Familial Mesothelioma of the Pleura
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1 Industrial Health 2004, 42, Original Article Familial Mesothelioma of the Pleura A Report of 40 Cases Claudio BIANCHI 1 *, Alessandro BROLLO 1, Lucia RAMANI 1, Tommaso BIANCHI 1 and Luigi GIARELLI 2 1 Center for the Study of Environmental Cancer, Laboratory of Pathological Anatomy, Hospital of Monfalcone, Monfalcone, Italy 2 Institute of Pathological Anatomy, University of Trieste, Trieste, Italy Received December 13, 2002 and accepted November 25, 2003 Abstract: A survey of 610 pleural mesotheliomas disclosed 40 familial cases. The diagnosis was histologically based in 39 cases, and confirmed by necropsy in 30. Occupational data were collected from the patients or from their relatives by personal interviews. Routine lung sections were examined for asbestos bodies in 32 cases. In 15 cases asbestos bodies were isolated after chemical digestion of lung tissue. Familial mesotheliomas included 31 men and 9 women (age range yr, mean 70.7, median 71.0). In 15 families there were blood relations between (or among) the members involved. All the patients had been exposed to asbestos, mostly in the shipyards. Asbestos bodies were found on routine lung sections in 27 cases. Asbestos bodies after isolation ranged from 70 bodies to about 900,000/g dried lung tissue. Latency periods (time intervals between first exposure to asbestos and diagnosis) ranged between 25 and 70 yr (mean 52.0, median 54.0). The occurrence of mesothelioma among subjects with blood relations suggests that genetic factors might play a role in determining the susceptibility to asbestos-related cancer. Familial cases among persons without blood relations raise the question if environmental factors that members of a family share, may act as co-factors in asbestos-related mesothelioma. Key words: Mesothelioma, Pleura, Familial cancer, Occupational cancer, Asbestos exposure, Epidemiology Introduction The occurrence of mesotheliomas affecting more members of the same family has been the object of numerous reports 1 32). Generally, in such reports there is no reference to a denominator. Consequently, the prevalence of familial mesothelioma is not easy to evaluate. In the Trieste-Monfalcone area, a small industrial district in Northeastern Italy with a total population of about 300,000 inhabitants, studies on mesothelioma are going on since the early 1970s 33). In the present investigation a series of 610 malignant mesotheliomas of the pleura seen in the above area has been reviewed. The analysis of such series disclosed some cases involving members of the same family. Familial *To whom correspondence should be addressed. pleural mesotheliomas of the Trieste-Monfalcone series differ from the majority of the cases reported in the literature by the fact that a denominator is available. The present report, an extension of previous studies 22 24), regards 40 familial mesotheliomas of the pleura observed in 19 families. Thirtyseven of the current cases belonged to the original series of 610 pleural mesotheliomas. Methods The diagnosis of mesothelioma was based on/or confirmed by necropsy findings in 30 cases; in 9 cases mesothelioma was diagnosed on material obtained at surgery; in one case a diagnosis of pleural cancer had been made on the basis of clinical and radiological data. The histopathological diagnosis of mesothelioma was made or confirmed at the
2 236 C BIANCHI et al. Monfalcone laboratory in 37 cases; in two cases histological slides were not available for review. Occupational histories were obtained from the patients themselves or from their relatives by personal interviews. The latency periods, defined as time intervals elapsing between first exposure to asbestos and diagnosis of the tumor, were calculated in 32 cases. Routine lung sections were examined for asbestos bodies in 32 cases. In 15 cases asbestos bodies were isolated and counted after chemical digestion of lung tissue, after the Smith-Naylor method 34). Results The group included 31 men and 9 women aged between 44 and 93 yr (mean 70.7, median 71.0). The principal features of the 40 cases are summarized in Table 1. The mesotheliomas were diagnosed between 1958 and 2002, mostly after All the cases belonged to the original series of 610 cases except from the cases 2, 13, and 25. In the case 2, the pathological diagnosis was made on a surgical sample, not available for re-evaluation; in the case 13 a diagnosis of pleural cancer was made on the basis of clinical and radiological findings; in the case 25 the diagnosis was made on surgical samples in another country. There were blood relations in 15 of the 19 families. All the patients had histories of asbestos exposure, with a majority of them (28 cases) having been occupationally exposed in the shipyards. In the case 10, the patient had worked for three years at the crocidolite mine in Wittenoom (Western Australia). In the cases 13 and 14 the source of exposure was a small chemical factory that the family had at home. Five patients (cases No. 16, 31, 33, 35, 37) had been exposed at home, having cleaned the work clothes of their relatives (the father in cases 16 and 37, and the husband in the remaining cases). The latency periods ranged from 25 to 70 yr (mean 52.0, median 54.0). Asbestos bodies were observed on routine lung sections in 27 cases. Lung asbestos body burdens ranged between 70 bodies and about 900,000 per gram of dried lung tissue. The patient with very high asbestos body amount (case No. 39) had also worked for some periods as an insulator. Discussion Despite major improvements in immunohistochemistry, the diagnosis of mesothelioma remains frequently difficult 35), so that the first question with a mesothelioma series, is the reliability of the diagnosis. In the present group the histological diagnosis was made on surgical material, and there was a necropsy confirmation in 75% of the cases. In one case (case No. 13), pathological studies were not carried out. In this case a generic diagnosis of pleural malignancy was performed in 1958, a time in which primary tumors of the pleura were very rarely diagnosed. It is relevant that the sex and age distribution of the present cases dit not differ from that seen in the Trieste-Monfalcone series 33). Asbestos is generally recognized as the principal etiologic agent in malignant mesothelioma 36). Among the familial mesotheliomas reported in the literature nearly all the cases were asbestos-related. In addition, familial cases are a common occurrence in erionite-related mesothelioma 32). All the patients of the present group had histories indicative of not trivial exposure to asbestos. The principal source of exposure was the shipbuilding. The severity of asbestos exposure in the shipyards 37), as well as the high incidence of pleural mesotheliomas in the shipyard areas 33, 38), have been well documented. In a large majority of the current cases the exposure was corroborated by objective signs. Asbestos body quantitation, performed in many cases, showed very marked variations in the amounts of lung asbestos bodies, a not unexpected finding given the different settings of the exposure. The latency periods were longer than 50 yr in a majority of cases, a pattern strictly similar to that seen in the general series 33). In most families there was a blood relation between (or among) the members affected by mesothelioma. This fact arises the question if a susceptibility on genetic basis does exist to the oncogenic effect of asbestos. Recently, it has been stated that genetic factors may play a larger role in the etiology of mesothelioma than currently appreciated 39). In fact some case-control studies suggest a possible role of genetic predisposition in the development of this tumor 26, 40). This is a question of fundamental relevance 32, 41 43). The role of cofactors, including host factors, in the pathogenesis of asbestosrelated mesothelioma is poorly understood 44). If a genetic susceptibility exists, it would be logic to expect some variation in the natural history of the tumor, for instance the development of mesothelioma with shorter latency periods. However, this does not seem to happen at least in the present group. Among the patients without blood relations, the conjugal cases are of particular interest. Cancer among spouses in general has been the object of various studies 45, 46). Conjugal mesothelioma has rarely been observed. In each of the present couples there was a very marked difference in the intensity of the exposure. The members of a family generally share a given type of diet. Moreover, they share the exposure to various environmental agents (radon, electromagnetic fields, Industrial Health 2004, 42,
3 FAMILIAL MESOTHELIOMA OF THE PLEURA 237 Table 1. Familial mesothelioma of the pleura: main features in 40 cases Family No. Case No. Sex Age Incidence year Relation Asbestos exposure data L. P. A. B. 1) 1 M Father Shipyard worker ,000 2 M Son Maritime machinist 25 n. a. d. 2) 3 M Father Asbestos firm agent M Son Shipyard labourer 41 n. a. d. 3) 5 M Father Shipyard worker + 6 M Son Shipyard worker ) 7 M Father Shipyard worker M Son Shipyard worker ) 9 M Father Shipyard worker M Son Crocidolite miner ) 11 M Father Shipyard worker M Son Shipyard worker 230,000 7) 13 F Mother Chemical industry n. a. d. 14 F Daughter Chemical industry + 8) 15 M Father Shipyard worker 58 18, F Daughter Domestic exposure M Brother of 15 Shipyard worker 60 n. a. d. 9) 18 M Brother Shipyard worker 42 2, M Brother Shipyard worker ) 20 M Brother Sailor M Brother Shipyard worker ) 22 M Brother Shipyard worker 70 1, M Brother Shipyard worker 61 n. a. d. 12) 24 M Brother Shipyard worker M Brother Shipyard worker n. a. d. 13) 26 M Brother Shipyard worker 52 n. a. d. 27 M Brother Railways + 14) 28 M Brother Shipyard worker 41 59, F Sister Shipyard worker 61 3,700 15) 30 M Brother Shipyard worker 41 1, F Sister Domestic exposure n.a.d 16) 32 M Husband Shipyard worker F Wife Domestic exposure ) 34 M Husband Shipyard worker , F Wife Domestic exposure ) 36 M Husband Shipyard worker F Wife Domestic exposure ) 38 F Mother-in-law Shipyard worker M Son-in-law Shipyard worker , M Brother-in-law of 39 Shipyard worker 58 88,000 Age = age at diagnosis. L. P. = latency period. A. B. = lung asbestos bodies; the figures indicate the number of asbestos bodies per gram of dried tissue; n. a. d. = not available data; + = present in routine lung sections; - = absent in routine lung sections. pets, etc.). The possible role of such factors should be explored. As far as the diet is concerned, some studies suggest that dietetic factors may be relevant in the genesis of asbestosrelated mesothelioma 47, 48). Conjugal cases represent a special entity also for other aspects. Viral infection has repeatedly been proposed for explaining the development of diseases, neoplastic as well as non-neoplastic, in couples husbandwife 49 52). Viral infection, in particular SV-40 infection, is
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