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deceived 04/0^2002 Cl :02PM in 21:10 on line fll) for 40ALSTOH * Pfl B/37 IFR1) 4 E 02 t2 = C6AeT. 12: 01-'NO. 4662209470 P THOM BIOMEDICAL information service 8 * : i a, i i :: i; h i t: 11 t Malignant Mesothelioma in Women V I L : :,1 r L . K r; IT l i . .VI p T i )M ft . C.) II l y , \I ft , P /l ft L t i ; ,i / c / /* j . \l t: j j a t z , M ft l(jj NOTICE: THIS MATERIAL MAY BE PROTECTED BY COPYRIGHT LAW (TITLE 17 U.S. CODE) 147 Shelved W/05/200? 01:07Ptt 'n il'.IQ on tloe PH *<>r *0ALST0 Pg V/37 5 02 12:C6/ST. 12,01/NO 4562209470 P THOM B ! oMEL>l CA L INFORMATION SFfUMCL Anatomic Paihobgy 1997 Malignant mesothelioma, once a relatively lung amphiboie (crocidolite, amosite, and tremo- rare disorder, now occurs in industrialized nations Lite) burden than the mean burden in 31 female in epidemic proportions. The majority of cases controls was found in iis l9ti.%).nt u7 women are the result of the widespread use of asbestos tested. ' prior to 1972, especially in the construction and From the perspective of differential diag shipbuilding industries. Because workers in these nosis, special consideration must be given ro industries have traditionally been men, there is a papillary peritoneal tumors in women. Peritoneal striking gender bias in this disease. Nonetheless, mesotheliomas must be distinguished from mesotheliomas of both the pleura and peri primary and secondary serous papillary carci toneum occur in women as well, although little nomas ol the peritoneum.1*'15 Furthermore, the information is available regarding the uiell-ditferentiated papillary mesothelioma of the histopathologic features or the primary sites of peritoneum is a special variant characterized by such tumors. Furthermore, little is known Tfn indolent clinical course and prolonged regarding the types of asbestos exposure (if anyT survival.1'* L.'eciduoid peritoneal mesothelioma is- or the lung asbestos burdens in women coi arteers young with men. women.17 Interestingly, in the (Joldblum and In 1980, McDonald and McDonald reported ~ "Hart Study, 13 women with diffuse malignant on a survey of all fatal malignant mescuhelial peritoneal mesotheliomas had no known history tumors in NorLh America.1 Among 557 mesothc-f of asbestos exposure,15 liomas reported through the end uf 1972, 162 The purpose of the present study is lo review occurred~in women; of these. 99 (61%! our experience with malignant mesothelioma in "were pleural lrTorigin. The annual incidence of women, including clinical and histopathologic mesothelioma in 1972 was estimated.to be 0-7 features as well as asbestos exposure. Mineral cases per million women aged 1 `i yearsand older, fiber analysis of lung tissue was performed m jncheridence waepreffnrprl rhsj,. ,r, i 'ana.-I/ rV.r about one third of the cases- Patients with serous rate of mesothelioma in women had remained papillary carcinoma of the peritoneum were somewhat constant over a 15-year period. A excluded-15 ' history of occupational exposure to asbestos was _ "found in only of the women in the study. MiJIerctal reviewed the literature on mesothelioma and found 47IG published cases through 1982.2 Information regarding gender was Materials and Methods available in 286? of rhese cases, and 619 (ZZ%) occurred in women. Among ten subsequent series of patiems with mesothelioma, a mrai of if>l tumors were reported. 342 nf thrm in Among 770 patients with malignant mesuthelioma from one of the authors' (VLR) files, 62 (8.0%) were women. All rumors were women.5"12 Thus the percentage of women with pathologically confirmed based on open or thora mesothelioma has remained fairly constant coscopic biopsy, decorrication, pneumonectomy, ' worldwide over the past sevcraldecades. or autopsy specimens using previously described In 199-S, Dawson et al reviewed 1.77 eases of criteria.information regarding occupational or women with mesothelioma from the United other exposures to asbestos was obrsined by Kingdom; this is the only large study dealing direct patient interview. Age, sex, and primary ^exclusively with mesothelioma in women.13 The site of the mesothelioma (ie, pleura or peri ^aurhors found little difference in tumor sire or toneum) were also recorded in each instance. nistologic type between men arid women. The presence or absence of asbestosis or parietal TTmong those women for whom asbestos expo pleural plaques was also noted in patients for sure information was available, 7~4 (50%) of 91 whoir. such information was available. Criteria ~4racf~a history of such exposure. Lung fibrosis was for the pathologic diagnosis of these conditions identified in Yl (47%) of 152 "cases. A higher have been published previously.2^22 148 Received 0a,'/200Z Cl:02PK in Zl:10 on line (111 for 40AISTOM Bg 10/37 FBOM BIOMEDICAL INHUMATION SEKV1CE (FEU 4. 5' 02 1 2 : C7/ST. 12 Ot /NO. 4662209470 P 10 Malignan: Mesothelioma in Women li&E-stained sections of each rumor were reviewed- Immunohistochemical studies were performed using the avidin biotinylated complex technique on trypsinized sections. Antibodies employed included monoclonal antibodies against cytokeratins (AE1/AE3. Boehringer Mannheim, Indianapolis, Ind, and CAM 5.2, Becton Dickinson, San Jose, Calif) and Leu-Ml (CD-15, Becton Dickinson), and polyclonal anti bodies against carcinoembryonic antigen (CEA; Dako, Carpinteria, CaliO- Antibodies were local ized using diaminobemidine as the color reagent. came first. Fibers were defined as particles with an aspect ratio (length co widrh) of at least 3:1 and roughly parallel sides. The concentration of fibers for each sample was calculated based cn the fiber density (per mmz) on the filter surface times the effective area of the filter, divided by the weight of the lung sample. The results are reported as total uncoatcd fibers 5 pm or greater in length per gram of wet lung (UF/g). The normal range for our laboratory is less than 440 to 13,000 UF/g (median, 3100 UF/g), and the detection limit for a 0.3-g sample size is approxi Negative controls included normal rabbit serum mately 440 UF/g. Uncoatcd fibers were detected and an irrelevant mouse monoclonal antibody. in all samples analyzed. Positive controls were used with each study. Fiber types were determined using a combi Formalin-fixed or paraffin-embedded periph nation of fiber morphology assessed by SEM and eral lung parenchyma was available for analysis of elemental composition assessed by energy disper tissue asbestos content in 20 of the 62 cases. sive x-ray analysis (EDXA). Fibers were classified Most of these were from autopsies where lung as asbestos or nonasbestos mineral fibers as previ tissue was available for analysis, although some ously described.21 Asbestos fibers were further were from surgically resected specimens, in rhe classified as amosite, crocidolite, tremolite, other 42 cases, only tumor tissue was available or anthophyllite, accinolite, or chrysotile. Amosite i the amount uf lung Tissue sampled was insuffi and crocidolite were grouped together as cient for analysis- Lung tissue was processed for commercial amphiboles; tremolite, anthophyl- digestion using the sodium hypochlorite tech. lice, and actinolitc were grouped together as nique as previously described.21 The residue was noncommercial amphiboles. Between 5 and 28 collected on 0.4-jjm pore filters (Nuclepore fibers were analysed for each sample (mean. 14 Corp, Blasingame, Calif). For light microscopic fibers per sample). The proportion of each fiber analysis, the filter was mounted on a glass slide type and the total uncoatcd fiber concentration for asbestos body quantification. Filters were were used to determine the tissue concentration counted at magnification of x400, and only of amosite and crocidolite; tremolite, anthophyl- bodies wirh typical morphology and thin, translu lice, and oetinolite; chrysotile; and nonasbestos cent cores were counted as asbestos bodies.11 mineral fibers for each case. For those where no Results were reported as asbestos bodies per gram fibers of a particular type were detected, the of wet lung tissue (AB/g). The normal range for value was recorded as less chan che detection, our laboratory is 0 to 2D AB/g, and the detection limit for that fiber type. limit for a G.3-g sample size is approximately 3 AB/g. For samples in which no asbestos bodies were detected, the value was recorded as less \ than the detection limit. For scanning electron microscopic (SEM) Results analysis, the filter was mounted on a carbon scub with colloidal graphite, sputter-coated with gold or platinum, and examined in a JEOL JSM 6400 scanning electron microscope (JEOL inc, The demographic, pathologic, and exposure information for the 62 women with mesothe lioma is summarized in Table b-K The median, Peabody, Mass) at a screen magnification of xlOOO. Fibers 5 pm or greater in length were counted using a protocol in which 100 consecurive fields or 200 fibers were counted, whichever age of the 61 patients for which this information was available was 59 years (range, 28-82 years). These values are similar to those previously reported for che overall series of mesothelioma in 149 n Table 8-H Demographic, Pathologic, and Exposure Information for 62 Women With Mesothelioma Case No. Age Exposure History/Occuparinn Diagnosis Case No. Age Exposure History/Occupation Diagnosis |JJ OXnv r> r 1 2 3 4 3 rt 7 8 9 10 II 12 Ln 13 O 14 IS 16 17 Id 19 20 11 11 2.1 24 23 20 27 28 29 .30 31 32 58 Spinner/wauler/wenvrr, asbestos textile plam, 14 vi wife of insulator 62 Wifi of shipyard worker, 29 y 28 Status poiidiemotlierapy and radiation for . Wilms' tumor 52 Laundry worker, military institute 57 Wife of shipyard worker NA NA 45 3 ran is postchemorherapy and radiation tor lymphoma, 1977; wife of auto mechanic 75 Wife of shipyard pipe-r.overer, 30 y 41 Wife of merchant marine seaman, 4 y 43 Schoolteacher 58 Teacher's aide, 18 y 38 Tugboat worker, 15 ino 32 Daughter of insulator, 18 y; wife of insulator, 7 y 66 Company nurse, Johnj'ManviUc, 40 y 44 Dry-cleaning plant assembler 55 Household contact {asbestos worker) 69 E UuiicinnliiT; no known exposure 71 Wife of insulator, 27 y 31 Household contact (pipecovorer), If y 60 1 louscIn'IJ counter (mother of pipelInert, 2.5 y 61. Household contact (ashesios worker'1 69 Shipyard worker, I y 48 Optical plant worker 45 Elementary school student, 6 y 71 Laborer oil cleanup crew, iron works. 3.5 y 33 Daughter of amnsite asbestos plant worker 68 Smoked Kent cigarettes 70 Wife of construction worker 49 Household contact (aunt of Case 13), 11 y; radiation for breast carcinoma. 4 y prior to diagnosis 70 Homemaker; no known exposure . 65 Wife of shipyard worker 65 Household contact (wife ofpluinher/pipefitter), 15 y E PI DPI CPI EPI E PI Pc E PI CPI tin EPI SPI EPI BP! EPI HP! S PI BN B PI BPI SPI BN EPI EPI EPe EPI EPI BPI SPI R PI SPI SPe EPI n, I'lciirjil; t, cpirliflialt I'c, piTitimcn]; S1*5tiirc,*iNA* nm AVHiljiMc. 33 34 35 36 37 38 39 40 41 42 43 44 . 45 46 47 48 49 50 51 52 53 54 55 56 57 53 59 60 61 62 73 Braider operator, Johns-Manvilte 45 Daughter of insulator who died of mesothelioma 31 Daughter ofinsulator, 10 y 59 NA BPe BPI EPI EPI 5* 0go n4* 1a 66 Smoked Kent cigarettes 46 Ha lighter and wife of asbestos insulators, 30+ y 41 Household contact (father and uncles), 18 y 70 Smoked Kent cigarettes 56 1 lousehold contact {daughter of machinist], 7 y EPt BPI BPe SPI EPI \* Zs fji S i--srj 48 Administrative assistant, polyurethane EPI 2 e manufsctixing plant > 61 Radiation therapy for breast cancer, 21 y prior to diagnosis SPI g S 82 Household contact (shipyard worker) PI a 76 Household contact (arbestos worker), 5 y EPI PV 71 Radiation ro pelvis, 50+ y priOT to diagnosis 74 Household contact (wife of insulator) ' EPe EPI 46 Household contact (stepdaughter of shipyard F. Pe 5 worker), 6 y 41 Household contact (daughter of tire presser), 13 y 63 Household contact (wifcofpapermakcr), 30 y BPI " * EPI 53 Lahorer, aluminum and chemical plants, 2 y 52 NA 71 Household contact (mother of steatnfitrer), 5 y 55 Household contact (wife and daughter of shipyard EPI B Pc SPI EPe 5/1 oN> and refineiy workers), 30 y 29 Household contact (father, cousin, uncle). 20 y BPI o 78 Household contact (wife ufshipyard worker). 30 y EPI 74 Household contact (wife ofoil refinery worker), 27 y EPI 68 Household contact (wife of insulator), 25 y EPt \ H 78 Shipyard worker, 2 y; household contact ' EPI (wife of iniulator), many years o- 47 Aunt smoked Kent cigarettes 81 Household contact (wife and mother of pipcfittets/wdders),4L y 71 Shipyard wotker, 2 y : EPI EPI : EPI zc Af*MKn> C A-4 T7 deceived tH/0$/2Q02 81.-02P* m 21:10 oo line 113 -for tOAlSYOM * Pg 12/37 ROM BlOKCn>CAL IKMSHATI3N SSHVICE * 5 02 12 : CB^ST. 1 2: 01 /NO. 4662209470 P 12 Malignant Mesothelioma in Women I men and women.^ Fifty-three of the tumors than in the pleura. Only one of the peritoneal arose in the pleura and nine in the peritoneum. mesotheliomas in women was a purely sarcoma TThc ratio of nleutal to peritoneal tumors was " toid variant "Image 8-4-. 5.9:1 for women compared with 1076din men~ Ancillary evidence of asbestos exposure (unpublished data from the author's [VLR] includes the findings of parietal pleural plaque series). formation or asbestosis in sections of lung Twenty-nine (56%) of 52 pleural mesothe parenchyma. Parietal pleural plaques "Image 8-5< liomas in women were epithelial variants, were noted in 13 (50%) of 26 patients for whom including tubulopapillary and solid epithelial such information was available. Asbestosis "Image patterns "Image 8-K Nine tumors (17%) were 8-6-* was present in 5 (16%) of 31 patients from sarcomatoid, including three with a predomi whom lung tissue was obtained, and 4 of these nantly desmoplastic pattern "Image S-2. The were occupationally exposed to asbestos (see remaining 14 mesotheliomas (27%) were next section). These percentages for exposure in biphasic "Image R-3V- The ratios of epithelial to women are lower than those far men with biphasic to sarcomatoid tumors showed a preater mesothelioma (73% pleural plaques and 24% proportion of epithelial mesotheliomas ;n w'fflyp asbestosis) in the author's (VLR) series. compared with men (56:27:17 for women vs Results of immunohistocliemical studies were I 41:35:23 for men). Similar ratios were observed available for 47 women "Table 8-2-'. Positive among the 9 peritoneal mesotheliomas in women staining for cyiokeratins was observed in 42 of 46 (56:33:11). The proportion of epithelial peri instances. 1 he four that were keratin negative toneal tumors was also increased compared with involved the use of polyclonal beef-muale keratin those occurring in men (49:46:5 for peritoneal antibodies in sarcomatoid or biphasic tumors. The tumors in men)- In both sexes, purely sarcoma author (VLR) currently uses a monoclonal anti toid tumors were less common in the peritoneum keratin cocktail that includes AE1/AE3 and CAM "Image 8-H Cate 60. Malignant mesothelioma showing a tubulopapillary pattern- (I I1S.E, x25l 151 Received 04/05/MBZ 01-.02PH in 21:10 on tine 111] for WAISIOH * Py 13/37 THOM PIOMED'CAL tNFORMATI t>N SERVICE (FEM 4 5 02 12:C$/ST. 12:01./NO. 4665208470 Anatomic Pathology 1997 13 Image 8-2 < Case 20- Malignant mesothelioma showing a detmoplastie poncm. consisting til' duck collagen bundles arranged in 9 storiform pattern and separated by tumor cells with plump, often hyperchromatic, nuclei. (HdtE. X75) Image 8-?- Cu.se 55. Biphasic variant of malignant mesothehoma, showing predominantly epithelial morphology in the upper pan of the field and a sarcomatoid pattern in the lower parr. (Keratin immunopcroxidase. *75) 152 Received Q4/0V2Q02 01:02PM in 21:10 on tine HU for 4OALST0H * Pg 14/37 INFORMATION SERVICE FROM RI OHEDI CAL IFR]) 4 5 02 12:10/ST. I 2:OI/NO. 4662200470 P 14 Malignant MotItelicma in Worr>en Image S-4-* Case 31. Sarcomatoid mciothttioma of die peiiiuneum showing a flbiosarcmnatnuspattern. (H6tE, xjiji Image S-S* Case t. Peribronchiolar fibmsis associated with asbestos bodies (upper leit and tight lower Center). Note the irwltinucleate giant cell (right upper center). (I litE. *100) 153 Received 04/05/2002 01:02PM in 21:10 on line till for 40AIST0N * Pb 15/57 TR'JM BIOMEDICAL INKOflKATlOK SERVICE (FRIJ 4- 5 02 1 2 : 11/ST. I 2 : > t/NO. 4662 209470 P 1 .Anatomic Fathology 1997 Image 8-6-* Cine 2 . Parietal pleural plaque consisting :>t layers of nre!I||I>r hyalmiirc collagen arranged in a "3ket^veak'e" pattern. (HStb, k25) ' Table 8-2* lmmunohistochemical Findings in Women With Mesothelioma Antigen No. of Cases (Posirive/Total)* Cymkeratins Care inoembryonic antigen (CEA) Leu M-) (ODI5) HBME-1 42/46 i/46 1/41 5/8 'Number ofcases with poditivc saining nv*i r~nal nuittber uf eases fot ":iLb luinrnv with the indicated aniihnd,' xtt performed. See text Jot Jewilti regarding the antibodki used. 5.2. All mesotheliomas studied in women were keratin positive using this particular cocktail Image 8-7'*. Forty-six tumors were stained using a polyclonal antibody against carcinoembryonic^ ancigen; one stained focally positive. Similarly, one of 41 tumors stained focally positive for Leu M-l (CD15). Eight tumors were stained using a monoclonal antibody raised specifically against mcsothelial cells,26 and five of these were positive -Imace. b-8'<. in our experience, this antibody does not significantly sLain the sarcomatoid compo nent of mesotheliomas. Immurtostaining for vimentin, epithelial membrane antigen, and B72J was performed in too few cases for mean ingful interpretation. The overall immunohistochemical results were quite similar to those observed for mesotheliomas in men.19 Exposure Information Information regarding potential exposure to asbestos was available in 59 cases Table 8-1". Eleven women (19%) had an occupational expo sure to asbestos. Three worked in shipyards for 1 to 5 years, and one worked on a tugboat for 15 months. Three patients worked at an asbestos manufacturing plant for 14 to more th.an.4C years (one asa~ braider, one as a spinner, winder, and weaver; and one as a company nursej. ~l~he other four patients were exposed to asbestos while employed at a power plant (13 years), as a lalxirer at an iron works (3.5 years), as a laborer at a 154 FROM BIOMEDICAL Received W/05/2002 01:C2PH in 21:10 on line 111J for 40ALST0N * Pg 16/37 INFORMATION service <frd 4- 5 02 1 2 r 1 2yST. 12:01/HO. 4E62209470 P 16 Malignant Mesothelioma in Women Image 8-7 Case 31. Sarcomatoid peritoneal mesudietioina showing keratin-positive spindle cells invading adipose tissue. (Keratin lmmunopcronidase, x50) Image 8-8-< EpiihcUat malignant mesothelioma seamed with monoclonal antibody HBVIE-l, showing * predominantly membranous pattern nfsrainmg (HBME-1 immunoperoxidase. xlOO) 155 Received 04/05/20M 01:02PM in 21:10 on tine till for 40AIST0N Pg 17/37 FROM eiohedica: INFORMATION SERVICE (FR1I 4- 5' 02 1 2 : 1 3/ET. 12 01 /NO. 4662209470 F 17 ATuaomic Pathology J997 chemical plant (2 years), and at an optical manu- elementary school for 6 years as a child. Another 'tactunng plant (no time available). Four ot the '"pbiential exposure to asbestos on clothing women with occupationaV'exposiires also had occurred in a laundry worker at a military insti - pathnlagic~ii5begg5is~(CasMl, 14,~25, and 33), tute (Case 4). Three other cases had no known ' and Tout had pleural plaques (Cases 25, 33, 51, exposure to asbestos: One was a dry-cleaning and 59*------------------------------------- plant assembler (Case 15) and two were home- By far the most common form of exposure makeis (Cases 17 and 30). was through household contact with an asbestos Therapeutic radiation has been associated worker, from asbestos brought home on the with the development of mesothelioma many clorhes of a worker living in the same household. ~yeairs later,15 and live patients gave a history of ThiiLv-six (61%) of 59 women with mesothe ^prtor radiation, une (Case if had received radia lioma were household contacts of asbestos tion and chemotherapy for Wilms' tumor as a workers. For 34 of these cases, this was the only child.25 Analysis of her lung tissue demonstrated identifiable exposure to asbestos. All gave a an asbestos content no different from "History ot washing the work clothes in the house ground. Another patient (Case 7) had received hold. The household contact was a husband in radiation and chemotherapy for lymphoma 7 11 cases, a father in 6, a husband and a father in years prior to the diagnosis of mesothelioma* She 3, and a son in 2. There was one case each of was also the wife of an asbestos-exposed indi contact through a husband and a son; a father vidual. A third patient (Case 29) received radia and uncles; and a father, a cousin, and uncles. tion and chemotherapy for breast cancer 4 years The household contacts' occupations were as prior to the diagnosis. This is a rather short follows: insulator (10 cases); shipyard worker (6 larency for radiation-induced mesothelioma, and cases); pipefitcer/welder (3 cases): oil refinery the patient also had exposure as a household worker (2 cases); and steamfitter, paper-maker, contact. Analysis of her lung tissue disclosed rire presser. machinist, construction worker, considerably increased levels of asbestos. A merchant marine seaman, auto mechanic, and fourth woman (Case 43) had received radiation asbestos plant manufacturer (1 case each). In 7 therapy for breasr cancer 21 years prior tc- the cases. I lie occupation of the household contact diagnosis of mesothelioma in the ipsilatcral was not available. The duration of exposure for pleura, while a fifth (Case 46) with peritoneal the household contact was known in 27 cases mesothelioma had received pelvic radiation more and ranged from 1.5 to 41 years (median, 17 than 50 years prior to the diagnosis. None of years). Nine of the women in this group had pari these patients had pleural plaques or asbestosis. etal pleural plaques (Cases 2, 13, 18, 19, 21, 28, Studies have shown that there is no relation 44, 47, and 59), .and two also had asbestosis ship between cigarette smoking and the subse (Cases ] and 47). Three had pctiloneal mesothe quent development of mesothelioma.J0 However, liomas (Cases 31, 39, and 48), and one parient's jt special case is Kent cigaretces, the Micronite (Case 34) father died of mesothelioma. filteFof which contained crocidofire asbestos The disease-producing potential of aslxtstos between 1952 and 1956. lalcott et al reported~a~ in buildings has stimulated considerable contro smiting incidence of mesothelioma among versy.27,28 In this regard, it is interesting to note ^ workers who manufactured the titters,jl and that two of the women with pleural mesothe Longo et al showed that substantial numbers of lioma had potential exposure to asbestos as fibers were released when chese cigarettes were teachers within schools with friable asbestos- smoked.n Nonetheless, there has been no containing materials (Cases 10 and 11). One of convincing evidence to dare of ar. increased risk these patients (Case ] 1) had pleural plaques, and of inesnrhelioma among individuals who smoked tissue asbestos analysis was performed (see next these cigarettes. One of the difficulties in such section). An additional case was a 45-year-old studies is that occupational exposure to asbestos woman with peritoneal mesothelioma (Case 24) is such a major factor in the causation of whose only known exposure to asbestos was in an mesotheliomas in men that any effect due to low- 156 Heceived 04/05/M02 01:02PH in.21:1C on tine til] for AOALSTON * Pg 18/37 FROM P tOUE'IUCAL INFORMATION SERVICE (FRJ) 4. 5' 02 t2:14./S.T 12:OiyWl 4e6220V470 P 16 Maiigrurrsi Mesothelioma in Women dose exposure from smoking Ken: cigarettes is 10 years (including 1952-1956) with her aunt, lost in epidemiologic studies. In contrast, occupa tional exposure is less prevalent in women, and therefore this group may be ideal tor measuring the effects of low-dose exposure to cigarette smoke. jSmoking histories were obtainec for the 62 women in this study Table 8-3-*. Twenty-four who smoked Kent cigarettes. Analysis of lung fiber burden in this case was unremarkable. These data suggest an association between smoking Kent cigarettes with Micronite filters and the subsequent development of pleural mesothelioma among women. Our observations need to be confirmed in a larger population- were smokers or ex-smokers, and 19 were lifelong based study, such as the Surveillance, Epidemi nnnsmokers. Among the 24 smokers, three were ology and End Results (SEER) Program.^ too young {less than 12 years old in 1956) to have smoked during the Kent Micronitc-filter era. Smoking histories were unavailable for 19 patients, but four of these were coo young to have smoked Kents with Micronite filters. Three women actually reported a history of smoking Kents from 1952 to 1956, which is 14% (3/21) of Tiber Analysis Analysis of lung parenchyma for mineral fiber concent was performed in 20 cases Table 8-4-*. The median asbestos body count for 19 cases studied by light microscopy was 31 AB/g those who were known to be smokers and were old enough to have smoked during the time in question. If one assumes that among the 15 women for whom smoking information was (range, 2.0-8200). The asbestos body count exceeded our normal range of 0 to 20 AB/g in 11 (58%) or 19 cases. SEM with fiber-type analysis was performed in 18 cases. Of these, 9 had, an unavailable and who were old enough to have elevated level of commercial amphiboles smoked during the relevant year:, all were "(imoslte or crocidoltte) and 8 had an elevated smokers and none smoked Kents from 1952~tcT content of noncommercial atnphiboles (tremo 1956,the n the percentage of women smoking" lice, actinolitc, or anthophyliite). Chry:sotilej Kents among chose who smoked would be as low levels were outside our control range in 3 cases! as 8% (3/36). In contrast, the market share for An elevated fiber burden was detected in H Kent Micronite filcer cigarettes from 1952 to (70%) of 20 cases. 1956 was less than 1%.^ One other patient s Tissue for asbestos analysis was available for only known exposure occurred when she lived for only two of the women with occupational expo sures (Cases 1 and 12), and both demonstrated an elevated pulmonary asbestos burden. One * Table 8-3 h (Case 1) was a spinner, winder, and weaver of chrysotile asbestos textiles, and she had a Smoking Histories in 43 Women With Mesothelioma* Smoking Category Ho. of Cases Smokers/e x -smokers 24 Were nW enough to have smoked Kent 2tf cigarettes with Micronite filters Smoked Kent cigarettes with Micronite filcers 3 Lifelong nonsmokeis 19 markedly increased chrysotile burden, including chrysotile asbestos bodies Hmage 8-9'. This patient also had an elevated burden of amosite asbestos, probably derived from washing the clothing of her husband, an insulator. The other woman (Case 12) had a mildly elevated asbestos body count and increased levels of both commer cial and noncommercial amphibotes. Fiber burden analysis was performed on lung tissue from 13 women who were household `Smolcng histories wt uiiiiviiilablt fot 19 patients, 15 of whom '.vers <lc! tmwgh > have smoked during the Kent Mn:roniie-Aleer cm. rMtcmnir liIrrrc contained criiJolitesubettibetween 1952 ?nd 1956- PatieriT* n^ed 11 y&tt etniMer in 1956 were cunsliiereJ old em.nigh rif have enneeivahly *in:>ked Kents during the riir.e in questiiin. contacts of asbestos workers, and 10 (77%) of these had an elevated tissue asbestos burden. The median asbestos body count for these 13 samples was 300 AB/g (range, 2-8200 AB/g] and exceeded the background range in 8 (62%) of 13 157 Received 04/05/2002 01:0ZPH in 21:10 on line till for tQALSTOtl * Pfl 19/37 INFORMATION SERVICE trom biomedical (PR!) 4. 5'02 12:14/ST. 12: 01/NO. 4E62209470 P 15 Anatomic Pathology 1997 ^Table 8-4^ Tissue Asbestos Content in 20 Women With Mesothelioma Case No. AB/eUM) IJFfe AC TAA Chrys NAMF 1 2 3 5 It 12 13 15 17 18 19 20 29 32 34 39 44 47 55 60 Controls) 5100 8200 9.4 2.0 2.9 31 233C 64 9.8 300 415 29 1650 590 8-4 17 3.3 7480 5.0 -- 20 67,030 -- 3900 24,300 13.000 24,000 17,000 6S00 3300 4550 8490 45,000 31,000 23,900 2920 11,300 117,000 40,000 4400 4290 12,700 14,000 -- <4860 <870 4800 5460 <680 <660 3250 450'' <4500 4650 2920* <490 <660 2280 34.000 490 <310 <2540 6700 -- - -- 9720 4330 4300 2430 5440 1980 <650 <^1060 <4500 1550 7170 490 1990 9360 4000 1960 1220 2540 33,503 -- -- <4860 <870 <2400 1820 <630 <660 <650 <1060 <4500 1550 <2390 <490 <660 <4680 <2000 <490 <310 <2540 26,800 -- -- 14,600 8670 14,400 7300 1360 1320 1300 8490 45,000 23.250 16.700 2430 9300 133.C0O 2000 1960 3060 10,200 N-M). a.s*vs<ni bodiei ptx gram, of *et ling liisjc as Jeiciriim*J by tight microscope':. L'Fg. urcoatcd fibers 5 nr greater in lengrhper gwm of wet lung msuc as d-teirnmed icsinnmi!' clecrrnr. iriicifrtcoj''yi AC, anfsice or cr3cidn|irc (crceidnlitc dcTrcdortly in Case 41); TAA, tr:m<>I;ce,acrinnlirr, ot anthorhyllite; Chrys. ckryspcileiKAMr. nniidbbc*ns mlatral fibers. Omred fibers only. "C"nwol values represent ihe upper limit of values identified in luj(g tissue* from IS male control case? da pcfcvioubjy polfolKJ.fc"* 1 I cases. Among the 12 samples for which SEM and EUXA were performed, commercial amphibpf^s were elevated in 7 cases, noncommercial amphiboles in 4 cases, and chrysorile in 1 case/ In one unique situation, both the woman {Case 18) and hei husband presented with mesothelioma and pleural plaques; the husband also had asbestosis. Analysis of the husband's lung tissue demon strated about 80 times as many asbestos bodies and 30 times as many uncoated fibers as those found in his wife's lungs. Among the three patients expused through household contact but without an elevated tissue asbestos burden, one was a 29-year-old woman (Case 55) with pleural mesothelioma,who was exposed to dust on the clothes of her father, cousin, and uncles over a 20-year period, A single amosite fiber was detected by SEM, which Is considered an ambiguous result (none expected in controls). Another patient was a ^5-year-old woman (Case .34) with pleural mesothelioma who was exposed to dust on her father's clothes for 18 years; her father was an insulator who died of mesothelioma. The third patient was a 41year-old woman (Case 39) with peritoneal mesothelioma who had been exposed to asbestos on the clothes of Her father and uncles during the summers over a 2C-year period- Tissue asbestos analysis was performed in five additional cases. One patient (Case 11) was a teacher's aide for 18 years in a school wirh chrysotile-comaining asbestos ceiling tile. This patient had a normal range asbestos body count out an increased tremolite (a known contami nant of chrysotile) burden by SEM/EOXA.1"1 Another patiem (Case 15) was a dry-cleaning 158 I Received 04/05/2002 01i02PH (n 21:10 on line til) for 40AIST0K * Pg 20/37 FROM BIOMEDICAL INFORMATION SERVICE (FEU 4. 5' 02 12:15/ST. 12:01/1*0.4662209470 P 20 Mulignuni MawiheUoma m Women * Image 8-9* OilhC t< Nudepord filler witil .1 cinder til v.'hrvsorilo ushtsms fitvrt LsoLltaJ hoot ch<; luixpi. Free fiber c:vi$ appear tn .ipu\ **t| rhe central ma>* like ihtt urm* >l a npirjf g;i|xv wtiJ Iv-vc bicoiv.e couteJ ic ft-^TTi ntintfr*u,< i;hry,<i>tilc .ishcsruji bi^Ovt* (^"printcJ with permission ItxhTi Rutigli 1,1) 4Sc;inr,injj elec nor. microscopy, x$50) plane assembler with an elevated asbestos body Discussion count and an increased cremolite burden; the source of Lreinolite exposure was not Identified. The pathologic features of malignant A third patient (Cose 3) was a 28-ycar-old ,, mesothelioma in women arc similar to those woman with pleural mesothelioma who had observed in men. Pleural mesotheliomas received radiation and chemotherapy treatments outnumber peritoneal tumors in both sexes, fnr Wilms' tumor of the kidney at A years of although the proportion of peritoneal mesothe aged9 A fourth patient (Case 60) lived fot 10 liomas is slightly higher in women. Epithelial years with an aunt who smoked Kent cigarettes. varianrs predominate, and the percentage of A fifth patient (Case 17) had no known exposure to asbestos. The tissue asbestos burden in all three of these last cases was indistinguishable from background. epithelial types is slightly greater in women compared with men. The immunohistochemical features are also similar in both sexes: both epithelial and spindle, cell components of the Nonasbestos mineral fibers were identified tumors stain positive for cytokeratins when a in all 18 cases in which SEM was performed. The fibers included talc, rutile, silica, aluminum silicates, and potassium aluminum silicates. cocktail containing antibodies directed against both low and high molecular weight keratins is used. Fewer than 5% of mesotheliomas stain Such fibers generally have low aspect (length to diameter) ratios, and there is no evidence that they play any role in the pathogenesis of mesothelioma.*5 positive for CEA.or Lcu-Ml, and such staining is usually focal. Caution must be exercised in diagnosing epithelial variants of peiitoneal mesothelioma in 159 Received 04/05/2002 01:02m in 21:10 on line (111 for 40ALST0H * Pg 21/17 PROM BIOMEDICAL IN FORMAT I ON SERVICE (EH!} 4- 5 02 J 2: I 6/ST. l:t>lvT'IO- 4S62209470 P 21 Anatomic Pathology 1997 women, as these may be confused with serous papillary carcinomas of' the peritoneum. The distinction can usually be made based on careful attention to histologic, histocheinical, immuno- has been demonstrated in support of an asbestos etiology. ' A history of occupational exposure to asbestos was identified in 19% of our cases, and histochemical, and ultrastructural features. Budding or tufting is commonly seen in serous papillary carcinomas, as are numerous psam moma bodies- Intracellular mucin can be demon' an elevated tissue asbestos burden was found in each of rhe two instances in which lung tissue was available for analysis. These findings differ from those repotted 5y~McDonald ancT scrated with the periodic acid-Schiff stain in as many as half of papillary carcinomas, but only rarely in mesotheliomas. Staining with OCT25 is identified in more than 90% of serous papillary 'McDonald1 and by Dawson et al.lJ "Ihe former 'reported art occupational history of exposure ro asbestos in only 5% of women with mesothe lioma in North Ameiica. Thai siudy depended carcinomas, but in only 14% of mesotheliomas. on occupational histories obtained by inter Uirrasrrucniratlv. mesotheliomas possess long viewing surviving relatives, and thus may have . surface microvilli that are often quite numerous, underestimated the actual prevalence of expo whereas the microvilli of serous papilTary carci sure. Furthermore, the reports were collected nomas are more sparse and tend to be stubby prior to 1980, and it is difficult to know how ~racKer than long and slender.18 ' many might have been serous papillary carci Ancillary histologic findings supportive of nomas of the peritoneum misdiagnosed as an asbestos etiology may be found in women but mesothelioma. In the study by Dawson et al, are somewhat less common. In our series of cases, occupational exposure to asbestos was identified pleural plaques were found in half of the women in 51 (55%) of 93 cases for which information but in nearly three quarters of the turn. was available. This series contained a substantial Asbestosis was identified in 16% of the women numher (20) of women who were exposed to with mesothelioma compared with 24% of men. asbestos during the manufacture of gas masts The exposure histories and results of tissue during World War II. Qur cases are largely asbestos analysis in the women studied resulted med icoleaal referrals, and thus may not be repre in some interesting observations. A history of sentative oTali mesotheliomas in women in the exposure to asbestos through household contact United btates. Therefore, it is diffic.ulr ro know with an asbestos worker was found in 61% of out "the precise percentage of US women wirh cases. This type of exposure was first reported as a mesothelioma who are occupationally exposed to cause of mesothelioma by Newhousc and asbestos. Thompson in 1965,36 and Anderson ec al Considerable scientific controversy and reported 5 cases uf pleural mesothelioma in a debate has surrounded the problem of how to study of 756 household contacts of asbestos manage the large amount of asbestos presently in factory workers in 1979.JJ Gtbbs ct al reported place in public buildings in this country. One the results of tissue asbestos analysis in a series of review of this subject noted that no cases of 10 patients with mesothelioma who were house asbestos-related disease have been reported hold contacts of asbestos workers and found among individuals whose only known exposure elevated counts beyond those of a reference was as occupants of buildings with friable population in 8 of the 10 cases.M These findings asbestos-containing materials. Contrary to this are almost identical to those presented here, in assertion, two cases of pleural mesothelioma have which an elevated tissue asbestos burden was heen reported in such a setting. Stein et al noted in 10 [77%) of 13 of the household described a 54-year-old woman with pleural contacts with mesothelioma. One of die tumors mesothelioma whose only known exposure to (Case 31) was a sarcomatoid peritoneal mesothe asbestos was as an office worker in a building lioma. To our knowledge, this ;s the first case of with ceiling material composed oi 70% ainosiie peritoneal mesothelioma in a household contact asbestos.'9 Amositc asbestos fibers were identified in which an elevated pulmonary' asbestos content in samples of this patient's lung tissue. Roggli and 160 Received 04/05/2002 01:02PM in 21:10 on line till for 4QM.STOK * P( 22/37 FROM BIOMEDICAL INFORMATION SERVICE (FBI) A. 5' 02 1 2: I 6/ST. I 2-. 01/NO. 4662209470 P 72 Malignant Mesothelioma in Women Longo described a 58-year-old woman with ashesros on the pleura.45 If tumor suppressor pleural mesothelioma, pleura] plaques, and a genes are- involved in such a predisposition, then work history including 18 years as a teacher's aide in a building containing tremolite-contaminated chrysotile in ceiling tiles. Analysis oi pulmonary fiber burden demonstrated an elevated tremolite content in this patient.54 The risk of this occur rence must be extremely low when one considers a possible mechanism would be hereditary' dele tion of one copy of the suppressor gene, so that interaction of asbestos with mesothelia! cells would inactivate, or delete the single remaining copy Ad A history of asbestos exposure was elicited in _ the rarity of this association and the large 45 (76%) of 59 of our cases, and an abnormal number of individuals with presumed exposure. tissue asbestos content was found in 14 (70%) of Some mesotheliomas have no demonstrable 20 cases. The main fiber type identified was _ .association with asbestos exposure.40 In this "'commercial amphibolc (mostly amosiie)j, with regard, it is interesting that a history of thera noncommercial amoRiboles (mostly tremolite) peutic radiation to the site of subsequent'' Identified less frequently and chrysotile identified mesothelioma development was reported in five' least Recent studies have shown chat as many as of the patients in this study. One of these women SS'KToF women with mesothelioma in Australia had a brief period of only 4 years between the and 30% of women in France have a positive radiation and the diagnosis of mesothelioma but asbestos exposure history.47 44 These observations also had a strong history of household exposure have important implications for estimates of the and an elevated tissue asbestos content. We background race of mesothelioma. McDonald therefore believe that this case is asbestos related. and McDonald estimated the background rate to The other four women received radiation from 7 be one to two cases per million population per to more than 50 years piior to the development . year, based on the observed rates in worner. and of mesothelioma. The association hetween prior the authors' finding that only 5% were occupa treatment for Wilms' tumor and subsequent tionally exposed to asbestos.1 However, if half of development of mesothelioma, as seen in Case .5, rhese women are exposed, the background esti has been reported by others as well.41-1' The mate would be closer to one case per million per discovery of a Wilms' tumor suppressor gene aud year. This would amount ro an expected numberthe identification ot the gene product in a large_ of 25CTinesotlieliomas per year in rhe United proportion of mesotheliomas is fascinating45 and States. The teal number observed is ZZ00 cases may provide a lead in the study of familial or __per year, which implies that 89% ((220C hereditary predisposition to mesothelioma. The Z5017220U) arc asbestos related. In this regardTIt association between prior radiation for breast . is interesting that an elevated asbestos content cancer and subsequent development of mesothe- was observed in 89% of cases for our entire series liinna, as seen in Case 43. has also been reported (both men and women).45 previously.44 The occurrence of familial mesothelioma suggests a~gerrerlc predisposition, as already noted. Three of our cases may he examples of genetic predisposition. Two patient.-; (Cases 13 Summary and 29) belonged to families in which mesothe lioma occurred in the mother, daughter, aunt, and uncle. In another instance (Case 34), the About 6% of our cases of mesothelioma occur in women, with a median age of 59 years. father and daughter both developed mesothe Our peicciiLage is lower than other series lioma. In the present series, a history of asbestos reported in the literature because of the large exposure antl/or an elevated pulmonary asbestos fiber burden was presenr, which indicates that the genetic factor probably makes the individual more suscepcible than usual ro the effects of number of occupationally exposed men referred to our laboratory. Tumor arose in the pleura in 36% of the women in our study, and the majority were epithelial. Pleural plaques were lound in 161 Received M/05/2002 01:02PM in 21:10 on tine C11J for 40ALST0N * Pg 23/37 FROM EF0MED1CAL INFORMATION SERVICE IFRIt 4. 5' 02 12-1 V/'ST. 12:01^0.4662202470 P 23 Anatomic Parftoiogy 1997 half of the women for which this information was available, and asfcestosis was found in only 16%. A history of exposure to asbestos was identified in three quarters of the women, more than half of whom were household contacts of asbestos workers. Occupational exposure to asbestos was identified in only 19% of patients. An elevated tissue asbestos burden was noted in 70% of women from whom lung tissue was available for analysis. The main fiber type identified whs amosite, followed by tremolite and chrysoctle. These findings and those from other countries suggest a need for reassessment of the background rate of mesothelioma in industrialized nations. References 1. McDonald AD, McDonald JC. Malignant mesothe lioma in North America. Career. 1980:46: 1650-! 656, 2. Hit.erdal (J. Malignant mesothelioma 1982: review of 4710 jmblished cases. Br } Has Own. 1983;77:321-345- 3. Alberts A5, Falksun G. GnedhalsL. ct ai. Malignant pleural mesothelioma: a disease unaffected by current therapeutic maneuvers.} CtnOncoi. 1988:6:527-555. 4. Browne K, Smither WJ. Asbestos-related mesothelioma: factors discriminating between pleural and peritoneal sires. Hr j IruJMei 1985;40:145-132. He Lsjartre M, dc Lajarue AY. Mescihelioma on rhe coast c:f Brinany. France. Arm tJY Acad Sci. 1979;J30; 323-352. 6. l.emer HJ, Schoenfeld DA, Martin A, et al. Malignant mesorlrelioma: The Eastern Cooperative Oncology Giryjp (ECOG) experience- Cancer. 1983;52:1981-1985. 7. Musk AW, Dohn PJ, Armstrong BK, et al The inci dence of malignant meauillelioma in Australia, 1947 1930. Med; Australia. 1989;ISC;242- 246. 8. Rtiggll VL. Malignant mesothelioma and duration of ai.heitOs exposure: Correlation wiih tissue mineral fibre o.mtem. Ann Occup Hyg. 1995139:363-374. 9. Kuffie r, Feld R. Minkin S, et al. Diffuse malignant mesothelioma of the pleura In Ontario and Quebec: a retrospective study of 332 patients J C/rn Oncol. 1989. 7 1157-1168. 10. Trinmi T, Huuskcnen MS, Tammikhto L, ct al. Occu pational expusure to asbestos as evaluated from work histones and analysis of lung tissues from patients with mcioiiidUma. Br J fruJMed. 1991;48:48-52. 11 Vogelsang NJ. Schultz SM. .'annucci AM el al. Malig nant mesothelioma: the University jf Minnesota expe rience. Cancer. 1984;53:377-333. 12. Watnoclc ML- Lung asbestos burden in shipyard and construction worker* with mesothelioma: comparisons with burdens in subjects widr asbestusis or lung cancer. Environ Res. 1989,5068-85 13. Dawson A, Gihbs AR, Pooley FD, et al. Malignant mesothelioma tn women. Tliorcur. 1993;48:269-274- 14. Foyle A, Al-Jabi M. McCaughev WTE. Papillary peri toneal tumors in women- Am] Snrg Bfltfcof. 1981;5:241249. 15. Goldblum J. Harr WR, l_oea liied and diffuse mesorhe1tomas of the genital tract and peritoneum in women: a cliiij(juptllolugic study of nineteen true mesnthrllal neoplasms, other than adenomatoid tumors, multtcysttc mesotheliomas, and localized fibroin cumors. Am ) Surg ParW. 1955;19:1124-1137. 16. Daya D, McCaughey WTE. WcCI-differenttated papil lary mesothelioma of the peritoneum; a clinicopathologic study of 2 2 cases. Cancer 1990:65:292--296. 17. Nascimenrn AG, Keeney GL, Fletcher CDM. Deciduoid peritoneal mesothelioma: an unusual phenotype affecting young female*. Am j Sutj Pathol. 1994:18:439- 445. 18- Bollinger DJ, Wick MR, Dehner L?, ei al- Perirnneal malignant mesothelioma versus serous papillary adeno carcinoma: a hisiuchenucal and immunohistOChcmical ronpsnson. An 7 Sing Pcuhof. 1989;l 3:659-670, 19. Roggli VL. Ssnfilippo F, Shelburne JD. Mesothelioma, in: Roggli VL. Gieenberg SD. Pratt PC, cds. Pedology of Asbestos-Asscirinred Diseoses. Boston, Mass: Little, Brown; 1992:109-164. 20. R-jggli VL, Pratt PC. Asbeitosis. In: Rogeti VL. Green berg SD, Pratt PC. :ds. Pathobgy of Asbe.str.s-Assoriatfd Diseases. Boston, Miss: Little, Brown; 1992:77 108. 71 Greenbetg SD. Benign asbestos-related pleural diseases. In: Roggli VL, Greenberg SD. Pratt PC. ed. Pathology of Asheiios-Atsociaied Diseases. Boston, Mass: Little. Bio*at,; 1992:165-187. 22. Roggli VL, Pratt PC, Btody AR. Analysis of tissue mineral fiber content. In: Roggh VL, Greenberg SD, Pran PC, eds. Pathology of Asbestos-Associated Diseases. Bostuti. Mass: Little. Bmwn: 1992:299-345. 23. Roggli VL Asbestos bodies and nonasbestos femiglnoi.it bodies- li>; Roggli VL, Greenberg SD. Pratt PC. cds. Pct/wfcgy of Asiiesioj-.AssociaKd Diseases. Fiosion. Mass: Link Brown; 1992:3^-75. 24. R oggli VL. Mineral fiber conrent of lung tissue in patients with malignant mesothelioma, hi: Henderson DW, Shilkin KB, Langlois SLP, et al, eds Malignant Mcsodtelioma. New Yoik, NY; Hemisphere; 1992:201 222 25. Roggli VL, Pratt PC. Brody AR- Asbestos fiber type in malignant mesothelioma; an analytical e.eciron micro seopic study of 94 cases. Am J Jnd Med. 19P3;23;605tM, 26. Shrtihani K. Esteban JM, Bailey A. et al- tmmunopaihologie and molecular studies as an aid rn the diagnosis of malignant mesothelioma. HumPatM. 1992;23:107-116. T 62 Received 04/05/2002 01:02PH in 21:10 on line Oil for 40ALSTOH * Pa 24/37 FROM BIOMEDICAL INFORMATION SERVICE (PR!) 4 5 02 I 2 I 6/ST. 12: 01/NO 4E62209470 P 24 (Malignant Mesothelioma in Women 27. Lsndrigan PJ, Kflicmi H, edj- The third wave uf asbestos disease: exposute to asbestos in place. Ann NY .Acad Sci 1991;643:1-625- 28. Gacnslcr EA- Asbestos exposure in buildings. C/in Chen Med. 1992;13:231-241 29. Austin MB, Fechner RE Rojgli VL Flcjral malignant mesochc'.ioina following Wilms' tumor. Am / Clin Pathol. 1986;86:227-230. 30. Amman KH. Malignant mesothelioma. N Eitvf/ Med. 1983003-200-202. 31. Talonrr JA. Thurber WA, Karuor AF, et al. Asbestosassociated diseases in a cohort of cigarette-filtei workers. NEnel/Mda. 1989:321.1220-1273. II. I.c-ngo WE, Rigler MW, Slade J. Crocidolite asbestos libers in Smoke from original Kent cigaiettes. Cancer Res. 1995:55:2232-2235. ` 31. Spiiras R, Connelly RG, Tucker MA. Survival patterns for malignant mesothelioma: the SEER experience im J Cancer. 1988;41:525-530. 14. RoggU VL, Longo WE. Mineral fiber content of lung tissue in patients with environmental exposum: Iwusehold contacts v* building occupants. Ann NV Acad 5-:i1991643:511-519. 35- McDonald JC, Armstrong B, Case B, et al. Mesothe lioma end asbestos fiber type; evidence horn lung tlssje analyses. Cancer. 198S;63:1544-1547. 36. Newhouse ML, Thompson H. Mescthelionic of pleura and peritoneum folio wing exposure :0 asbestos in the London area. 6r,J fnd Med. 196S;72: 261-269. 37. Andersor HA, LJlis R, Daum S.M, ei al. Asbestosii a.-nong household eontaets of asbestos factors' workers. A..71 NY Acad Set. 1979;330:387-399. JB Gibbs AR, Griffiths DM. Pooler FD, et al. Compar ison or fibre types and site distribution: in lung tissues of paiaoccupational and occupational cases of malignant mesorheboma. BtJ fnd Med. 1990:47:611 626.' 39. Stein RC, Kitujewssa JY. Kirkham JB. et al. Flcural ii.esothelicma resulting from exposure ro amojite asbestos in a building. Ifespir Med. 1989;83;237- 239. 40. Peterson JT. Greenberg SD. Buffler PA- Nrm-ashestnerehtci! malignant mesothelioma: a review. Cancer. 1984:54:951-960 41. Ancman KH. Ruxer RL AisnwJ. rr al Mesothelioma following Wilms' tumor tn childhood. Cancer. 1984:54: 367-369 42. Anderson KA, Horley WC. Hurley BT, et at. Mai goant pleural mesothelioma following radiotherapy in a 16year-old hoy. Cancer. 1985;56:273-276. 43. Amin KM. Liidry LA, Smythe WR, et al. Wilms' tumor 1 susceptibility fWTl) gene prnduers are selectively expressed in malignant mesothelioma. Am / fWiol. I995;146:344-JS6. 44. Shannon VR, Nesbitt JC, Libshitz HI. Malignant pleural mesothelioma after radiation therapy (or breast cancer: a report of two additional patients. Cancer. 1995,-76:437-4^1. 43. Hammar SF, Boc<us D. Remington F. et ai. Familial mesorhelioma: a -eport of two fair.i.ies. Hum Radio1.. 1989;iai07-:l2- 46. Lynch HT, Anton-Culver H, Kurosaki T. Is there a genetic predisposition ro malignant mesothelioma.' In: Janraml IA-C Bignon J, eds. The Mtioihelicl Cell and Mesothelioma. New York, NY: Marcel Dekker; 1994: 47-69. 47- Leigh J. Malignant mesothelioma in Australia !9fl2-l994. Prrsenied at the Inrernational Mesothe lioma Interest Group, Third International Mesorhe lioma Conference; September 12-15, 1995; Crdteil. France. 48 Iwatsubu Y. Bignon J, Boutin C, et al. Fast exposure to asbestos and pleural mesothelioma: dose-response rela tionship. Presented at the International Mesothelioma Interest Group, Third international Mesothelioma Conference; September 12-15, 1995, CicLcl [, France. 49. SrrhnsSH, Koggii VL. Sumsu CF. M.i lignum: mesothe liutna associated with low pulmonary tissue asbestos burdens: a light and scanning electron microscopic analysis of 18 cases. Mod Fadiol. 1995;8:614-621. 50. Roggli VL. Scanning electron micnrseopic analysis of mineral fibers in human lungs- In: Ingram P, Shelburne JD, Roggli VL, eds. Mieroprobr Analysis in Meditine. New York, NY: Hemisphere; 1969:97-1 !0, 1 163