Document 2Jga2177Xj9LEam1nw9MpRv7L

-------- 'HTllTimiTT* - i IS: Pregnancy Category C. Animal nducted with Quibron/SR Tablets ither Quibron/SR Tablets or when administered to a pregnant actty. Quibron/SR Tablets or egnant woman only if clearly 1 whether use of this drug during yed adverse effects on the fetus, abor or increases the possibility of i ervention. | sn reported to be excreted in ; ility in a nursing infant. : cqmitant administration of ycin and erythromycin have been ice and in turn increase serum illine has been reported to Interda, lithium, propranolol and -ay of uric acid, especially the /nunc acid levels may be (ent adverse reactions are usually 'jot beer; reported with Quibron/ wing reactions may be considJ. Central nervous system: c/orlic sole twitching, reflex hyperessness, and irritability, Cardio1' arrhythmias, hypotension, and flushing. Gastrointestinal: iistric pain, and nausea, Renal: ; is and red blood cells, albumin iea. Others; hyperglycemia and considerations, > PHARMACEUTICAL DIVISION REVIEWS Occupational Carcinogenesis: The Louisville Experience with Vinyl Chloride-Associated Hepatic Angiosarcoma CHARLES L. DANNAHER, M.D.* CARLO H. TAMBURRO, JvJ.D. LUNG T, YAM, M.D. /.ouiswTfe, Kentucky i \ From the Divisions of Hematology-Oncology, and Digestive Diseases and Nutrition, Depart ment of Medicine and the Vinyl Chloride Project, Cancer Center, University of Louisville; and the Veterans Administration Medical Cen ter, Louisville, Kentucky. Portions of this work wore supported by the National Cancer Institute Contract NO l-CN-55212 and by a Vetorons Administration Medical Research Grunt. Rotpieals for reprints should bo addressed to Dr, Charles L, Dannaher, Manuscript accepted Au gust 21, mao. * Present address; Columbus Hospital Re gional Oncology Center. P.O. Box 50)a, Croat Falls, MT 60403, Hepatic angiosarcoma in man was first associated with exposure to vinyl chloride In Louisville, Kentucky, where it was Identified in 10 persons from a single vinyl chloride polymerization plant; clinical manifestations are summarized herein. Following prolonged expo sure to vinyl chloride, the onset of this disease is Insidious and the clinical picture is that of nonspecific hepatic Injury with mildly ab normal biochemical liver test results. Carcitioembryonic antigen and alpha fetoprotein are undetectable. Radionuclide and angiographic studies of liver show characteristic but nondiagnostic abnormalities. A definite diagnosis is usually made only by open liver biopsy. Treatment Is unsatisfactory but chemotherapy seems to prolong survival. Average survival from diagnosis is about 12 months, Overt liver failure usually occurs only as a preterramol event and Was the major cause of death in all of our patients. Preventive measures are now In effect in the plant. This experience illustrates the importance of the clinician in occupationally-related cancer. Most cancers in man result from exposure to environmental factors. The occupational environment may account for as many as 10 percent of these malignancies [lj. We present the course of evonts and clinical findings of an industrial epidemic of hepatic angiosarcoma, a rare tumor considered to originate from the vascular lining cells of the liver [2,3]. This experience demonstrates the importance of the clinician in recognizing and controlling occupationally-induced cancer. In 1974, several patients in Louisville, Kentucky, were found to have angiosarcoma of the liver [4], All of these patients were men who were chemical workers at a local industrial plant that polymerizes vinyl chloride, Subsequently, additional cases in which the patients had a history of prolonged exposure to vinyl chloride were reported in Louisville [5,6] and elsewhere [7-11]. Various aspects of this malig nancy including histology [ll], angiographic and radionuclide char acteristics [12], urine [13] and tissue [14] glycosaminoglycan patterns and epidemiologic studies [15] hove been reported from Louisville. In addition, interest in this disease has propagated elsewhere, both nationally and Internationally [16-16]. However, the total experience of vinyl chloride-associated angiosarcoma in the Louisville area has never been told. With a cohesive summary one begins to appreciate how the initial clinical observation of a patient with hepatic angio sarcoma led to the realization of u possible etiologic association, This, in turn, has cast a profound influence on the health of those working in a major worldwide industry Involving the production of polyvinyl chloride. February 1881 The American Journal of Medicine Volume 70 278 T !! ! I!. SL 06S528 OCCUPATIONAL CARC1NOCENESIS-DANNAHER ET AL. This concentration of cases of hepatic angiosarcoma gave us the opportunity to study the clinical manifesta tions of this unusual cancer, In view of concern re garding Its Increasing Incidence [7,19-21 J, we believed a summery of this information would be valuable in detecting and managing future patients, In this paper wo present the natural course, diagnosis and treatment of this disease as well as possible preventive measures that we have learned from study of the patients dis covered in the Louisville area. Characteristic features of the disease, including a long period of asymptomatic laboratory abnormalities, the difficulty in diagnosis and the poor response to treatment, are demonstrated by the following illustrative case, CASE REPORT The patient, a 51 year old man who entered the vinyl chloride Industry 28 years ago as a vat cleaner, worked in the vinyl chlorldo polymerization aroa for 18 yoars, During medical screening of plant employees In April 1074, he was found to have mildly abnormal serum biochemical liver test results, Liver-spleen scan disclosed no abnormalities, and he was asymptomatic. Because of persistently abnormal biochemical liver tests, he was evaluated further In December 1974, He remained asymptomatic, Bnd findings on physical examination were within normal limits. A hepatic angiogram showed multiple distended sinusoids throughout the liver with pooling of con trast material within these lesions. Trnnsjugular liver biopsy specimens were histologically interpreted as showirig chronic inflammatory reaction and fibrosis, attributable to the patient's previously known liver involvement with malaria, He was removed from the vinyl chloride processing area and contin ued active employment without symptoms. His liver profile continued to deteriorate; by September 1975, he began to complain of tiredness and easy fatigability, The findings on physical examination remained within normal limits, Liver scan now demonstrated hepatomegaly with multiple defects throughout the liver. Biopsy Specimens demonstrated sinusoidal dllntntion and Kupffer cell prolifer ation in some of the specimens, but the diagnosis of angiosar coma oould not be made. The patient did not return to work. His fatigue Increased ovor the next two months and vague abdominal pain devel oped, In January 1978, gross hepatosplenomegoly with a bruit over the Uver and Blgns of high output cardiac decompensation were detected, Ltver-spleen scan and angiogram showed further enlargement of the previously Identified lesions. An Increase In arterial-venous shunting was demonstrated. At abdomlnnl operation, direct examination rovealed that the veins of the portal system worn somewhat distended and that tho surface of Iho Uver was slightly nodular with some areas of bluish discoloration which wore somowhat sorponttno In nature, There were multiple nroas on tho liver In which tho tissue was slightly elevated with a central depressed area of o somowhat cyanotic appearnneo, A strong thrill could be felt when palpating the liver. Tho hepatic artaries were ligated, and there was complete disappearance of the thrill. Wedge biopsy of the liver demonstrated areas of angiosar coma among areas of fibrosis and sinusoidal dilatation with hypertrophy and hyperplasia of sinusoidal lining colls. Postoperatlvoly, the cardiac decompensation was corroded and the spleen size was reduced to normal, but iho llvorslzo remained tho same, Chemotherapy with doxorubicin, cyclephosphamldo and methotrexate was started, and tho llvor was reduced to Its normal slza but the biochemical liver lost results remained abnormal. The reduction In llvor size lasted four months during which the patient was unable to carry on nor mal activity without fatigue. Over tho noxt four mouths thoro was a gradual Increase In tho size of the llvor will) the devel opment of ascites and abdominal pain with deteriorating biochemical liver test results, The patient died In December 1976 with hepatic encephalopathy and gastrointestinal bleeding, Autopsy revealed an enlarged liver with multiple small nodules of angiosarcoma throughout, The tumor was metastatic to tho spleen and lungs. BACKGROUND AND METHOD OF STUDY Vinyl chloride Is tho raw material with which the common plastic polyvinyl chloride is made. Vinyl chloride monomer (GHgCHCll is a gas made by the reaction of ethylene and chlorine, which, whan processed commercially, Is polymerized In largo vats under Increased temperature and pressure to form a white solid. Workers are exposed to gaseous vinyl chloride by leakage from the manufacturing vats during processing, upon opening the vats after the processing is complete, or, most intensely, In tho cleaning process whon the worker enters the vat and chips residue off the interior wall releasing pockets of gBS. Vinyl chloride was initially thought to be completely harmless, and there was no iiihit to the exposure workers re ceived In tho 1940s and early 1950s, however, a voluntary re striction of 50 pnrts per million was eventually adopted, The gas was considered to be so harmless that It was even used as a propellant in aerosol sprays [22] and a general anesthetic [23). It gradually became apparent that prolonged exposure could Induce Injury In many tissues Includingsldn, blood vessels and the reticuloendothelial system [24-26], Evidence of liver injury was soon found [27,28], which was associated histologically with changes iri the hopatocytes, fibrosis and sinusoidal dila tation [29.30], In animal experiments, prolonged inhalation of vinyl chlorldo Was shown to Induce cancoHn rats |3i], Soon thereafter an employee of tho Louisville vinyl chloride polymerization plant died of hepatic angiosarcoma, but the significance of this was not appreciated until nearly two years later when a second employee also died of this rnro tumor. Sinco these workers were cared for by different physicians at different hospitals, this might stiil have gone unnoticed were it not for the plant physician, whose system of requesting re ports of illnesses and deaths of employees brought the diag noses to his ntlnntlon. Hts memory of the oarlinr patient with the disease led him to initiate a search for other casos among farmer employees and to Institute n medical surveillance program of nil present employeos which was lalnr supported by the Notional Cancer Institute and tho University of Loulsvilln. This program involved testing nearly 1,200 employees with a standard automated biochemical profile and radionu clide liver-spleen scan. Workers with persistent biochemical liver abnormalities or with abnormalities of their radionuclide scan were then examined by selective hepatic arteriography, 280 February 1981 The American Journal of Medicine Volume 70 hepatic vonog' [20,32,33]. Patients with Divisions of Hon Nutrition, Lin!v January 3, 1977 Chlorldo Projor. the Louisvilln ni In n search of ai of 11 patients hn Industrial expos a woman, refnn longed usn of hi pnllant. Only til vinyl chloride n< derived from on' polymerization j of this report, j RESULTS ! Epidemiology) employees of i 1942 to the on been extreme, total of 1,055 1,184 are cu 'ployeos. During the j died. Sixty-six 39 of cancer, j in 34 the cans mary brain c exposure [34, were from th tion adjusted pected [36], Ten coses tlflod among period, All a plant with h these cases in by review o surveillance the surveilln one case cnci 1973 and 191 were identifi of anglosarcc area. The Inc is 0.54 peref population p U.S. in 0.00 mean age a o range of 3f refloating on. duration of with a range first exposur of hepatic a 'f SL 068529 lilalalinn with ing coils, was corrected ;t the liver size rtiblein, uyclod the liver was - vur tost results I ze lasted four ) curry on nor, months there 'nth the dovel- doteriorating in December istruintestinul with multiple no tumor was 1'UDV | the common do monomer : Mhylene and ,; polymerized ; jssuro to form inyl chloride j g processing, dote, or, most ,or enters the ng pockets of completely workers re* Voluntary red opted. The : jvon used as ' esthetic (23], Uosure could ; 1 vessels and i f liver injury istologically isoidal dila. nhalation of i s 133], ! nyl chloride ; ma, but ihe , ly iwo years ; rare tumor. hysicians at /jticcd were ri nesting re;')((ho diag'.'iiionl with isos among irveillance 'supported ty of Louisemployees d radionuochemlcal dionuclldo . riography, occupational carcinocenesis-dannaheh KT Ah. hopatic venography and transjugulnr hepatic biopsy TABLE I Early Clinical Features Related to Hepatic [20,32,33], Angiosarcoma In 10 Patients Patients with hepatic angiosarcoma soon by the staff of the Divisions of 1 lnmatology-Oncology and Digestive Diseasoa and Nutrition, University of Louisville, front January 1, 1074, to Symptoms Patients (no.) Signs Patients (no.) January 3, 1077, include thoBe occruod through the Vinyl Chloride Project as well os patients referred by physicians in the Louisville area end elsewhere, and u few patients found In u search of uutopsy records und deulh certificates. A total of VI patients have boon studied, 10 of whom liuvo had heavy industrial exposure to vinyl chloride. The other patient was a woman, referred from Florida, who had a history of pro longed nse of hair spray containing vinyl chloride as a pro Pain Fatigue 5 Hepatomegaly fi Splenomegaly 7 5 Weakness 4 Abdominal tenderness 3 Weight Loss 3 Hepatic bruit 1 Anorexia 3 Indigestion 1 Abdominal fullness 1 Melena 1 pellant. Only ihe 10 patients with occupational exposure to vinyl chlurldu are Included in this report. In addition, data are derived from employee records of the Louisville vinyl chloride polymerizulion plant during its 35 year operation to the date of this report, W,' RESULTS from 12 to 28 years. No differences were noted between the retrospective group and the surveillance group. Three patients had known heavy exposure to alcohol, and none of tho patients hod previously had viral hep atitis or exposure to any other known hepatotoxlns. Epidemiology, The cohort for this analysis are the Clinical Features. The earliest clinical features which employees of the Louisville plant from its opening in could ba-related to the angiosarcoma are presented in 1942 to the end of 1976. The employee population has Table I. Pain wa? localized In the right upper abdominal been extremely stable and during this 35 year period a quadrant or in fhe lower right hemithorax,In two of the total of 1,855 persons have been employed. Of these, patienUj the pain was acute, but in the others it ranged 1,184 are current employees and 671 are past em from two to si* plonths In duration.' Fatigue and weak ployees, V, ; During the 35 year period, 187 members of the cohort ness had`been-present from one month to one year, Weight loss ^ (significant, averaging's pounds over died. Sixty-six of these died of heart disease and stroke, 39 of cancer, 10 of accidents aqd[ nine of othor disease: four and a -Half months, Hepatomegaly was the most common physical sign. The fiver measured from 15 to in 34 the cuiise of death could not be determined, Pri 24 cm in total vertical span at the right mid-clavicular mary brain cancer has been related to vinyl chloride line by percussion. When splenomegaly was present the exposure [34,351, and five of the 39 deaths from cancer spleen was easily palpable 3 to 7 cm below the costal were from this cause. The mortality rate in our popula margin, Two patients, both in the surveillance group, tion adjusted for age is approximately twice that ex had no physical signs, and one of these patients was pected [30], asymptomatic. Ten cases of hepatic angiosarcoma have boon iden Laboratory Findings. Hematologic evaluation at di tified among our 1,855 employees during lha 35 year agnosis showed three patients with normal complete period. All of these employees wqrked in areas of the blood counts, Mild anemia was found in five patients, plant with high vinyl chloride exposure. We divided but reticulqcyte counts were not determined. Two of the these cases into a retrospective group--cases discovered patients had abnormal erythrocyte morphology with by review of hospital and pathology records, and a target celW'and schisfocytes. In one patient the anemia surveillance group--coses discovered prospectively in the surveillance program. In the retrospective group, was combined with leukocytosis and in three patients with thrombocytopenia. Each patient with thrombocy one case each was diagnosed in 1964,1967,1970,1972, topenia had splenomegaly. Two other patients had 1973 and 1974. In the surveillance group, three cases leukocytosis as their only hematologic abnormality. In were Identified in 1974 and one in 1976. No other cases, two patients the bone marrow was examined: one was of angiosarcoma have been identified in the Louisville normal; the other demonstrated erythrold hyper area. The Incidence over the 35 year period in our cohort plasia. is 0,54 percent, equivalent to 15.4 cases per 100,000 No patient was Without some abnormality In at least population per year, (Predicted annual incidence in ihe one of the standard biochemical liver testa. Most of the U.S. in 0.0014 cases per 100,000 population [37],) The . values were qnly minimally abnormal initially, There mean age at the time of diagnosis was 47.6 years, with ' ; was np consistent abnormality of any single test result a range of 36 to 58 years. All patients were white mpn, y ' or apparent pattern of groups of tests, although the al reflecting employment patterns at the plant. The mean * duration of exposure to vinyl chloride was 17,4 years, ^ with a range of 12 to 28 years, The mean duration from first exposure to vinyl chloride to the time of diagnosis kaline phosphatase level was most frequently elevated. Hepatitis B surface antigen and alpha fetoprotein were not found in four patients who were tested, and cardnoembrypnic antigen was not present in two pa of hepatic angiosarcoma was 19.8 years, with a range tients. February 1981 The American Journal of Medicine Volume 70 281 SL 068530 e. OCCUPATIONAL CARCINOQENE8JS--DANNAHER ET AL, W1 UlM iSfe "v< SWA\ B Figure 1. Liver scan In hepatic angiosarcoma. A, anteroposterior view. Large peripheral defect In the right lobe with other smaller defects, B, right lateral view. Results of routine roentgenologic studies and gas trointestinal contrast studies were normal in most in stances. However, special roentgenologic studies re vealed many abnormalities, Radionuclide liver scan disclosed abnormalities in all patients; however, the abnormalities were not consistent. Six patients had hepatomegaly. In eight patients a mass was demon strated which usaliy appeared as a single negative defect greater than 4 cm in diameter in the periphery of the liver. In four patients this was accompanied by one or more additional defects, and two patients had only ev idence of diffuse hepatocellular disease, Typical ab normalities on liver scan are demonstrated in Figure i. Splenomegaly was demonstrated in five patients by radionuclide scan, Hepatic arteriograms were obtained in six patients and demonstrated enlarged sinusoidal spaces in each of thorn, with a mass demonstrated in five patients. The masses were supplied by normal-sized hepatic arteries and were characterized by persistent peripheral tumor stains with some degree of central hypovascularlty as shown in Figure 2. Hepatic ultra sound was performed in only one patient and demon strated a solid mass. Clinical Diagnosis. Methods: Although the signs and symptoms of our patients were fairly nonspecific, there was some finding In almost every patient that would direct one's attention to the liver in an effort to explain the clinical features. Biochemical tests of blood usually revealed nonspecific hepatic injury, but no pattern of abnormality coUld distinguish angiosarcoma. Figure 2. Hepatic arteriogram In hepatic angiosarcoma. A, arterial phase demonstrating dilated sinusoids In both lobes. B, venous phase demonstrating a large mass In the right lobe with peripheral staining and central radlolucent area. 282 February 1881 The American Journal of Medicine Volume 70 <4. ' '} Figure 3. Gross secticj displaying multifocal pattern with a large ruptd The radionuclide liu: of the liver by a malign ative defect, however, mistaken [or a rib imi normal anatomic vari^ defects could give ti metastatic to the liver, indicated malignancy diagnostic of angiosan The abnormal vnset hopatlc arteriogram wi stain and central radio of hepatic angiosnrenn this appearance conic, liver cell adenomas o is the most accurate cli angiosarcoma and sh whom the diagnosis i regarding special roc tailed in (he literature Extent of disease; A was determined usln mation obtained at e: the patients disease w and in six patienls th lobe of the liver. Dii phrngm was prosen I one patient. Porta ho in one patient. One lung. Pathology. Gross d enlarged with blunt red-orange color, Th< SL 068531 ited enlarged sinusoidal nass demonstrated in five jpplied by normal-sized iracterlzed by persistent some degree of central Figure 2. Hepatic ultrBone patient and demon- Although the signs and fairly nonspecific, there ivory patient that would :?er in an effort to explain cal tests of blood usually injury, but no pattern of angiosarcoma. . Jlolucent area. OCCUPATIONAL CARCINOGENESIS--DANNAHUH ET AI,. displaying multifocal solid and hemorrhagic cystic growth pattern with a large ruptured cyst, The radionuclide liver scan suggested Involvement of the liver by a malignant process ipecause of the neg-/ ative defect, however, the peripheral location could be mistaken for a rib impression, porta hepatis pr other normal anatomic variation. The presence of multiple defects could give the Impression of a malignancy metastatic to the liver. Although the liver scan frequently indicated malignancy in the liver, it was not specifically diagnostic of angiosarcoma. The abnormal vascular pattorn demonstrated by the hepatic arteriogram with the persistent peripheral tumor stain and central radiolucent urea is strongly suggestive of hepatic angiosarcoma. Under unusual circumstances this uppearance could mimic bohign vascular lesions, liver cell adenomas or hepatic infarction. However, it is the most accurate clinical means of diagnosing hepatic angiosarcoma and should be obtained in all patients in whom the diagnosis is suspected. Purthor information regarding special roentgenologic studies has been de tailed in the literature [12]. Extent of disease: At diagnosis the extent of disease was determined using clinical parameters and infor mation obtained at exploratory laparotomy. In four of the patients disease was confined to one lobe of the liver and in six patients the disease involved more than one lobe of the liver. Direct extension involving the dia phragm was present in two patients and the stomach in ono patient, Porta hepatis lymph nodes were involved in one patient. One patient had distant spread to the lung, Pathology. Gross description: The liver is usually enlarged with blunt edges and u variegated brownred-orunge color, The surface may contain one or more purple-blue nodules with spongy consistency varying in slzo from 1 to 4 cm. In two coses these ruptured and caused hemoporiloneum. The cut surface is diffusely involved with cystic areas filled with dark blood with occasional cysts measuring up to 20 cm in diameter (Figure 3). In one case the tumor had a primarily solid appearance, Definitive diagnosis: Tissue for histologic examination was obtained by percutaneous biopsy, transjugular bi opsy, open liver biopsy and nulopsy, Although six tissue specimens obtained by percutaneous and transjugular biopsy did Identify other liver abnormalities, specimens were insufficient for accurate diagnosis of malignancy. All definitive diagnoses of angiosarcoma in this group of patients were made by tissue obtained at open liver biopsy (seven patients) and at atuopsy (throe patients). In our experience, in a patient with biochemical evi dence of hepatic injury with a history of prolonged ex posure to vinyl chloride, open liver biopsy under direct vision Is needed for diagnosis, We have no experience with laparoscopy and directed biopsy, which may be associated with less morbidity, but this approach should be tempered with caution in such a vascular tumor with major potential for hemorrhage, Histology: All tumors were primary angiosarcoma of the liver with a wide range of patterns and differentia tions seen between different tumors and within the same tumor (Figures 4 and 5). Areas of extensive hem orrhagic necrosis end areas of enlarged spindle-shaped endothelial cells lining irregular vascular channels appearing as a spongy network of sinusoids were present, Tumor cells occasionally projected into these channels. Large cavities lined by sarcomatous cells contained fresh or altered blood and, at times, organized clot. Three putients had histologic evidence of cirrhosis, two of whom hud histories of heavy alaohol Intake. One additional patient had fibrosis, and two patienls had evidence of toxic hopatitis, The variable histology of angiosarcoma and the difficulties of diagnosis have been described previously [3,11,38], Metastatic spread: Nine of the 10 patients have died, and eight of them have had postmortem examination, The single patient without a postmortem had an ex tensive clinical evaluation and exploratory laparotomy two weeks prior to his death. His data have been com bined with the autopsy data regarding extent of disease at death. One patient with extensive hepatic fibrosis considered to be secondary to radiotherapy had mi croscopic angiosarcoma in tjie minimal remaining liver tissue with no other evidence of disease, Eight patients had extensive disease throughout the liver, Five of these eight patients had regional dissemination with in volvement of diaphragm (three of five), lymph nodes (two of five), abdominal wall (two of five), gallbladder (one of five) and bowel (one of five). Four of these eight patients had distant spread with Involvement of lung (four of four), bowel (two of four), adrenals (two of four), lymph nodes (one of four), brain (ono of four), hope (one February 1881 The American Journal of Medicine Volume 70 283 Tl i f i i'i Si ' '? V ' him:: h'"\y SL 068532 Figure 5. Multifocal minute angloeareometous growths are conspicuous among liver cell cords In locations distant from grossly vlsable tumors, Hematoxylin and eosln stain; mag nification X 600, reduced SO percent. of four), spleen (one of four), pleura (one of four), peri cardium (one of four), myocardium (ono of four) and kidney (one of four), Ono patient had distant metflstases without evidence of regional spread, and two patients had no evidence of regional or distant spread. Therapy, In no patient was a surgical attempt at re section made, In those patients with disease confined to one lobe of the liver, fibrosis or cirrhosis in the re mainder of the liver was thought to contraindicate sur gery. One patient underwent hepatic artery ligation with no benefit. Radiotherapy to the liver was given to one patient early in his course with minimal tumor found at autopsy one year later, but extensive hepatic fibrosis led to his death. However, another patient, following tumor recurrence during chemotherapy, received radiotherapy seven months after diagnosis. He was found to have extensive angiosarcoma in the liver at autopsy two months later, with no apparent response to the radio therapy, Both patients received 6,000 rads in five weeks Major Clinical Events Occurring Prior to Terminal Events During the Course of Angiosarcoma Seen In 10 Patients Evtnt Pneumonia Pleural allusion Staphylococcal septicemia Peripheral platelet destruction Microangiopathic hemolytic anemia Congestive heart failure Renal failure Hypertension Gastrointestinal bleeding Hepatic failure Hemoperltoneum Fever Psllents {no.) 1 1 1 2 1 3 1 1 1 2 2 1 to a major volume of the liver. Seven patients who re ceived chemotherapy had some evidence of response by reduction in liver size or tunior size, and one pntldnt continues to fespond to chemotherapy 66 months from the time of diagnosis. Various drugs hove been used individually and in combination including fluorourncil, vincristine, cyclophosphamide, doxorubicin and methotrexate. Clinical Course. Major clinical events during the course of each patient's disease are listed In Table II. Congestive heart failure was preceded by a period of high output cardiac volume overload in patients with demonstrated arterial-venous shunts, Microangiopathic hemolytic anemia and platelet destruction in the pe ripheral blobd were present without evidence of dis seminated intravascular coagulopathy or sepsis, and were possibly due to coll damage in the abnormal tumor vasculature [39-42]. Symptoms of overt hepatic failure were unusual until very late In the clinical course. The factors contributing to death in these patients are listed in Table III, The major cause of death was the sudden onset of Irreversible rapidly progressive hepatic failure. Survival. One patient remains alive 56 months from the time of diagnosis. Survival of the other nine patients from the time of diagnosis ranged from four months to TABLE III Contributing Causes of Death In Nine Patients with Angiosarcoma \ 0*UM Hepatic talluro Gastrointestinal bleeding Ruptured tumor with hemoperltoneum Cardiac tamponade Hemothorax Psllsnls (so.) 9 2 2 1 1 February 1981 The American Journal of Medicine Volume 70 29 months, with n mot measured from the lb; survival was five mo duration of 14.9 mont ognosls wns distinctly received chomothornj throe patients who dlj Preventive Measure] an epidemic of nngiij chloride polymorizalj ployee exposure lo ppm. Adherence by iho polymerization leakage into the aml> process is now perfo live respirators. A rc< tinted for all worker mont and potential work environment and othor chemicalsl from exposure befoni this process involve;! ployecs, and some , iongthy, an cducatir plemenlcd In nn offn in a potentially care mote understanding program resulted ir veillartce and prevrj angiosarcoma have] plant since 1976 amd past employees folij years. COMMENTS The Louisville hep folds In many ways a fatal Incident oa; revealed vinyl chic; Investigation and concerned quickly criminate vinyl chi patic angiosarcoma | rence of angiosarc exposed to high co n long period of tir in other plants pro production of si mil animals exposed to (43,44). The deled ; recognized the in Importance, instill, Initialed a cancer d demonstrates Iho trolling occupatior The early fears of angiosarcoma c<^ SL 068533 comatous growths are locations distant from and eosin stain; mag- /on patients who rel/idonce of response sino, and one patient apy 56 months from igs have been used duding fluorouracil, doxorubicin and events during the o listed in Table II. udod by a period of jad in patients with ts, MIcrpangiopathic stmction in the pe)ut evidence of disiathy or sepsis, and the abnormal tumor overt hepatic failure : clinical course, in these patients are se of death was the '' progressive hepatic ive 56 months from e other nine patients from four months to I Death In Nine rcoma (no.) 9 2 n2 1 1 OCCUPATIONAL CARCINOGENE3IS-DANNAIIER ET AL. 20 months, with a moan survival of 11.7 months. When measured from the time of first symptoms, Ihe range of survival was five months to 34 months, with a mean duration of 14.9 months. Survival from tlm lime of di agnosis was distinctly longer in the six patients who received chemotherapy (mean 15 months) limn in the three putlents who did not (moan five monlbs), Preventive Measures. Shortly after the dlshovory of an epidemic of angiosarcoma in the bouisville vinyl chloride polymerization plant, new limitations of em ployee exposure to vinyl chloride wore imposed at l ppm. Adherence by industry involved tighter seals on (lie polymerization vats and conduits which lessen leakage into the ambient atmosphere. The vut cleaning process is now performed by workers wearing protec tive respirutors. A record keeping systom has been ini tialed for all workers which relates length of employ ment and potential chemical exposuro levels in each work environment to possible harm from vinyl chloride and other chemicals, so that a worker con be removed from exposure before he is likely to sustain injury. Since tins process involved a change in behavior for all em ployees, and some jobs were more cumbersome and lengthy, an education program was designed and im plemented in an effort to relieve anxiety rejated to work in a potentially carcinogenic environment and to pro mote understanding of good health maintenance. The program resulted in better cooperation with the sur veillance and prevention programs. No now cases of angiosarcoma have been discovered in the Louisville plant since 1976 among 1,184 current employees and 504 pas! omployeos followed at regular Intervals for four yours. , COMMENTS The Louisville hepatic angiosarcoma experience un folds in many ways as a medical detective story. First, a fata! incident occurred, A diligent search for clues revealed vinyl chloride as a potential suspect, Further investigation and intimate cooperation among al) those concerned quickly gathered sufficient evidence to in criminate vinyl chloride as the etiologic factor for he patic angiosarcoma, The evidence included the occur rence of angiosarcoma In Louisville only in workers exposed to high concentrations of vinyl chloride over a long period of time, the discovery of similar pationts in other plants producing vinyl chloride [8,9], and the production of similar hepatic lesions in experimental animals exposed to high concentrations of vinyl chloride (43,44), The detective was an observant clinician who recognized the initial incident, realized Its potential importance, Instituted a systematic investigation and initiated a cancer control effort, This entire experience demonstrates tho importance of the clinician in con trolling occupationally-induced cancer, The oarly fears of progressively increasing numbers of angiosarcoma cases related to vinyl chloride exposure [7,19-21] have not come to pass. Tho ubsonce of new cases, however, should not be looked on as the end of the story. The Louisville plant is one of the oldost vinyl chloride polymerization facilities in the nation, and these workers have had the longest potential exposure lo tho carcinogen, In addition, because of ihu early luck of concern regarding exposure levels, they also have had the highest exposure, Wo have soon that the incubation period may range from 12 to 28 years, and It Is difficult to imagine that the recently instituted preventive mea sures have resulted in the absence of new cases. More likely, this has resulted from the voluntary reduction in exposure levels or some other alteration in the work environment in the past, Moreover, we know that the level to which vinyl chloride exposure was voluntarily reduced is still carcinogenic [45], We have probably seen a dose-response effect with a large number of cases occurring after exposure to a large dose. A smaller number of cases resulting from lower exposure levels will probably continue to develop In the ensuing years because of the lppg inaubatipn period, This problem mqy become more pressing in other parts of the country In which workers in vinyl chloride polymerization plants, opened in the 1950s and early 1960s, are now nearing tho mean incubation period for this disease. Mandatory restriction of atmospheric vinyl chloride levels to 1 ppm has only been in effect for five years, and it is not known whether lowering exposure levels re verses the possibility of cancer in those already exposed to higher levels, This must continue to bo Investigated, In the group of workers with high exposure to vinyl chloride, close surveillance should be continued in definitely. Although the Louisville experience has re vealed the close association between vinyl chloride exposure and hepatic angiosarcoma, the mechanism by which vinyl chloride triggers carcinogenesis remains to be studied through animal model experiments [40]. It is intriguing that angiosarcoma is so frequently associ ated with environmental factors, such as thorium dioxide [47-49], arsenic [50-52],end vinyl chloride, each of vyhich results In stimulation of the hepatic sinusoidal lining cells [38], Other associated factors include hemochromatosis [53-65], copper [56] and estrogens [67], However, some cases discovered during early childhood are apparently congenital , When faced with a patient with angiosarcoma wit rout one of these recognized factors, a diligent search or other possible environmental factors should be pursued so that pre ventive measures can be undertaken. Many new chemicals are introduced into our work -, and home environments each year, There is increasing concern that environmental factors are responsible for many cancers In man. Although sophisticated laboratory techniques and specialized knowledge are essential in cancer research, the Louisville experience in vinyl chloride-associated hepatic angiosarcoma demonstrates how a careful clinical observation followed by a woll conceived clinical approach may reveal on environ- February 1881 The American Journal of Medicine Volume 70 205 l ] i i i r SL 068534 occupational carcinogenesis--dannaher et al, mental etiology of nooplosla and result in profound benefit for all of us. ACKNOWLEDGMENT We acknowledge the encouragement and assistance of Laszlo Makk, M.D., John Creech, Jr,, M.D., Joseph G. Whelan, Jr., M.D. and Barbara Miller, B.S.N., and the cooperation of the B. F. Goodrich Chemical Company, Bells Lane, Louisville, Kentucky. 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