Document 0gzaLRJ3znp5gXwgrezvGprGb

\^<^fo^AocuicZ&) To From INTEROFFICE MEMORANDUM Bays Barr Subject Date 13 September 1983 Edwards Case Insurance (LOtiaiii or OVMrtmtnl) Regulatory Response (Location. OritAititlefl, or 0MMmAl} I enclose 2 copies of an article by Evans, et al, frrm Hlstopatholoov. 7 377 (1983) which I just obtained, and which you may wTsfc to pass on to Ed Edelsteln. These authors state that they found carcinoma In two of five cases of anglo among BP workers. They also reference other supporting reports. See especially the discussion on page 386. This may be of Interest In the Edwards Case. JTBicsb Enclosure (320) AP00019397 kt ina >47 M. Vs na. Ihe the ntd no- fibiopaihoiogy 1983, 7. 377-388 Angiosarcoma and hepatocellular carcinoma in vinyl chloride workers D. M. D. EVANS, W. JONES WILLIAMS & I.T.M.KUNG Histology Department, Uandough Hospital and Department of Pathology, University of Hong Kong Accepted for publication 23 September 1982 Evans D.M.D.. Jones Williams W. & Kuno i.T.M. {1983) Histopethology 7, 377-388 Angiosarcoma and hepatocellular carcinoma ia vinyl chloride workers The livers from five vinyl chloride workers are described. They show angioformative and hepatocellular growth disturbance in varying proportions: angiosarcoma in four cases, liver cell hyperplasia in all. hyperplastic nodtiles in three cases and hepatocellular carcinoma In two cases. In one case the transition between hyperplSshc nodule and hepatocellular carcinoma is demonstrated. The relationship between these changes and vinyl chloride exposure is discussed, with evidence that they are causally related. Keywords: liver tumours, angiosarcoma, hepatocellular carcinoma, vinyl chloride, occupational cancer Introduction Polyvinyl chloride (PVC) had been produced commercially for 40 years by poly merization of vinyl chloride before it was discovered that the tatter substance was carcinogenic (Creech & Johnson 1974). Although many different tumour types have been described in animals (Viola, Bigotti & Caputo 1971, Maltoni St Lefemine 1975, Keplinger et af, 1975) angiosarcoma of the liver has been the main type described in humans following vinyl chloride exposure (Heath, Falk & Creech 1975. Lee & Harry 1974, Makk et al. 1976. Popper et al. 1978). Angiosarcoma of the liver (ASL) is so rare that only about 200 cases have been reported in the world literature (British Medical Journal 1981). However, a number of papers have now been published indicating that hepatocellular carcinoma (Gokel, Liebezeit St Eder 1976) and cancers at other sites (Monson. Peters St Johnson 1974, Tabershaw St GafTey 1974, Nicholson et al. 1975, Duck St Carter 1976, Waxweiiler Address for correspondence: Dr D.M.D.Evans, MD. FRCP, FRCPath, Histology Department, Llandough Hospital, Penarth, Glamorgan CF6 1XX, Wales. 0309-0167/83/0500-0377 *02.00 1983 Blackwell Scientific Publications 377 378 D.M.D.Evans et ah et ah 1976, Dyr&i et ai. 1976, von Reinl, Weber & Greiser 1977). may also result from vinyl chloride exposure. It is of some importance to determine whether angiosarcoma is the only type of liver cancer to be produced by vinyl chloride. As an industrial disease it has medicolegal implications. We accordingly report our investigations into the histological characteristics of liver tumours occurring in five vinyl chloride workers to demormtate the diversity of histological types. One of the cases has been previously reported (Smith, Williams & Evans 1976). Materials and methods The study is based on liver biopsy and autopsy material obtained at Liandotigh Hospital between 1973 and 1981 from live male workers who had been exposed to vinyl chloride before it was known to be a health hazard. An autopsy was performed on every case. The degree of exposure was assessed from the very complete works records of the continuous monitoring for vinyl chloride in the atmosphere where the men were working. The tissues obtained were fixed in 10% buffered formalin, processed and embedded in paraffin. Sections were stained by H & E, Van Gieson and retieulin stains. In addition glutaraidehyde fixed material from two cases was examined by electron microscopy. Results The results are summarized in Table 1 which gives details of vinyl chloride ex posure. case 1 From the age of 29 years this worker was exposed for a period of only 3} years to vinyl chloride at a constant working level of over 200 parts/10*. At tho>age of 35 years liver biopsy revealed a vascular lesion consistent with angiosarcoma. Alpha-fetopro tein was not detectable in his serum 10 days before death. He died at the age of 37 years from liver failure. Autopsy disclosed a multifocal vascular haemorrhagic liver tumour showing the characteristic histological features of angiosarcoma (Smith et ah 1976). One part of liver not affected by tumour showed portal tract fibrosis and fiver cell hyperplasia, characterized by twin cell plates. The lobular architecture on the whole was still preserved. There was no nodule formation and no liver cell dysplasia could be found. Angiosarcoma cells were present in lung vessels but no metastastic tumour deposits were seen. case 2 From the age of 44 years this worker was exposed to vinyl chloride over a period of 21 years. No record of serum alpha-fetoprotein estimation was found. At the age of AP00019399 from ;pe of cdico* ogical istrate 'orted dough >sed to ssessed hlortde ixed in stained laterial ide ex- o'ears to .35 years fetopro of 37 gic liver ith et al. .md liver : on the 'iysplasia itastastic period of te age of Vinvi chloride and liver tumours 379 65 years he died with spontaneous haemoperitoneum from a liver tumour. The liver at autopsy contained multiple large masses of vascular haemorrhagic liver tumour. Deposits of haemorrhagic tumour tissue were present in lymph nodes of the porta hepatis. On light microscopy the tumour was found to be an angiosarcoma. The rest of the liver showed features similar to Case 1, displaying portal tract fibrosis and diffuse regenerative hyperplasia of hepatocytes with preserved lobular architecture and no nodule formation. However, an occasional focus of liver cell dysplasia was observed. On electron microscopy malignant vascular endothelial ceils were clearly distinguished from dysplastic hepatocytes. CASE 3 * From the age of 26 years this worker was exposed to vinyl chloride for a period of 24 years. Four months before his death at the age of 57 years he developed lethargy, anorexia and weight loss, followed by jaundice and evidence of increasing liver failure from which he died. Serum alpha-fetoprotein 10 days before death was 19 mg/I (normal 30 mg/I). At autopsy the liver was enlarged (2900 g) and contained multiple masses of vascular haemorrhagic tumour with large blood-filled spaces, mainly in the right lobe (Figure 1), which was shown histologically to be an angiosarcoma. Blocks from the liver far away from the tumour again showed portal fibrosis. Liver ceil hyperplasia was more exuberant than in the two previous cases. Hyperplastic hepatocytes formed nodules (Figure 2) which encroached upon pre-existing lipofuscirtladen liver cells. The general microanatomy of the liver was still well maintained, precluding the diagnosis of cirrhosis. Small foci of liver cell dysplasia (Figure 3) were readily detectable. No metastatic tumour deposits were found. AP000J9400 3X0 D.tVf.D.Evans ct a/. Figure 2. Case 3. Hyperplastic nodule in liver, a has an ill-defined circular outline. Twin cell plates can be seen towards the bottom and left of the picture. H A E. x too. CASH 4 From the age of 30 years this worker was exposed to vinyl chloride over a period of 12 years. No record of alpha-fetoprotein estimation was found. Shortly before his death at the age of 48 years he developed portal hypertension with bleeding varices which were controlled by sclerotherapy. Death was from haemoperitoneum due to spontaneous rupture of an apparently single vascular haemorrhagic liver tumour which replaced nearly all the right lobe of the liver. Histological sections from different areas of this lesion however disclosed two different tumours, an angio sarcoma (Figures 4 & 5) and a hepatocellular carcinoma (Figure 6). No alphafetoprotein was detected in paraffin sections. In the tumour-free areas of the liver, hyperplastic nodules similar to those seen in Case 3 were again recognized, in addition to portal tract fibrosis. No metastatic tumour deposits were found. Figure 3. Case 3. Liver cell dysplasia. There Is considerable variation in nuclear size, shape and chromatin pattern. H A E. x 225. Figure 4. Case 4. Angiosarcoma. The tumour tissue contains large vascular spaces. H A E. x 40. Figure 5. Case 4. Angiosarcoma, showing characteristic pattern of tumour extending between liver cell plates. H A E. x 225. Figure 6, Case 4. Hepatocellular carcinoma. The tumour cells can be recognized as hepatocylic. The pattern is partly trabecular (upper tight) and partly more irregular, with much cellular pleomorphism. H A E. x 144. ZOfr6H)OOdV 09fd Jt OI)/(DO ` J9.M| uf. oP >| pus ad! 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Vinyl chloride exposure Exposure to vinyl chloride Age Survival Duration at after 1st death, exposure Total Period Level Case (yr) (yr) (yr) <yr) (parts/io> Constancy Cause of death Histology 1 37 ft a 65 28 3 37 31 4 48 18 3 54 17 3t 3i 200+ Constant Hepatic failure Angiosarcoma. Regenerative liver cell hyperplasia 21 1 200+ Constant Haemoperitoneum Angiosarcoma. 18 + 50-200 Constant Uivercell t + O-20 Intermittent regerative hyperplasia and dysplasia 24 IS 6 200+ Constant 50-200 Constant Hepatic failure Angiosarcoma. Hyperplastic liver cell nodules and liver cell dysplasia 12 8 50-200 Intermittent Haemoperitoneum Angiosarcoma. J 10-25 Constant Hepatocellular 1 25-SO Intermittent carcinoma and hyperplastic nodules 8 2* 200 + Constant Hepatic failure Hepatocellular 5* 50-200 Constant carcinoma and hyperplastic nodules and liver cell dysplasia Discussion The great rarity of angiosarcoma facilitates the recognition of a clustering effect due to carcinogens such as Thorotrast (thorium dioxide). arsenic and v inyl chloride, in 1963 an angiosarcoma of liver (ASL) panel, set up by the Employment Medical Advisory Service (EMAS), commenced to monitor the occurrence of this tumour in Figure 9. Case 5. Malignant hepatocytic nodule (fowcr left) with necrotic tumour tissue (upper right). H4E. x too. Figure 9. Case 5. Hepatocellular carcinoma showing trabecular pattern, in places becoming irregular. H & E. x 108. APOOO19406 386 D.M.D.Evans et a!. the British population, in the I5*year period 1963-1977 the ASL panel (Baxter et al. 1980) found only two cases of angiosarcoma in which there was a history of significant exposure to vinyl chloride out of a total of 35 cases; one of the two was Case 1 above, leaving only one other such case in Britain. Four additional cases had been exposed to only minimal levels of vinyl chloride, suggesting that even low level exposure .could be significant in susceptible individuals, a possibility envisaged in a leading article (British Medical Journal 1974). In animal studies more than one cell type has been shown to be affected by ex posure to vinyl chloride. Maltoni & Lefemine(i975) found angiomas, angiosarcomas, hepatomas, hepatoblastomas, zymbal gland carcinomas, neuroblastomas, skin carcinomas and mammary gland carcinomas in rats, mice and hamsters exposed to vinyl chloride. Keplinger et al. (1975) exposed animals of the same species to vinyl chloride and produced various tumours, including angiosarcoma of the liver and liver cell carcinoma. Gokel (1976) ascribed a case of human liver cell carcinoma to vinyl chloride exposure. A number of workers in different countries have reported an increased incidence of various types of cancer in vinyl chloride workers, particu larly of liver, pancreas, alimentary tract, lung, brain, lymphatic and haemopoietie systems. (Monson et al. 1974, Tabershaw & Gaffey 1974, Nicholson et at. 1975, Duck Sc Carter 1976, Waxweiller et al. 1976, Byr6n et al. 1976, von Reinl et al. 1977). The livers from the five vinyl chloride workers in the present series show arigioformative and hepatocellular growth disturbance in varying proportions. Angio sarcoma is present in cases 1 to 4. Liver cell hyperplasia is present in ail five cases, with hyperplastic nodules in the last three. Hepatoceilular carcinoma is present in cases 4 and 3. There is evidence that hyperplastic nodules are precursors of hepatocellular carcinoma. This is most commonly seen in animal experiments employing chemical carcinogenesis, e.g. nitrosamines to induce liver cell cancer (Medline & Farber 1981). It is well known that tissues with a high turnover rate stand an above average chance of developing malignancy. The same applies to tissue that has become hyperplastic. Cirrhosis of liver with subsequent hepatocellular carcinoma is a relevant example. Liver cell hyperplasia, in addition to portal fibrosis has been seen regularly in livers alfected by vinyl chloride, although cirrhosis as such is not a commonly described feature (Berk et al. 1976). It is therefore not surprising that these livers should be prone to develop hepatocellular carcinoma (HCC). The finding of hyperplastic nodules strengthens the link between HCC and vinyl chloride; lending more support to our belief that the two are causally related and not just the result of coincidence. Further evidence is provided by the liver cell dysplasia which was seen in four of Jhe present cases. Liver cell dysplasia has been recognized as a premalignant change associated with liver ceil cancer (Anthony, Vogel & Barker 1973). This is a common i phenomenon in HBsAg positive livers with HCC, whether cirrhosis is present or not (Ho, Wu St Kung 1981). It is therefore entirely possible that vinyl chloride can induce liver cell dysplasia and hyperplastic nodule formation, both terminating in HCC. There is thus a growing body ofevidence that vinyl chloride is a carcinogen affecting not only the endothelial cells of the liver, but also a variety of other cell types. It is APOOOf9407 i .. . -r et oL lificant above, kposed .posure leading by *.comas, 5, sfcin lOicd to to vinyl ver and toma to eported particuopoietic d, 1975. I 1977). v angiongioVe cases, esent in oediular chemical er 1981). average become ma is a <een seen : is- not a hat these riding of ; lending he result n four of it change i common nt or not m induce jHCC. affecting pes. It is Vinyl chloride and liver tumours 387 of note that angiosarcoma was originally thought to be the most common type of liver cancer produced by Thorotrast, a carcinogen which, like arsenic and vinyl chloride, can also cause a lesion resembling non-cirrhotic portal fibiosis (Patrick & McGee 1980). However in the more recent cases of Thorotrast-induced liver tumours, hepatomas have exceeded angiosarcomas (Baserga, Yokoo & Henegar i960, Ishak J976, Battifara 1976). This s attributed by Baserga et at. (196c) to the longer mean induction period for liver carcinomas (19.4 + 4.0 yr) than for liver sarcomas (12.6 4-3 yrtWe should therefore have an open mind to the possibility that vinyl chloride may eventually be found to promote not only angiosarcoma of tlte liver and hepato cellular carcinoma but also other tumour types comparable in range to those caused by Thorotrast. Acknowledgements We wish to acknowledge the help given by B.P. Chemicals Ltd, Sully, and in particular Dr David Williams for information on vinyl chloride exposure; Dr Paul Smith and Dr Peter Beck for access to clinical information; Dr Barrat Jasani for undertaking immunoperoxidase tests far alpha-fetoprotein; Mr Brendan Cleary for assisting in the photo-micrography; Mr Robert Boothby and Mr David Llewellyn for processing the photo-micrographs; and Mrs Andrea Holloway for typing the manuscripts. References Anthony P-P-, Vogel C.L. A Barker L.F. (1973) Liver cell dysplasia: a premalignant condition. Journal of Clinical Pathology 26, 217-223 Baseroa R., Yokoo H. A Heneoar G.C. (i960) Thorotrast-induced cancer in man. Cancer 13, 1021-103! Battifora H.A. (1976) Thorotrast and tumours of the liver. InHepatocellular Carcinoma, p. 87, eds K.Okuda A R.LPeiers. John Wiley, New York Baxter P.S., Anthony P.P., Macsween R.N.M. A Scheuer PJ. (1980) Angiosarconla of the liver: annual occurrence and aetiology in Great Britain. British Journal of Industrial Medicine 37, 213-221 Berk P.D., Martin J.F., Young R.S., Creech J., Seukoft I.J., Falk H., Watanabe P., Popper H. A Thomas L. (1976) Vinyl-chloride-associated liver disease. Annals of Internal Medicine 84, 717-731 British Medical Journal (1974) More facts on vinyl chloride and cancer. Editorial. British Medical Journal lr, 486-487 British Medical Journal (1981) Angiosarcoma of the liver: a growing problem? Editorial. British MedicalJournal 282, 504-303 Byr8n D., Engholm G-, England A. A Westerholm P. 11976) Mortality and cancer morbidity in a group of Swedish VCM and PVC production workers. Environmental Health Perspectives 17 167-170 Creech J.L. A Johnson M.N. (1974) Angiosarcoma tn the manufacture of polyvinyl chloride. Journal ofOccupational Medicine 16, 130--151 Duck B.W. & Carter J.T. (1976) Vinyl chloride and mortality? Lancet il, 193 26 APOOO19408 388 D.M.D.Evans ei al. Corel J.M., Liebezeit E. A Eoer M. (>976) Haemangiosarcoma and hepatocellular carcinoma or the liver following vinyl chloride exposure. Virchow a Archives. 4 Pathological Anatomy 37a. 195-203 Heath C.W., Falk H. 4 Creech J.L. (1975I Characteristics of cases of angiosarcoma of the liver among vinyl chloride workers in the United States. Annals cf Sew York Academy of Science *46, 231-236 He.'., Wjj PC. A KuncT.M. f 19S r > An autopsy study of hepatocellular carcinoma in Hong Kong. Pathology 13, 409-416 Ishak K.C. (1976) Mesenchymal tumours of the liver, in Hepatocellular Carcinoma, p. 296, eds K.Okuda A R.L.Pcters. John Wiley, New York Kepunoer M.L.. Goode J,W., Gordon D.E., Calanora J.C. 4197S) Interim remits of exposure of rats, hamsters and mice to vinyl chloride. Armais of New York Academy of Science 246, 219-224 Let F.I. St Harrv D.S. (1974) Angiosarcoma of the liver in a vinyl chloride worker. Lance/ I, 1316-1318 Makk L., Delmorb F.. Creech J.L., Ogden L.L., Fadell H,, Sonoster C.L., Clanton J., Johnson M N. & Christorhbrson W.M. (1976) Clinical and morphologic features of hepatic angiosarcoma in vinyl chloride workers. Cancer 37, 149-163 Maltoni C. Sl Lefimine G. (1975) Carcinogenicity bioassays on vinyl chloride: current results. Annals ofNew York Academy of Science 246, 195-217 Medline A. A Parser E.L. <1980 The multi-step theory of cancer. In Recent Advances in Hhto- pathology, Vol. n, p. 28, eds P.P.Anthony St, R.N.M.MacSween. Churchill Livingstone, Edinburgh Monson R.R., Peters J.M. St Johnson M.N. (1974) Proportional mortality among vinyl chloride workers. Lancet ii, 397-398 Nicholson W.J., Hammon E.C., Seidman H. A Selikoff IJ. U975) Mortality experience of a cohort of vinyl chloride-polyvinyl chloride workers. Annals of New York Academy of Science 246, 223-230 Patrick R.S. A McGee J.O'D. (1980) Biopsy Pathology of the Utter, p. 193. Chapman A Hall, London Popper H.. Thomas L.B., Telus N.C., Falk H. A Seukoff IJ. < 1978) Development of hepatic angiosarcoma in man induced by vinyl chloride, Thorotrast and arsenic. American Journal of Pathology 92, 349-370 von Reinl W., Weser H. A C reiser E. (1977) Epidemiological study on mortality of VC exposed workers in the Federal Republic of Germany. Medichem, September, pp. 2-8 Smith P.M., Williams D.M.J. A. Evans D.M.D. (1976) Hepatic angiosarcoma in a vinyl chloride worker. Bulletin of New York Academy of Medicine 52, 447-432 * Tabershaw I.R. A Gaffey W.R. (1974) Mortality study of workers In the manufacture of vinyl chloride and its polymers. Journal of Occupational Medicine 16,309-318 Viola P.L., Biootti A. A Caputo A. (1971) Oncogenic response of rat skin, lungs and bones 1o vinyl chloride. Cancer Research 31, 516-522 Waxweilleh R.J., Stringer W., Wagoner J.K., Jones J., Falk H. & Carter C. (1976) Neoplastic risk among workers exposed to vinyl chloride. Annals of New York Academy of Science 271, 40-48 f | I . j ' )