclavian, jugular, pulmonary ant None basilic veins 1 Jugular, axillary and iliac veins, ant None - inferior vena cava 576 CARCINOMA AND VENOUS THROMBOSIS 577

TABLEIV-Conlinucrl

Location of Thrombi Factors Responsible for Thrombosie Tumor - Duodenum 1 Splenic vein None or Ampulla 1 Iliac vein None of Vater -1 Prostatic veins None Colon 3 Mesenteric and splenic veins One periarteritis. Two none 1 Aorta Sclerosis 3 Pulmonary arteries None 1 Iliac vein None 1 Iliac and splenic veins Peritoneal abscesa 1 Iliac vein and inferior vena cava None Mesenteric vein Vein ligated at operation Splenic vein One suppurative phlebitis. One tumor approximating vessel Portal and mesenteric veins None Adrenal vein Tumor in vein formation in the patient described by Stern (36) can well be ascribed to an inflamm'atory process, since there was a true thrombophlebitis of the leg veins with a suppuration of the portal vein. Among the 22 cases of carcinoma in the present series, originating either from the intrahepatic bile ducts or liver cells, 6, or 27.2 per cent, had a thrombus in some vein but there were no examples of multiple thrombosis. The only factor of importance, as indi- cated in Table IV, is the invasion of regional veins by the primary tumor. There were, in addition, several cases where tumor tissue was found in these veins and no thrombus formed, strengthening the assumption that these cells had no particular tendency to stimulate blood coagulation. Since, however, so many of the cases were accompanied by cirrhosis of the liver with jaundice, a deficiency in prothrombin may have been present, tending to inhibit clotting. Carcinoma of the Gallbladder: The location of carcinomas of the gall- bladder is also such that jaundice is a frequent finding. In our group of 30 cases it was described in half, leaving ample opportunity for a coagulant effect to manifest itself if the tumors of this organ behaved as those of the pancreas seem to do. There were no instances of multiple thrombosis in this group. The individual thrombi recorded in Table IV are of little significance. Carcinoma of the Kidney: Another tumor prone to invade the vascular system is the so-called hypernephroma. Judd and Scholl (37) described a case and quoted Foulds as stating in a persond communication that of 200 renal tumors seen at the Mayo Clinic 22.5 per cent had involved at least the renal vein. Jacobson and Goodpasture (38) presented a striking case in which the tumor filled the inferior vena cava and reached the right auricle and ventricle, Necroses in the liver resulted from occlusion of hepatic veins. In this series all the malignant epithelial tumors arising in the kidney were included in one group, amounting to 27 cases, among which there were no examples of multiple thrombosis. The causes of the individual thrombi are listed in Table IV. Other carcinomata invaded the renal vein without com- plete occlusion, and thiombus had not formed about the tumor tissue. 578 E. E. SPROUL Carcinoma of the Prostate: Although direct growth of the tumor into large vessels is not so commonly encountered in prostatic carcinoma, the tumor cells often travel widely through the body in the blood. In none of the 43 cases examined did this initiate thrombosis in more than one situation. No sig- nificance could be assigned to the single thrombi recorded in Table IV. Carcinoma of the Femde Pelvic Organs: The tumors arisingh either the fundus or cervical portion of the uterus ordinarily receive vigorous radio- therapy, and the primary tumor in many instances had completely disappeared at the time of post-mortem examination. The two factors which might be expected to enhance the coagulability of the blood in the presence of a uterine carcinoma are the amount of radiotherapy and, in untreated cases, the size of the mass within the pelvis, providing a barrier to venous flow from the extremities. The mechanism of the latter is obvious. The former has been studied first by determining the effect of radiation on various organs. Saelhof (39) demonstrated an increase in prothrombin and a diminution in clotting time with radiation of the spleen, liver, and intestine. The platelets were more numerous when the liver was stimulated. Pagniez et al (40) pointed out that it mattered little what part of the body was treated, irradiation shortened the time of blood coagulation. Rud (41) reported a diminution in coagulation time in his study of 40 cases of uterine carcinoma. In 5 the clotting time was within normal limits (three minutes); in 20 it was between two and three minutes and in 15 it was one to two minutes. There was some increase in fibrinogen but no absolute relation to the number of platelets was noted. Irradiation was not mentioned. Despite these factors, only 6, or 22.2 per cent of the 27 cases in our records, had a single thrombus and no example of more extensive involvement of the veins was found. The thrombi were usually local and due to venous com- pression either by the primary tumor or scar tissue. The few thrombi asso- ciated with carcinoma of the ovary were close to the site of origin of the tumor. Carcinoma of the Stomach: Gastric carcinoma proved to be of interest second only to those arising in the body or tail of the pancreas. Moser (42) took exception to Thoenes’ implication that a carcinoma of the pancreas should be suspected when many veins were thrombosed and described a case pre- senting a similar pattern except that the primary tumor arose in the stomach. In this series there were 32 instances of thrombosis in the 147 cases of carcinoma of the stomach, of which 2, or 1.3 per cent, were multiple to an extent comparable with the thromboses accompanying pancreatic tumoys. The 30 individual thromboses appeared in a variety of situations, as indicated in Table IV. In most instances there was no assignable cause for the forma- tion of thrombi even in the two cases where these were more widely distributed. The pancreas was grossly and histologically normal in one and, while the liver included a small amount of tumor tissue and an echinococcus cyst, there was well preserved parenchyma amounting to at least half the normal organ. In the second case the pancreas and liver had been invaded to a slight degree by tumor nodules but there remained a good proportion of apparently func- tioning tissue. No operation had been performed. There was no infection. Carcinoma of the Intestine: Thrombi rarely occuped in association with carcinoma of the duodenum. Carcinomas arising in the large intestine com- CARCINOMA AND VENOUS THROMBOSIS 5 79 prise a relatively large group, yet the incidence of thrombosis, 1s of the 94 cases, or 15.9 per cent, was low and there was no tendency to multiple thrombosis. And this was true despite the fact that the great majority of patients had undergone one or more operations of considerable extent. In none of the tumors of various origin could any correlation be discovered between the histologic type of tumor and the condition of the pancreas or the extent of liver involvement. Nor were the vessels thrombosed any more fre- quently in one sex than in the other. The age distribution was comparable in those with and without thrombi.

DISCUSSION From this study it would seem fair to conclude that the chief factors responsible for thrombosis in the presence of a malignant tumor are direct invasion of a large venous trunk by tumor tissue, compression by the primary mass, or irregular invasion of the vein wall following extension of the tumor along the perivascular lymphatics. The first was found especially when the site of the primary tumor was the lung, liver, or kidney. Carcinomata arising in the pelvis often formed an obstructive mass. Not all thrombi, however, could be thus explained. When an individual vein was involved the significance was too slight to warrant additional inquiry into the causative factors. But the frequent occurrence of venous thrombi in remote parts of the body in patients having carcinoma of the pancreas and, less often, of the stomach, without morphologic changes to account for their formation, deserved further consideration. Previous workers have been interested in the relation between the pancreas and clotting of the blood. In a series of studies Boldyreff (43, 44) followed the effects of complete extirpation of the pancreas in dogs. His ‘‘ pancreatic triad ” included a‘rise in blood sugar, decrease in coagulability of the blood, and leukocytosis. ’ The rapidity of coagulation was diminished from a normal level of 40 seconds to 250 seconds in nine hours, and a similar but less pro- nounced effect was evident when partial pancreatectomy was performed. The fact that complete loss of coagulability was never attained and that there was grdual restoration toward the normal state led him to believe that additional sources of the “fibrin ferment” might exist, or that enzyme previously se- creted by the pancreas was stored in other organs. Turcatti (46) corroborated these findings. Interference with the clotting mechanism of the blbod was noted not only with pancreatectomy but when a pancreatic fistula was created. Turcatti believed the external secretion of the pancreas to be the responsible factor in maintaining blood coagulability, but stated that the effect is probably indirect through the liver. Ferrari and Cortese (47) also studied the external secretion of the pan- creas for its influence on blood coagulation. In addition to the lengthening of clotting time they reported a reduction in thrombin when the pancreas was resected or a fistula formed. The rise in fibrinogen they attributed to operative trauma as it occurred in control operated animals. They assumed that the substance responsible for these effects usually enters the intestine, is absorbed there, and influences the formation of prothrombin by the liver. 5 80 E. E. SPBOUL Since no changes were noted following ligation of the ducts, they suggested that the substance, under these circumstances, passes directly into the blood. It might be well to point out that this conclusion should be reached only if great care has been taken to establish beyond a doubt that no accessory ducts carrying a small quantity of pancreatic secretion into the duodenum have escaped detection. It is well known that separation of the head of the pan- creas from the intestine is required in addition to duct ligation in order to ensure a complete interruption of the flow of secretion. Dogs have usually been the subject for such investigations but the same effects have been noted in rabbits. Hiruma (48) found that the prolonga- tion of clotting time paralleled the increase in fibrinogen in the blood when the pancreatic duct of the rabbit was ligated. Other factors of possible influence were not measured. Pancreatic activity might dter the coagulability of the blood in a variety of ways, the most plausible of which are by its protease action, by the effect of its lipases and esterases on cephalin or on the absorption of the coagulating vitamin K, or by secondary alterations in liver functions. There is no infor- mation associating amylase activity with the phenomenon of coagulation. Trypsin could increase the tendency to clotting of the blood either directly or by improving digestion and absorption of proteins in the duodenum. In 1916 Douglas and Colebrook ($Q) stated that the blood clotted more rapidly in vitro when a weak solution of trypsin was added, while its use in large quantities delayed coagulation. Heard ($0) also found that trypsin in certain concentrations clotted oxalated blood. He attributed this effect to a disturb- ance in the calcium and phosphorus in the protein molecule, bringing about alterations in surface forces which cause the clotting. That the calcium con- tent of the trypsin preparation used could not be the important factor seemed probable since the dilution was such that the quantity of calcium present was below the significant level. Waldschmidt-Leitz (~)believed thrombin to be a proteolytic enzyme related to trypsin and explained the phenomenon of blood coagulation as an enzymic hydrolysis of fibrinogen to an insoluble product. Trypsin, he stated, accelerated clotting by hastening the hydrolysis. Other proteolytic enzymes including papain were ineffective. The objection to ascribing the relation of the pancreatic secretion and blood clotting to tryptic activity in the blood itself lies in the antitryptic sub- stances which are constantly present. It seems quite unlikely that free trypsin would remain in the circulating blood as long as antitryptic substances were active to a normal degree. Oelgoetz and Wittekind (52) did not succeed in increasing the level of the pancreatic enzymes (amylase, lipase and pro- teases) in the blood of a normal animal, although it could be restored by oral administration in the presence of pancreatic hypofunction. When fed in excess the enzymes were stored in the liver and spleen rather than in the blood. It is also stated (53) that antitryptic activity of the serum is especially in- creased in carcinoma as in other cachexia-producing diseases, The only indication that enhancement of protein digestion in the intestinal tract might influence blood coagulation was found in a discussion by Mills (54). In order to avoid thrombosis following operations, trauma, or child- CARCINOMA AND VENOUS THROMBOSIS 581 birth, and in febrile disease and cardiac decompensation, he suggested a low protein diet, believing that the resulting drop in serum protein would decrease the tendency to coagulation. Certainly the protein level of the blood falls when pancreatic secretion fails to reach the duodenum, but whether the reverse situation exists and a hyperproteinemia accompanies hypersecretion of the pancreatic acini has not been established. The possible r61e of the pancreatic lipases and esterases in maintaining the coagulability of the blood is also of interest, but little experimental work on this question has been reported. The two substances, probably of lipid nature, having greatest effect on the clotting of blood are the phospholipid cephalin and vitamin K. The former, present in all tissues but especially in the lung and brain, presumably aids in conversion of prothrombin to thrombin. Its identity as the coagulating lipid has been established by Wadsworth et al. (55) and by Fischer and Hecht (56). There seems to be no doubt that variations in the amount of pancreatic secretion are reflected in the level of the lipids in the blood. Chaikoff and Kaplan (57) demonstrated the diminution in all lipids following pancreatec- tomy and were able to bring about a rise in blood lipid above normal by feeding raw pancreas. The phospholipids were not so strikingly increased but were elevated. The link between high blood cephalin and thrombosis is less clear. The only work found relating these two changes was that of Rabinowitz and Kahn (58), who reported a great increase in cephalin of the blood plasma in thromboangiitis obliterans. They also studied the effect of injection of an insulin-free extract of the pancreas and found that, while the lecithin dropped, the cephalin rose above the normal level. No experimental evidence has been found, however, for such a mechanism in venous thrombosis. The nature, source, and mode of action of the coagulating vitamin K has been elucidated only within the last decade. A summary of the more im- portant facts can be found in the recent papers of Almquist (59) and of Dam and Glavind (60). The antihemorrhagic vitamin has not, to date, been completely identified, but it is known to be fat-soluble and is found in the non-sterol part of the unsaponiiiable fraction of active materials. Its absence in the diet of chicks is followed by diminution in the prothrombin level of the blood and the Occurrence of multiple hemorrhages. Other animals, including dogs, rats, and guinea-pigs, do not develop these changes on a deficient diet, indicating an ability to synthesize the vitamin. Human subjects have not been studied extensively, but Dam found a large quantity of vitamin K in the lipid fraction of the feces in persons limited to a K-free diet for a week, indicating that they too may be able to manufacture the vitamin. Interest lately has been focused on the correlation of our knowledge of vitamin K with the changes in coagulability of the blood in obstructive jaundice and in some degenerative diseases of the liver. Hawkins and Brink- hous (61) found a definite drop in the level of prothrombin in the blood of bile fistula dogs, hemorrhage occurring at a certain level. Greaves and Schmidt (62) reported a similar finding in rats with bile fistulae and an excess of vitamin K in the diet was found to counteract the hemorrhagic diathesis. Warner, Brinkhous, and Smith (30) also succeeded in restoring the prothrombin level of the blood yith an extract of alfalfa rich in ‘‘ K ” 582 E. E. SPBOUL mixed with bile, and found this more effective than bile alone. Recently reports from the Mayo Clinic (63) bear out these findings in cases of ob- structive jaundice. To summarize then, vitamin K is a fat-soluble substance, probably a lipid, absorbed from the intestinal tract in the presence of bile, and there seems to be adequate proof that it is responsible for the level of prothrombin in the blood. Prothrombin has been shown to vary directly with the coagulability of the blood more consistently than any other known factor. No studies on the relation of pancreatic secretion to the activity of the vitamin have yet been reported, but it is possible, in view of its solubility in fats, that the lipases and esterases elaborated by the pancreas might influence the absorption of the vitamin or even be responsible for its apparent synthesis in the intes- tinal tract. An increase in pancreatic secretion such as seems to occur at times when a carcinoma is present in the body or tail of the pancreas and the duct is patent might be expected to increase the quantlty of prothrombin in the blood. Such a rise would probably not, in itself, precipitate thrombosis since we normally have more than the amount utilized in clot formation, but an increase in prothrombin with the initiating factor of tumor cells in the blood stream might be responsible for the many thrombi. It is possible that the effect of the pancreas on the blood is an indirect one, brought about by secondary changes in the liver. The fact that fat appears In the liver cells, often in large amounts, in the absence of external pancreatic secretion has frequently been stressed. Allan and his co-workers (64) demon- strated that the administration of insulin to depancreatized dogs led to the disappearance of the fat which had accumulated in the liver but that the fat returned after a long period of time. They concluded from this that the external secretion of the pancreas was necessary for proper metabolism of fat. Chaikoff, Connor and Biskind (65) reported the development of cir- rhosis of the liver in dogs after a period of two to five years when they were deprived of the pancreas but maintained with insulin. Aubertin et al. (66) found large fatty livers in three dogs in which the pancreatic duct had been resected. The degeneration of the liver cells was progressive from the periphery of the lobule toward the center. The functions of the liver are so complex that, even if it were known that this organ was primarily responsible for alterations in blood coagulability in the absence of external pancreatic secretions, the manner of production of such a change would remain uncertain. Fluctuations in fibrinogen level of the blood are not well correlated either with the degree of liver damage or with clotting time of the blood. T The effect of variations in heparin production are far too nebulous to deserve discussiom The plasma globulins in general tend to be elevated, but their relationship to clotting time is questionable. Trautwein (67) concluded that the globulin was more often elevated when thrombosis was present. However, cases such as multiple myeloma from our records showed a low incidence of thrombosis' despite a great increase in plasma globulin. In one case the blood clotted rapidly after death, forming an almost solid cast of the vascular system, yet thrombosis had not occurred. The specific globulin, prothrombin, is more closely correlated with liver activity and with the coagulability of the blood. In order to establish the CARCINOMA AND VENOUS THROMBOSIS 583 hypothesis mentioned sometime previously-that the pancreas, independent of the liver, may directly affect digestion and absorption of vitamin K and thus the prothrombin level-it would be necessary to demonstrate that such a change antedated any degenerative process in the liver. In the cases de- scribed in this study there was no morphological evidence that liver damage was any more common in the group having thrombosis than in those without it. While functional deviations undoubtedly occur before there is a change in the microscopic appearance of the cell, damage sufficient to be reflected in a significant blood dyscrasia would probably have been recognized in histo- logic study. It seems likely that the liver did not play a very important r8le. The hypotheses presented so far have assumed that the pancreatic tumor cells may have exercised a general effect by discharge of enzymes into the circulation or by alteiation of some process of digestion in the duodenum. It is also possible that their effect is entirely a local one wherever metastatic pancreatic cells chance to be in the blood stream. Coagulation of blood at those points due to the secretory activity of a few tumor cells could initiate the process of thrombosis and the responsible cells be missed in the sections examined. Since, however, carcinoma of the stomach is sometimes, though less fre- quently, accompanied by venous thrombosis, we have additional intimation that the mechanism is one of disturbance in some digestive process. Achylia gastrica, which accompanies so many gastric carcinomata, would provide a more favorable medium for the action of pancreatic lipase and trypsin. It has also been suggested that achylia is accompanied by a “ compensatory ” increase in pancreatic secretion (68). This mechanism probably does not function alone, since the cases of pernicious anemia with achylia in our records, 37 in all, show a single thrombus in but 3 instances. Pernicious anemia, however, is frequently responsible for a fatty liver, which may well have interfered with the production’of prothrombin. SUMMARY ( The incidence of thrombosis in any portion of the circulatory system and the associated conditions were noted in a series of 4258 consecutive necropsies. A carcinoma was found to be the most common cause of thrombosis of the neck, abdominal, and pelvic veins and those of the extremities. Thrombosis of the cerebral veins was more often accompanied by a local infectious process. In the lung, carcinoma was second to arteriosclerotic heart disease as a pre- cipitating factor. Thrombosis of the arteries was usually dependent upon arteriosclerotic chyges in the wall. Coronary sclerosis and rheumatic heart disease, as would be expected, were found most frequently when the thrombus occurred in the heart. The cases of the more common carcinomata were studied and distribution of venous thrombosis recorded. In 56.2 per cent of the cases of carcinomata in the body or tail of the pancreas at least a single thrombus was present; in 31.3 per cent of these cases widely disseminated venous thrombosis occurred. Inflammation or invasion of the vessels by tumor tissue could not be in- 584 E. E. SPROUL crimhated as a cause of the thrombosis except in one case. There was no correlation between age, sex, race, or the type of carcinoma and the formation of thrombi.) Jaundice was usually absent in the group having extensive throm- bosis, but the degree of involvement of the liver by tumor was variable. Carcinoma arising in the head of the pancreas was associated with multiple thrombosis in 9.7 per cent of the cases. Bronchogenic carcinoma often penetrated the venae cavae and at times thrombi formed distal to the invading tumor. Multiple thrombi were found in 2, or 2.5 per cent of the cases. Invasion of the walls of the veins or obstruction by the main tumor mass accounted for these. Carcinoma of the stomach showed a high incidence of thrombus formation, and in 2, or 1.3 per cent, the thrombi were widely distributed. No morpho- logic changes in the walls of the veins were found to actount for the formation of thrombi. It is suggested that achlorhydria may affect the process of digestion of the coagulating vitamin by pancreatic enzymes in the duodenum. Carcinomata arising in the liver, gallbladder, duodenum, colon, kidney, prostate, uterus, and ovary were not associated with multiple thrombosis. The apparent causes of formation of the individual thrombi found are discussed. The possible mode of interference with the blood-clotting mechanism by pancreatic activity is discussed. It has been suggested that the pancreas might be directly responsible by increasing the trypsin content of the circu- lating blood, or by an improved protein digestion and absorption. Objections are offered to both these hypotheses. The possible effect of alterations of pancreatic lipases on the blood cephalin are mentioned. It is thought more likely that an increase in lipase in the intestine may influence the coagulability of the blood by a more efficient digestion of fats and absorption of the fat-soluble vitamin K. 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