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Reprinted from the Journal of the American Medical Association October 7, 1974 Volume 230 Copyright 1974, American Medical Association Liver Damage and Angiosarcoma in Vinyl Chloride Workers A Systematic Detection Program Laszlo Makk, MD; John L. Creech, MD; Joseph G. Whelan, Jr., MD; Maurice N. Johnson, MD BFG65983 Liver Damage and Angiosarcoma in Vinyl Chloride Workers A Systematic Detection Program Laszlo Makk, MD; John L. Creech, MD; Joseph G. Whelan, Jr., MD; Maurice N. Johnson, MD Recently, Hve cases of hepatic angiosarcoma were found in Louisville. All of the patients had worked In a plant engaged in the production of polyvi nyl chloride (PVC) from vinyl chloride. A systematic health surveillance pro gram was instituted to detect existing liver damage or angiosarcoma and to find early signs of developing liver damage. A protocol was devised that be gan with on-site phlebotomies done in the plant and progressed to sophis ticated hospital studies, If important abnormalities were found. All of the 1,183 employees of the plant were tested. Two new cases of he patic angiosarcoma and three cases of portal fibrosis were discovered by this program at the Initial screening. It is hoped that continuous health moni toring will aid detection of liver abnormalities while still in a reversible or curable state. (,JAMA 230:64-68, 1974) ANGIOSARCOMA of the liver is one of the rarest human malignant neo plasms. The annual incidence in the United States is about 21 cases per year. Recently, seven cases of angio sarcoma were discovered in Louis ville. These patients were scattered in various hospitals in the area and were cared for by their personal physi cians. Initially, one of us noted the diagnosis of angiosarcoma of the liver on a death certificate and recalled that three years earlier he had per formed a biopsy of a liver with the same diagnosis. After he found that both of these patients had worked in a plant engaged in the production of polyvinyl chloride (PVC), careful data collection was begun. Thorough From the departments of pathology (Or. Makk), surgery (Dr. Creech), and radiology (Dr. Whelan). St. Anthony Hospital, and the Medical Department (Drs. Creech and Johnson), B. F. Goodrich Co., Louisville. Reprint requests to 1313 St. Anthony Place, Louisville. KY 40204 (Dr. Makk). search of plant and area hospital medical records resulted in the dis covery of three more cases from ne cropsy reports recorded over a tenyear period. Two additional cases were diagnosed by biopsy in the past two months as a result of this pro gram. Each of the patients with angiosar coma who were under our care, and some without angiosarcoma, had fi brosis of portal areas and other path ologic changes apparent on liver biopsy specimens. None of these pa tients had any specific abnormal find ings on physical examination or rou tine laboratory tests. In view of this, a systematic detection program was devised and instituted with three ob jectives: (I) to find any presently ex isting liver damage or angiosarcoma in workers exposed to vinyl chloride or its polymers, (2) to detect early liver damage, if possible while in a re versible state, with continuous health monitoring, and (3) to provide infor mation for preventive measures. Materials and Methods A program was designed whereby large numbers of workers could be screened for liver disease with rela tive ease. The significant abnormal ities were evaluated by a combined clinical, comprehensive laboratory, and roentgenographic study. The re sults of this evaluation served as a basis for the treatment of the pa tients (Fig 1). The initial laboratory procedure for detection was a 12- or 18-factor automated chemical analy sis. The 12-factor analysis consisted of tests for the following: calcium, in organic phosphorus, glucose, blood urea nitrogen (BUN), uric acid, cho lesterol, total protein, albumin, total bilirubin, alkaline phosphatase, lactic acid dehydrogenase (LDH), and se rum glutamic oxaloacetic transami nase (SGOT). The 18-factor analysis consisted of the preceding plus cre atine phosphokinase (CPK), creati nine, and serum electrolyte determi nations. The blood was drawn at the plant's Medical Department; trans portation, centrifugation, and te-i determinations were done promptly. If the initial laboratory re-nits were normal, the tests were repeat,-i in three months. If abnormal it i.- n..t related to the liver were found l>\ m\ of the screening procedures, they were followed up according to their severity. If one liver-related ai,n..r- 64 JAMA, Oct 7, 1974 e Vol 230, No 1 Liver Damage--Makk et at BFG65984 Plant Population Fig 1.--Liver disease detection protocol. mality was found, the 12-factor anal ysis was repeated in three weeks. If the single abnormality presisted, or if two or more liver-related abnormal ities were found on fhe initial labora tory tests, the patient underwent a comprehensive examination consist ing of tests for the following values: a 12-factor automated chemical analy sis, serum electrophoresis, LDH isoenzymes, fractionated alkaline phosphatase, direct and indirect bili rubin (if total level was elevated), se rum glutamic pyruvic, transaminase (SGPT), y-glutamic transpeptidase (GGTP), isocitrate dehydrogenase (ICD), a-fetoprotein (fetoglobulin), and carcinoembryonic antigen (CEA). Also, a complete blood cell count (CBC), platelet count, chest roentgen ogram, and liver and spleen scan were done. Abnormalities found in the initial 12-factor chemical analyses indicat ing the need for comprehensive pro Table 1.--Liver Enzyme and Bilirubin Results Test Alkaline phosphatase, mil (milliunits)/ml y-Glutamlc transpeptidase, mll/ml Serum glutamic oxaloacetic transaminase, mll/ml Bilirubin, mg/100 ml Serum glutamic oxaloacetic transaminase, mll/ml Isocltrate dehydrogenase, mll/ml Lactic dehydrogenase, mll/ml No. of Patients Studied 72 70 68 72 73 59 72 No. (%) With Abnormal Values 35 (49.4) 31 (44.3) 19 (29.8) 19 (26.4) 13 (18.0) 9 (18.0) 8 (11.1) Normal Range 3-85 6-28 4-25 0.15-1.0 12-40 0-7 90-225 Abnormal Range 87-135 29-575 27-559 1.1-2.6 48-150 8-88 237-475 files were grouped according to the following work areas: (1) PVC pro duction, (2) synthetic rubber produc tion, and (3) all others (including maintenance, shipping, laboratory, and other salaried employees). Liver Abnormalities Dictated Hospital Studies If abnormal scan or other findings suggested serious liver disease or the possibility of angiosarcoma, the pa- JAMA, Oct 7, 1974 Vol 230, No 1 Liver Damage--Makk et al 65 BFG65985 Table 2.--Twelve-Factor Analysis Abnormalities and Comprehensive Screening Cases According To Work Area 12-Factor Analysis No. (%) Work Area Polyvinyl chloride production Synthetic rubber production All other Total Total No. 274 203 706 1,183 Abnormality 59 (21.5) 58 (28.6) 189 (26.7) 306 (26.7) Profile Needed 26 (9.8) 14 (6.9) 35 (4.9) 75 (6.3) Case No. Diagnosis Angiography 1 Angiosarcoma Tumor right lobe ^ ~Filli cirrhosis 2 Angiosarcoma Tumor, both lobes'--Filli and cirrhosis 3 Portal Fibrosis, fatty change 4 Portal Fibrosis, moderate Normal ^ "S5ug ~ ~Sug 5 Portal Fibrosis, slight Normal ^ " Sug 6 Normal Normal ^ ~ Nor 7 Normal ' " Nor *f Indicates elevated values; 4, depressed values. TN Indicates normal values. Fig 2 --Technetium 99m sulfur colloid liver scan, anterior view. Typical filling defect in right lobe of liver. Fig 3 --Hepatic arteriogram, six seconds. Circumferential tumor vessels are present in right lobe of liver (arrows). Main hepatic artery is normal size. Intrahepatic vessels are small and tortuous suggesting cirrhosis. Fig 4.--Hepatic arteriogram, ten seconds, portal venous phase; Circumferential tumor stain is present with a central area of radiolucency (arrows). Stain persisted through the late portal hepatogram phase, up to 34 seconds. tients were hospitalized and hepatic panangiography was performed, con sisting of hepatosplenic arterio gram and phlebogram with free and wedged hepatic pressure measure ments. The hepatic arteriogram was performed by the Seldinger tech nique.1 A mixture of diatrizoate so dium and diatrizoate meglumine (Renografin-76) was used as contrast medium. If the angiograms demon strated findings suggestive of a tu mor, open-liver biopsy was advised with consideration of hepatic lobec tomy, if so indicated at exploration. If angiosarcoma was limited to one lobe, a biopsy specimen of the unin volved lobe was obtained first to eval uate the extent of fibrosis or other damage and render diagnosis by fro zen section. Then, a biopsy specimen of the tumor was obtained and stud ied likewise. If the uninvolved lobe had no no table disease, lobectomy of the neo plastic lobe was to be performed. If the nonneoplastic lobe was diseased (ie, showed fibrosis to a degree that lobectomy might have led to ii\.r failure), or if the angiosarcoma in volved both lobes, chemotherap> a as to be considered. On biopsy, a a edge and deep Vim-Silverman ne.oie specimen was obtained from .h lobe when no gross tumor was f..imd. In the presence of neoplasm, "mv wedge biopsies were taken. Results Screening profiles were from 1,183 employees by the I if- r is. 66 JAMA, Oct 7, 1974 Vol 230, No 1 Liver Damage--Ma -t e BFG65986 Table 3.--Tissue, Roentgenologic, and Laboratory Examination Correlation Liver Scan 'Filling defect and cirrhosis 'Filling defect, both lobes 'Suggestive of cirrhosis 'Suggestive of cirrhosis "Suggestive of cirrhosis 'Normal " Normal Alkaline Phosphate t y-Glutamic Transpetidase ft T T t t T t______ T t t N N Level of Serum Glutamic Pyruvic Transaminase T Bilirubin t NN Tt tN NN NN NN Serum Glutamic Oxaloacetic Transaminase t t t N N N N Lactic Dehydrogenase Nt T N N N N N Platelet Count l t N N N N N factor chemical analysis. Of these, 75 (6.3%) had either two liver-related ab normalities on the initial screening or one such abnormality that persisted. These patients had comprehensive evaluations. One patient had initial screening in the plant, further eval uation and biopsy elsewhere, and then was transferred to our institu tion for further studies. Results of al kaline phosphatase, GGTP, SGPT, bil irubin, SGOT, ICD, and LDH examinations are listed in Table 1. Significant Biochemical Findings Other tests of the comprehensive liver profile yielded the following sig nificant results: moderately elevated total protein values were found in three patients with a similar eleva tion in y-globulin content. Serum electrophoresis showed slight to mod erate increase in y-globulin in 11 pa tients. The /3-globulin value was slightly lowered in six patients. In 32 patients with elevated alka line phosphatase values, 15 had in creased liver fractions. In 37 patients with normal levels of alkaline phosphatase, fractionation was also performed. Thirteen showed relative elevation of liver fractions. Eight of 72 patients (11.1%) showed elevated values for total LDH. Four of these had isoenzyme 4; two, isoenzyme 5; and one, isoenzyme 3 elevation; one had normal isoenzyme proportions. Of 64 cases with normal LDH val ues, 44 showed relative elevation in level of isoenzyme 4 (68.7%); two, rela tive isoenzyme 5; and one, relative isoenzyme 1. Fetoglobulin determinations gave normal results in all cases. Results of carcinoembryonic antigen radio immunoassays were normal in all pa tients, with one marginal result in a patient who smoked. Complete blood cell counts disclosed normal values for hemoglobin, hematocrit, red blood cell (RBC) count, and corpuscular indexes in each patient. Four patients had slight to moderate granulocytosis. One patient showed relative lym phocytosis. Twenty-three patients showed slight, and seven moderate, monocytosis. Three patients had mod erately increased eosinophil counts. One patient had thrombocytopenia with a platelet count of 98,000/cu mm, and another had thrombocytosis with a count of 750,000/cu mm (nor mal range, 140,000 to 440,000). The number of 12-factor abnormalities and comprehensive profiles according to work areas is listed in Table 2. Radiological Studies Seventy-four patients had liver scans: 11 of these scans (14.8%) were abnormal, and 2 were borderline. Six patients had filling defects (Fig 2). Three of these and another five pa tients had irregularities suggestive of cirrhosis. Spleen scans were per formed concurrently with liver scans in 71 patients. Three patients had had splenec tomies in the past. Nine patients (12.7%) had enlargement of the spleen to 22 cm (normal spleen size is consid ered less than 14 cm in length-'). Splenomegaly with abnormal liver scan was present in three patients. Hepatic panangiography was per formed in seven patients. By pan angiography, two of the liver scan filling defects were found to be tu mors (Fig 3 and 4). The anomalous po sition of the gallbladder in one case, and dilatated short gastric and collat eral portal veins in another correlated with the defects on the scans. The other angiograms were normal. Of the six splenic arteriograms, two showed splenomegaly; one of these with multiple splenic aneu rysms and the other, intrasplenic ar terial strictures. The other four were normal. Surgical Findings Exploratory laparotomy was per formed in seven patients; in two, an giosarcoma was found. Resection could not be carried out in one patient because of the extent of neoplasm. In the other patient, angiosarcoma was limited to one lobe, but because of portal fibrosis in the other lobe, resec tion was deferred. In three patients, varying degrees of portal fibrosis was found on lap arotomy. Of the remaining two pa tients, one had a cholecystectomy, the other an incisional hernia repair. Liver biopsy was performed con comitantly on each. Both of these liv ers were essentially normal on biopsy and on laboratory testing. Correla tion of biopsy, roentgenographic, and laboratory findings is given in Table 3. ' JAMA, Oct 7, 1974 Vol 230, No 1 Liver Damage--Makk et al 67 BFG65987 Chest roentgenograms and labora tory examinations not related to liver function disclosed only occasional ab normalities. These were followed up appropriately. All were within the findings expected from a screening of this size male adult population. No lung tumors were found. Comment Nonneoplastic liver damage in polyvinyl chloride production workers has been reported.34 Acro-osteolysis was also observed in such workers.5 Viola et al6 reported the development of skin, lung, and bone neoplasms in rats exposed to vinyl chloride. Maltoni: reported hepatic angiosarcomas and other neoplasms in rats exposed to high doses of vinyl chloride. To our knowledge, the Louisville cases are the first recognized human angiosar comas of the liver associated with working in vinyl chloride monomer polymerization. Creech and Johnson* reported the first angiosarcoma of the liver among vinyl chloride workers. Block* also reported on the subject; one of our cases is included in his re port. The report of Falk et al (p 59) on the epidemiology of this disease also includes two cases of angiosar coma discovered with our program. As the results indicate in Table 2, the percentage of abnormalities on the 12-factor examination seems higher than would be expected among a presumably healthy working popu lation. These results also indicate that a somewhat smaller proportion of persons engaged in PVC production had abnormalities on initial 12-factor analysis than either those who worked in synthetic rubber produc tion or all other workers in the plant. However, considerably larger num bers and percentages of the PVC workers had liver disease serious enough to warrant comprehensive profiles. All the patients who needed angiography, the two patients with angiosarcoma, and two of the three with portal fibrosis had worked in PVC production. In our experience, the logistics of this program worked well from on site screening to sophisticated test ing. This surveillance discovered two new, otherwise unsuspected angiosar comas of the liver and three cases of portal fibrosis. The good correlation between normal liver biopsies and es sentially normal liver function tests in cases 6 and 7 was reassuring. In addition this program provided a wealth of base-line liver function test results and other health information. These data formed the basis of a con tinuing health monitoring program for these workers. GGTP Reflects Extent of Damage Of the liver function tests, the GGTP determination seemed to be most useful in detecting abnormal ities and reflecting the extent of liver lesions by the degree of elevation. Alkaline phosphatase, SGPT, SGOT, LDH, and bilirubin tests were also useful. The large number of LDH* isoenzyme elevations are noteworthy, but they merit further study before specific significance can be attached to them. Fetoglobulin and carcinoembryonic antigen determinations were normal. No test was specific for angiosarcoma. The liver function studies appeared to reflect quite well the extent of liver damage, except in patient 2, where this correlation was poor. He had extensive angiosarcoma and only slight elevation in LDH val ues on the initial screening that per sisted. This prompted his astute per sonal physician to request more sophisticated studies and biopsy ex amination. It is therefore quite im portant than even borderline abnor malities be carefully followed up. Scans and Angiograms Liver scans and angiographic stud ies corresponded well with results of laboratory tests and biopsy examina tions in the detection of cirrhosis, even in early stages. When roentgenographic studies indicated cirrhosis, the concomitant histopathologic ex amination disclosed a peculiar fibro sis of the portal areas instead of cir rhosis. It is our understanding that when communications refer to cir rhosis in the context of this condition, the histological findings are those of a peculiar portal fibrosis and Kupffer cell hyperplasia. Hepatic panangi ography with pressure measurements as described by Viamonte et al10 was very helpful in the differentiation of neoplastic from nonneoplastic lesions that appeared as a filling defect on scanning. It also proved helpful in the preoperative evaluation of the extent of the tumor. In addition to angiogra phy in selected cases, we are planning liver biopsies through the right jugu lar vein as described by Rosch et al." The experience gained from this study enabled us to modify our method. We added GGTP and SGPT determinations to the 12-factor initial examination. Tests for fetoglobulin, ICD, and carcinoembryonic antigen as well as electrophoresis were de leted from our comprehensive profile. Until specific tests for hepatic angio sarcoma or vinyl chloride-induced liver damage are available, in our ex perience such a surveillance program of laboratory testing, roentgenographic examinations, and clinical evaluation will help to detect liver damage in an early, possibly rever sible or curable state. James T. Kurfees, MO. Anchorage. Ky, gave permission for inclusion of the results from one of his patients in this study. References 1. Seldinger SI: Catheter replacement of the needle in percutaneous arteriography. Acta Ra diol 39:368-376, 1953. 2. Siegel RM, Becker DV, Hurley JR: Eval uation of spleen size during routine liver imag ing with *"Tc and scintillation camera. J Nucl Med 11:689-692,1970. 3. Marsteller HJ, et al: Chronisch-toxische-leberschaden bei arbeitem in der PVC-production Dtsch Med Wochentehr 98:2311-2314, 1973. 4. Suciu T, Drejam T, Valaskai M: Etude des maladies dues au chloride de vinyl. Med Lar 58:261-271, 1967. 5. Wilson RH, et al: Occupational acroosteolysis: Report of 31 cases. JAMA 201:577, 1967. 6. Viola PL, Bigotti A, Caputo A: Oncogenic response of rat skin, lung, and bones to vinyl chloride. Cancer Ret 31:516-522, 1971. 7. Maltoni C: Exhibit 6: Judge Myatt's hearing on oncogenic potential of vinyl chloride 43-63. 1974. 8. Creech JL, Johnson MN: Angiosarcoma of liver in the manufacture of polyvinyl chloride ./ Occup Med 16:150-151, 1974. 9. Block JB: Angiosarcoma of the liver follow ing vinyl chloride exposure. JAMA 229:53-54. 1974. 10. Viamonte MJ, Warren WD. Foreman JJ: Liver panangiography in the assessment of por tal hypertension in liver cirrhosis. RaduJ Clin North Am 8:147-167, 1970. 11. Rosch J, et al: Transjugular approach to liver biopsy and transhepatic cholangiography. N Engl J Med 289:227-231, 1973. 68 JAMA, Oct 7, 1974 Vol 230, No 1 Liver Damage--Makk et al Printed and Published in the United States of America BFG65988