1183

Familial Mesothelioma Details of 17 Cases with Histopathologic Findings and Mineral Analysis

Allan Dawson, M.B., Ch.B.,* Allen Gibbs, M.B., Ch.B.,* Kevin Browne, M.B., B.S.,t Fred Pooley, Ph.D.,S and Me1 GrifithsS

Nine new cases of mesothelioma clustering in four fami- lies are described, and additional information is provided on four previously reported families. All of the members of these families had some exposure to asbestos. Diag- noses were confirmed histologically, and the relevance of the histologic pattern is discussed after the literature re- view. The lung mineral fiber burden was quantified in patients by transmission electron microscopic examina- tion and energy-dispersive x-ray analysis, and this con- firmed significant exposure to amphibole asbestos in all patients. Evidence supporting an increased incidence of mesothelioma in family members is discussed. Cancer 1992; 70:1183-1187.

Key words: mesothelioma, familial, asbestos, pathol- ogy, mineral analysis.

The clustering of malignant mesothelioma within fami- lies has been reported in several articles,'-19 and these unusual coincidences, taken together with the absence of a history of occupational exposure to asbestos in many of the cases, have led authors to propose a genetic

From the *Environmental Lung Disease Research Group and the Department of Histopathology, Llandough Hospital, Penarth, and the $Department of Mining, University College, Cardiff, Wales, United Kingdom.

This study was performed as part of Health and Safety Execu- tive Commission No l/LMD/126/270/88 entitled Biological Effects of Mineral Dust.

The authors thank Drs. A. W. Musk and K. Shilkin of The Sir Charles Gairdner Hospital, Western Australia, for their permission to include Family G and their light microscopic asbestos body count; the authors also thank Dr. G. C. Ferguson for granting his permission to include the histopathologic and mineralogic results obtained by the authors for Family H.

t Former affiliation: Cape Industries plc, Iver Lane, Uxbridge, Middlesex.

Address for reprints: Allan Dawson, M.B., Ch.B., Department of Histopathology, Llandough Hospital, Penarth, South Glamorgan, CF6 l X X , United Kingdom.

Accepted for publication November 25, 1991.

susceptibility to the Despite the lack of occupational exposure in many instances, most of the patients had some exposure to asbestos, often domestic or environmental, but histologic confirmation of this exposure, in the form of visible or detectable asbestos fibers, rarely was mentioned. In only three reported cases was the fiber burden in lungs quantified by light microscopic analy~is .~ Energy-dispersive analysis has been applied to lung tissue in an additional three cases, but only in a qualitative fashion.16

Several author^^^"^'^ reported a striking similarity in the histologic pattern of the mesotheliomas in rela- tives, and Lynch et al." and Martensson et a1.I2 implied that this supports a special genetically determined host response.

In this article, we report the cases of an additional four families and provide the details of three families mentioned previously by one of u s 3 We performed transmission electron microscopic (TEM) examination and energy-dispersive x-ray analysis (EDXA) to quan- tify lung mineral fiber content in seven members of these seven families. We reviewed and confirmed the histologic diagnosis in an additional previously re- ported family4 and performed TEM examination and EDXA of the lung fiber content of one of the siblings.

This study was performed to determine whether the age of occurrence, site, and histologic appearance of mesothelioma occurring in the familial setting were dif- ferent than those in the more usual nonfamilial meso- theliomas and to quantify the lung asbestos fiber bur- dens by TEM examination with EDXA in such cases.

Case Histories

Occupational, histopathologic, and mineralogic infor- mation was obtained for 17 persons in eight families (see Table 1). Four families were not reported previ- ously. Three other families (Families C, D, and E) were reported briefly by one of us3; the full details and analy-

1184 CANCER September 1, 1992, Volume 70, No. 5

Table 1. Case Histories ~~ ~

Latency in yr Age at

Familv death Mesothelioma (time from

Duration first exposure Asbestos Lung Family member (yr) Exposure (yr) until death) bodies fibrosis Site Pattern

Brother 1 50 Brother 2 49 Brother 1 46 Brother 2 57 Brother 3 54 Brother 1 72 Brother 2 50 Brother 1 60 Brother 2 47 Brother 1 57 Brother 2 53

Brother 68

Sister 74

Father 68

Son 46

Sister 1 71

Insulation worker Insulation worker Insulation worker Insulation worker Insulation worker Engineer in asbestos factory Engineer in asbestos factory Estimator in asbestos factory Engineer in asbestos factory Worker in asbestos factory Toolmaker; parents died of

asbestosis Asbestos sheet trimmer in

asbestos processing plant Worker in asbestos processing

plant Office manager at Wittenoom

mine Holidayed at Wittenoom as a

child; Haulage contractor with asbestos

None known

33 Unknown 5 5 5

25 20 37 5 2

Unknown

46

8

10

3 9

Unknown

34 Unknown 31 42 39 31 34 45 31 40 Unknown

52

52

Unknown

41 26

Unknown Sister 2 68* None known Unknown Unknown

Seen Seen Seen Seen Seen Seen Seen Seen Unknown Unknown Seen

Mild Mild Mild None None Mild None Mild Unknown Unknown Mild

Peritoneal Peritoneal Peritoneal Pleural Peritoneal Pleural Pleural Peritoneal Peritoneal Pleural Pleural

Epithelial Epithelial Epithelial Epithelial Mixed Spindle Spindle Epithelial Unknown Mixed Epithelial

None None Pleural Spindle

None None Pleural Epithelial

Seen None Pleural Mixed

Seent Mild Pleural Epithelial

Seen None Pleural Spindle Unknown Unknown Pleural Epithelial

* Age at diagnosis. t Light microscopic examination of lung digest showed 500 asbestos bodies/g (normal, < 2OO/g).

sis are given here. The last family (Family H) was re- ported briefly by Ferguson and W a t ~ o n . ~

All diagnoses followed postmortem examination, except in Case H2, in which the diagnosis of mesotheli- oma was established by biopsy alone.

Histopathologic Diagnosis

Conventional hematoxylin and eosin-stained sections were prepared from tumor and lung. Lung fibrosis was assessed after elastic van Gieson staining. Tumor glyco- gen and mucin were assessed by the periodic acid- Schiff /diastase reaction. Immunohistochemical studies were performed to detect cytokeratin and carcinoem- bryonic antigen, with the use of peroxidase-conjugated avidin-biotin staining with commercially available anti- bodies (Diagnostic Products Corporation, Los Angeles, CA). Mesotheliomas were assigned to epithelial, mixed (biphasic), or spindle (sarcomatoid) histologic subtypes.

Of the 17 tumors, material was available for review of 14 (the other 3 were verified originally by Dr. J. C. Wagner and at least one other pathologist). Results for periodic acid-Schiff/diastase were negative in all 13 cases tested. Immunohistochemical studies were per- formed on 12 cases; all had negative results for carcino-

embryonic antigen, and 10 had positive results for cyto- keratin.

Mineral Analysis

Wet lung tissue was available for analysis in four cases; wax-processed tissue was used for the remaining four (Families B and H). Lung mineral fiber burdens were quantified by TEM mineral analysis with EDXA, with the method of Pooley and Clark.'' Briefly, nontumor- ous lung was digested in 40% potassium hydroxide, washed, and ashed in an atmosphere of oxygen. Di- gested lung residues were filtered and carbon coated; 100-200 fibers were analyzed and identified by EDXA; and percentage values were obtained for all the differ- ent fibers present. Fiber length and diameter were mea- sured directly from the screen at a magnification of X 20,000. The results are given in Table 2.

Discussion

Asbestos-related mesothelioma can occur not only in those exposed occupationally, but also in their families, as a result of exposure to asbestos dust brought home on clothing. Very rarely, more than one case of mesothe-

Familial Mesothelioma/Dawson et al. 1185

Table 2. Analysis of Lung Mineral Fiber*

Family member bodies Crocidolite > 5 pm Amosite 1 5 pm Tremolite Chrysotile > 5 pm Total fibers

A 1 Many 30.8 50% 221.7 40% 6.2 308.0 5% 615.9 A 2 Many 83.9 14% 50.3 33% 0 43.6 4 yo 209.7 B 1 Many 40.1 10% 200.3 41% 0 12.6 27% 280.6 B 2 Many 17.5 12% 22.5 39% 0 2.8 0% 88.8 B 3 Occasional 1.6 43 % 5.8 29% 0 1.2 0% 11.5 E 2 Few 0 0 Yo 4.4 25% 0 21.7 6 % 65.1 F 1 None 3.4 32% 0.8 13% 0 9.8 0% 16.9 H 1 Occasional 0 0% 1.5 100% 1.5 56.1 5 % 71.1 * All counts X lo6 fibers/g of lung.

Family Asbestos

lioma has occurred within the nuclear family. The current literature included 19 reports of 23 families comprising 55 We have collected an addi- tional 9 cases from 4 families and provided additional information on 8 previously reported persons (Table l), bringing the total of reported patients to 40 male and 24 female patients in 27 families, with a mean age of 54 years.

Thirty patients (47%) had a history of occupational exposure to asbestos, 11 (1 7%) domestic exposure, and 6 (9%) environmental exposure; 17 (27%) had no known exposure. Of the cases in which the site was known, 38 (67%) were pleural and 19 (33%) peritoneal. Histologic pattern was given for 16 of our cases and 25 previously reported cases (total, 4 l), with the following distribution: 58% were epithelial, 27% mixed, and 15% spindle.

The mean age of 54 years for these patients is lower than that reported in several large nonfamilial series (e.g., male patients, 59 years; female patients, 60 years [Adams et al.,” 92 cases]; male patients, 59 years; fe- male patients, 58 years [Elmes and Simpson,” 327 cases]; 59 years [Greenberg and Lloyd DaviesfZ3 246 mixed cases]; male patients, 62 years; female patients, 65 years [Jones et al.,24 72 cases]) but not all series (e.g., male patients, 52 years; female patients, 47 years [Le- mesch et al.,25 52 Israeli patients]). Therefore, this young age cannot be argued as evidence for a genetic pathogenesis. The mean age of our environmentally ex- posed patients (48 years) is lower than that of the occu- pationally exposed patients (59 years), as in the nonfa- milial series,’ but these differences are not statistically significant.

The histologic profile of the familial cases is similar to that of a large literature review of nonfamilial meso- thelioma (HillerdaP; of 922 cases, 52% were epithelial, 33% mixed, 15% spindle), and there would seem to be little evidence to suggest that there is anything special in the pathologic appearances of the familial type of tumor. On review of the 16 families in whom the histo-

l o p pattern of 2 or more members was known, tumors of the same pattern occurred in 2 members in 10, whereas tumors of differing patterns occurred in 6. With the data of Hillerdal, there is a 40% chance that any two tumors will be of similar histologic pattern, and there is no statistically significant increase in the occur- rence of pairings with similar patterns in the familial group (chi-square test).

At first, the proportion of tumors affecting the peri- toneum seems rather high (33%), but the literature on nonfamilial mesothelioma included quite widely differ- ing figures, ranging from 7% (HillerdalZ6; 2482 male patients) to 64% (Selikoff et aLZ7). The proportion of peritoneal cases is believed to be dependent on sex, type of asbestos, and degree of exposure. The peritoneal site is said to be favored in heavily exposed patients who usually have been exposed occupationally (Elmes and Simpson,” and Browne and Smither”); 18 of the 19 familial cases occurring peritoneally had been exposed occupationally. The EDXA data suggest heavier expo- sure in the patients with peritoneal rather than pk iral cases (Table 2). Although the proportion of tumors af- fecting the peritoneum may not be excessive, in family groups with one peritoneal case there is a tendency for other members to have peritoneal tumors too, although this effect is nonsignificant.

Do mesotheliomas occur in these families without the involvement of asbestos? Most patients had been exposed; the 17 with no known exposure may have had some subtle but significant exposure that was forgotten. It is of interest to observe that only 15 of the total cases reported included comments on the presence or ab- sence of asbestos bodies in the lungs of family members and that only 7 of the 17 cases with no known exposure included such comment. The unreliability of predicting true exposure from the history taken is well k n o ~ n . ~ ~ , ~ ~

Our results of quantitation of lung asbestos fiber burdens (Table 2) showed exposure in all eight patients examined. Of particular interest is the result of Patient H1, one of the sisters originally reported by Ferguson,

1186 CANCER September I , 1992, Volume 70, No. 5

who allegedly had only 4 days exposure, received while scrubbing corrugated asbestos roofing (which is 90% cement, with the remainder chrysotile and possibly 1 % amosite), 6 years before the first sister was seen with mesothelioma. Her lung fiber burden of 3 X lo6 amphi- bole fibers/g lung clearly could not have been acquired by this brief episode alone. In these sisters, the too brief interval between this putative exposure and develop- ment of their tumors also indicates some prior undis- closed exposure.

The result of Case F1 is also of interest because no asbestos bodies were seen in the lung, and, without the TEM mineral analysis, the tumor might have been at- tributed to some other cause. Because amosite forms asbestos bodies more readily than crocidolite, such mis- interpretation is more likely to occur in patients with significant but low-level exposure to crocidolite when TEM examination is not used.

Only one of the cases subjected to quantitation of lung mineral fiber burden has had a result within the normal range (Hammar et a1.: Son 2). The quantitation in that case was performed by light microscopic count- ing of asbestos bodies in a lung digest, and it should be emphasized that, when only bodies are counted during light microscopic examination, the total number of fibers present is underestimated; also, even if uncoated fibers are counted, significant numbers of long thin fibers may be overlooked. However, the discovery of a familial case in which TEM examination and EDXA have proven the absence of significant asbestos fibers in the lung would do little to support a genetic factor in the causation of the tumor because it is well known, in the nonfamilial setting, that cases of mesothelioma occur with minimal exposure to asbestos.

Of interest among the cases in the literature are the families in which the affected members are not related genetically (i.e., husband and wife pair^).^,'^,'^ The oc- currence of mesothelioma in these pairs implies that the shared predisposition may be environmental, not ge- netic. There is also no association between blood group or HLA type and mesothelioma.12

However, there are indications that case clustering may not result solely from a common exposure to as- bestos at work or in the home. First, Families C, D, and E were identified in a case-controlled study of 102 meso- thelioma deaths occurring in the same amphibole pro- cessing factory; none of the 204 controls included a fam- ily pair. Second, Anderson et al.' reported a father/ daughter pair among 19 employees of an asbestos factory and their family contacts who had mesotheli- omas. There were 14 cases among 1664 employees and 5 among their families, and the probability of a meso- thelioma occurring in an employee and a family con-

tact in the same household can be calculated as less than 0.04.

In conclusion, we have detailed an additional 17 cases of mesothelioma occurring in 8 families, bringing the literature total to 64 persons in 27 families. We re- viewed the literature and showed that the age at which these mesotheliomas occur, their site, and the histologic pattern are similar to these characteristics in mesotheli- omas occurring in the nonfamilial setting. We quanti- fied lung asbestos fiber burden in eight cases and found significant levels of amphiboles in them all, despite a potentially misleading history in one case.

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