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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

1Center for the Study of Environmental Cancer, Laboratory of Pathological Anatomy, Hospital of Monfalcone,

34074 Monfalcone, Italy

2Institute of Pathological Anatomy, University of Trieste, 34100 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 44–93 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 reports1–32).

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 1970s33). 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

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 studies22–24), regards 40 familial

mesotheliomas of the pleura observed in 19 families. Thirty-seven 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

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Industrial Health 2004, 42, 235–239

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 method34).

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 1980. 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 difficult35),

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 series33).

Asbestos is generally recognized as the principal etiologic agent in malignant mesothelioma36). 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 mesothelioma32). 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 shipyards37), as well as the high incidence

of pleural mesotheliomas in the shipyard areas33, 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 series33).

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 appreciated39). In

fact some case-control studies suggest a possible role of genetic predisposition in the development of this tumor26, 40). This is

a question of fundamental relevance32, 41–43). The role of

co-factors, including host co-factors, in the pathogenesis of asbestos-related mesothelioma is poorly understood44).

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 studies45, 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,

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pets, etc.). The possible role of such factors should be explored. As far as the diet is concerned, some studies suggest

entity also for other aspects. Viral infection has repeatedly been proposed for explaining the development of diseases,

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 75 1980 Father Shipyard worker 57 193,000

2 M 44 1975 Son Maritime machinist 25 n. a. d.

2) 3 M 84 1990 Father Asbestos firm agent 63 +

4 M 55 1991 Son Shipyard labourer 41 n. a. d.

3) 5 M 93 1987 Father Shipyard worker +

6 M 72 1993 Son Shipyard worker 57 +

4) 7 M 75 1985 Father Shipyard worker 52 +

8 M 59 1999 Son Shipyard worker 42 +

5) 9 M 67 1970 Father Shipyard worker 34 +

10 M 67 2000 Son Crocidolite miner 41 +

6) 11 M 79 1991 Father Shipyard worker 52 +

12 M 61 2001 Son Shipyard worker 230,000

7) 13 F 66 1958 Mother Chemical industry n. a. d.

14 F 78 1998 Daughter Chemical industry +

8) 15 M 80 1995 Father Shipyard worker 58 18,000

16 F 58 2000 Daughter Domestic exposure 46 70

17 M 75 1997 Brother of 15 Shipyard worker 60 n. a. d.

9) 18 M 61 1990 Brother Shipyard worker 42 2,500

19 M 69 1993 Brother Shipyard worker 53 100

10) 20 M 82 1988 Brother Sailor 65 +

21 M 87 1995 Brother Shipyard worker 70 +

11) 22 M 85 1996 Brother Shipyard worker 70 1,000

23 M 78 1993 Brother Shipyard worker 61 n. a. d.

12) 24 M 73 1996 Brother Shipyard worker 55 +

25 M 68 1989 Brother Shipyard worker n. a. d.

13) 26 M 66 1999 Brother Shipyard worker 52 n. a. d.

27 M 62 1999 Brother Railways +

14) 28 M 56 1984 Brother Shipyard worker 41 59,000

29 F 79 2001 Sister Shipyard worker 61 3,700

15) 30 M 60 1994 Brother Shipyard worker 41 1,800

31 F 70 2002 Sister Domestic exposure n.a.d

16) 32 M 66 1971 Husband Shipyard worker 36 +

33 F 77 1990 Wife Domestic exposure 59 +

17) 34 M 77 1982 Husband Shipyard worker 62 117,000

35 F 83 1992 Wife Domestic exposure 62 110

18) 36 M 62 1997 Husband Shipyard worker 47 +

37 F 63 2000 Wife Domestic exposure 500

19) 38 F 73 1984 Mother-in-law Shipyard worker 58

-39 M 58 1981 Son-in-law Shipyard worker 44 921,000

40 M 87 1994 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.

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Industrial Health 2004, 42, 235–239

currently suspected of playing a role in the genesis of mesothelioma53, 54).

In conclusion, familial mesothelioma does not offer an alternative etiologic explanation to asbestos. Various points remain to explore in the present cases as well as in familial mesotheliomas in general; for instance the role of SV40 and the molecular features of these tumors. The study of familial mesothelioma deserves great attention since it represents a model, in some way unique, in which to investigate the interactions occurring between asbestos (or erionite) and other factors, genetic as well as environmental.

Acknowledgments

The present study has partly been supported by a grant from the Italian League against Cancer (Trenta Ore per la Vita).

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