Document ZJZd7q2RZGq4ngXYKzrL4Q3OJ

Ten Cases of Angiosarcoma of the Liver in Shawinigan, Quebec Fernand Delorme, M.D., end GiRes Theriault, M.D. Ten uses el angiosarcoma of the liver have been diagnosed In Shawinigan, Quebec since 1955. Ail have occurred in men who worked in a vinyl chloride polymerizing plant. Cigarettes and alcohol do not seem to be associated with this tumor. The amount of vinyl ctitsridc to which these people were exposed, according to information obtained through questionnaires, appears elevated. Angiosarcoma of the liver is accompanied bya fibrosis of the liver which may precede its appearance. In d*scribing the Canadian cases of angiosarcoma, this study at* tempts to shed more light upon the causal relationship be* tween vinyl chloride monomer and angiosarcoma of the liver and thus to provide some clues to understanding the patho* gentile of this disease. In January 1974. three cases of angiosarcoma of the liver were discovered among workers of a chemical plant.1 This finding ap peared abnormal and the agent suspected of being responsible for the disease was identified as vinyl chloride monomer (VCM). Since then, many reports on the occurrence of this cancer among vinyl chloride workers have appeared around the world*'* and the Unit ed States Occupational Safety and Health Administration has enacted a new threshold limit value for concentration of this chemical in the air of the working environment.4 Ten cases of angiosarcoma of the liver were diagnosed among workers of a vinyl chloride polymerizing plant in Shawinigan, Quebec. This is the largest number of cases ever to take place in a single plant The present study describes occupational history, drinking and smoking habits and some histological features of these Canadian case*. Data on some of these Canadian cases jointly with cases of angiosarcoma from,the United States have al ready been described in another article by one of the authors.* Since more accurate and complete information was retrieved on the Canadian cases, It Is being presented separately in the present article. Fran the Departown! el Pathology. Carur* HoapXilwr Zegenal de b Mauncs. Jtwwlnlgjn, Quebec Dr. Detoemt) and the Department c* Sot lal and fnwntwt Medieine. laval Unwemty. fce-Foy, Quebec Dr. Thertauhl. 338 Methods Casa Finding. -- A starch for cases ofangiosarcoma of the liver beginning as far back as 19SS and extending over two decades was carried out by scrutinising files of the regional hospitals In the Shawinigan vicinity. Alt cases of primary tumors of the liver were collected and the histological material (slides, biopsy reports, autopsy reports! were reviewed for the presence of angiosarcoma To confirm the diagnosis of angiosarcoma of the liver, the cases were submitted to consultants from the United States familiar with this disease. Occupational History. -- The questionnaires used to obtain a detailed occupational history of each case culled information con* ceming past and present residence, medical history, smoking and drinking habits along with past occupations and employer* in chronological order. The answers to most of questionnaires were given by spouses of the men who died from the disease, in one in stance. however, the answers were given by the sister and brother-in-law. and in another, by the worker himself. Two former co-workers of the men who died of an angiosarcoma of the liver confirmed and completed the information obtained through the families. Plant Description. --The Shawinigan vinyl chloride plant start ed operating in 1943. At that time, it produced and polymerized vinyl chloride monomer. Later Fn the 1950s. it stopped producing VCM and kept operating the polymerization unit. The workforce varied from 100 to 350 workers. At the moment, it employs 250 men. Production of PVC has fluctuated with time. Present produc tion is estimated at 50 million pounds annually. Exposure to VCM in the working atmosphere, though not documented, is believed to have been very high in the past. Sharp improvement has taken place In recent years and it is estimated at less than 3 ppm at the moment Results Table 1 shows the age at death, the smoking habits and alcohol consumption for the ten cases of angiosarcoma of the liver diag nosed in the Shawinigan region over the last two decades. All were male*, tl average of V it Is somev. type of tumo(we were mo or less per < cigarettes pe moderate an smokers w * The men very Sght do bottle of be* regularly. As be associate workers. Past diset the devetot history of t hepatic tro Table 2 vinyl chlor being direc tions they worked fo an average e> Journal AP00008418 f*W 1. -- Sea. A| al DaitK tmeUnt MaMtt iM Aleahat Camunatlon at Tan Cam cf Aa|tMareM of aha Urar In a CMSdiaa Cemnanitt. Cm *- t 2 ) 4 0 1 7 S * 10 T S ' mit mil* mjH nk tmk nv IPSIf nit rale ran At* at Until 11 U f <1 sa si S3 U S3 1 SOS tMtk| HiMi tiuto I t & 1 1 lumektr Mu--tit i % tittaaflaa et Optra CemraMi Nt. *1 Of*r*nt a*. r rm ft Day Smekad 20 27 11 27 -- --' 10 10 42 40 S3 2S M 2$ IS 20 ss 2$ 13 Aithe! OtimraiiM 0. OtttlM ( Mw Pat teh S 1 1 -- t 4 21 11 4 -- M. f Vat* fciiUm 4 25 2$ -- <0 s .# 30 >0 -- .eemales. the age at death ranging from 41 to 61 years With an j.rage of 50.5 years. I is somewhat doubtful that smoking has much to do with this .,p* of tumor. Out of the ten cases, one man was a nonsmoker, >c were moderate smokers, smoking an average of 20 cigarettes y less par day. and the remaining four smoked one pack of : eirettes per day or more. The tumor appeared earlier in the noderate and nonsmokers 5 age 47 years) than in the heavy .nokeri ix 54 years). The men who developed an angiosarcoma of the liver were %trv light drinkers. Only two men out of ten drank more than one mttle of beer per day. None of the ten men.drank wine or liquor '<$ularly. As with cigarette smoking, drinking does not appear to :* associated with an angiosarcoma of the liver in vinyl chloride workers. Past diseases of the liver may also be ruled out as potentiating re development of angiosarcoma of the live/ since the medical uteri' of the ten cases showed no previous liver diseases nor epstic troubles. Table 2 shows die length of time the. men were exposed to vnvl chloride either bv working in the polymerization unit or by Ming directly exposed to vinyl chloride. It also shows the occupi es they performed and whether they worked overtime. They noticed for periods ranging from 11 to 29 years in the plant with in average of 21 vear$ and 4 months. Direct exposure to vinyl chloride monomer was obviously shorter, ranging from S years 3 months to 26 years with an average of 16 years. 10 months. from the job descriptions, it can be seen that most of the men worked either as operators or maintenance workers, or both. Seven men worked as "reactor cleaners.1' an operation which seems to have been the worst in exposing people to vinyl chloride monomer. One woman said of her husband's exposure. "He went down into the autoclaves many times. Once, they had to take'him out unconscious." It is difficult to get a fair idea of the amount of vinyl chloride monomer to which these people were exposed. Many spouses (six out of tenl insisted upon mentioning that their husbands worked overtime. As shown in Table 3. the time elapsed between the first ex posure to vinyl chloride monomer and the diagnosis of the disease ranges from 11 years to 28 years with an average of 203 years. This concur* with previous findings that an angiosarcoma of the liver can develop after a minimum exposure of four years, but that actual manifestation does not occur for at least ten years.* Residence history revealed that all workers lived within a two mile radius of the VCM plant since the beginning of their employ ment at that plant. However, no particular pattern in thr residen tial history could be identified that could lead to finding environ mental factors common to everyone. ' Past occupational history showed that all these workers spent IT 1|r :n ( | a m H t.,l.tin ii AP00008419 I \ I Pie I I 1 As to of WUlia the greeter pert of their active lives working for the tame em ployer. The longest period anyone worked outside the plant was four years. ' Once the tumor t$ diagnosed, the survival period is very short. In the present study, the longest survival period was eight months, the average 4.1 months. It must be pointed out that angiosarcoma Is not the only liver pathology found in vinyl chloride monomer workers.* '* There are two types of benign lesions -- sclerosis and cellular transforma tion. Sclerosis manifests itself by a thickening of the capsule of the liver, a portal fibrosis with proliferation of the bile ducts and lym phocytic infiltrate, a sclerosis of the wall of the portal vein and eentroiobular veins and a perlslnusoldal fibrosis with sinusoid dila tation. Cellular transformation shows a sinusoidal cell proliferation with atypic. dysplasic and reactional liver cells. The tumor itself is a malignant angiosarcoma type tumor appearing in four definite histological patterns: a cavernous pattern, a sinusoidal pattern, a nodulo-papillar pattern and a sarcomatous pattern. In our exper ience. the cavernous pattern is the most constant and frequent one (Table 3). Discussion The present study is an epidemiological and a histological de scription of the ten cases of angiosarcoma of the liver found In the region of Shawinigan, Quebec. Although the selection of cases was made from hospital records, it happened that all were men who worked In the same factory -- a vinyl chloride 'polymerlaatlon plant THit type oftumor being very rare, a causal relationship between the exposure to vinyl chloride and the development of an angiosaccoma of the liver is established. The present study reveals that the exposure necessity to develop the cancer must be relatively high. Cleaning reactors and operating production units were occupations carried out in an en vironment with a high concentration of vinyl chloride monomer. Furthermore. It is possible that in the 1940'*, the men worked more ttun 40 hours a week. To this, one must add overtime work, another contributing factor. It will be necessary to assess with as much accuracy as possible the exposure of these people to vinyl chloride monomer to 'discover a dose-response relationship be- > tween the chemical and the disease. It seems that benign noc-tumoral reactions are the first re- ' sponse of the liver to the chemical. Eventually they give way to * malignant transformations/*" Obviously, more studies win be necessary to discover whether the benign and malignant lesions are two steps of a unique phenomenon or two different diseases. References 1. Creech 1L and lohnson MM: Angiosarcoma of liver in the manufacture . of polyvinyl chloride, tOM 16:150-151. 1974. 2. Lee Ft and Harry DS: Angiosarcoma of the liver in a vinyl chloride worker. lancer 131-1318. June 29. 1974. 3. Block. Bradford ): Angiosarcoma of the liver following vlnvl ehlortd* exposure /avia 229 S3`54. 1974. 4. Rtty |. Sauvage. Tualllon. and Habnrd A: le 3&me cat francab d'angiosarcome htfpaiique eheZ un ouviier du ehlorure de vinyle. Arch Mil Prof 551-555. 12 dec. 1975. 5. Center for Disease Control. Morbid!tv and Mortality. Weeklv Report 25(8):1-2. Feb 1976. 6. Department of Labor. Occupational Safety and Health Administration; Exposure of vinvt chloride. federtl Rentier 39<.194i:35890-35B98, Part W. Oct 4. 1974. 7. Makk L Delorme f, et al: Clinical and morphologic features of hepatic angiosarcoma in vinyl chloride workers. Cancer 37:149-163. 1976. B. laszto M. Delorme f. et al: Clinical and morphologic features of hepatic angiosarcoma in vinyl chloride workers. Cancer 37<1>, Jan 1976. 9. Delorme F and Makk l: Angtosarcome du foie chez les oovriert avant dtf *n contact prolong^ avec le ehlorure de vinyle. Description marphioiogique des listens. Union Med Canada 104:834-841. 1975. 10. Deiorme F and Makk L; Angfosarcome du foie chez les ouvriert ayant Al en contact profongl avec ie ehlorure de* vinyle. Description morphokaglque dei lesions. Revue franc gantroent 119 May 1976. 11. Thomas LB and Popper H: Pathology of angiosarcoma of the liver among vinyl chloride-polyvinyl chloride workers Ann MV Acad $ci 346^68-277, 1975. 12. Thomas LB. Popper H. et ai: Viny4<hlorlde-induced liver disease. New tngl I Med 292:17-22. 1975. 13. Cedigk P. Muller R, et al: Morphology of fiver damage among polyvinyl chloride production workers. A report on 51 cases. Ann NY Acad Scl 246:276-265. 1975, 14. McDonald RS; Primary carcinoma of the liver. Arch Ini Med 99:266279. 1957. 15. Popper H and Thomas LB; Alterations of liver and spleen among worker* exposed to vinyl chloride. Ann NY Acad Sci 246:172-194.1975. M f < v ) I I < <* 340 Angiosarcoma of me Liver in Shawinigan, Quebec/Detortne and Theriault The two ) wlthoi only c amail perfo< In Pt* thick* nor w there pleur. retail pteur ppe; ashes In cigart auto; repo: In 19 geno lowe foun< Sir wou1 cigar diset obse som less ings Anv of p Fro Coll* Phdac lour AP00008420 . fc-' SEP 23* 1980 , FILE NUMBER 150 , ^AUTHOR<S> * MfrLHBERG* B.? KRONEVI, T.> MINELL M. 757 TITLE * THE PATHOLOGY OF UTNVI PHIfttiTnF FtfPOSFn MTrP. t PUBLICATION TSOURCE t ACTA VET. SCAND. 17;32B-342. 1976. * LANGUAGE * ENG. ^------------------------------------------------------------------ COUNTRY t SME. k-^-x-m- EXPERIMENTAL DEG IGN >** 4*+fr ^*1 THIS INHALATION STUDY USED OUTBRED ALBINO fIMRI MICE <12 * WKS. OF AGE). TWENTY FOUR_MI.CE -<12 WALES AND 12 FEMALES)/ ` GROUP WERE EXPOSED TO A VC CONCENTRATION-OF pf* (for'32>-^;V, wks. > OR 500 ppm <ftr 26 wkt.it 6MRS./DAY* FIVE DAYS/Wk. . CONTROL GROUPS OF 24 ANIMALS WERE RUN `CONCURRENTLY WITH ' : EACH SERIES* HOWEVER* ONLY ONE GROUP WAS EXPOSED TO AIR IN AN .INHALATION CHAMBER, IN THE EXPERIMENTAL GROUPS FOUR NICE OF EACH SEX WERE SACRIFICED AND SUBJECTED TO *' PATHOLOGICAL EXAMINATION ON THE 26th WEEK AND THE REMAINING ANIMALS EXAMINED WHEN MORIBUND OR DEAD. FOUR MICE IN THE CONTROL GROUP WERE SACRIFICED ON THE 52nd WEEK. THE VC CONCENTRATION IN THE DARK* CYLINDICAL METAL INHALATION CHAMBER WAS ANALYZED BY G.C. REGULARY. THE MICE WERE WEIGHED <TOTAL BODY WEIGHT) EVERY TWO WEEKS. -M-*-M- KEYWORDS VINYL CHLORIDE! INHALATION? MICE; PATHOLOGY; BENIGN TUMORS? ALVEOLOGENIC ADENOMAS? LUNG? HEMAN61OSARCOMA? FAT TISSUE? CARCINOGENICITY? BLOOD VESSELS RUPTURE? TELANGIECTASIS? LIVER? MAMMARY ADENOCARCINOMA? PARARENAL HEMANGIOSARCOMA; PARAINTESTINAL HEMANGIOSARCOMAi RHABDOMYOSARCOMA? REMOCOELIA? BROWN FAT? SUBCUTANEOUS? SUBPERITONEAL? VC ANIMAL STUDY. ABSTRACTS IN THIS INHALATION STUDY MICE WERE EXPOSED TO VC AT 50 OR 500 ppm FOR'A HR. /DAY, S DAYH/ UK. FOR 52 AND 26 WKS. RESPECTIVELY. THERE WAS A DECREASE IN BODY WEIGHT IN THE EXPOSED GROUPS AFTER 40 WEEKS. THREE OF THE 4B CONTROL. SERIES ANIMALS WERE OBSERVED WITH TUMORS: ONE ANIMAL HAD A .MAMMARY ADENOCARCINOMA WITH PULMONARY METASTASIS? THE SECOND ANIMAL HAD DISGERMINOMA OF THE OVARY? AND THE THIRD DIED WITH A RETICULUM CELL SARCOMA OF THE SPLEEN AND tIESENTRIC LYMPH NODES. . IN THE MICE EXPOSED TO 50 ppm AND SACRIFICED ON THE 26th WEEK Al \rm PGFMir APFMQMAg WERE OBSERVED IN 2/4 MALES* HOWEVER NO TUMORS WERE FOUND IN THE FEMALES . THE REMAINING ANIMALS IN THE LOW EXPOSURE GROUP THAT WERE NECR0P5IED BETWEEN THE 36th AND 56th WEEK ALL BORE TUMORS. IN THE WHOLE GROUP 13/24 HAD ALVEOLOGENIC ADENOMAS. THE LUNG TUMORS WERE SINGLE OR MULtlPLE WflH A FEW FOCI WITH AP00008421 DIAMETERS UP TO tt-2 cm. THERE MERE 14/24 ANIMALS WITH FUBPER1 TONF.'AL HLMANGIOSARCOOMA WHICH WERE FOUND IN THE PARARENAL* PARAINTEST1NAL OR IN THE PELVJC/CAUDAL PART OF 1 WIRED SUBCUTANEOUS TISSUE OF THESE ANIMALS THERE WAS ONE HR-1AN610SARC0NA IN THE BROWN FATt fWR -WENANG1OSARCOMAS IN ' V" w- :-4V OTHER SITES AND A MAMMARY ADENOCriRClNQMA.ONE OF THE ANIMALS THAT BORE AN ALVtOLOGEN 1C ADENOMA 'ALSCj VJAD A ' f - i* SECONDARY HEMANSIOSARCOMA IN THE LUNG ORIGINATING' FROM A ! , ' PRIMARY SUBCUTANEOUS HEMANGIOSARCOliA OF.^THF THROAT. THERE" WAS ONE ANIMAL THAT REVEAUiD -RHABDOMYOSARCOMA AS WELL AS ALW.OC-EN1C ADENOMA WHEN NLCROPSJIfD ON THE 51 it WEEK. EIGHT Of- THE 24 MICE HAD-RUPTURE OF HEMANGIOSARCOMAS CAUSING ULMOCOU IA TO OCCUR, y~, * L* "* ' THE AN3MALI' EXPOSED TO VINYL CHLORIDE WERE WO LONGER EXPOSED AFTER THE 2&TH Wi-EK* SINCE THEY WfcRi* CONSIDERED IN POOR CONDITION. AM. MI OF IN THIS SERIES SHOWED ALVSOLiiLENIC AnrNOMA WITH t.UNSLTUMfiBS^I4L.AU. LOBES WITH 10 Of: MO!'*' FOCI. TI ft* DIAMETERS OF THE FOCI WERE AROUND 0.9 cm. THE SU3PERI7ONLAL HEMANGIOSARCOMAS WERE FOUND IN THE PARARENAL <3 CASES) AND PELVIC/CAUDAL PART OF THE ABD0M1NAL CAVITY <B CASES). IN THE SUBCUTANEOUS TISSUE THERE WERE FOUR CASES OK MAMMARY ADENOCARCINOMA AND ONE CASE OF MUV.NGJOSARCOMA IN THE t-.ROWM I AT. in THE ORGANS OF THESE ANIMALS THERE WAS REPORTED ONE CASE OF HGMANGtOBARCOMA OF I HE LIVER* AND ONE CASE OF ADENOMA OF THE KIDNEY. THE OTHER Pathological changes othlp than neoplastic lesions were TELANGIECTASIS OF THF LIVER JN TWO ANIMALS AND MEM0CQEL1A IN TWO ANIMALS EXPOSED TO THE HIGHER CONCENTRATION. THE AUTHORS CONSIDER THFRE RESULTS TO BE INDICATIVE OF A DOSli-RKSPONSE REt. ATIONSHT P SINCE THE FREQUENCY OK ANIMALS BEARING TUMORS IS 1007. IN THE 500Krr. GROUP AND 717. IN THE Sflr'prn GROUP. THE 500irr< GROUP ALSO HAD MORE MULTIPLE TUMORS OVER THE WHOLE LUNG AND LARGER LUNG TUMOR FOCI THAN THE LOW DOSE GROUP. THE IMPORTANCE OF HEMANGIOSARCOMAS IN VARIOUS ORGANS AND FAT TISSUE OF SUBCUTANEOUS AND SUB PER 1T ONEAL AREAS INDICATES THE ROLE OF THF Bl-OOD VESSELS AND FAT TISSUE IN THF BIOLOGICAL ADTIVITY OF VC.