Document wDg8y4J3EqyJ5ppB6Mpv2rmXV

>FU A fipi<S *CtttR*g lcs\ ivuk^- fct-kiut 8, Strew* -nti< (U icad: nwuftv O! j c<n*joflofomcl<r. Br j i lead e\posurf Scand I i laM. JM fcdJ: ""Publiv1 >p 6M-GJ5. and. Sw*nd j Vk&l En- **nlT lead inu>\u;*!Jtin 'l\ pUm. Report \o ihc sphere of Three urban xVuaiityn Cm- cn*va *orK$ Health American Journal of Industrial Medicine 3:413-422 0982) Features of Asbestos-Exposed and Unexposed Mesothelioma A Hirseh, MO, P, Brochard, md, H, Oe Cremoux, mo, L. Erkars, MO, P. Sebastian, poo, L, Ot Menxa, mc, and J. Bignon, md Thtn;-M\ histoiogical Is confirmed eases of pleural and peritoneal mesothelioma hast been observed m a chew unit over a period of 53 months. The past asbestos exposure * as assessed bv a standardised Questionnaire m ail eases and the asbestos iung burden was de termined b> means of mineralogies! analysis of lung-related biological specimens (sputum, bronehoaheolar las age fluid, lung tissuesMn 28 cases. The results of these two methods were found in good agreement. Past asbestos exposure has been definite!; im plicated in 17 eases and definite!; eliminated in lOcases. The results were nonconclusise w other cases The group nh definite past asbestos exposure was different from the nonasbestos-exposed group b> clinical, biological, pathological, and prognosis features that wereanabred In caves without past asbestos exposurethere were no other possible causame agents 1 oungcr age and similar incidence in men and women suggest an envi ronmental or natural disease. Rev words: mrsoihetiwm*. asbestos, fiberglass, paraffin, radiodiagnoslie irradiation, non-asbesios exposare . INTRODUCTION Mesothelioma is a rare tumor, but significantly associated with past occupational exposure to asbestos |Greenberg and Lloyd Davies. 1974; SelikofT, 1976], More re cently, an association bet ween mesothelioma and exposure to erionue-zeolite fibers has also been highly suspected in Turkey (Anvinii and Baris, 1979], The mesothelioma registries conducted in various countries reveal widely differing proportions of cases with past asbestos exposure (from 20% to 72%), However, in all these st udies there was a significant proportion of histologically confirmed mesothelioma in which past occu pational asbestos exposure has been definitely eliminated; the consecutive mesotheli- CIhiiquc tie Puthoione Rnpiratoirt a Envirormetnetil. INSERM U 139 ct ERA CN8S No. 84J, Centre Hospiiaiirr tnirrcommunnl. 40 Ave <je Verdun. SJOtOCfeteit cedes. France. Dr. Erkan's present address is Department of Chesi Diseases, School of Medicine. Hacettepe Unnersns. Ankara. 7urkrj. Address reprint requests 10 Jean Bignon, Centrr Mospualier Inicrcommunai. 40 A'C de Verdun. 94010 Crrnd cedes. France Accepted for publication Juts 22. 1982. 0271-3586 82-G.VfU-04! JMi.V.fif) 1982 Alan R. Use. Inc, S3? 414 Hirscb et stl oma cases referred to a chest hospital unit in the district of Val de Marne, France (1,2 million inhabitants) have been investigated in order (1) to study the percentage of asbes tos-related mesothelioma by means of standardized questionnaires; (2) to compare the number of coated fibers in sputum and/or lung tissue samples in asbestos-related and nonasbcstos-related mesothelioma; (3) to discover in the mesothelioma cases not re lated to asbestos a possible significant association with other occupational hazards; and (4) to compare on the basis of clinical, radiological, histological, and etiological data the asbestos-related and nonasbestos-relased mesothelioma. MATERIALS AND METHODS Thirty-six mesotheliomas (34 pleural and 2 peritoneal) have been observed be tween October, 1976 and February, 1981. In all cases, the diagnosis was based on pathological specimens. Mamoux test with 0.1 ml of purified protein derivative RT 23 was performed (Deck and Guld, 1964). Chest X-rays (posteroamerior, lateral, and 45 oblique films) [Mackenzie and Harries, 1970) were classified by two readers (LDM and AH) according to the Internationa! Classification of Pneumoconiosis 1980 [Hirsch, 1979) . A cytologies) and biochemical analysis of pleural fluid was carried out including the measurement of hyaluronic acid content (Boersmaet al, 1980). Pathological speci mens of the pleura were obtained either by one or iterative-needle biopsies and, since June. 1979, by thoracoscopy under general or local anesthetic [Boutin and Viallat, 1980) . This technique presided a good view of the parietal and visceral pleura and made it possible to obtain large samples of tissue. An open thoracotomy or laparotomy was needed in a few cases. All tissue samples were reviewed for pathological confirma tion using light microscopy, and electron microscopy when necessary [Stoebner et ai, 1979), by the pathologists of the French Mesothelioma Register. The following data were collected by means of a standardized questionnaire designed to investigate causative agents; previous chest diseases and radiodiagnosis ir radiation of the thorax; smokmg habits (expressed in pack/year); occupational, paraoccupational, environmental, and domestic past exposure to asbestos according to the criteria proposed by the European Communities [Zielhuis, 1977); complete work his tories using a standardized questionnaire designed to detea other occupational hazards and administered direaly to the patients by LDM.' In 28 cases, measurement of asbes tos fibers was carried out in various biological specimens: coated fibers in sputum and/or bronchoaiveoiar lavage fluid samples flight microscopy) and in lung tissue (di gest ion -microfill rat ion method) [Bignon et al, 1974; Gaudichet et ai, 1979; Sebastien, 1980, 1982), Results have been analyzed using Student's t-test and chi-square approximation. Probabilities (p values) equal to or less than 0.05 were considered significant. RESULTS Pathological and Clinical Data During the 53-momh duration of this study, pathological samples from 45 cases were submitted to the National Mesothelioma Register Panel: 36cases have been con- 'Quraionnasre sample* are available from the eensriit staff of the Jovritai. - ~+~- m firmed hifusiform sufficient case was | specimen biopsies, case by m diagnosis In I and chesi showed i cases; it cytologic Etiologi Or were divi (2) 10 ci definite, the sever were ma were po: malities mesothe 8): the 1 O.OODtl tumor w asbestos in SO*!1#, male an mineral! in case n Asbesto cases(T In 6 out tos pleu Compa Para mi Mesoth Se lated m younger greater; bestos-r cases an tologica lated mi asbesto: me. France (1 entageot avtw1 to compare the stos-ttrfaicd ami na eases not re nal hazards; and etiological data en observed be ts was based on derivative rt 21 . lateral, and 45 aders (LDM and is 1980 (Htrsch, icdout including tthologicai spevtJpsies and. since uttn and Viallat, ceral pleura and ny or laparotomy logical con firm a' IStoebner et al, ed questionnaire adiodiagnosis ir:upai tonal, paraaccotdingto the mplett work hisspationaJ hazards irement of asbesfibers in sputum in lung tissue (di1979; Sebastien. e approximation, gnifkam. rles from 45 cases es have been con- Asbestos-Exposed and Inexposed Mesothelioma 4L5 firmed histologically as mesoihelioma. The histological type was epithelial in 30 cases, fusiform in 2 cases, and mixed in 4 cases. The other nine cases were excluded; 3 had in sufficient material, 5 cases were classified secondary pleural adenocarcinomas, and 1 case was pleural sarcoma. The pathological diagnosis was possible by analyzing pleural specimens obtained in 6 cases by one-needle biopsy, in 3 cases by two- or three-needle biopsies, in 9 cases by thoracoscopic biopsies, in 14 cases by open chest biopsies, in 3 case by mediastinoscopic biopsy, and in 1 case by laparoscopic biopsy. In two cases, the diagnosis was made at autopsy. In the 36 confirmed cases, the chief complaints were dyspnea on exercise (47> and chest pain (37%). In two cases (cases 12 and 19), a routine screening chest X-ray showed pleura) opacities. The first pleural fluid collected was exudative in 96% of cases; it was clear in 67%, bloody in 30%, and opaque in 3% of cases. No particular cytologicai pattern was noted from the examination of pleural fluid. Etiological Data On the basis of the standardized asbestos questionnaire, the 36 mesotheliomas were divided into four groups: (1)7 cases with heavy, definite, past asbestos exposure; (2) 10 cases with moderate, definite, past asbestos exposure; (3) 10 cases without definite, past asbestos exposure; and (4) 9 cases with inconclusive questionnaires. In the seven heavy , definite, past asbestos-exposure mesotheliomas (Table 1), all patients were male; the tumor was epithelial in 57%, all the mineralogical analyses performed were positive, and asbestos pleural or parenchyma! controlaieral radiological abnor malities were present in 71%, in the 10 moderate, definite, past asbestos-exposure mesotheliomas (Table 11). 2 patients were female, one with household contact (case 8): the length of asbestos exposure (30.3 8.2 years) was significantly greater (p < 0.001) than in the heavy, definite, past asbestos-exposed group (11.4 9.5 years), the tumor was epithelial in 80%, the mineralogical analyses were positive in ait cases, and asbestos pleural or parenchymal controlaieral radiological abnormalities were present in 80%. In the 10 nonasbestos-related mesotheliomas (Table ill), 4 patients were fe male and all the tumors were of epithelial type. In 3 out of (he 6 investigated cases, mineralogical analyses were positive for asbestos bodies but at a very low level, except in case no. 27, where 6,903 coated fibers per gram of dried lung tissue have been found. Asbestos -related radiological abnormalities were seen in one cast. In the 9 inconclusive cases (Table IV), 5 patients were female and 89% of the tumors were of epithelial type. In 6 out of the 7 investigated cases, the mineralogical analyses were positive, and asbes tos pleural or parenchymal radiological abnormalities were seen in 44% of the cases. Comparison Between Clinical, Histological, Radiological, and Biological Parameters In the Heavy and Moderate Definite Asbestos-Related Mesotheliomas and in the Nonasbestos-Related Mesotheliomas Several parameters were different between asbestos-related and nonasbestos-re lated mesothelioma (Table V), In the nonasbestos-related group, (1) patients were younger; (2) their mean survival time was longer; (3) the diameter of PPD test was ` greater; (4) the contralateral chest X-rays opposite to the mesothelioma showed no as bestos-related abnormalities; (5) the sex ratio male to female was 1.5 for unexposed cases and 7 for exposed cases; and (6) the tumors of exposed cases were of various his tological types while unexposed cases were only of epithelial types. The nonasbestos-re lated mesotheliomas were diagnosed by open thoracotomy in 50% versus 35% in the ' asbestos-related mesotheliomas. 1 TAILS 1, Cttoktl *4 Mliwmto^cii Fnlwn In S^* DeflBft?, Past A^M hpOMrt ( tin OccupMkm AvhcMON fUfMMIff (questionnaire! Histological Ikiratiun No. sTM A*t type (years! 1 afcncy period (years) Asbestos <onnt two bojrs* 1 M 56 I: IS 15 builder Baltfry bo, nnmi!#tiurrr 2 M 66 M 5 32 Steam-flittr 3 M 72 1 i 36 Locomm ivf insutaior 4 M 69 1 12 55 Boilermaker % M 55 li 16 35 Asbesios-joint culler M 62 li 2 26 Asbestos-sprayer 7 M 59 M J1 3! ICcy words: epithelial, M * mixed, F * fusiform, BALE ~ brotvchoafvcolar lavage fluid. No. coated fibers in Sputum Dried BAI 1 (ml| hing (ymt 16 l.44t 1,1*3 .3 3 1.43ft Contralateral radiological abnormaliite* _ 4 * t 4 TABUEII. Oink*! ir< Mffniioiktf iHiwnii fra Modfraif, fkffatie, fi^ Askifoj-NfWiirf (*h AsheMO* fXftovyTf Asbestos-Exposed and Cnexposed Mesothelioma Occupation latency 1 httological Ihiratioft _ No- Sex A(ie iyr* lyeatxj pffHHl (years) StramfiJtfr'J wife Secretary in rubbish chute factory Rowei plant operator Railway joiner Railway maintenance worker Aluminum fwrtaceman Jeweller Electronic finer (medical equipment | Chemical facioty mason Station maintenance worker 8 F 5T 9 t 45 to M 51 MMn 12 M 68 1J M 58 14 M 15 M n 16 M n IT M 62 ___ i1 1: 1 v. M t: V 1 fi Hi M 20 20 26 2b it 4fl 10 43 25 25 11 40 50 60 23 31 i5 44 ____ Key words: epithelial, M * mixed, E' * fusiform, HALF bronchoalveolar lavage fluid. No coaled fibers (ft Sputum Dttcd BM I (mil Urn* tgm) 2 2.7 Contt elate,at radiological abnormalities 4 + 0,2 f .040 4 i4 1.6 - 0.8 2,000 0.2 60.000 2k400 _ 4 4 21 2.2 f.OOft 4 f Hirschctal ,'- TABLE V. C Conclusi't Qi Pa; Mean age t: Mean sunr PPDiew Id Comralater abnorma Ma\e. (pcrc Histologies Epiiht Fusifo Mixed Open ihoi DISCUSS Ifwi the basis < coroparisc Green berj Donald [1 in the Fre esi of mei [Bignon e a better a methods, other exp was a leai mesothel: observed construct posure h cupation best os ex sures wet [Hasan e ing the It and the [Selikofi McDont A toneal c have be aldehyd didrour ] +* 1 9 Asbestos-Exposed and tnexpostd Mesothelioma 419 TABLE V, Oinkml. HHtologkal, Radiological, and Siotogkat Feature* in 27 Mesotheliomas WHb Ctwcitifivr QwnioaMlm _____________________ Parameter* Asbestos^exposed eases (qucsiVormiire +) (n - 1?) Nonasbestos-exposed cases (questionnaire --) (n - 10) p Value Mean age (yrs) Mean survival time (months] PPD test (diameter mm) Contralateral radiological abnormalities (percentage) Mites (percentage) Histological type (percentage) Epuheiial Fusiform Mixed Open thoracotomy (percentage) 641 * io.t 11.9 * 4.6 5.3 76 SB 70 12 u 35 56.8 10.3 31 * 12.6 12.2 10 60 100 50 NS <0.01 <0.05 <0.001 NS NS NS "a u m tt u s > m 'im m* ** dD i_ i *i 6 1! t 5 * i -i 3 - II l?Ml* lSilst " 5 2 ,o j < U DISCUSSION if we consider only the cases for which an asbestos exposure has been assessed on '7 1 the basis of the questionnaire, the percentage of exposed cases (47%) is very low in comparison with the percentage found by others (72% for Pianteydt [1979], 68% for Greenberg et at [1974], 66% and 72% for McDonald 11979] and McDonald and Mc Donald (19801 in Canada and in USA, respectively, and 77% for Bignon et a! [1979b] in the French national mesothelioma register). We have previously validated the inter est of measurement of coated and unseated fibers in pulmonary biological specimens jp . [Bignon a &l, 1979a), The use of both methods, questionnaire and measurement led to a better assessment of past asbestos exposure [Di Menza et al, 1980). Using these two methods, we found 6 additional cases in the 9 inconclusive questionnaire cases and 3 other exposed cases in the 10 negative questionnaire eases. One of these cases (case 27) was a leather goods maker, who probably had been exposed to asbestos in the past, (A mesothelioma case has been described in shoemakers [Decoufie, 1980J.) We have observed two cases with atypical asbestos exposures. The first one was a farmer who constructed hen houses using asbestos cement several years ago. A case with similar ex posure has been published by Ashcroft [1973]. The second one was a jeweller, an oc cupation already noted in the case published by Cochrane and Webster [1978], The as bestos exposure was occupational in males, but household and paraoccupational expo sures were noticed in females. This sex-related type of exposure has been already noted [Hasan et al, 1977; Vianna and Polan, 1978; McDonald, 1979]. Our findings concern ing the length of the asbestos exposure, the latency period, the mean age, the sex ratio, and the pleural or peritoneal localization are similar to the data previously published [Sdikoff, 1976; Greenberg and Lloyd Davies, 1974; Hinds, 1978; Pianteydt, 1979; McDonald, 1979], - A great number of agents, when introduced experimentally into pleural or peri toneal cavities, may induce pleural or peritoneal tumors, in that regard, mesotheliomas have been induced in animals with glass fibers and glass powder [Wagner et al, 1973], aldehyde wood lignin constituents (Schocmal and Gibbard, 1972], l-nitroso-5,6- didrouracile [Petfrene and Garcia, 197S], sterigmatocystin [Terao, 1978], methyl ''Em. I i k t i r f t' i i l i i t 410 Hind) ft al (actixoxymethyl) nitrosaminc [Berman and Rice, 1979], and herbicides [Donna et al, 1980]. On the other hand, several agents have been shown to have a synergistic carcino genic effect with asbestos: irradiation [Lafuma al, 1980], irradiation and 3-methylcholamhrene [barren al, 1981], N-methyl-N-nitrosuourethane [Kawai, 1979), and dimerhyl benztaiaru.hiscene [Topping and Nenesheim, 1980], The complete work histones of the nonasbestos exposed cases (Table HI) point out some hypothetical etio logical factors that have to be discussed in regards to these experimental data, Twopa tients (cases 32 and 33) have been exposed to glass dust during the destruction of I mishapen lamp bulbs or glasses. One patient (case 28) was a white-coliar worker who presented with a radiological opacity in the right costophrenic angle and who had been systematically X-rayed in that region (cumulative exposure of 9.5 rads over 26 years) and who developed a mesothelioma at the same place. This resembles a cast one of us (J. Bignon)observed after collapsotherapy for pulmonary tuberculosis [Chretien al, i f 1968J. Another patient (case 29) used melted paraffin. This finding must be compared # to a recent case of pleural mesothelioma developed in close contact to a paraffin lung granuloma in a subject regularly ingesting paraffin oil [Meyniard et al, 1980]. '. The group of cases without asbestos exposure showed several features signifi cantly different from those of the asbestos-exposed group, particularly if we consider the case no. 27 to have been exposed in the past according to the great number of coated fibers found in the lung (Table III). Amongthose features, age and sex ratio are in dose analogy to the observations made by Peto et al [ 1981 ] in the cases where no asbestos ex posure was reported among mesothelioma diagnosed in Los Angeles County: (1) The nonexposed subjects were younger (almost 10 years) than the exposed subjects. (2) A similar incidence in men (6 cases) and women (4 cases) was observed in the unexposed group contrasting with a male predominance in the exposed group. Peto et al [1981, 1982] found that for exposed cases, the mesothelioma rate was related to time since first exposure, while for unexposed cases the rate was related to age. This suggests that the "unexposed" cases may be due either to an environmental exposure to fibers from childhood1, as seems to be the case in Turkey (Saracci et al, 1982] or to another agent. However, in our study no etiological factor has been discovered. It could be also a natural disease! Elsewhere, in these series, other discrepancies have been noted: (3) The contralateral asbestos-related radiological signs were present in !3 out of the 17 asbes tos-exposed cases and absent in 9 out of the 10 unexposed cases. (4) In the 17 asbestos- exposed cases, mesotheliomas were of epithelial type in 12 cases, mixed in 3, and fusi form in 2. In the 10 cases without past asbestos exposure, mesotheliomas were exclusively of epithelial type. Peto et al [1981] suggested that such cases could not be mesothelioma at all! However, in our cases, there was a total agreement of the meso thelioma panel. (5) The survival time after diagnosis of the unexposed cases was signifi cantly longer (by a factor of two) than that of the exposed; we have no explanation for this difference. ' ACKNOWLEDGMENTS Grateful thanks are due to Drs. P, Lancret and M. Nebut who examined patho logical specimens, the pathologists of the French Mesothelioma Panel, and J. Peto for criticisms and helpful advice. `Since the proofing of (his paper, we obwrved two addit tonal cases without definite asbestos exposure: on* is the ner of case no. 36 (Tabic IJi>. years old. who worked as a philosophy teacher. The two siblings spent their childhood m the vicinity of idm> plant making glue. The other case is a man, 51 years old. rcvhiary, who lived from bmh to 19 years in the neighborhood Oess than SOOmetersI of the Gironde shipyard cides [Donna a al. synergistic carcinoition and 3-methyl. [Kauai. I979J, and lie complete work ie hypothetical etioental data. Two pa- the destruction of -collar worker who* e and who had been rads over 26 years 1 des a case one of us osis [Chretien et al. must be compared t to a paraffin lung al. 1980]. # ral features signifilarly if we consider 4 number of coated <x ratio are in dose lerc no asbestos ex es County: (1) The tsed subjects. (2) A d in the unexposed i. Petoet al |1981. d to time since first ts suggests that the tire to fibers from r to another agent. It could be also a seen noted: (3) The ut of the 17asbesIn the 17 asbestosixed in 3. and fusi- rsotheliomas were cases could not be mem of the meso- d cases was signifi- no explanation for o examined pathoel, and J. Peto for sbtfloi exposure: one tfher. The i *o sibling* n*n. 57 ytirsold. mill* tht Gironde shipyard- Asbestos-Exposed and L'nexposed Mesothelioma 411 REFERENCES Anvinii M. Baris 1 (19791: MaFgnan; mesotheliomas in a small village in she Anatolian Region of Tur key: An epidemiological study. JNCI 6S.T7-22. Ascferoft T (197)1: Epidemiological and quantitative relaiionship between mesothelioma and asbestos on Tyneside. J Clin Paihoi 26:832-840. Berman J). Rice 3M (1979): Mesotheliomas and proliferative lesioni of the testicular mesoihetium pro duced in Fisher. Sprigue-Dassiey and Buffalo rais by methyl (actexoxymethyS), mtrosamitte (DMN-OAc). Vet Pathol 16:574-582. Bignon 1. Sebastian P. Jaurand MC. Hem B (1974); Microftlttaiion mtihod fot quantitative study of Fi brous panicles m biological specimens. Environ Health Perspect 9:155-160. Bignon J, Sebastian P, Bientz M (1979a): Review of some factors relevant to the assessment of expo sure to asbestos dust - In Berhn A, Wolf AH. 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Broun CZ* Chute R V Federtnan \1 ij9S.lt: Mesothelioma relame to asbestos. radiation and meihvlcholanihrene Aich Pathol lab Med 105:305-312. 2ielhuis RL i I9""i "Publk Health Risks os Exposure to Asbestos." Oxford: Pergamon Press <f?r the Comfnt-cion oi the European Communities! Does ( Lung C David f. Donald f Sitic by h rato folk four mini the! silici gesi whe path key monk: INTROD Mo sis (such 1976]. Tt between disease ai have not that oca Operai (D.F.C Dnisit Unnei A vcts Egypt. Addro Tnang Accem 2?C35Kf