Document RJRye9wvv54rwy5M4kGxjG75n

REVIEWS Occupational Carcinogenesis: The Louisville Experience with Vinyl Chloride-Associated Hepatic Angiosarcoma CHARLES L. DANNAHER, M.D.* CARLO H. TAMBURRO. M.D. LUNG T. YAM. M.D. Louisville, Kentucky From the Divisions of Hematology-Oncology, and Digestive D.^eascs 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 were supported by the National Cancer Institute Contract NO l-CN-55212 and by a Veterans Administration Medical Research Grant. Re quests for reprints should be addressed to Dr. Charles L. Dannaher. Manuscript accepted Au gust 21,198(1. * Present address' Columbus Hospital Re gional Oncology Center. P.O. Box 5013, Great Falls, MT 59403. 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. Carcinoembryonic antigen and alpha fetoprotein are undetectable. Radionuclide and angiographic studies of liver shov. 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 preterminal 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-rclated cancer. Most cancers in man result from exposure to environmental factors. The uccupational environment may account for as many as 10 percent of those malignancies [l]. We present the course of events 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 [11], angiographic and radionuclide char acteristics [12], urine [13] and tissue [14] glycosaminoglycan patterns and rpidemiologic studies [15] have been reported from Louisville. In addition, interest in this disease has propagated elsewhere, both nationally and internationally [16-10]. 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 a possible ctiologic association. This, in turn, has cast a profound inliuenee on the health of those working in a major worldwide industry involving the production of polyvinyl chloride. February 1981 The American Journal of Medicine Volume 70 27S y EC- 1706 OCCUPATIONAL CARCINOGENESIS--DANNAHER ET AL. This concentration of cases of hepatic angiosarcoma pave 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), we believed a summary of this information would be valuable in detecting and managing future patients. In this paper we present the natural course, diagnosis and treatment of this disease as well ns 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 chloride polymerization area for 18 years. During medical screening of plant employees in April 1974, 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, and 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. Transjugular liver biopsy specimens were histologically interpreted as showing chronic inflammatory reoction and fibrosis, attributable to the patient's pievionsly known liver invo'vement 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 Logan 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 lives. Biopsy specimens demonstrated sinusoidal dilatation and Kupffer ceil prolifer ation in some of the specimens, but the diagnosis of angiosar coma could not be made. The patient did not return to work. His fatigue increased over the next two months and vague abdominal pain devel oped. In )anuary 1976, gross hepatosplenomegaly with a bruit over the liver and signs of high output cardiac decompensation wore detected. Liver-spleen scan and angiogram showed further enlargement of the previously identified lesions. An increase in arterial-venous shunting was demonstrated. At abdominal operation, direct examination revealed that the veins of the portal system were somewhat distended and that the surface of the liver was slightly nodular with some areas of bluish discoloration which wore somewhat serpentine in nature. There were multiple areas on the liver in which the tissue was slightly elevated with a central depressed area of a somewhat cyanotic appearance. A strong thrill could be felt when palpating the liver. The hepatic arteries 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 cells. Postopcratively. the cardiac decompensation was corrected and the spleen size was reduced to normal, but the liver size remained the same. Chemotherapy with doxorubicin, cyclo phosphamide and methotrexate was started, and the liver was reduced to its normal size but the biochemical liver test results remained abnormal. The reduction in liver size lasted four montlis during which the patient was unable to carry on nor mal activity without fatigue. Over the next four months there was a gradual increase in the size of the liver with 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 the spleen and lungs. BACKGROUND AND METHOD OF STUDY Vinyl chloride is the raw material with which the common plastic polyvinyl chloride is made. Vinyl chloride monomer (CH2CHCI) is a gas made by the reaction of ethylene and chlorine, which, when processed commercially, is polymerized in large 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 the cleaning process when the worker enters the vat and chips residue off the interior wall releasing pockets of gas. Vinyl chloride was initially thought to be completely harmless, and there was no limit to the exposure workers re ceived in the 1940s and early 1950s, however, a voluntary re striction of 50 parts per million was eventually adopted. The gas was considered to be $0 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 including skin, blood vessels and the reticuloendothelial system [24-26]. Evidence of liver injury was soon found [27,28], which was associated histologically with changes in the hepatocytes, fibrosis and sinusoidal dila tation [29,30]. In animal experiments, prolonged inhalation of vinyl chloride was shown to induce cancer in rats [31], Soon thereafter an employee of the 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 rare tumor. Since these workers were cared for by different physicians at different hospitals, this might still 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 attention. His memory ol the earlier patient with the disease led him to initiate a search for other cases among former employees and to institute a medical surveillance program of all present employees which was later supported by the National Cancer Institute and the University of Louis ville. 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 EC- 1707 OCCUPATIONAL CARCINOGENESIS-DANNAHER ET AL. hepatic venography and transjugulnr hepatic biopsy |20,32,33]. Patients with hepatic angiosarcoma seen by the staff of the Divisions of Hematology-Oncology and Digestive Diseases and Nutrition. University of Louisville, from January 1, 1974, to January 3. 1977. include those accrued through-the Vinyl Chloride Project as well as patients referred by physicians in the Louisville area and elsewhere, and a few patients found in a search of autopsy records and death certificates. A total of 11 patients have been studied, 10 of whom have had heavy industrial exposure to vinyl chloride. The other patient was a woman, referred from Florida, who had a history of pro longed use of hair spray containing vinyl chloride as a pro pellant. Only the 10 patients with occupational exposure to vinyl chloride are included in this report. In addition, data are derived from employee records of the Louisville vinyl chloride polymerization plant during its 35 year operation to the date of this report. RESULTS Epidemiology. The cohort for this analysis are the employees of the Louisville plant from its opening in 1942 to the.end of 1976. The employee population has been extremely stable and during this 35 year period a total of 1,855 persons have been employed. Of these, 1,184 are current employees and 671 are past em ployees. During the 35 year period, 167 members of the cohort died. Sixty-six of these died of heart disease and stroke. 39 of cancer, 19 of accidents and, nine of other disease; in 34 the cause of death could not be determined. Pri mary' brain cancer has been related to vinyl chloride exposure [34,35], and five of the 3f! deaths from cancer were from this cause. The mortality rate in our popula tion adjusted for age is approximately twice that ex pected [36]. Ten cases of hepatic angiosarcoma have been iden tified among our 1,855 employees during the 35 year period. All of these employees worked in areas of the plant with high vinyl chloride exposure. We divided these cases into a retrospective group--cases discovered by review of hospital and pathology records, and a surveillance group--cases discovered prospectively in the surveillance program. In the retrospective group, one case each was diagnosed in 1964,1967,1970,1972, 1973 and 1974. In the surveillance group, three cases were identified in 1974 and one in 1976. No other cases of angiosarcoma have been identified in the Louisville area. The incidence over the 35 year period in our cohort is 0.54 percent, equivalent to 15.4 cases per 10C,000 population per year. (Predicted annual incidence in the U.S. in 0.0014 cases per 100,000 population [37].) The mean age at the time of diagnosis was 47.6 years, with a range of 36 to 58 years. All patients were white men. reflecting employment patterns at the plant. The mean duration of exposure to vinyl chloride was 17.4 years, with a range of 11 to 28 years. The mean duration from first exposure to vinyl chloride to the lime of diagnosis of hepatic angiosarcoma was 19.9 years, with a range TABLE t Early Clinical Features Related to Hepatic Angiosarcoma in 10 Patients Symptoms Pain Fatigue Weakness Weight Loss Anorexia Indigestion Abdominal tuliness Melena Patients (no.) 5 54 3 3 t 1 1 Signs Hepatomegaly Splenomegaly Abdominal tenderness Hepatic bruit Patients (no.) 7 5 3 1 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 the patients had previously had viral hep atitis or exposure to any other known hepatotoxins. Clinical Features. The earliest clinical features which could be related to the angiosarcoma are presented in Table I. Pain was localized in the right upperubdominal quadrant or in the lower right hemithorax. In two of the patients the pain was acute, but in the others it ranged from *wo to six months in duration. Fatigue and weak ness had been present from one month to one year. Weight loss was significant, averaging 25 pounds over four and a half months. Hepatomegaly was the most common physical sign. The liver measured from 15 to 24 cm in total vertical span at the right mid-clavicular line by percussion. When splenomegaly was present the spleen was easily palpable 3 to 7 cm below the costal margin. Two patients, both in the surveillance group, had no physical signs, and one of these patients wa^ asymptomatic. Laboratory Findings. Hematologic evaluation at di agnosis showed three patients with normal complete blood counts. Mild anemia was found in five patients, but reticulocyte counts were not determined. Two of the patients had abnormal erythrocyte morphology with target cells and schistocytes. In one patient the anemia was combined with leukocytosis and in three patients with thrombocytopenia. Each patient with thrombocy topenia had splenomegaly. Two other patients had leukocytosis as their only hematologic abnormality. In two patients the bone marrow was examined: one was normal; the other demonstrated erythroid hyper plasia. . No patient was without some abnormality in at least one of the standard biochemical liver tests. Most of the values were only minimally abnormal initially. There was no consistent abnormality of any single test result or apparent pattern of groups of tests, although the al kaline phosphatase level was most frequently elevated. Hepatitis B surface antigen and alpha fetoprotein were not found in-four patients who were tested, and carcinoembryorric antigen was not present in two pa tients. February 1881 The American Journal of Medicine Volume 70 281 EC- 1708 OCCUPATIONAL CARCINOCENES1S-DANNAHER ET AL 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 usally 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 ara demonstrated in Figure 1. Splenomegaly was demonstrated in five patients by radionuclide scan. Hepatic arteriograms were obtained in six patients and demonstrated enlarged sinusoidal spaces in each of them, 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 hypovascularity 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 radiolucent area. 282 February 1981 The American Journal of Medicine Volume 70 EC- 1709 OCCUPATIONAL CARCINOGENESIS--DANNAHER ET AL. Figure 3. Gross section of an angiosarcomatous liver displaying multifocal solid and hemorrhagic cystic growth pattern with a large ruptured cyst. The radionuclide liver scar suggested involvement of the liver by a malignant process because of the neg ative defect, however, the peripheral location could be mistaken for a rib impression, porta hepatis or 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 pattern demonstrated by the hepatic arteriogram with the persistent peripheral tumor stain and central radiolucent area is strongly suggestive of hepatic angiosarcoma. Under unusual circumstances this appearance could mimic benign 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. Further 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 one 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 a variegated brownred-orange color. The surface may contain one or more purple-blue nodules with spongy consistency varying in size from 1 to 4 cm. In two cases these ruptured and caused hemoperitoneum. 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 autopsy. 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 (three 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 and 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 patients had histologic evidence of cirrhosis, two of whom had histories of heavy alcohol intake. One additional patient had fibrosis, and two patients had evidence of toxic hepatitis. 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 the 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 fivel 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 (one of four), bone (one I7 t0 February 1S81 The American Journal of Medicine Volume 70 283 OCCUPATIONAL CARCINOGENESIS-DANNAHER ET AL. * % -w fc> r** V r: -+ -r-. a,- **t...;*V**!). A *-1**,T* Flgure 4. Undifferentiated angicsarcoma with tumor giant cells replacing the usual histologic pattern of liver tissue. Hematoxylin and eosin stain; magnification X 500, reduced 50 percent. .> lf* * t .A -* . V. w* - 1 *- \ir< fc'r vv -Vi < ; > * v* ' U?*C V C~ * %*& fv. <% V*1 ->> C. 7. -v ^ * > "A* *A Figure 5. Multifocal minute angiosarcomatous growths are conspicuous among liver cell cords in locations distant from grossly visable tumors. Hematoxylin and eosin stain; mag nification X 500, reduced 50 percent. ot four), spleen (one of four), pleura (one of four), peri cardium (one of four), myocardium (one of four) and kidney (one of four). One patient had distant metastases 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 5,000 rads in five weeks TABLE II Major Clinical Events Occurring Prior to Terminal Events During the Course of Angiosarcoma Seen In 10 Patients Event Pneumonia Pleural effusion Staphylococcal septicemia Peripheral platelet destruction Microangiopathic hemolytic anemia Congestive heart failtre Renal failure Hypertension Gastrointestinal bleeding Hepatic failure Hemoperltoneum Fever PH*nU (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 tumor size, and one patient continues to respond to chemotherapy 56 months from the time of diagnosis. Various drugs have been used individually and in combination including fluorouracil, 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 blood were present without evidence of dis seminated intravascular coagulopathy or sepsis, and were possibly due to cell 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 Hepatic failure Gastrointestinal bleeding Ruptured tumor with hemoperltoneum Cardiac tamponade Hemothorax Potlont* (no.) 9 2 2 1 1 284 February 1981 The American Journal of Medicine Volume 70 EC- i7l1 OCCUPATIONAL CARCINOGENESIS-DANNAHER ET AL. 29 months, with a mean survival of 11,7 months. When measured from the time of first symptoms, the range of survival was five months to 34 months, with a mean duration of 14.9 months. Survival from the time of di agnosis was distinctly longer in the six patients who received chemotherapy (mean 15 months) than in the three patients who did not (mean five months). Preventive Measures. Shortly after the discovery of an epidemic of angiosarcoma in the Louisville vinyl chloride polymerization plant, new limitations of em ployee exposure to vinyl chloride were imposed at 1 ppm. Adherence by industry involved tighter seals on the polymerization vats and conduits which lessen leakage into the ambient atmosphere. The vat cleaning process is now performed by workers wearing protec tive respirators. A record keeping system has been ini tiated for all workers which relates length of employ ment and potential chemical exposure levels in each work environment to possible harm from vinyl chloride and other chemicals, so that a worker can be removed from exposure before he is likely to sustain injury. Since this 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 related 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 new cases of angiosarcoma have been discovered in the Louisville plant since 1976 among 1,184 current employees and 504 past employees followed at regular intervals for four years. COMMENTS The Louisville hepatic angiosarcoma experience un folds in many ways as a medical detective story. First, a fatal incident occurred. A diligent search for clues revealed vinyl chloride as a potential suspect. Further investigation and intimate cooperation among all 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 patients 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 the importance of the clinician in con trolling occupationally-induced cancer. The early fears of progressively increasing numbers of angiosarcoma cases related to vinyl chloride exposure [7,19-21] have not come to pass. The absence of new cases, however, should not ire looked on as the end of the story. The Louisville plant is one of the oldest vinyl chloride polymerization facilities in the nation, and these workers have had the longest potential exposure to the carcinogen. In addition, because of the early lack of concern regarding exposure levels, they also have had the highest exposure. We have seen 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 long incubation period. This problem may 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 the 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 be investigated. In the group of workers yvith 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 [46]. It is intriguing that angiosarcoma is so frequently associ ated with environmental factors, such as thorium dioxide [47-49], arsenic [50-52] and vinyl chloride, each of which results in stimulation of the hepatic sinusoidal lining cells [38], Other associated factors include hemochromatosis [53-55], copper [56] and estrogens [57], However, some cases discovered during early childhood are apparently congenital [58], When faced with a patient with angiosarcoma without one of these recognized factors, a diligent search for 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 arc essential in cancer research, the Louisville experience in vinyl chloride-associated hepatic angiosarcoma demonstrates how a careful clinical observation followed by a well conceived clinical approach may reveal an environ* February 1981 The American Journal of Medicine Volume 70 285 EC- 1712 OCCUPATIONAL CARCINOCENESIS-DANNAHER ET AL. mental etiology of neoplasia 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. The help of Mark Howzc, Betty Bailey, Bctsi Zimmerman, Lou Wilmot, Sr. Margaret LaPorte and Harvey Finkel, M.D. are greatly appreciated. REFERENCES 1. Wynder EL, Gori GB: Contribution of the environment to cancer incidence; an epidemiologic exercise.) Natl Cancer Inst 1977; 58; 825-832. 2. Fortwenglcr HP, |ones D, Tambnrro CH, Espinosa E: Factor VIII content as evidence for endothelial origin of vinyl chloride associate'' liver angiosarcoma (VCA), Fed Proc 1979; 38: 999. 3. Thomas LB, Popper H: Pathology of angiosarcoma of the liver among vinyl chloride--polyvinyl chloride workers. Ann NY Acad Sci 1975; 246: 268-277. 4. Creech JL, Johnson MN: Angiosarcoma of the liver in the manufacture of polyvinyl chloride. | Occupational Med 1974; 16:150-151, 5. Block JB: Angiosarcoma of the liver following vinyl chloride exposure. JAMA 1974; 229: 53-54. 6. Falk H. Creech JL, Heath CW, Johnson MN, Key MM: He patic disease among workers at a vinyl chloride polymer ization plant. 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