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vn: a rapid screening ie\i tutu*- kaui B. Sirou m kad: rrsy/r-, o', j .cmaiofluororneter. Br J i lead exposure. ScanU J i Last. JM (edj: "Public p 64K-655. and. Scand i *orls En- * with lead intoxication lioff U(fV8!l A%xess')> plant. Report \o the oxphere of three urban slicaiion 15-119." Cm- *eneva Uorld Health American Journal of Industrial Medicine 3:413-422 (1982) Features of Asbestos-Exposed and Unexposed Mesothelioma A Hirsch, mo, P. Brochard, md, H. De Cremoux, md, L. Erkan, MO, P. Sebastien, pno, L. Oi Menza, md, and J. Bignon, mo Thirts-six histologically confirmed caves of pleural and peritoneal mesothelioma have been observed m a chest unit over a period of 53 months. The past asbestos exposure seas assessed b> a standardized questionnaire in all cases and the asbestos lung burden ttas de termined b> means of mtneralogical anahsis of lung-related biological specimens (sputum, bronchoalseolar las age fluid, lung tissues) in 38 cases. The results of these tvso methods were found in good agreement. Past asbestos exposure has been definitels im plicated in 1' cases and definitels eliminated in lOcases. The results ssert nonconclusise in other cases The group ssnh detinue pasi asbestos exposure was different from the nonasbesios-exposed group bs clinical, biological, pathological, and prognosis features that were analszed In cases uuhoui past asbestos exposure there were no other possible causatoe 3gems A ounget age and similar incidence in men and women suggest an ens ironmental or natural disease. key words: mesothcl,ma. asbestos. fiberglass. parafTin. radiodiagnustic irradiation, nun-asbestos exposure . INTRODUCTION Mesothelioma is a rare tumor, but significantly associated with past occupational exposure to asbestos [Greenberg and Lloyd Davies, 1974; Selikoff, 1976). More re cently, an association between mesothelioma and exposure to erionite-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 ail these studies there was a significant proportion of histologically confirmed mesothelioma in which past occu pational asbestos exposure has been definitely eliminated; the consecutive mesotheli- Clinique de Pathologie Respiraiotre et Environnemem. INSERM U 139 et ERA CNRS No. 845, Centre Hospualier Intercommunal. 40 Ase de Verdun. 94010 Creteil cedex. France. Dr. Ertan's present address is Deparimem of Chest Diseases. School of Medicine. Hacenepe Umsersits. Ankara. Turkrs Address repnni requests to Jean Bignon. Cenire Hospualier Intercommunal. 40 Ase de Verdun. 940)0 Creteil cedex, France Accepted lor publication Jul> 35. 1985. 0271-3586 85/0.VW-04I3M3.00 1985 Alan K. I.iss. Inc. 414 Hirscb el al 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 nonasbestos-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-related 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. Mantoux test with 0.1 ml of purified protein derivative RT 23 was performed [Deck and Guld, 1964). Chest X-rays (posteroanterior, lateral, and 45 oblique films) [Mackenzie and Harries, 1970) were classified by two readers (LDM and AH) according to the International Classification of Pneumoconiosis 1980 [Hirsch, 1979) . A cytological and biochemical analysis of pleural fluid was carried out including the measurement of hyaluronic acid content [Boersma et 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 provided 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 al, 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; smoking 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.1 In 28 cases, measurement of asbes tos fibers was carried out in various biological specimens: coated fibers in sputum and/or bronchoalveolar lavage fluid samples (light microscopy) and in lung tissue (di gestion-microHitration method) [Bignon a al, 1974; Gaudichet et al, 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-month duration of this study, pathological samples from 45 cases were submitted to the National Mesothelioma Register Panel: 36 cases have been con- 'Questionnaire samples are available from the editorial staff of the Journal. me. France (12 -emageol asbv'(to compare the stos-rriated and na caso not re nal hazards: and etiological dau en observed bcis was based on derivative RT 2? . lateral, and 45 aders (LDM and is 1980 IHirsch. icdout including ithological specijpsies and. since atm and Viallat. ceral pleura and ny or laparotomy logical confirma [Stoebner et al. ed questionnaire adiodiagnosis ir:upaiional. paraaccordmg to the mplete work hisipational hazards trement of asbesfibers in sputum in lung tissue (di1979; Sebastien. e approximation, gnificant. lies from 45 cases es have been con- Asbestos-Exposed and Lnexposed Mesothelioma 415 firmed histologically as mesothelioma. 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 pleura) 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 1 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 cytological 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 parenchymal controlateral 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 all cases, and asbestos pleural or parenchymal controlateral radiological abnormalities were present in 80%. In the 10 nonasbestos-related mesotheliomas (Table 111), 4 patients were fe male and all the tumors were of epithelial type. In 3 out of the 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 case. 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 parenchyma] radiological abnormalities were seen in 44% of the cases. Compariaon 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. I m 416 Hirsch el al ra < S I e - --E II e| s II - t; %* c 11 /c II < ^ n fM < Wi *T1 iC -- ^ -- IN M ^K Wt ^ 522222 O-- m ^ n *e r*> 5 2s 2 5 t S 6 .0 & t f ,= li=s1 I Ii SSC w! *!t *> Ji<I<i Ji O./-7 I I 4 Asbestos-Exposed and L'nexposed Mesothelioma 417 Ilf co j2; 8 I c-- Ii E - S CT *o T g" II - v* c 11 11 k u X ^*4 c^ ' *n 5J 5 It V C fc ^ ^ * * Jii 5 ^ ; C > ^ r *"\ -- <M jl * 555 555 55 B ^ O -- *N iB f- .21 *= *8 a k E 6g ka 11t 1 tS Et 3* s .2. >> a E >. a J_t*.cEo V*. ..o. |22 'OaC 'fait * =E *iv nc ill iEt .w c * 0a TABLE V. C Conclusive Qi Pai DISCUSS If Wl the basis < comparisc Green berj Donald [1 in the Fre est of me; [Bignon e a better a methods, other exp was a leal mesothel; observed construct posure h, cupation bestos ex sures wei [Hasan e ingthe 1< and the [Selikofl Me Don; A toneal c have bei aldehyd didrour I l tbi&k'in m Co I* .* 5s oj S t ilhi s f 1-Si ^ s_ ?S* Sm 25s *co j.wat -J < U > ! Asbestos-Exposed and Enexposed Mesothelioma 419 TABLE V. Clinical. Hlttolo|icml. Radiological, and Biological Features in 27 Mesotheliomas With Cotciasive Quettloaniim Parameters Asbestos-exposed cases (questionnaire +) (n - 17) Nonasbestos-exposed cases (questionnaire --) (n - 10) p Value Mean age (years) Mean survival time (months) PPD test (diameter mm) Contralateral radiological abnormalities (percentage) Males (perctniage) Hisiological type (percentage) Epithelial Fusiform Mixed Open thoracotomy (percentage) 64 1 * 10.7 ) 1.9 * 4.6 5.3 76 88 70 12 18 35 56.8 10.3 31 12.6 12.2 10 60 100 50 NS <0.01 <0.05 <0.001 NS NS NS DISCUSSION If we consider only the cases for which an asbestos exposure has been assessed on the basis of the questionnaire, the percentage of exposed cases (47%) is very low in comparison with the percentage found by others (72% for Planteydt {1979], 68% for 4 Greenberg ei al [1974], 66% and 72% for McDonald [1979] and McDonald and Mc Donald (1980] in Canada and in USA, respectively, and 77% for Bignon et al [1979b] in the French national mesothelioma register). We have previously validated the inter est of measurement of coated and uncoated fibers in pulmonary biological specimens [Bignon et al, 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 cases. 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 [Decoufle, 1980].) 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; Planteydt, 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 [Schoental and Gibbard, 1972], l-nitroso-5,6- didrouracile [Pelfrene and Garcia, 1975], sterigmatocystin [Terao, 1978], methyl SSL 1 l t 1 i | r l i I j i ;'|sa -Tf: 420 Hindi ct al (aaixoxymethyl) nitrosamine [Berman and Rice, 1979], and herbicides [Donna et al, REFERENCI 1980]. On the other hand, several agents have been shown to have a synergistic carcino genic effect with asbestos: irradiation [Lafuma et al, 1980], irradiation and 3-methyl- Anvmii M. Bari key: An e cholanthrene [Warren et al, 1981], N-methyl-N-nitrosuourethane [Kawai, 1979], and Aschroft T <197j dimcihyl benzfa>anthtacene [Topping and Nettesheim, 1980]. The complete work histones of the nonasbestos exposed cases (Table III) point out some hypothetical etio logical factors that have to be discussed in regards to these experimental data. Two pa tients (cases 32 and 33) have been exposed to glass dust during the destruction of Tyneside. Berman JJ. Rice duced m (DMN-a Bignon J. Sebast mishapen lamp bulbs or glasses. One patient (case 28) was a white-collar worker who brous par i presented with a radiological opacity in the right costophrenic angle and who had been Bignon J. Sebas 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 case one of us sure to asi for the As don: Mar (J. Bignon) observed after collapsotherapy for pulmonary tuberculosis [Chretien et al, Bignon J, Sebast 1968]. Another patient (case 29) used melted paraffin. This finding must be compared 0 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 330:455-4 Boersma A, Deg: oma. Bui! Boutin C, Vialiai copy 12:1 Chretien J. Delol the case no. 27 to have been exposed in the past according to the great number of coated fibers found in the lung (Table 111). Among those features, age and sex ratio are in close analogy to the observations made by Petoet al [ 1981 ] in the cases where no asbestos ex posure was reported among mesothelioma diagnosed in Los Angeles County: (l)The nonexposed subjects were younger (almost 10 years) than the exposed subjects. (2) A des sequel Cochrane JC. W. S Afr Met Decoufle P (I98C Deck F. Guld J ( Di Menza L. Hin similar incidence in men (6 cases) and women (4 cases) was observed in the unexposed in patient; 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 JC ted): "1 614 Donna A. Betta 1 genesis. A Caudichet A. Ja childhood1, as seems to be the case in Turkey [Saracci et al, 1982] or to another agent. bronchoal 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 13 out of the 17 asbes tos-exposed cases and absent in 9 out of the 10 unexposed cases. (4) In the 17 asbestos- pulmonan Greenberg M. LI Hasan FM. Nash oma: A 21 Hinds MW (1978 exposed cases, mesotheliomas were of epithelial type in 12 cases, mixed in 3, and fusi Hirsch A (1979): 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 7:69-72. Kawai T (1979): neoplasm; thane. Aci Lafuma J. Hirsch by intrapli this difference. ACKNOWLEDGM ENTS * gens. In V tions. no. Mackenzie FAF, 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. Med Serv McDonald ADO exposure. McDonald AD. N Meyniard D, Bois de para ffir 'Since the proofing of this paper, we observed two additional cases without definite asbestos exposure: one 8:259-264 is the sister of case no. 36 (Table 111). 44 years old. who worked as a philosophy teacher. The two siblings Pelfrene A. Garc spent their childhood in the vicinity of a dirty plant making glue. The other case is a man, 57 years old, mili Tumori 61 tary. who lived from birth to 19 years in the neighborhood (less than 500 meters) of the Gironde shipyard cides [Donna et al. synergistic carcino- ion and 3-methyl- [Kawai, 1979). and "he complete work ie hypothetical etio- ental data. Two pa- the destruction ol -collar worker who* z and who had been rads over 26 years) >les a case one of us osis [Chretien et al. must be compared t to a paraffin lung et al. 1980). # ral features signifi- larly if we consider a number of coated ex ratio are in close tereno asbestos ex es County: (1) The >sed subjects. (2) A .d in the unexposed >. Petoet al [1981. d to time since first is suggests that the ure to fibers from r to another agent. It could be also a >een noted: (3) The >ut of the 17 ashes- Inthe 17asbestos- ixed in 3. and fusi- csotheliomas were cases could not be tnent of the meso- d cases was signifi- no explanation for o examined pathoel.and J. Peto for asbestos exposure: one *eher. The two siblings nan. 57 years old. mill* the Gironde shipyard. Asbestos-Exposed and L'nexposed Mesothelioma 421 REFERENCES Anvinii M. Baris Y1 (1979): Malignant mesotheliomas in a small village in the Anatolian Region of Tur key: An epidemiological study. JNC1 63:17-22. Aschroft T (1973): Epidemiological and quantitative relationship between mesothelioma and asbestos on Tyneside. J Clin Pathol 26:832-840. Berman JJ. Rice JM (1979): Mesotheliomas and proliferative lesions of the testicular mesothelium pro duced in Fisher. Sprague-Dawiey and Buffalo rais by methyl (actexoxymethyl). nitrosamine (DMN-OAc). Vet Pathol 16:574-582. Bignon J. Sebastien P. Jaurand MC. Hem B (1974): Microfiltration method for quantitative study of fi brous panicles in biological specimens. Environ Health Perspect 9:155-160. Bignon J. Sebastien P. Bientz M (1979a): Review of some factors relevant to the assessment of expo sure to asbestos dust. In Berlin A. Wolf AH. 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Mesoihelioma relative to a<bestos. radiation and meihvichoUmhrene Arch Pathol Lab Med 105*305-312. Zielhuiv RL |19** "Publu Health Risks ol Exposure to Asbestos.** Oxford: Pergamon Press (far the Cs'vmmi'Sion ol the European CommunuieM Does ( Lung ( David F. Donald F Silic by h rato folic four mini the! silici gest he path Kfv - ords INTROD Mo sis (such 1976], Tf between disease a: have not that oca Operations (D.F.G.. D Depart men Division of University, A version c Egypt. Sep Address re Triangle P; Aecepied I 027I-J5KI