Document NGo8zJ1e1Km06JLXn1OVd8Eg8

K-tllhOoo) 936 findings appeared in abstract form in ihe Scottish Mediea! Journal, January 1974. Requests for reprints should be sent to Dr R M Pearson. Reference* 1 Lcishnuui, AWD, *od Sandler, G, Angiology, 1967, IS, 709. * Dorph, S. and Binder, C, Acta Medico Scandinavico, 1972, 185, 443. * Motolcsc, M, Mulesan, C, and Columbi, A, European Journo] of Pharma cology, 1975,8, 21. 4 George, C F, et at. Archives of Internal Medicine, 1972, 130, 361. * Bulpitt, C J, Dolicry, C T, and Came, S, Jcntmal of Chrome Diseases, 1974, 27, 309. * Jack, D Bf*an*A Reiss, W, Journal of Chromatography, 1974, 88, 173. ' Armicafe, P, Statistical Methods in Medico] Restarch, p 226, Oxfcfd, Blackwell Scientific, 1971. BRITISH MEDICAL JOURNAL 17 APRIL 1976 1 Brcckcnridge, A, M,*nd Dollcry, C T, Lancet, 1966, 1, 1074. * Zacctt, R. Gilmore, E, and Koch-Weser, J. Netr England Journal of Medicine, 1972, 286, 617. * Sweet, C S, and Mandradjieff, M, Clinical Science, 1975, 48, 147. >i BuhJef, F, et at, American Journal of Cardiology, 1973, 32, 511. * Salvcni, A, et at. Journal of Nuclear Biology and Medicine, 1973,17, 142. 11 George, C F, in Biological Effecti of Drugs in Relation to their Plajma Concentrations, cADS Davie* and B N C Prichard, p 128. London, Maaniilan, 1973. u Cuihbcn, M F, and Collin*, R F, British Journal of Clinical Pharmacology, 1975, 2, 49. " Rem, W, Hueneler, H, and Rasehdorf, F, Xmobtouca, 1974, 4, 365. u Brunner, C, Imbof, P, and Jack, D, European Journal of Clinical Pharma cology, 1975, 8, 3. 17 Lconeni, G* el ol, CUmcal Science, 175, 48, 491. |B Veteran* Adnunistratw Journal ,#/she American Medical Association, 1967, 202, 1628. Immunological mechanisms in the pathogenesis of vinyl chloride disease A MILFORD WARD, SOPSAMORN UDNOON, T WATKINS, ANNE E WALKER, C S DARKE British Medical Journal, 1976, 1, 93^938 Summary Vinyl chloride (VC) disease U a multisystem disorder incorporating Raynaud's phenomenon, acro-ostcolysis, thrombocytopenia, portal fibrosis, and hepatic and pulmonary dysfunction. Immunological and immuno chemical investigations showed the presence of circulat ing immune complexes in 19 out of 28 patients with the disease and in a further two out of 30 workers exposed to VC. The immunological data were reviewed in relation to the clinical picture of the disease and to the available evidence on the metabolism of VC. The results suggest that VC disease Is an Immune cnmnlex disorder and that thy i*j initiated by the adsorption of VCT or a metabolite on to tissue or plasma protein. Introduction Vinyl chloride (VC) i, known to be oncogenic,1 * but hepatic angiosarcoma may not be the most serious of its medical hazards. Acro-ostcolysis was first described in 1966 in workers employed in the polymerisation of VC,* and since then other cases have been described.4 4 In all these reports the affected workers helped in cleaning the autoclaves after the polymerisation process. Stewart ti al,` however, reported a case in a worker who had never done this job. Their report widened the possible exposure to toxic levels of VC to other workers in the industry. The descriptions of acro-ostcolysis do not describe adequately Protein Reference Unit, Dc^ftmcat of Laipaaohny, HaUatnshlrc Hospital Medical School, Sheffield S10 XRX A MILFORD WARD, MS, mxo-sth, director SOPSAMORN UDNOON, BSC, roearrh student J WATKINS, use, rmr, principal scientific officer Chesterfield Royal Hospital, Chesterfield ANNE E WALKER, md, Macr, consultant dcrmatolopst Respiratory Function Dolt, Royal Infirmary, Sheffield --- r .... .......... i..,,. the full extent of the disorder as it may affect VC workers. The syndrome for which Tange ei a/' suggested the name vinyl chl'iride disease includes sclerotic changes in the skin, osteolysis, circulatory disturbances, thrombocytopenia, portal fibrosis, and impaired hepatic and pulmonary function. Despite considerable effort in many countries little is under stood about the aetiology and pathogenesis of VC disease. We therefore outline the immunological investigations performed on 58 workers from a VC polymerisation plant. The results explain the pathogenetic mechanisms of the disease and allow some conclusions to be drawn about its aetiology. Patients The 58 patients were referred to a hospital clinic from a single VC --polymerisation plant. They represented 18% of the past and present work force (320). Referrals of those still working at the plant were from either the factory tnedica]*'officer or local general practitioners; ex-employees were referred after investigations made by the Employ ment Medical Advisory Service. For the purposes of the study the patients were divided into four clinical groups. ; Group 1 (Spadata)--These patients were diaahled by pain in limbs and bands and by dyspnoea. AS had symptomatic Raynaud's pheno menon, which in five was clinically dmmtriable; the others had severely cold hands. Four bad sdereedana of the bands or face, four a mild clawing deformity of the bands, and two mild radiological evidence of acro-osreolystt, ...... ..-.O' -r- Group 2 (19 pariwso)---Thh gre*g> ana moderately dinbird and mulasymptomatic, excessive fotigue. Iamb pain. d patamrhciial being the most common complaints. RaynwnFs phenomenon was symptomatic but never observed, although manypatients were found to have cold or feet, Sderisiltaa like rhanys ef the face were evident in two patients. No radiological aixmrmalities were wa, Group 3 (25 patitrut)--These pstienn Were: net disabled and were continuing in active employment. They presented with mjscciiancocs symptoms that were not confirmed by visible abeaxeoalim or overt clinical signs. Group 4 (5 padtna)--This group was asymptomatic, the patients having been referred because of expressed concern or because they *wisbcd to seek ocher anployn*mt. The patients* ages racked from 23 to 59 ymn with * hac*n of 39*7 years. There vu do significant difference between the group*- The duration of apoiure to VC varied from six to 75 taoadtf with * mean of 39 roomhs. As the degree of exposure varied with the job at the plant thr patients were divided into 'high- aod tow < ijamiit groups, * *! - - - ---- ,n4,n mti *4 n* }>v*wvtniv R & s 026820 ptani. nd Ihc litter maintenance fitters and warehousemen. Fifty of the pinenii (86",,) had at sometime worked tn the reactor building or dry-bagging plant. Altogether 46 patients (70';..) admitted to having suffered from VC narcosis on at least one occasion; the incidence of admitted narcosis tended to decrease with diminishing severity of the disease--g- iup 1,100'',.; group 2,80";,; group 3,76",;,; group 4, 60%, The differences do not approach statistical significance. Methods Immunoglobulins were estimated by an automated immunoprt.:ifiitin technique. Complement was determined in fresh EDTA plasma. C3 and G4 being estimated by single radial immunodiffusion tind conversion st4erf by two-dimensional immunoelectrophorcsjCryoprotnn studies were performed on warm-separated citrated plasma, the cold aliquot being kept at 4 C for seven days before separation of the cryoprecipitate. Rheumatoid /tutor was determined by passive haemagglutination of sensitised cells, and the presence of amirissue antibodies by indirect immunofluorescence, Lymphocyte transformation was assessed by a modification ofThe technique of Schellekens and Eijsvoogel,* Lymphocytes were separated from beparinised whole blood by a Ficoll-bascd centrifugation method.* Duplicate culture tubes were set up containing culture medium, autologous plasma, and either 0-2 Mg purified phytohacmaggjutirun (PHA) (Burroughs Welcome) or 2 >g purified protein derivative of tuberculin (PPD). Control cultures were set up using Ivmphocytcs from healthy donors. All cultures were incubated at 37-C for 72 hours (PHA) and 120 hours (PPD). Transformation was assessed by the incorporation of tritiated thymidine into active DNA svnthesis. Similar cultures were set up with test lymphocytes supplemented with normal plasma and normal lymphocytes supplemented with test plasma to assess possible plasma inhibitory effects, l.ympho* evir subpopuiations were defined as spontaneous E-rosattc-forming cells or T cells1" and as membrane-fluorescent cells or B cells.11 Absolute numbers of T and B cells were determined as a percentage of the total lymphocyte count. Biopsy specimens were snap-frozen and cryostat sections stained for IgG, IgA, and JgM, C3 and C4, and fibrinogen/fibrin by direct immunofluorescence. Results The major abnormalities observed were a polyclonal increase in one of the immunoglobulin classes, usuallv-leG: the presence of mined cryoglobulins, including TgG7~C3. and fibrinogen; and in-vivo conversion of both C4 and C3. Tabic 1 shows the mean values and ranges of immunoglobulins, C3, C4, and lymphocytes for each clinic*.1! group together with the numbers of patients with cryoprorein-. S'*'I showing C3 conversion. The abnormalities were present in almost all cases in group 1, and showed a progressively decreasing incidence in the other groups. The presence of circulating immune complexes was inferred when there was evidence of mixed cryoglobulins, in-vivo conversion of complement, and depressed values for C3 or C4; the presence of immune complexes showed a close relationship with clinical grouping, with 88':,,, 58%, 8";,, and 0% respectively for Ihc four groups. Eight of the 58 patients were classified as of low exposure, six of them being in group 2. No abnormalities were detected in these six patients. When the low-exposure workers are removed the inci dence of circulating immune complexes in group 2 (85%) closely approximates that in group 1. Autoantibody screening (table II) showed no abnormalities except for a high incidence of antinuclear antibodies in group 1. These were all of low litre (JgG 1/20-1/50) and probably resulted from tissue damage rather than an autoaggressive disease process. The only other obsi rvation of note was the presence of thyroid autoaniibodics in ihret patients in group 2. There was evidence of a reduction in the T cell population with a slight increase in B cells; this was most pronounced in group 1 but was also evident in group 2 and to a less extent in group 3. In-vitro stimulation showed few abnormalities except for an apparently increased frequency of reduced or absent responses to PPD. PHA transformation studies showed minor degrees of suppression, and inhibition by plasma was not seen. Direct immunofluorescence studies of biopsy specimens or skin (10 cases), muscle (one case), and lung (one case) showed aggregates of IgG, C4, C3, and fibrinogcn/fibrin in the lumen of vessels and adherent to the vascular endothelium, IgG, C4, C3, and fibrin were also detected in rhe media and subintima! regions of small and medium-sized arterioles. Discussion The major immunological features of VC disease in this series are hypcrimmunoglobulinacmia, cryoglobulinacmia and cryofibnnogenaemia, and in-vivo conversion of complement involving the classic activation pathway via C4 and C3. There was additional evidence of a cellular disturbance in the form of a reduced T cell population and a modest increase in B cells. The presence of non-organ-specific antitissue antibodies in those most severely affected clinically may have related to tissue damage rather than to a pathogenetic mechanism. Immunofluorescence studies of the biopsy material confirmed the immunochemical evidence of circulating immune com plexes with the identification of immunoglobulin, complement, and fibrin/fibrinogen in the lumen of vessels, adherent to endo thelium, and in the vessel wall. An immune complex or cryoglobulinaemic vasculitis would be consistent with the findings of a perivascular inflammatory infiltrate as described by Markowitz TABLE I--Mean values and ranges Jar immunoglobulins, complement, and lymphocytei each group and nunibers of patients in each group uhlh cryoproteins and showing C3 conversions 1 Group'1 No of , patient* i Immunoglobulins (g/1) I*G j I*A IgM cc u 9 *O U Z Complement (g/l) .......... C3 : 1 c E2 i j"ES* 1 i z f5 j i s0 Lymphocytes k 1C n Toul T edit B ccUs ii34 'i 3"55 14 3 (10-0-19 0)1 2 8 (J-8-4'7) n*9 (8*3-18 5) i 2-4 (O 6-5*0) 19215 ((69-85*-1116--04)) 1{ 2-0 (0-9-4 1) 3-6 (1*1-5 2) 1 3 (0 4-2 7) 0 9 (0 >2 l) 0l 90 ((00 45--11--94)) 8 13 2 5 13 ) 1-0 (0 6-15) 0-K (0-6-1 3) o-e (o 5-1 i) 0-8 (0 6-1 0) : 0 45 (0 19-1 10)' 1 0 38 (0 22-0 7) 1 ij 00'43H5 ((Q0`2372--00-4669))! 6 9 103 I j | 1-8 (1-0-3 1) 2-4 (1-3-5-4) 2 0 <0-7-3 0) 2 5 (2-0-3 0) 0*4 (O`M'5) 0-5 (0 J-1`8) 00--44 ((00--3M-0--04)) 0*6 (0-1-1-5) 0*7 (0!3-l'5) 0 5 (0 1*0 8} 0-5 (0*3-0 6) )-*oeiu#l value* 9-5 (60-14*0) j I S (0-5-3 0) 0-9 (0 5-1*7) i-a tos-i'7) |6 45 (0-30-0 75)j | 2 0 (1-5-2-5) 1-0 (0-6-1 *5) 0 7 (0*4-1-0) TAXbX tl Rendu of awoam-.hody screening in the four groups of patients Group No of pxuxnu No wuh rheumatoid factor Nuclei (ANA) | No with tnuiuiuc antibodies to: (AMA) \ Smooth tnu*cJc Gastric panctaJ cdla Thyroid \; r';::h-f-/ej \ :;yA ; j- ^* \ 938 BRITISH MUSICAL JOURNAL 17 APRIL 1976 cl alf although the severe narrowing of dermal vessels with subintimal fibrosis described by Harris and Adams' could be construed as an end-stage phenomenon of a similar process. Both histological features were present in this senes, although the subintimal proliferation was seen only in the cases of longest duration. The tendency towards thrombocytopenia noted in many patients could be construed as confirmatory of an immune complex disorder with complement activation." The persistence of disease activity as evidenced by the presence of cryoprecipitate and conversion of complement in workers who had been removed from exposure to VC for more than six months is in accord with the observations of Veltman ci al." Respite these pronounced abnormalities a search o? published work on VC disease failed to disclose any similar investigation, most reports having concentrated on the hepatotoxic effects of VC and its oncogenic properties. naqieW.ky antj Egorev" showed that tissue damagc_rom VC could~pfoduce allergenic _ suhstances. Hcrvieux and Tcssier" had shown that a chemical dermatitis could be induced among workers in the industry. One patient in group 1 complained of skin irritation a year before, with evidence of Raynaud's phenomenon and dyspnoea, and gave a positive reaction to a patch test with polyvinyl chloride (PVC) powder. One other patient (group 3) had also complained of severe generalised pruritus. I n a detailed study of 13 pafients employed in PVC production with circulatory disturbances, thrombocytopenia, splenomegaly, and hepatic malfunction. Lange e: a!' concluded that there was no evidence for an autoaggressive disorder. A more recent report" detailed the investigation of 70 patients from a work force of 128 at a single plant, the findings of which did not change the earlier conclusions. These workers did make the point, however, that although skin and bone changes may disappear when the patient is removed from contact with VC, the thrombocytopenia may persist for 12-18 months after t-vnosure. In a study of 36 workers exposed to vC. who were shown to have leucopcnia, thrombocytopenia, and splenomegaly, Suciu ci aP` showed an increase in the y-globulin in 11. Although they found only a 6",, and 2-9",, incidence of clinical Raynaud's phenomenon in two scries of VC workers, they noted thai the phenomenon cleared spontaneously on removal from exposure and that the different incidence figures were associated with a 22-fold decrease in VC levels. They also quoted a much higher (66",, and 55``,, respectively) incidence of vasospastic changes in discussing the significance of the splcnogmcaly, they suggested that VC acted as an irritant in the reticuloendothelial system to produce a reactive splenic enlargement. Marstellcr et a!,1' in an extensive investigation of 50 VC workers, introduced some immunological tests into the initial protocol but abandoned them when they failed to give positive results. No comment was made on the presence or absence of hypcrgammaglobulinacmia. These workers also suggested the possibility of reiicul.c. endotheliarstimulation as a cause of the splenomegaly and the hcpannTttoral cell hyperplasia, although they regards latter ns a possible pathogenetic factor in the development of hepatic angiosarcoma.----- j T5ic metabolism of VC in man is not fully understood. Hefner et al1' showed that in rats metabolism is by the alcohol dehydrogenase pathway at low concentration, and via an inter mediate chlorocthylcne oxide at higher concentrations. William son" proposed that the intermediate product is more likely to he a cyclic dioxide. Both the oxide and dioxide would BeTiTghly reactive molecules and would be able to bind to free sulphydryl and amino radicals. The incorporation of these into protein synthesis would give a conformationallv altered molcculc~thai would be antigenic. The inclusion of this intermediate product with its chloride residue in a protein molecule would have a haptenic effect in the incitement of antibody synthesis. The theoretical interaction between VC and plasma proteins was partially confirmed by (JstgT11 In Ms ubseit'aillins t)f rWThmding of VC or its mctabblittrnrrerffmTIffumifl, The association of the observed results with the experimental metabolic data allows the construction of a theoretical model for the pathogenesis of VC disease and explains many of the features of this multisystem disorder. A metabolic product of VC, presumably the dioxide, binds to plasma protein, producing either a haptenic group or a conformational change within the protein molecule. This acts as an antigen that escapes tolerance and stimulates B cell proliferation and immunoglobulin produc tion. The antibody and antigen interact to produce a soluble complex that is both cryoprecipitable and capable of initiating the complement sequence by the classic activation pathway. The cryoprecipitate and reactions secondary to complement activation will produce platelet aggregation and apparent throm bocytopenia, fibrinogen/fibrin conversion, and vascular occlu sion. The vascular occlusion, either temporary or permanent, is enough ftTexplaiii then'llseWeti clinical, radiological, and histo logical findings itTthe skm, skeletal and soft tissues, and lungs. By producing ischaemia the vascular occlusion would also stimulate new collagen biosynthesis, as observed by Jayson ci a This final episode in the pathogenesis of the disease process would then be further augmented by the interaction of collagen and complement," resulting in further activation of the com plement pathway and thus reinforcing the terminal recycling phenomenon. The frequency with which abnormalities were detected in exposed workers in this series, especially in those groups C2 and 3) in which there were fesv or no overt clinical signs, suggests that the disease process may be more common than is generally supposed. Further studies are in progress to investigate the total exposed population at the factory and to study populations from other related industrial plants. References 1 Lancet, 1SI71, 1, 13:3 2 British Medical Journal, 1974, 1, 590. ' Cordier, J M, ./ al, Cahters de Medeane, 1966, 4, 3. 1 Harris, 1) K, and Adams, W G F, Hr,tish Medical Journal, 1967, 3, 712. Markowitz. i> ,V s' al, Ar^mvcs of Dernutotog\, 1972, 106, 219. * Stewart, J ID, Willums, D M J, and McLachlan, M S P, Journal of Social and Ocmpotional Medicine, 1975, 25, 103. 7 C }., el ol. Internationales Archtv fur Arbeiizmediztn, 1974, 32, 1. h iJcheilekcnv, P T A, and Hjjsvoogel, V P, Clinical and Experimental ImtnuHOlogX, 196f\, 3, 571. * Bovum, A, Scandinavian Journal of Clinical and Laboratory Investigation, 19oS, 21, suppl No 97, p 9. 1,1 Steel, C". M, Evans, J, and i>miih, M A, British Journal of Haematology, 1974, 2K, 245, M Papamtchai!, M, Brown, J G, md Holborow, E J, Lancet, 1971, 2, 850. 12 Pfueller, b L, and Luscher. h F, Immunoehemitiry, 1972, fl, 1151. ,a Veltman, G, ei al, Annals of the SIao York Academy of Sciences, 1975, 246, 6. 11 Darushevsky, S *,, and Egorev, N M, Ciigtena <Truda j Professional' nye Xuauicvunnu, 1961, No 9. p 2to Hervieux 3nJ Tessicr, Arian-ei des ,\tatadies ProJessionneUes, de Medeahe do 7 ravail et de Secunie Soeule, 1959, 20, 6). 14 Suciu, I, ei at, Annals of the NeteVark Academy of Sciences, 1975, 246, 53. Marstellcr, H J, et al, /Ifine/* of the \'eu York Academy of Sciences, 1975, 246, 95 l" Hefner. R li. Waunabe, P G, and Gehnng, P J, Annals of the Sew York Acadtmv of Sciences, 1975, 246, 135, ,f Williamson, K, Proceedings of ihe Royal Society of Medicine, 1976* 69, 281. 10 Osier, G, Annuls of the A'et. York Academy of Sciences, 1975, 246t 149^^ ,l Jayson, M 1 V, Baile>, A J, and Llgyd-Jones, K, Proceedings of the Royal Snciav of Mediant, 1976, 69, 295. 11 Jubin, 1*', and Tremblay, F, Thrombosis et Diathesis Haemorrhagtca, 1969, 22, 450 *3 Takahashi, M, Kawachi-Takjhashi, S, and Malsulira, M, International Archives of Allergy and Applied Immunology, 1975, 48, 642, Reprinted from CANCER, Vol. 37. No. I. January 1976. Copyright. 1976. hy the American Cancer Society. Inc. J. B. Lippincott Company. Printed in U.5.A. K- I'll l-(I [Miuj CLINICAL AND MORPHOLOGIC FEATURES OF HEPATIC ANGIOSARCOMA IN VINYL CHLORIDE WORKERS Laszlo Mark, md,# Fernand Delorme, md,* John L, Creech, Jr., md,1 Lynn L. Ogden, II, md,1 Ed H. Fadell, md,1 Curtis L, Songster, md,** Jerry Clanton, md,h M. N. Johnson, md,11 and WllfMAM M, Christopherson, md11 Fifteen male worker* exposed to vinyl chloride developed angiosarcoma of the livttv Thirteen died of disease and two are currently living for short periods after'1 diagnosis. Their ages ranged from 36 to 58 years (average *17.5 years). Th*ir Cxjiosure time ranged from 4 to 27.8 years (average 16,9 years). The most common presenting symptoms were fatigue, weight loss, and abdominal pain. Hepatomegaly followed by splenomegaly were the most common physical find* mgs. Biochemical profiles yielded variable results and proved to be of little vain* in the detection or diagnosis. Of eight patients autopsied, distant organ thvolvdfheni was present in two cases, duodenal involvement in one, and direct extension of tumor to adjacent organs or tissues in four additional ones. The r*hi&irider, diagnosed by open liver biopsy, revealed no tumor extension. The groft' features of the tumors were hemorrhagic necrosis, cystic degeneration, fibrosis, and apparent multicentricity. The histologic features were those of the typical- angiosarcoma found in a variety ol sites with a wide range of cellular differentiation. The histologic diagnosis was often impaired by the extensive rumor necrosis. Elsewhere in the liver suhcapsular fibrosis, a distinct type of pttfraf fibrosis, and endothelial cell hyperplasia with or without sinusoidal dilatarfcnv Wet5* noted. The reduction of industrial chemical, exposure has already bfctft5 achieved and will hopefully eliminate this chemically related tumor in the future. There is, however, a significant group of previously exposed workers who WiH fcquire careful monitoring to detect functional abnormalities of the liver and possible early neoplastic changes. Canter 37:149-163, 1976. RIMARY ANGIOSARCOMA OF THE LIVER IS Ex in Louisville. Kemuck- r.nd seven in Shawini- Ptremely rare, with an estimated incidence gari, Quebec, Canada, ill were in men who of 20 to 25 cases in the U.8. annually. Rew orked in a section of a chemical plum that cently fifteen cas?s have been observed, eiglu produced polyvinyl chloride (PVC) horn vinyl Presented at the 23th Annual Meeting of the James Ewing Society, New Orleans. LA, Ma^ch 25-29. 1975. From St. Anthony Hospital. Louisville. Kentucky, e.H.R.M. Shawinigaii, Quebec. University of Louis ville, School of Medicine, and Jewish. Methodist, and Suburban Hospitals, Louisville. Kentucky. * Director, Dept, of Clinical and Anatomical Pathology, St. Anthony Hospital, Chn, Asst. Prof, of Pathology, University of Louisville. t Pathologist, Centre Hospitaller Regional dc la Maurice, Shawinigan. Quebec, Canada. Asst. Prof. Dept, of Pathology, Fatulte de Medicine. Univcrshc dc Montreal. Quebec, Canada. I Attending Surgeon, St. Anthony Hospital and Chn. Asst. Prof, of .Sutgcry, Univeisity of LoutVxlle. I Pathologist. Jewish Hospital, Clin. Asst. Prof, of Pathology. Univeisity oT Louisville. * Director of Lahoraloi tes, Methodist Hospital, Chn. Asst. Prof, of Pathology, University of Louisville. De ceased. ** Asst. Prcf. of Pathology. University of Louisville. tt Director of Laboratories. Subuiban Hospital. Louisville. tt Director of Medical Dept., B. F. Goodrich Cheifficals, Avon Lake, Ohio. ii Prof, of Pathology, University of Louisville. Address for reprints: Laszlo Makk. MD. Department of Clinical and Anatomical Pathology, hi. Anthony Hospital, Louisville, KY 40203. The authors thank Simon Lauzc. MD, Rene Vauclair, MD. Richard Dcssureault. MD. G. Berry, MD. Anne C, D. Ridiman. MD. Robert Arnold. MD, and James Kurfees, MD for providing them with informa tion from their cases, and the valuable suggestions ol Cailo Tamhuro, MD, Associate Piolessor and Chief Section of Gastroenterology and Diiector Vinyl Chlo ride Project, University of Louisville. Received tor publication June 25. 1975. 150 Cancer January 1976 Vol. 37 chloride. PVC is an essential component of most plastic products, including water pipes, wrapping materials, building materials, blood containers, and many others. To our knowl edge there have been no proven cases of angio sarcoma among- workers not exposed to the gaseous vinyl chloride. After encountering the first two patients, a retrospective study was undertaken. The study yielded three additional cases in Louisville. An independent retrospective study in Shawinigan, Quebec resulted in the discovery of seven cases. Through a systematic health screening program and general awareness of the occupational association three more pa tients were found within a year in workers or former workers in the Louisville plant. An additional exposed worker with a liver lesion mimicking angiosarcoma will be discussed. Clinical Material Six weeks later a "coin lesion" was found in the apex of the right lung as well as in the mid lung field. Death occurred 3 months after admission. Ne cropsy revealed a 5200-gram liver, most of it cotnposed of a spongy hemorrhagic and necrotic hemangiosarcoma. There was involvement of the lungs, pleura, pericardium, myocardium, kidneys, left adrenai gland, and small and large bowel. The cause of death was exsanguinating hemopericardium and hemothorax. Case 3 A 48-year-old man sought medical advice be cause of weight loss anti right upper quadrant abdominal pain of 5 months duration. He had hepatomegaly. On liver scan about one half of the upper part of the right lobe was nonfunctional and suggestive of a tumor mass. In the remainder or the liver there were numerous small lesions. He died 4 months later. At necropsy the liver weighed 5000 g. Most of it was replaced by hemorrhagic tumor with extensive necrosis. For the sake of brevity the case reports will be limited to pertinent information. Histo logic material from seven of the cases was pro vided at the request of the National Cancer Institute and was included in their prior publication,'!u Case 1 A 42-year-old man was hospitalized because of lower abdominal pain suggestive of appendicitis. At the time of appendectomy the liver appeared normal. Three months later he was seen because of fatigue and abdominal pain. The liver was en larged with multiple palpable nodularities. Peri toneoscopy revealed voluminous nodules on ihe lower surface of the liver. Hepatic scan showed multiple nonfunctioning areas mainly in the right lobe. The patient died 1 month after admission. Postmortem examination revealed a 5150-g liver containing many hemorrhagic and necrotic tumor nodules essentially replacing the right and pari ol the left lobe. The tumor extended to the right adrenal and right kidney. Case 2 A 51-year-oM Caucasian male developed right upper quadrant pain after fatty meals. Guarding and rebound tenderness were present in the right upper quadrant. The gallbladder was not visual ized with a cbolecystogram. At exploration hematoperitoneum was present. The source of bleeding was a 1,5-cra spongy lesion on the dome of the right hepatic lobe. On compression, it decreased to 1 cm. This was interpreted as a ruptured hemangioma. A biopsy of the noninvoKed portion disclosed slight fatty metamorphosis and minimal nonspecific hepatitis. Case 4 A 43-year-old Caucasian man sought medical advice because of severe epigastric pain. He had noted fatigue for 10 weeks. On physical examina tion, he had an epigastric mass extending 7 cm below the right costal margin. The spleen ex tended 7 cm below the left costal margin. A liver scan disclosed a large defect. Exploratory lapa rotomy revealed a large hemangioma-like defect in the liver and a large spleen. The User was biopsied. He received two courses of intraarterial 5F-U and one of Cytoxan during the next 3 months. The liter decreased in size; however, he then startetl to deteriorate anti died 2 months later in liver failure. z\t necropsy, the liver weighed 3150 g and was largely replaced by friable hemor rhagic angiosarcoma which also involved the dia phragm and abdominal wall. Case 5 A 56-year-old man was hospitalized because of anorrbexia. nausea, vomiting, anti an upper ab dominal mass. The liver edge was palpable 8 tin below the right costal margin. Exploratory celi otomy revealed a large neoplastic mass occupying nearly the entire left lobe of the liver with many smaller nodules in the right lobe. No other tumor was noted. The tumor was biopsied and the diagnosis of angiosarcoma established. He tlied 3 months later. Postmortem examination could not he obtained. Case 6 A 56-year-old Caucasian man was admitted to the hospital with tarry stools. On physical exami nation, the liver was palpable 4 cm. and the spleen 3 cm below the costal margins. (Five months he- R&S 026823 ! 1 5 I i 1 Vol. 37 was found in |11 as in the mid- admission. N'cmost of it cointnd necrotic hellvement of the Irdiurn, kidneys, large bowel. The tiling hemoperi- [jlical advice be[jipper quadrant Jration. He had one half of the nonfunctional the remainder nail lesions. He he liver weighed oy hemorrhagic [sought medical pain. He had M lysical examina- Bxtending 7 cm |~he spleen ex[jnargin, A liver jloratory lapana-like defect 8 The liver was of intraarterial j.g the next 3 lie; however, he Blied 2 months Jc liver weighed 1 friable hemornolved the dia led because of I an upper abjpaipable 8 cm Iploratory ccliliass occupying I'cr with many jo other tumor Jsied and the ltd. He died 3 lion could not ji admitted to nysical examil.nd the spleen 1 e months be- No. 1 Hepatic Angiosarcoma and Vinyl Chloride Makk et al. 151 for there were no palpable abdominal organs on physical examination.) Upper gastrointestinal ra diologic studies revealed anterolateral displacement of the stomach and deformity of the duodenal cap, A liver scan showed a large lesion involving both lobes. On celiotomy, hepatosplenomegaly was found with an irregular hemorrhagic mass in the right lobe of the liver adherent to the stomach. A biopsy was performed which established die diag nosis of angiosarcoma. Postoperatively, the patient received 5-FU, Cy toxan, and irradiation to the liver. His response to therapy was excellent. The liver si/c decreased to where it was no longer palpable, and the liver function tests approached normal. Twelve months later, however, he developed ascites and marked abnormalities in liver function tests. On explora tion no tumor masses were found. Two liver biopsies showed marked fibrosis but no neoplasm. He died 3 weeks later from liver failure. Permis sion for postmortem examination was not obtained. Six months aicr the patient sought medical adiice at an out-of-iown clinic because of persistent weakness and weight loss. Hepatic angiogram dem onstrated a tumor blush iu the liver. A liver scan disclosed a filling defect in the same area, T he previous iis-cr biopsies were restudied and inter preted as "anaplastic hepatoma anti portal fibrosis. During the next eighteen months, the patient received chemotherapy. The liver si/e did not change during that period and die liver [unction tests were normal. This raised tlie question as to whether the patient did indeed have a hepatoma. In the next 4 months, however, he had a gradual deteriorating course and died. Necropsy revealed 2 liters of hemorrhagic peritoneal fluid. The origin of hemorrhage appeared to lie a 1-cm perforation in the central portion of the liver. Tiiis defect was contiguous with a 20 cm diameter cavity con taining blood (Fig. 1). Tile spleen weighed 6<K1 g and was not involved by neoplasm. Microscopic sections demonstrated angiosarcoma in the iiver. Case 7 A 51-year-old man was hospitalized because of indigestion and jaundice. His liver and spleen were both palpable 7 cm below the costal margin. On celiotomy, the liver was markedly enlarged and extensively replaced by tumor. He died 2 months later. Necropsy revealed ne crotic and hemorrhagic tumor occupying most of the liver. A large tumor mass in the posterior part of the right lobe invaded the vena cava ami ex tended by contiguous growth into the right atrium. The histologic diagnosis was poorly differentiated angiosarcoma. Case 9 A 52-year-old man was hospitalized because of diarrhea, abdominal pain, and tarry stools. On physical examination a markedly enlarged liver was found. Exploratory celiotomy revealed the en larged liver replaced in part hy lumor nodules. The spleen was also enlarged Inn not involved by tumor. The histologic diagnosis was angiosar coma of the liver. He died 7 months later. Per mission for postmortem examination was denied. Case 10 A 58-year-old Caucasian male sought medical advice because of a 25-lb weight loss and anor- Case 8 A 39-year-old Caucasian man sought medical attention because of nausea, mctcn.i, and hcraatemesis. A peptic ulcer of the duodenum was diag nosed and treated with good response. Eighteen months later, he was again hospitalised because of melcna and hematemesis. The liver edge was at the right costal margin and the spleen was palpable 5 cm below the left costal margin. Esophagoscopy demonstrated varices. Celiotomy revealed portal hypertension. A portacaval shunt and liver biopsy were performed. The liver biopsy revealed mild portal fibrosis with lymphocytic infiltration. Later his liver func tion tests returned to normal and lie returned to work in a nonexposurc area of the plant. Five yean later, he was hospitalised because of weak ness, fatigue, lew-grade fever, and sweating. Physi cal examination revealed hepatic enlargement. A needle biopsy of the liver disclosed hepatitis pro gressing to cirrhosis. A second exploration was per formed and a liver biopsy obtained- The liver re vealed very slight, acute, and chronic inllammatory changes. There was no neoplasm. yv Fig. I. Liver largely replaced by angiosarcoma. Much of the tumor is hemorrhagic and necrotic. Rupture site is at top of photograph (Case 8). R&S 026824 -$aly-^v s 152 Cancer January 1976 Vol. J7 Fic. 2. Solid and spongy tu mor is seen replacing much of the liver. Large dilated vascular channels are a conspicuous part of the tumor, seen best at top of photograph (Case 10). rhexia over a 3-month period. On physical ex amination the liver and spleen were 7 cm below the costal margin. Exploratory laporotomy dis closed a moderately enlarged liver with multiple tumor nodu'es. Six months later he died. Postmortem examination revealed an IK00-g liver. There were fibrosis and multiple hemor rhagic nodules which collapsed partially when cut. leaving a spongy network (Fig. 2). There were many large cavities which contained organizing blood clots. The remainder of the liter was con gested and scarred. The duodenal mucosa was hemorrhagic and had superficial ulcers. Micro scopic examination of the liver resealed angio sarcoma, fibrosis, and many infarcted and hemor rhagic areas. The duodenum contained superficial ulcers with angiosarcomatotis-like endothelial pro liferation in the capillaries in the submucosa. Case II A 52-year-old man sought medical attention be cause of fatigue, abdominal pain, and weight loss of 7 months duration. On physical examination he was cachectic. His liver could he palpated 8 cm below the right costal margin. One month later, he died. On necropsy a markedly enlarged liver had extensive hemorrhagic and necrotic multifocal nodular tumor involvement. There was a 1-l-cm cavitary lesion in the right lobe. There were no other tumor masses. The microscopic diagnosis was angiosarcoma. Case 12 A 53-ycar-old man complained of t.uiguc and slight jaundice. Hepatomegaly was noted on physi cal examination. Three months later he died. Ne cropsy revealed numerous hemorrhagic and necrotic tumor nodules in a 2260-g liver. In the right lobe extending partially to the left lobe there was a 14-cm cavitary lesion. The spleen was markedly enlarged. There were no other tumor masses. His tologic diagnosis of the liver tumor was angio sarcoma. Case 13 A '12-year-old Caucasian male was admitted vath no specific complaints. He had abnormal liver function tests on health screening provided by his plant. On physical examination, no organomegaly svas detected. The liver scan revealed a Tcm lesion in the right lobe. An hepatic arteriogram was con firmatory. His past history was significant in that he ingested considerable ethanol and had previ: ousfy been hospitalized for this problem. Exploratory laparotomy revealed a -1-cm hard, slightly elevated, umbilicatcd dark lesion on the surface of the right lobe of the liver (Fig. 3). Frozen section diagnosis was angiosarcoma. No other tumor masses were felt in the liver or else where. Frozen section examination of biopsies from the remainder ot the liver disclosed cirrhosis and a peculiar portal fibrosis (Fig. 4). It was felt that loocctomy would not be well tolerated. Postoperativcly the patient was treated by chemo therapy, bat he died 1 year later. At necropsy the skin was icteric. There was hemorrhagic fluid (3500 cm3) in the abdominal cavity. The liver weighed 2810 g anti was about 50% replaced by hemorrhagic, cystic tumor involving both lobes. A ruptured cystic lesion in the right lobe was the source of the bleeding. There was tumor involve ment of the diaphragm, gallbladder, regional lymph nodes, both lungs, scalp, and skull. I tul:h ot Icular part "t top No. 1 Hepatic Angiosarcoma and Vinyl Chloride * Makh et al. 153 ,:t lobe jri was a rkedl-y il with 1 liver i by his I'.megaly. 11 lesion | (as conin that 11 previ- | n hard, IB ,o`nB- thJe)|m,i. No or elseI'biopsies 1 cirrhosis was felt B.esl. ! \ cbemojKlr opsy the I ;ic fluid be liver j -laced by I tb lobes. was the |- involve- regional III- 1 ``^y Y VK,.- Y'wy* *V-V * tA >mk- ..4 ~ YtrA- T -*^4 a--. ,:V V ': 1 \' r*>r a Fic. 3. Umbilicated angiosarcoma on the surface of the lj-cr as seen on suigical explora tion (Case 13). Fic. 4. The remainder of the liver in the a.mc case as Fig, 3 showed a serpentine or speckled light beige appearance in contrast with the normal or slightly congested background. The light areas correspond to foci of hbro&is. ' T J -V ' ,,*, " 154 flANCER January 1976 Vol. 37 R&S 026827 Fic. S. Area of an giomatous transforma tion with preserved liver cord cells adja cent to an area of frank angiosarcoma (H It . xlJO). Case 14 A 45-year-old Caucasian male was admitted for further liver studies because chemical health screen ing detected a moderate but persistent LDH ele vation. The liver scan was suspicious of a destruc tive process in the right lobe. Open liver biopsy disclosed angiosarcoma too extensive for resection. Hepatic angiogram revealed several space occupy ing lesions in the right lobe with a tumor blush. The patient was placed on chemotherapy. After 4 months a repeat angiogram showed that his liver lesions were decreasing in sire. Transjugular he patic biopsy rtvealed reactive fibrosis, but no tumor. Three months later a repeat angiogram revealed an enlargement of the masses in the liver. Explora tory laparotomy and biopsy documented angio sarcoma of the right lobe of the liver. Case 15 A 58-year-old Caucasian male was hospitalized because of lobar pneumonia. On SMA 12 exami nation, a moderately elevated alkaline phosphatase was found. Further studies revealed a markedly elevated serum gamma-glutamyl transpeptidase (CCTP). A liver scan displayed a large lesion in the donfe. By hepatic arteViogram the lesion was I t I ! Fig. 6. A classical pattern of angiosar coma of the liver sim ilar to that seen in angiosarcomas of other organs (H fe E. X55). lassical igiosarrr lim`im in I uihcr .. X55). No. 1 Hepatic Anciosarcoma and Vinyl Chloride Makk et al. 155 Fic. 7. A more solid pattern of angiosar coma with areas of fi brosis and extensive necrosis (H & E, X55). ; R&S 026828 limited to the right lobe and was suggestive of angiosarcoma. Transjugular liver biopsy performed at the time of hepatic arteriogram revealed normal liver tissue. An exploratory celiotomy revealed a large mass in the right lobe of the liver with ex tension to the diaphragm. The biopsy diagnosis was angiosarcoma. Resection was deferred because of diaphragmatic involvement. The patient currently is receiving chemotherapy and is doing well. It is noteworthy that he did not have any symptoms other than those attributable to the pneumonia. Patholocy The tumors were usually poorly circum scribed, multiple, pink to dark red hemor rhagic masses. Hemorrhage, cystic degenera tion, and extensive necrosis were present at the time of autopsy. In contrast, Lite tumors at time of surgical biopsy were often described as firm tumors with reactive fibrosis. Four of the eight cases with autopsy examination showed direct extension of tumor involving Fic. 8. A labyrin thine pattern with nu merous erythrocytes in the sinusoids can be seen (H Sc E. x340). Cancer January 1976 VS* Jv^r', * V. a ` Tpzsji?,v * #? Vol. 37 Fic. 9. The enlarged ovoid or elongated nu clei with ill-defined scanty cytoplasm and rather amorphous chromatin pattern are seen (H Sc E, X340). R&S 026829 adjacent structures. These included the dia phragm, abdominal wall, right adrenal, right kidney, and gallbladder. In one case, the tu mor invaded the vena cava and extended to the right atrium. Two cases, in addition to local extension, had distant organ involvement including lungs, pleura, pericardium, heart, kidneys, lymph nodes, left adrenal, small bowel, skin, and bone. These masses were simi lar in appearance to the liver lesions. An addi tional case had submucosal involvement of the duodenum. Since the tumor was submucosal it seemed questionable that direct extension was the source. Other gross findings of interest include three cases with hemorrhagic fluid in the abdomen and one with nonhemorrhagic ascitics. Four of the necropsied and three of the nonautopsied cases had splenomegaly. One case had esophageal varices. The microscopic features included the full range of patterns and differentiation seen in Fic. 10. An area of solid growth is shown. Elsewhere in the liver the tumor had a more characteristic angioma* tous pattern. Note the large hyperchromatic nuclei and lack of mi toses even in such an area of undifferentia- tion (H 8c E. X340). arged d nu- fined and houi are 10). Hej-atic Anciosarpoma and Vinyl Chloride Mahk cl al. Fig. II. Subcapaular fibrosis can be seen at the right. Alio shown i an area of portal fibrosis. There ii a moderate fatty infilttate. The iliuitirted area war far removed from the angiosarcoma (Trichrome stain, X55). angiosarcomas of other sites. The extensive hemorrhagic necrosis present in all the large tumors often increased the difficulty in histo logic diagnosis. In the better-differentiated areas, the enlarged spindle-shaped endothelial cells were found to line irregular vascular channels or spaces. The appearance was that of a spongy network of sinusoids or capillaries. At times, there were papilliferous projections with varying amounts of fibrous stroma. Large cavities lined by sarcomatous cells contained fresh or altered blood and, at times, organized clots. Other cystic areas were totally void of living cells and recognition as sarcoma was most difficult. An occasional, interesting pattern was that of angiomatous transformation within the sinusoids of recognizable residual liver cords R&S 026830 'r .f : 158 Cancer January 1976 Vol. 37 ^*r V; f?V rT'4 m Fic. 13. In Addition to the characteristic ami of portal fibrosis there Is a stellate area of bile duct prolifera tion and fibrosis (H & E, X55). (Fig- 5). This tended to blend imperceptibly into noninvolved liver and gave the impres sion of multifocal origin of the sarcoma. Rela tively normal-appearing bile ducts entrapped in Bn Brea of angiomatous transformation for tified ibis impression. Although the vascular pattern, characteristic of Qther angiosarcomas, was usually present (Fig- 6), at least in portions of the tumor, other area* at times showed a solid, undifferentiated pattern (Fig. 7). A labyrinthine pattern some what reminicent of endodermal sinus tumors was occasionally present (Fig. 8). The malignant endothelial cells were always enlarged with rather scanty amphophilic cyto plasm. The ovoid or irregularly shaped nuclei were hyperchromatic, often lacked a distinct chromatin pattern, and were void of nucleoli (Figs. 9 and 10). Mitoses were either absent or extremely sparse. Several changes were observed in nonneo plastic areas of the liver, as well as in biopsies, -&K -i Fic. 14, The gTeatly enlarged endothelial cells with hyperchroraatic nuclei, very sim ilar, if not identical with the malignant endothelial cells of the angiosarcomas arc seen. This area was remote from other foci of an giosarcoma within the liver. Aside from some enlargement and binucleaiion the liver cord cells appear normal (H k t. X3i0). IWK- .; 4 .* / ; >v Vol. 37 I addition racicristic II fibrosis (late area (arolilerafit (H lc I tumors : always fic cyto- nuclci Jistiiict Itcleoli 'absent lionneoliiopsies, r greatly ilulhelial i pcrthroI'cry simidentical lalignant il' of the me seen. ' remote it of an>lhin the nm some <>d binuiht cord normal No. i Hepatic Anciosarcoma and Vinvl Chloride Fic. 15. Liver cell enlargement, binudcation, and a' very deli cate peri-cellular fi brosis are teen. The endothelial cells in the center are very prominent (H lc , X340). 1 from vinyl chloride workers who had no angio sarcoma. These changes were also noted by Thomas et al.20 Multifocal delicate subcapsular fibrosis and a peculiar multifocal portal fibrosis were frequently noted (Fig. 11). The latter differed from the usual portal and peri portal fibrosis of other liver diseases in that the areas often were rounded rather than stel late, although both patterns were noted (Fig. 12). In portal areas where fibrous tissue prolif eration was found there was often an accom panying florid proliferation of bile ducts sur rounded by active fibroblastic proliferation (Fig. 13). In addition, there were enlarged, hypcrchromatic, and at times atypical sinu soidal cells with or without sinusoidal dilata tion. Some of these cells were indistinguishable from the malignant cells of the sarcomas (Fig, H). The liver cord cells in many areas were enlarged with large, often double nuclei and distinct nucleoli (Fig. 15). While probably not specific for vinyl chloride injury the changes were often impressive. Similar lesions have been observed in arsenic exposure.1''" Fic. 16, Spleen show ing dilated sinusoids and thickened trabec ulae indistinguishable from chronic passive congestion. The liver had foci shown in Fig. 12. but no angiosarcoma. The spleen was enlarged (H Sc E, X55). 160 Cancer January 1976 Vol. 37 Fic, 17. An enlarged spleen from a patient with liver angiosar coma shows extensive fibrosis and prominent endothelial sinusoidal cells (H k , x340). When present in other organs the tumors had a gross and histologic similarity to the liver tumors. They were multifocal and the margins were not well-demarcated. The spleens were often markedly enlarged, firm and congested. Hyperplastic sinusoidal cells were found in some specimens. The pic ture was similar to that of splenomegaly sec ondary to chronic passive congestion (Fig. 16). On the other hand, the evidence points toward a cell-specific response (endothelial cell) to vinyl chloride and the prominent, some times atypical endothelial sinusoidal cells and fibrosis might well have been the result of a combined effect of the chronic passive conges tion and the vinyl chloride (Fig. 17). In no instance was there angiosarcomatous involve ment of this organ. A careful evaluation of the other organs revealed no significant altera tions, except for those with sarcoma or changes explained by ancillary disease processes or treatment. Discussion Although the adverse effects of vinyl mono mer on the vascular system was recognized some years ago-3 the tumorigenic potential has only recently come to light. Just as acroosteolysis, secondary to vinyl monomer exposure, became preventable by simple industrial safe guards, so probably will liver angiosarcoma. Hepatic angiosarcomas have been reported to occur in the absence of known exposure to vinyl chloride or other carcinogens,*,511,*" as well as in conjunction with long term expo sures to specific agents. An increased incidence of this neoplasm was observed following Thorotrast (thorium dioxide) administration.*"l# Angiosarcoma and portal fibrosis have been reported following long-term administra tion of arsenic compounds and among vine yard workers exposed to arsenic.15 *7,18 The tumorigenic elfect of vinyl chloride in labo ratory animals has been described.3* Recently, vinyl chloride was reported to cause, among other malignant tumors, hepatic angiosar comas in. laboratory animals,*3,1'* The Louis ville cases were the first known hepatic angio sarcomas found in humans exposed to vinyl chloride. Certain aspects of these cases, the his tology, the hepatic scan, angiographic findings, and the results of a systemic detection program have previously been reported.2.3.a.7.i-.-o.z; Neither symptoms, signs, nor clinical labo ratory examination were found to be specific for this neoplasm. On the other hand, exposed patients presenting with symptoms, signs, or laboratory findings suggestive of hepatic disfunction or liver tumor have had the pre sumptive diagnosis made through the addi tional utilization of hepatic scans and angio graphic examination as exemplified by the three most recent cases. Table 1 summarizes the initial clinical and laboratory findings. It can be seen that some of the patients were asymptomatic and had only minimal liver function abnormalities in - a g -=s mT^Tc" `=2 5' ~ 5'm 2 g 2 %. S' 8 * - - 5 C. rs C. S?t-?o'S.?9 3^ `F'i. 9 n ? ? n > S "? K mm No. I H epatic A ngiosarcoma and V in y l C hlo ride M o k k et al. Table 1. Initial Available Clinical and Essential Laboratory Findings No Symptoms Signs Bilirubin SGOT LDH Alkaline Phos. SGTP 1 Fatigue, abdominal pain Hepatomegaly with nodularities* , 2 Fatigue, RUQ. pain RUQ. tenderness 3 Abdominal pain, weight loss Hepatomegaly* 4 Fatigue, abdominal pain Hepatosplenomegaly in epigastrium 7 cm below ribs 5 Anorexia, nausea, vomiting Hepatomegaly, 8 cm below ribs 6 Melenn Hepatosplenomegaly -4 cm below ribs 7 ]^digestion, jaundice H e pa t os p! e no mcgal y 7 cm below ribs S Nausea, hemntemesis melena l.ivcr at costal margin, -spleen 5 cm below 9 Diarrhea Marked hepatomegaly* 10 Anorexia, 12.5 kg. wt. loss in 3 months Hepatosplenomegaly 7 cm below ribs H Fatigue, weirht loss. abdominal pain Hepatomegaly, 8 cm below ribs 12 Fatigue Hepatomegaly* 13 Asymptomatic, abnormal liver function tests None 14 Fatigue, abnormal liver function tests None IS Asymptomatic in abdomen, abnormal liver function tests None in abdomen 1.9(1.0) 1.5(0.5) 1(1 0) 1.2(1.0) " 0.4(1.0) 2.8(1.0) 1.8(1.0) 0.81(1.0) 1.2(1.0) 0.5(1.0) 0.9(1.0) 62(40) 115(45) " 65(45) 58(50) 72(40) 55(40) 100(50) 201(40) 111(40) 35(40) 28(40) 25(40) 1390(500) 180(120) 215(200) 410(500) 180(225) 257(500) 230(500) 203(225) 311(225) 190(225) 14.8(3.5) - 45.9(4) 31(17) 31.2(3,5) 98(85) 6.7 1.7(3.5) 350(85) 108 5(3.5) 83(J.5) 160(86) 95(85) 24(45) " 29(35) " 16(40) 23(30) 21(45) 67(45) 53(25) 19(25) 105(85) 39(25) ( ) m The upper limit of normal range for the respective laboratory examination. Degree of hepatomegaly not recorded. FETO. GGTP GLOB. """ -- " --" CEA " ** " " ~ ~ ~ 500(28) 36(28) 90(37) - Neg. Neg. - _ 2.4(10) 8.5(10) Neg. . 0.1(10) ^08920 SSH i 162 Can'CEK January 1976 Vol. 37 Table 2. Age. Employment, and Survival Data Yearj-Months Worked in Diagnosed* Survival in months No. Age Diagnosed Plant PVC by Treatment1' after onset I 42 1962 17-2 17-2 2 51 1964 19-11 9-0 3 48 1967 22-1 19-5 4 43 1967 17-11 14-6 S 56 1968 15-6 4-0 6 36 1970 13-0 5-0 7 51 1971 27-10 27-10 8 39 1971 16-5 11-5 9 52 1972 22-5 22-5 10 58 1973 27-6 27-6 11 52 1974 25-3 25-3 12 53 1974 24-6 22-1 13 42 1974 19-0 17-6 14 45 1974 12-0 12-0 15 39 1974 19-1 18-1 * N: Necropsy, B: Biopsy. ' N.T.: No specific therapy, C.T.: chemotherapy, R.T.: radiotherapy. 1 Living, survival after biopsy. N N N B B B N B B N N N N B B N.T. N.T. N.T. C.T. N.T. C.T.-R. T. N.T. C.T. N.T. N.T. N.T. N.T. C.T. C.T. C.T. 4 3 8 5 5 16 2 22 7 5 8 3 12.5 11 * .3* the presence of extensive angiosarcoma. Other tumors were discovered while the patients were being treated for unrelated diseases. Only a general awareness of the occupational asso ciation, coupled with a high index of suspicion and a careful work-up of all patients with even minor liver function abnormalities ap pear to be helpful in establishing a diagnosis. There is need for a more specific detection test for hepatic angiosarcoma as demonstrated by Case 15. All of this patient's liver function tests, including gamma glutamyltranspeptidase (GGTP), were normal 3 months before a nonresectable angiosarcoma was found. Of pres ently available liver function tests, GGTP proved to be the most sensitive liver enzyme in our screening.8'1 It usually showed either the first or the highest elevation in patients with liver lesions. However, when applied to mass screening, GGTP with its high degree of sensitivity yielded a number of individuals with elevations who had no demonstrable liver disease. It was found to be-elevated in some who consumed even small quantities of alcohol a day or two before testing. Recently, we had experience with a 52-yearold male with a 20-year history of vinyl chlo ride exposure similar to Cases 13. 14, and 15. He had an elevated GGTP. Hepatic scan showed a nonfunctioning nodule in the right lobe. Hepatic angiography demonstrated a tu mor blush. The gross appearance at laporatomy mimicked angiosarcoma. On tissue ex amination, hemorrhage, necrosis, proliferating fibroblasts and capillaries with active endo thelial cells svere the conspicuous histologic features and presented a difficult diagnostic problem. The lesion was a .2.0 x 1-8 X 1.5-cm infarct. It was reassuring to know that so small a lesion could be detected. It further demon strates the need for careful histologic study regardless of the circumstantial findings. The large cystic cavities found in these tu mors led to the deferment of biopsies in Cases 1 and 2 because of the fear of hemorrhage and because the lesion was thought to represent hemangioma at exploration. The angiosarcomas in this study apparently differ from some of the other recently pub lished cases in that more of our cases were cystic, hemorrhagic, and necrotic with reactive fibrosis. Because of these characteristics, even generous biopsies often yielded nondiagnoslic hemorrhagic necrotic and fibrotic tissues. Therefore, we feel that if angiosarcoma is sus pected, the liver should be rebiopsied until a diagnosis can be established by frozen section. Another difference between two recently published series of nonvinyl-chloride-related hepatic angiosarcomas and our own cases is that three out of four of the patients in both reports1'10 had "distant metastases," whereas, only two among 13 of our deceased patients had proven involvement of distant sites, and one involvement of the submucosa of the duo denum. The two patients living have not R&S 026835 nl. 37 lerating, e cmloiitologic .ignostic .. 1.5-cm small emonu: study ngs. these tu rn Cases lage and epresent iparently nly pubties were i reactive tits, even mliagnosic tissues, nta is sus:tl until a n section. recently de-relatcd ti cases is ti in both whereas, l patients sites, and it the duohave not No. i Hepatic Angiosarcoma and Vinyl Chloride i\takk ft cll. 163 shown evidence of other organ involvement during recent examinations. We hesitate to consider those with multiple organ involve ment as metastases since multifocal origin is a distinct possibility. The problem cannot be settled from currently available evidence. Data are insufficient at present to delineate the pathogenesis of vinyl chloride related angiosarcomas in humans. Animal experi ments, however, show a dose-related effect with a sharp increase in hepatic angiosarcomas with exposure to high doses of vinyl chloride.13 -1 Thus, one might assume that in the early years of the industry, workers were exposed to considerably higher concentrations than ii. mpre recent years because of lack of informa- tion concerning the potential danger, as well as the lack of effective safety devices and tech niques available to the industry. All of the patients under discussion were employed in the plant over a long period of time and all were engaged in polyvinyl chloride production during the sears when exposure to high levels was more likely than it is at present. We could therefore postulate that hepatic angiosarcoma development in these patients was probably a late sequel of earlier and continued exposure to high concentrations. With knowledge of the risk of exposure and greatly improved indus trial methods, it seems quite probable that liver angiosarcoma among workers will be added to the list of preventable tumors. REFERENCES 1. Adam, Y. G., Huvos, A. G.. and Hajdu, S. 1,: Malignant vascular tumors of liver. Ann. Surg. 175: 575-383, 197k. 2. Block. J. B.: Angiosarcoma of the liver following vinyl chloride exposure. jAMA 229:53-54. 1974. 3. Creech, J. L... Jr., and Johnson. M. N.: Angio sarcoma of liver in the manufacture of polyvinyl chloride. J, Occup. Med. 16:150-151, 1974. 4. da Silva Horta, J,: Late effects of thorotrast on the liver and spleen and their efferent lymph nodes. Ann. N.Y. Acad, Sci. 145:676-699, 1967. 5. Edmondson. H. A.: Tumors of the liver and intrahepatic bile ducts. In Atlas of Tumor Pathology, sect. 7, Fasc. 25. Washington, D C., Armed Forces Institute of Pathology, 1958; pp. 139-145. C. Falk, H., Creech, J, L., Jr., Heath, C. W., Jr.. Johnson, M. N., and Key. M. N.: Hepatic disease among workers at a vinyl chloride polymerization plant. JAMA 230:59-63, 1974. 7. Lee, F. I.. and Harry, D. S.: Angiosarcoma of the Liver in a Vinyl Chloride Worker. Lancet 1:13161318, 1974, 8. I ooncy, W. B,: An investigation of the late clinical findings following thorotrast (Thorium di oxide) administration. Am. ]. Roentgenol. Radium Med. Nuci. Thcr. 83:163-185. 1960. 9. Lum. G., and Cambino, R. S.: Serum gammaglutamyl-iranspcptidase activity as an indicator ol disease of liver, pancreas, or bone. Clin. Chem. 18: 358-362, 1972. 10. MacMahon. H. E., Murphy, A. S., and Bates. M. I.: Endothelial cell sarcoma of liver following thorotnut injections. Am. J. Pathol. 23:585-595, 1947. 11. MacSwccn, R. N. M., Vetters. J. M.. Ross. S. U.. Ferguson, J.. Johnstone, J, M.. and Sandison. A. T.: Hacmangio-cttdoihclial sarcoma of the liver. J, Pathol, 109:39-44, 1973. 12. Makk, L.. Creech. J. L.. Jr.. Whelan, J. G,, and Johnson, M. N.: Liver damage and angiosarcoma in vinyl chloride w-orkers. JAMA 230:64-68, 1974. 13. Maltoni, C, and Lcfcminc, G.: Carcinogenicity bioassays of vinyl chloride. I. Research plan and early results. Environ. Res, 7:387-405, 1974, 14. Maltoni. C.: Occupational carcinogenesis. Pre print of International Congress Series No. 322. Ad vances in Tumor Prevention. Detection and Characterizaiion. Vol. 2. 15..Morris. J. 5., Schmid, M.. Newman. S.. Schener. P. J.. and Sherlock. S.: Arsenic and nonclrrhottc portal hvpertension, Gastroenterology 64:86-94, 1974. 16. Pollard. S. M., and Millward-Sadlcr, G. H.: Malignant hacmarigiocndothelioma involving the liver, Clin. Pathol. 27:214-221, 1974. 17. Regelson, W.. Kim, U., Ospina. J.. and Holland, J. F.: Hcmangiocndothelial sarcoma of liver from chronic arsenic intoxication by Fowler s solution. Can cer 21:514-521. 1968. 18. Roth, F.: Arscn-Lcber-Tumorcn (Hemangioendo(hc'lium). Z. Krebslorsch, 61:468-503, 1957. 19. Szasz, C.: A kinetic photometric method for serum gamma-glutamyl transpeptidase. Clin. CViem. 15:124-136, 1969. 20. Thomas. L. B.. Popper, H.. Berk. P, D,, Selikoff, T,. and Falk, H.: Vinyl chlorulc-indueed liver disease. .V. Engl. J. Med. 292:17-22, 1975. 21. Viola. P. L.. Biggotti. A., and Caputo. A.: On cogenic response of rat skin, lungs, and hones to vinyl chloride. Cancer Res. 31:516-522. 1971. 22. Whelan, G.. Jr.. Creech. J. L., Jr., and Tam* burro, C.: Angiographic and isotopic characteristics of hepatic angiosarcoma found in vinyl chloride work ers. (In piess). 23. Wilson, R. H.. McCormick. W, E., Tatum. C. F., and Creech. J. 1... Jr.: Occupational acroostcolssis-- Report of 31 cases. JAMA 201:577-581, 1967. WMfX . .ry~f.il.-