Document 15dGY0L58yp8JyqN71DebrMGm

f~7 R&S 116851 Med. Lavon, 6, J5J-J63. 1982 Cana 40 Lim "LMg" Latnedidna deiiavoro Vt Stn BtmtJit I. utltna. nttr HEPATIC ANGIOSARCOMA FROM VINYL CHLORIDE. REPORT OF A NEW ITALIAN CASE tlVff&M Ci/A'/iT/fL G. Chiappino, PA. Bertazzi, M. Baroni *, T. Masini2 Angiosarcoma epatico da cloruro di vinile. Uo nuovo caso italiano . Vienc descritto on caso di angiosarcoma epatico in on tiomo di 43 aani che aveva lavorato per 21 unni esposto a cloruro di vinile. Viene brevemente ricostruita la sum storia lavondrs, iniziata nel 1959 e svoltasi quasi esdusivamente in un reparto di produzione di PVC, e la storm fliniga cbe dopo modesti prodromi nell'aprile 1980 si e progressivameate evoluta a partire dal dicembre dello stcsso anno in manieta rapidamente progressiva. La morte c intervenuta tre mesi dopo la diagnosi per un massivo emoperitoneo. Vengono descritti in dettaglio i reperti macroscopici e micro scopic! ottenuti dopo esame autoptico. Dalla loro discussione si ricava cbe la rara neoplasia ha avuto verosimilmente origine policentries e che alia sua altissima ma lign!ta locale non fa riscontro alcuna capadta metastatizznnte. Inoltre Finsorgenza dell'angjosarcoma i stata preceduta da lesioni epatiche di natura sderogena. II caso e il quarto desezitto in Italia e compano tra i Javotatori esposti a cloruro di vinile e il novantatrccsimo comunicato neQa registraziane mondiale. The reports collected up to today in all countries are amply sufficient to confirm the experimental data (6, 16) demonstrating the carcinogenic action of vinyl chloride mono mer (VCM) and its peculiar capacity to pro voke, other, than brain, lung and lymphatic tumors (9, 15, 17), angiosarcomas with a peculiar hepatic localization (4, 5, 7) with a similar effect to that of thorotrast (3) and arsenic compounds (12). It is important, however, an accurate iden tification of all cases of VCM hepatic angio sarcoma and for each, a uniform collection of all possible information with the intent Institute of Occupational Medicine Clinics del Lavoro L. Devoto * . University of Milan - Director: Prof. G. Chioppino. 1 Deportment of Internal Medicine - Isticuti Qinici di Perfezionomento - Milan Primary: Prof. G.C. Scccbi. - Institute of Anatomy and Pathological Histology University of Milan Director: Prof. L Manurri. of better understanding aspects which are fundamental in carcinogenesis. One must in fact wait for clarifying information from the in-depth study of the behaviour of tumors like occupational angiosarcoma, whose patho genesis is influenced demonstrably less than others by a multifactorial etiology. For exam ple, the relationships between type, entity and/or duration of the exposure to the agent and the latency period and, more in gene ral, the complex relationships existing in the system agent-man-neoplasm can, at least in part, be better defined. After the first reports in the literature all the cases of hepatic angiosarcoma of ascer tained occupational origin were registered by the NIOSH: up to October 1977 the record comprised 64 cases (13) observed in Belgium, Canada, Czechoslovakia, West Ger many, France, Great Britain, Italy, Japan, 556 OBAPVmO, BEXTAZZI, BAB0NI, MASINI Med. Lavoro R&S 116852 Norway. Sweden, the United States and Yugoslavia and appeared for the most pan in the period 1973-77, after extremely varia ble latency periods: from the beginning ot the exposure to VCM to the clinical evidence of neoplasm, there were intervals of between 9 and 38 years. The most recent and up to date record of cases of hepatic angiosarcoma in workers exposed to VCM was made by (14) and updated to the end of August 1981, 91 ca ses, of which 41 occurred in the period 1973-1978. For 67 of the 77 cases for which the wor king history was known, the occupational exposure took place in the course of PVC manufacture: among them 29 were also exposed during autoclave cleaning operations. The mean latency between the beginning of exposure and the diagnosis was about 21 years. Up to now, in Italy, 3 cases have been diagnosed, respectively in 1971, 1972 and 1973 (2, 6): the first had worked in 1965 for about a year as a PVC extruder in bag production, the second from 1953 to 1961 in PVC manufacture, and the third from 1953 for eight years in cleaning autoclaves and then for 12 years checking the polyme rization reactions. The first of the Italian cases was not included in the international registration because it was considered aty pical and not homogeneous with the others in its clinical history (uncertainty of the pri mary site of the neoplasm): aside from that it is the only case appearing among workers who were not in production but in PVC uti lization: if this also is taken- into considera tion, the total cases collected amount to 92. Described here is a case of hepatic an giosarcoma which appeared after occupational exposure to VCM, observed at the Milan Ginica del Lavoro , which appears as the fourth in Italy and the ninety-third in inter national records. Case report Male bom in 1937; psycho-somatic development normal, never smoked, occasional wine at meals, no hard liquor; no major illness up to 1980. Work history In April 1959 he begins work at ANIC in Ra venna in charge of the refrigeration cycle in the department for VCM production (acctilenc-HQ me thod) for 8 months: successively m the department tor rvti production (polymerization in suspension) with duties in teactioncontro^jmdjeeoveQrJn^t in cleaning the insides of the reactors) un to 1963: then, as foreman, he was present at all production phases (polymerization, autoclave discharge, filtra tion, drying) up to 1975 and as supervisor, but always with dudes involving direct control of the diverse production phases, up to December 1980. Clinical features April 1980; right-side abdominal pains of brief duration appeared, attributed to ureteral colic. De cember 1980: because of the reappearance of abdo minal pains apart horn meals, localized prevalently in the epigastrium and the left hypodiondrium, radiating backwards and associated with nausea and vomiting, he was admitted to the Division of Ge neral Surgery at the Faenza Hospital. Among others, the following examination were done: Hematochemicd tests'. Gamma GT -- 145 UI/1 (ilv. 6-35). Alkaline phosphatase = 551 UI/1 (n.v. 50-220). AST, ALT = within the norm. Lister Scan: liver lighdy enlarged, vast cold area occupying the rtgnt looe partially and the left almost completely. Spleen lighdy enlarged. Litter-Pancreas Ultrasound Scan: hepatic echostrue-1 tuxe altered by the presence in the left lobe I and in the anterior region of the tight lobe of I a vast area of nan-homogeneous echo-structure I with less reflective rones next to highly ieflec-| tive areas. Laparoscopy: liver modesdy enlarged, some rarescars, colored red-brown with obvious yellow tones on the surface. Needle biopsy: Endothelial cells with striking aty pical cytonudear characteristics ... typical ap pearance of malignant angioendothclioma (dr. Tison). ... single or grouped hepetocytea, so metimes intermingled with fibroblasts, lined with strongly atypical ceils in endothelial poaidon. Vol. n, n. 6. 1982 NEW CASE OF HEPATIC ANGIOSARCOMA FROM VCM Med. Lavnrt) Fig. 1 - Liver in toto: a vast dark subcapsuiar area corresponding to the neoplastic localization in the left lobe, bleeding next to the falciform ligament (raised and moved towards the right): some superficial nodules on the right lobe. Fig. 3 Greater enlargement of the preceding figure: spongy hemorrhagic aspect of the intrahepatic neoplastic moss. R&S 116854 Vol. 73, n, 6,1982 new case of hepatic angiosaxcoma fkom vcm 557 These cells are elongated, ovular or halfmoon endowed with voluminous nuclei, intensely hyperchromatic; the cytoplasms ate of variable extent, homogeneous and eosinophilic. This pre sents the picture of hepatic angiosarcoma with a high degree of cellular atipy (prof. Maltoni). 19 February 1981: admitted to the Ginica del Lavoto of the University of Milan. Inconstant abdo minal pains persisting, either piercing or characte rized by vague aching prevalently in the left hypochondrium. From December 1980 weight loss of about 20 kilograms. Among others, the following tests were done. - X-rays bands: no alterations attributable to acroo steoiysis. " Digital pbotopletismograpby: within the norm. Blood count: hematocrit 29%, hemoglobin 9J; red cells 4.070.000. Gamma GT = 108 mU/ml (n.v. = 4-18). Alkaline phosphatase = 83 mM (n.v. up to 44). AST, ALT -- within the norm. ' Ultrasound scan: no significant variations in re (spect to preceding exam. Computerised tomography upper abdomen: expansive hepatic process: pan creas, spleen, kidneys within the norm; no retro peritoneal adenopathies. Multiple transfusions and symptomatic therapy were done in preparation for chemotherapy. 28 March 1981: the abdominal pain intensifies suddenly involving both hypocondriac zones accom panied by accumulation of fluid in the peritoneal cavity. 30 March 1981: sudden increase of fluid in pe ritoneal cavity which at the exploratory puncture appears hematic; paleness, sweating, dyspnea. Death 2 April 1981: necropsy. Gross Pathology Abdominal cavity contains about 4,000 c.c. of uncoagulated blood; the peritoneum smooth and shiny, some reddish nodules on the anterior face of the omentum. Liver: shape and size within the norm, dimi nished consistency, multiple nodules on the surface, some whitish, others of a blueish-red color with hemorrhagic borders. A bleeding nodule near the falciform ligament (fig. 1). Two distinct zones are observed on the cut surface, respectively in the right lobe and in the left, where the hepatic tissue is substituted by newly-formed tissue, spongy in appearance, partially necrotic clearly defined by the surrounding parenchima, which presents a brownish yellow colour and with lacunas filled with blood (figs- 2, 3). Spleen: normal shape, size increased, consistency reduced. The macroscopic observation shows, in addition, brown myocardosis, signs of nefrosis and multiviscetal regressive changes. Microscopic features Liver: the newly-formed tissue in the hepatic site appears constituted of masses of highly atypical ceils, sometimes gigantic and multinudear but ten ding to be spindle-shaped with elongated and hyperchromatic nuclei, and with acidophilic cytoplasm (figg. 4-5) disposed sometimes in endothelial position lining the pre-existing vascular spaces (fig. 6) or newly formed blood vessels surrounding grouped hepatocytes (fig. 7). In some points, ample caver nous spaces are seen filled with erythrocytes and containing papillary elongations or solid masses of spindle shaped cells; in other points thrombotic or hemorrhagic phenomena are predominant. Special stains show a notable increase of reticulin fibers: newly formed collagen fibers are also evident (fig. 8). The histological characteristics are those of angiosarcoma. The hepatic parenchyma not involved in the neoplastic proliferation presents microscopic aspects of vacuolar degeneration and a moderate perilobular steatosis. The connective tissue of the portal-biliary spaces is clearly increased and enve lops the vascular and biliary branches in areas of compact sclerosis sometimes extending to the inter lobular spaces (figg. 9-10). The microscopic examination of the other tissues confirms the grossly observed impairment. No va scular alterations ate found with the exception of slight renal arteriosclerosis with hyalinosis of some glomeruli. Pathological diagnosis: haemoperitoneum in sub ject affected by hepatic angiosarcoma, splenomegaly, pulmonary edema, bilateral hydrothorax, myocar dosis, renal arteriosclerosis, nephrosis and multivi sceral regressive changes. 558 CHIAPPINO, BEXTAZZI, BAEONI, MASINI Med. Lavoro Fig. 4 - Microscopic feature: highly atypical elements, tending to be spindle shaped with elongated and hyperchrotnatic nuclei arranged sometimes in endothelial position (Haematoxylin-Eosin 500 x). R&S 116855 Fig. 5 - Microscopic feature: the characteristics described in the preceding figure are dearly evident (Haematoxylin-Eosin 480 x). Fig. 7 - Microscopic feature: neoplastic elements surrounding single or grouped bepatocyteg, with ample lacunas where red cells are distinguishable (HaematoxylinEorin 480 x). R&S 116856 R&S 116857 360 CHIAPPINO, bextazzi, barom, MASiNX Med. Lavoro Fig. 8 - Microscopic feature: obvious newly formed connective fibers (HaematoxylinEosin 120 x). ;. V t, 's'.' -- - ' -*r ', Fig, 9 Portal biliary space in the hepatic parenchyma distant from the neoplastic mass, with a notable increase of connective tissue (Van Gieson 120 x). Vol. 73, n. 6,1982 NEW CASS OF HEPATIC ANGIOSARCOMA FROM VCM .- ,, -. ` 1 >. * f./; * - V Vs '-1 ;'f# *_ * J *' \ r * "`. 1 ' - ^ 4 . r` A * *' , '* * 4 .x" * ." *' % * '* ' * .*. *i-VtTS'. ?^ -, * ^ \ ^ \- 561 ;''?y. ** * *'. rcV*..-t*--:*2- _ * . ,v .. . .t:-," ' . vV Fig. 10 - Area of connective formation with obvious collagen bundles, which extend into the interlobular space (Van Gieson 120 x). Discussion In accord with what has been noted for the majority of cases, this case also is con sequent to an exposure to VCM prevalently related to working on polymerization: the period of maximum exposure is that com prised between 1960 and 1963 when con centrations of VCM of thousands of ppm could be present near the autoclaves. In suc cessive years the change of duties (foreman) and the improvement of the equipment pro bably brought a reduction of the level of exposure. In the opinion of department te chnicians, the exposure in the decade 1963^ J.973 had a discontinuous character with fre quent peaks however on the order of hun dreds of ppm, in 1973, finally drastic technological modifications dramatically reduced the exposure. The latent period between first exposure and detection of cancer was 21 years, with maximum exposure in the first four years. The duration of exposure was also 21 years because the interruption of work coincided with the manifestation of symptoms which led to hospital admittance. No references to extrahepatic manifesta tions of VCM disease (peripheral circu latory disturbances with acroosteolysis, skin changes, thrombocytopenia) are present in the patient's history: liver damage was in stead certainly present, as manifested by the portal-biliary and intralobular sclerosis ana logous to those already described (7, 8) and probably preceding the appearance of an giosarcoma: the multivisceral regressive chan ges histologically observed are instead to be related mostly to recent metabolic changes connected with the neoplasm. The neoplastic localization in two clearly distinct, main masses, situated in the right and left lobes supports the possibility of a polycentric onset which moreover has been well documented in experiments by intense exposure (6). The complete absence of metastasis. in contrast with toe malignancy of the tumor, with its advanced evolution in the liver and with the evident tendency to endovasal pro liferation was already noted (7) and seems to be confirmed ever more with the enrich ment of the case-studies, as a characteristic R&S 116858 362 CHXAPPINO, BERTA2ZI, BAEONI, MASINI Med. Lavoro peculiar of VCM angiosarcoma, opposed to other forms unrelated to this toxic substance (1, ID* In cases involving VCM exposure where angiosarcomas were found in extrahepatic si tes, the possibility remains open however of a multifocal origin rather than a metastatic spread, hypothesized in various cases (6, 7, 10) observed also in experiments (6) and related to the vascular toxicity of the sub stance (18). In conclusion, the following information emerges from the case described: intense and prolonged exposure, latency period on the order of 20 years corresponding to the average of all the cases described, onset of cancer after liver sclerosis, origin probably polycentric, high histological malignity with a rapid evolution in loco, and, in contrast, total absence of metastadzing capacity. The ultimate significance of some of this information cannot, for now, be clarified: there is no doubt however that the obser vations of these peculiarities of behaviour of rare tumors which are the ultimate effect of single and well defined noxae like angio sarcoma or, for example, mesothelioma will improve our knowledge more than could the data from the study of high incidence tu mors, in whose etiology multiple endogeneous and exogeneous factors interact in a complex way. We are indebted to Prof. C. Zambiancbi, Ospedaie per gli Infermi Forma, for providing Hospital re cords and to Dr. Vittorio Tison and Prof. Cesare Maitoni for reviewing pathological material. We thank the Management and the Health Ser vices of ANIC for providing information on the exposure history in the plant. ABSTRACT The fourth case of angiosarcoma of the liver among workers exposed to vinyl chlo ride in Italy is reported. The case was a 43 years old man who worked from J959 to 1980 in a VCM/PVC production plant, mosdy in the polymerization area. He died in March 1981, four months after diagnosis, for a massive haemoperitoneum. Post mor tem examination was performed. According to four independent pathologists the histo logic appearance was typical of a highly de viating angiosarcoma. The tumor developed after a sclerotic liver lesions was already pre sent. The angiosarcoma was probably poly centric, had a high degree of malignancy and a rapid local evolution while, in contrast, no metastases were detected. REFERENCES 1. Adam Y.G., Huvon A.G., Haidu S.I.: Mali gnant vascular tumors of liver. Ann. Surg.. 175, 375-383 (1972). 2. Bertazzi PA, Villa A., Foa V., Saia B. er *1.: An epidemiological study of vinyl chlo ride exposed workers in Italy. Arh. za Hig. Rada I Toksikol., 30, (suppl.) 379-397 (1979). 3. Da Silva Horta J.: Late elfects of thorotrast on the liver and spleen and their efferent lymph nodes. Ann. N.Y. Acad. Sci., 145, 676^99 (1967). 4. Lloyd Y.W.: Angiosarcoma of the liver in vinyl chloride/polwinyl chloride workers. J. Occup. Med., IS, 809 (1974). 3. Maltoni C, Lefemine G., Chieco P., Caixetti D.: Vinyl chloride carcinogenesis: cur rent results and perspectives. Med. Lavoro, 65, 421-444 (1974). 6. Maltoni G: Angiosarcoma eoarico in operai esposti a cloruro di vinile. Resoconto dei primi due casi riscontrati in Italia. Med. Lavoro, 65, 443-430 (1974). 7. Mark L, Delmore F., Creech J., Ogden L., Fadell H., Songster C,, Clanton J,, Johnson M.N.: Clinical and morphological feature of hepatic angiosarcoma in vinyl chloride workers. Cancer, 37, 149-163 (1976). 8. Marsteller H.J., Lelbach W.K., MOller R.. Juke S., Lange Gil, Rohner H.G., Veltman G.: Chronisch-toxishe Lcbershdden bei Arbeitern in der PVC Produktion. Dtsch. Med. Wschr., 98, 2311-2314 (1973). 9. Monson RJt., Peters JM., Johnson M.N.: Proportional mortality among vinyl chloride workers. Lancer, 2, 397-398 (1974). 10. PouacowsKt P., Faure C, Aubeet M., Pawn M., Latxezlle R-, Barrie J.; Angiosorcome costal lid 3 une intoxication au chiorure dc polyvinyl, Nouv. Presse Med., 8, 2483 (1979). 11. Pollard Sid., Millward-Sadler Gil.: Ma lignant haemangioendothelioma involving the liver. J. Clin. Pathol., 27, 214-221 (1974). 12. Regelson W., Kim U., Ospina J., Holland JJP.: Haemangioendothelial sarcoma of liver from chronic arsenic intoxication by Fowler's solution. Cancer, 21, 514-321 (1968). Vol. 73, n. 6,1982 NEV CASE OE HEPATIC ANGIOSARCOMA FROM VCM 563 13. Spiztas R.t Kaminski R,, Hyg MS.: Angiosarcoma of the liver in vinyl chloride/polyvinyl chloride workers. J, Occup. Med., 20, 427-429 (1978). 14. Stafford J.: Written communication (1981). 15. Tabershaw IJt, Gaffey W.R.; Mortality stu dy of workers in the manufacture of vinyl chloride and its polymers. J. Occup. Med., 16, 309-518 (1974). 16. Viola PL., Bigotti A., Caputo A.: Oncogenic response of rat skin, lungs and bones to vinyl chloride. Cancer Res., 31, 516-522 (1971). 17. Waxwbiler R.I., Stringer W., Wagoner JiC,, Falk H., Carter C.: Neoplastic risk among workers exposed to vinyl chloride. Ann. N.Y. Acad. Sd., 271, 4048 (1976). 18. Wilson R.H., McCormik W.E., Tatum C.F., Creech J-L.: Occupational acroosteolysis. Re port of 31 cases. JAJ1A, 201, 577-581 (1967). Accettato il 18/2/1982.