Document 4J003ORVK1kYXBLZodpenbMBj
Malignant Mesothelioma in Japan: Analysis of Registered Autopsy Cases
yoshihiromurai
Department of Pathology faculty of Medicine Toyama: Medical and Pharmaceutical University Toyama, Japan
' ABSTRACT,: In the Annua/ of the fothological Autopsy Cases in Japan, issued by the Japan ese Society offafoofogy from 1958 to 1996, a total of 1,846 (Q.17%) malignant mesothe lioma ewes <1,287 male, 558 female, 1 unknown) were registered among 1,056,259 autop-
: sy cases. The frequency of mesothelioma (number of cases/tolat autopsy cases) war 0.10% (461/440,934) for the term 1958-1979,0.18% <716/390,124) for 1980-1999, and 8.30% (669/225,801) for 1990-1396; the frequency of cases increased significantly over (be time
v periods (jp < .0001). Among 1,785 cases for which tumor sites were ascertained, there were 1,213 pteuiaf- mesothelioma (68.0%), 431 peritoneal (24.1%), 108 pericardial (6,1%), 6 tunica vaginalis testis. (0,3%), and 28''others'' (1.6%). Histological cell type was notedin
. 58cases; 245 (41.0%)were epithelial, 168 (28.1%)werebipha5ic, and ias (30.9%) were sarcomatous. Seventy-three(0.007%) cases ofmalignant mesothelioma with asbesfosis were found during the entire 39y period. The frequency of those with ashestosis (number of cases/total autopsy cases) was 0.301% (5/44(1,334).for the term 1958-1979, 0.006% (277390,124) for 1989-19B9, and 0.018% (41/235,601) for 1990-1996; fob increase over time was statistically significant (p c .0001). Researchers expect that cates of asbestos-retat-
: ed mesothelioma wsll Increase in Japan In the future. Tumor sites and hfstologlcal cell types
of mesothelioma with asbestoses did not differ from those in individuals without asbestos!*,
:<Key words: asbestos; asbestosis, histological cell type, malignant nvesothefioroa>
:
MALIGNANT MESOTHELIOMA originates from "" Serosal cells of the pleural, peritoneal, and pericardial cavities, and framtbe tunica vaginalis testis. Since Wag ner et aU reported mesotheliomas from asbestos expo sure in South Africa in I960, many researchers have subsequently confirmed his conclusions, in Japan, con sumption or asbestos has increased, markedly since World War II, and it is one of the leading consumers in the world. - ; - - - - " ""
Since T958, autopsy cases in Japan have been regis tered in the Annual ofthe PathologicalAutopsy Cases fn Japan (hereinafter Annuafi by the Japanese Society of Pathology, Baba1 surveyed the annuals from 1974 through 19B0 and reported that although there were no pleural malignant mesotheliomas associated with asbestosis until 1977, there was 1 death in 1928, 3 in 1979, and 2 in 1980. His report suggests that the num
ber of occupational pleural malignant mesotheliomas has begun to increase in Japan, in this study, we sought to extend the survey of the Annuals and to elucidate foe features of malignant mesothelioma with asbestosis.
Materials and Method
The Annuals of the Pathological Autopsy Cases in Japan (years 1958-1996) by the Japanese Society of Pbthology were used. Until the annual for 1996 Was issued, a total of 1,846 (1,287 male, 558 female, 1 unknown) autopsy: cases with: malignant mesothelioma had been recorded among 1,056,259 autopsy cases. Thisdocumentation is- a passive system-for the record* tng of autopsy reports received from individual pathol ogists; no confirmatory reviews are provided- Tissue slides are not sent, in andarchived. Some diagnoses.
84
[j3:NOTie&lTHiS MATFiPilAli taAV BE BBOJIKCiTclr
ArchimofEnvironmenui Health
BY .OOPYRlfittT.LA%' (TI.Ti.ii 17
.
if
Table 4.--Frequency of Malignant Mesothelioma among Autopsy Case*
. ..: : o:-v;.
Mesothelioma
::: no-:: --I-- (if-autopsy
No;:;:: < No. --:
:: ;. Years-::.".:.":: - - Malls- ; Female -.r:-- Both - - rases- - Percentage : auto[Mies. -. - deaths ;;
..: .
s
1
.-'.Vy
: 1958-19S9 : 1960-1964 "
1965-1969 .197.0-1-9-74; . 1975-4979 : 1985-1989
1980-1964 1990-5994
1995-1996: ; Overall
1938-1979
1980-1989 :: 1990^1996
. 13-' -44: - -
8 17
21 61..
19,336 68,039
61 - 38
96
104,736
90 43 .. 133
112,905
97 53
150
135,298
278 137 - 415
197,249
210 90
301 It}* 192.875
335 120
455
169,345
162 1,287
52 214
56,456
550 . :f,846 (1:)*:: 1,056,259
302 159
461
-440)334
408 - 227 , :: 716 [lit-; :-!-390,t24
497 172
669
225,801
) -r:0:i:t> ;; 10,638
23,299 i: 45.7
0.09
4).;2;M:
98,839
43.8
0.09
77,274
165,791
46,6
0.12
89,463
240,446 - 37,2:--
- 0,11
117,910
325,676 ::35,6-
021
180895
6B2369
26,5
0.16
171,297
513,648
33.3
0,27
152,576
820,622
18.6
0-38
50,962 : 365,325 :-;f3.9-
0.1) ::::J94,27l:-- 3,240,015
27.6:
0,10)
338,541
858,051
39.5
-oiat::: 352,192 1,196,017
29.;+.-:-
O30f
203,538 1,185,947
17.2
rihe lUmn&etini parentheses Is (he: cSsefar.wftCirn "sex was not known.
^ =316751, pK.0001.
.
however, of mesothelioma have been confirmed by a panel or by consultation because mesothelioma i s a difficuh diagnosis.
The age, sex, clinical diagnosis, residence area, occu
pation, main pathological lesions, and some additional lesions are recorded in each Annua/, Malignant
mesotheliomas are regarded as the main pathological lesions, independent of tumor size. The space for the description of occupational history in the Annual is
restricted in that only the main or most recent occupa
tion js described, Tire life employment system has been
relatively maintained in Japan-
^
Thefrequency of malignant mesotheliomas and those
with asbestosis in autopsy cases in each of the three
terms--1956-1979 (22 y), 198CM9&9 (Hi y), and
1990-1996 (7 y)--as well as the change over lime,
were examined. We used the Chi-square test for stalls-
deal evaluations........ .
Results
Table 2.--Age and Sex Distribution of Malignant Mesothelioma Cate;
Ageiyl
Mate -,., n '%
Female. %
Total ;: %;;
Ot.9 : : ; a;- 0.6 3 :- : 0.5
u - - 0:6
10-19
4 0.3 2 0.4 :
6 013
20-29
33 1A :. .1:6 219- :: 49 2.7
30-39
so 3:9; 20 , 9.6 .. 70 . 3.8
4(M9
149 11,6 - < 53 - 9,5 202 11,0
;50^O: :; - 298 23.2 112 20.1 410 :, 223
60-69
374 29.1 170.: 30.5 544 29.5
-70^79-----
275 . 21-4 129 23.1 404 21-9
80-89
92 7,2 49 8.6 141 7.7
a 90
2 OJ 4 0.7
6 0,3
Overall 1,285 lOOiO: 358 1000 1,843 100.0
Mole.; The: ages of'3 peases:and the sax 61:1 cMe-vvere not
known.::;.
. v':s;.
The frequency of malignant mesothelioma (number
were categorized into four groups, relative to asbestos
of cases/total number of autopsy cases) was 0.17%
exposure:. (1) definite,1 (2) probable -or possible, (3)
(1,846/1,056,259) for the entile 39-y period from 1958
uncertain, or (4) unlikely (Table 3), Twenty-six cases in
I
to 1996 (Table ih The comparison over the three peri
the definite group were employed in asbestos-process
ods revealed a significant increase in the frequency of
ing plants. Among the 226 cases in the probable or pos
i
mesothelioma, from 0,10% (461/440,354) in 1958
sible-group, 96 had worked in the construction indus
1979, to 0.18% (716/390,124) In 1980-1989, to 0.30%
try, 33 had beet) shipyard workers, 31 metal workers,
(669/225,001) in 1990-1996 (^ = 216.75,1, p < .0001).
24 electricians, 22 railroad workers, 17 pipefitters, and
The age and sex distributions are shown in Table 2.
3 boilermen. Company workers, farmers, and factory
Seventy-four percent of all cases were between 50 y
workers were included in the uncertain group. Some
and 79 y of age, and the highest frequency of mal ignant
farmers held side jobs during the "leisure season" for
mesothelioma was found in both sexes in the 60-69 y
farmers In japan. On the other hand, there were many
age range. There were 17 (0*9%) cases under the age of
cases that belonged to the unlikely group; and asbestos
19 y.
exposure could not be identified only by their occupa
Among the 1,846 mesothelioma cases, occupational
tions, Housewives, schoolteachers, medical doctors,
histories were not described for 651 of them. Special
nurses, and clergy were Included:
attention was not given to asbestos exposure in ell
Tumor sites of 1,785 cases were noted in the Annual
mesothelioma cases. The occupations of 1,285 cases
(Table 4). There were 1,213 (68.0%) pleural mesothe-
Janiury/Febraaiy 2001 IVoL 56 (Mo. 1)]
as
f
I
il
TableT.--Occupational Histurte* of Malignant
Mesothelioma Cases
: . ;...............
Occupational
exposure to . -.NO* Of:..;
eshestoi
Ci&&
Occupation
Definite
26 worker: in asbestosprocessing -i
plant ( = 26), sbe*tns insula-
tioh wodter1tT*2)<
'
Probableor possible
226 Worker In construction industry (ft * 96), shipyard worker fn * 33), metal worker to *-31), elec trician tn 24), railroad worker t - 22), pipefitter (n = l7>, boJlorman<fl-3)
Uncertain . . 455
Company worker (n * 201), farmer, (ft *79), factory worker (n= 46), driver (r>*36), self-employed shop w *24), miners to =9), shlpman (it-- 7), faunrfryman (n * 6), other to *= 47)
Unlikely .
576 Housewife (n * 228), workers in feodanddfink service industry
In * 50), clerk <ri * 47), school teacher (n * 39), public servant
(in =27). medical doctor (n = 112, workerin elcthes-servlce . . industry (rt w.B); nurse (ft * 6), :::,7 religionist pi = 6), Sfatfeht pi-
policeman: (r 6),Other(rj * 142)
liomas, 431 (24,1%) peritoneal mesotheliomas, and 108 (6.1%) pericardial mesotheliomas. Six (03%) mesothe liomas arose from the tunica, vaginalis testis. Pleural mesotheliomas were predominant m both sexes; howev er; toe frequency in males (72,7%) was higher than that in females (56.9%}, On the contrary, the frequency of peritoneal mesothelioma in females (35.3%) was higher than that in males (19.3%>. The male to female ratio for each tumor site was also calculated and appears in Table 4. The ratios (male/female) of the pleural and peritoneal mesotheliomas were 3.0 and 13, respectively.
Histological cell types of 398 mesotheliomas were : ascertained in the Mntra/; and there were 24S (41.0%) epithelial, t$8 (28.1%) btphaslc, and 185 (30.9%) sar comatous types (Table 5). The frequency of epithelial ceFI type in peritoneal mesothelioma (52,4%) was high er than those in toe other tumor sites.
Of all 1,846 mesothelioma cases, 73 cases were :: accompanied with asbestosis (Table 6). The prevalence ....of asbestosis was higher among mesothelioma cases
(3,95%; 73/1846) than in toe overall data system (5,05%; 525/1 G56>259). The first peritoneal and pleural mesotheliomas with asbestosis were found in 1976 and in 1978, respectively. The frequency of malignant mesotheliomas with asbestosis (number of cases/total autppsy cases) was 0.001% (5/440,334) for the term 1958-1979, 0.006% (27/390,124) for 1980-1989, and 0.018% (41/225,801) for 1990-1996. There was a sig nificant increase during ali three periods i%2 = 62,582,
p < .0001). The tumor sits were ascertained in 71 cases, and there were $0 (70.4%) pleural and 18 (25,4%) peritoneal mesotheliomas. Histological cell typos of mesotheliomas with asbestosis were obtained In 40. cases. The epitheflal cell type was predominant (18 cases [45.0%]); the? next most-frequent cell type was biphasic (12 cases [25.07a]), followed by sarcomatous (10 cases [30.0%j).
Discussion
T&kahashi et al.J reported that recent mesothelioma incidence among the 10 Westpfn countries and Japan ranged between 5 (Japan) and 25 (Australia), with a : median of 15 per one million: per year (United States). They speculated that the asbestos consumption curve for . Japan in past years lagged behind that for Western coum tries, and that toe cumulative exposure effect has not yet reached toe level that cah be expected from other coun tries. In-autopsy cases, the frequency (0,17%) of mesothelioma in this survey (1958-1996) was also lower than that of Western countries.4'5 Hartmann and Schutzd* reported 106 cases of pleural mesothelioma among 33,500 autopy cases (032%) from 1957 to 1987 in Germany. GiaretH et ah5 reported 170 cases of malig-
Tabic *.--Tumor Sites ^ Malignant MMOtfidtoma
Mate
female
Total
Site
rt % n %
n
Mate:Femaie
Pfeur^i
906
Peritoneum
.
241
Pericardium
76
Tunica vaginalis testis
6
Pleura and peritoneum
6
:Pleura; and pericardium
5
Mediastinum
4
Diaphragm
1
Overall
1.247
72.7 306 56.9
193 190 35.3
6.1 32
5.9
0.5 ` ivi,.
0.6 0.4
21
0.2 0.4
0.3 7
T.3
0.1 100.0
yfSP:
tOQ.0
1,213* 431 106
6 9 "7 11 1 1,785
68.0
24,1 6.1 0,3 0.5 0.4 0.6 0.1
100.0
3JO 13 2+
6.0 2,5 . 0,6
2.3
The sex: of I pleural case w*6 not known.
8b , Archive* of Environmental Health
Tattle 5.--Histological CettTVpe of Malignant Mesotheliomas
- ;Sirconia-.::. Epithelial :::8iphaslc /(toys;?
>: (Site'. : -: fti:%=: . rt: ?(%..:
Total n%
Pleura
155 37,4 T15 27.8 144 34,8 414 fQ0,6
'Peritoneum 66 52.4 37 294 23 l63 126 100*0
Pericardium T8 40.6 10 27.0 9 24.3 37 100.0
other
6 28,6 6 28,6 9 47.9 21 100.0
Overall 245 41.0 168 28,1 185 303 598 1000
Tablet.--Description of Malignant Mesotheliomas Accompanied by Awestasis
><*
VOar
n&:d(cases' : . .total cases: \.
autopsted: - Percentage' ,
19SEM979 :: 1980-1989
1990-1996 ; .,1958-1996,
ftwjueocv
5/ 440,334 27/ 390.124 41/ 225,801 ... 73/1.056,259
0.001* 0.007* flOfO* ,0.007
-
Site .
Nd*o( cases
Percentage
. .Pleura, /.;
-
. Peritoneum -
Pleura and peritoneum
Mediastinum
Overall
Tumor site
vsv/.
50 16
2 .1:::71
. ' ;:; -
70.4 25.4
2.8 1.4 100.0
Celt type
Epithelial Biphasic ::(Sarcomatous
Overall
;
..... No. of eases
Percentage
Histologialcell type
18 12 10 40
.*
45.0 25.0 30.0 100.0
.
*Xl*:62-J82vj?<-.OOOT.
naht pleural mesothelioma among 40,826 autopsy cases <0.42%) during iheperiod 1969-1967 In Ifety. Compared with Western countries, there would foe a time Jag in the increase of mesotheliomas in Japan* The frequency for the term 1990-1936 fie., 0.3%) from Japanese autopsies was three times higher than that for 1358-1373 (i.e., 0.1 %). Present consumption of asbestos in Japan remains: high, and we expectthat asbestos-related mesotheliomas will increase in the future. ... In our study,, the .most common site of mesothelioma was pleura, followed by peritoneum, and pericardium. Mesothelioma of the tunica vaginalis testis was very rare. Hlllerdal* reviewed 4,710 cases of mesothelioma, and .88*8% of: the cases: were pleural in origin, 9.$% were peritoneal, 0.6% were pleural and peritoneal,
Jinuaiy/Februaty 1001 [Voi. 56 (No. 18
0,7% were pericardial, 0.2% were Irt the tunica vagi
nalis testis, and 0.1% occurred at an undetermined site.
The frequency (68.0%) of pfeuraf mesothelioma in
Japan is relatively low. Perhaps asbestos-related
mesothelioma may occur most frequently in pleura;
therefore, it may reflect the different cumulative expo
sure effect between Japan and Western countries* This
speculation is supported by the Fact that pleural
mesothelioma is more common in males than females*
Males have more opportunities to. be exposed to
asbestos by virtue of their occupations. However, in the
cases of malignant mesothelioma with asbeslosis, the
frequency of pleural mesothelioma is not so different
from those without asbestosis. The frequency of peri
toneal cases in asbestos-related mesotheliomas may be
higher in those with asbestosis (i.e., highly exposed
asbestos cases) than in the cases with lower asbestos
exposure, because a certain quantity of asbestos fibers
may need to reach the peritoneum.
Mesotheliomas are commonly diagnosed between
the ages of 50 y and 79 y. In our study, however, there
were a few cases under 19 y of age* Special attention
should be given to; childhood mesothelioma, whether::
or not it is diagnosed correctly. In the 22 childhood
cases Fra ire eta!/ reviewed, 45% of them were accept
ed as mesothelioma, and 14% were of "doubtful or
uncertain nature" in the remaining 41 %, the diagnosis
of mesothelioma was rejected. Given that the diagnosis
of mesothelioma in recent years has become more
accurate as a result of the development of immunohis-
tochemical staining, investigators must accumulate
more data concerning mesothelioma arid Its relation
ship with:asbestos exposu re* A few childhood mesothe-:
lioma patients were reportedly exposed to asbestos;
however, most cases had no such exposure.7 it js said
that asbestosrrelated mesothelioma needs: a long laten
cy period from the beginning of the asbestos exposure
to the time the tumor is manifested. Therefore, the exis
tence of childhood mesothelioma may foe one reason
why researchers do not attribute all mesotheliomas to
asbestos exposure,
.
The most common etiologic factor of mesothelioma
is asbestos. Other factors reported are erionite, radia
tion,9 chronic inflammation,10 among others.11 Investi
gators confirmed by animal experiment that SV4Q virus
caused mesothelioma in the hamster,13 McDonald and
McDonald13 reported that in approximately one-half of
the male mesothelioma cases, no potential for occupa tional-asbestos exposure could be identified* Other
.researchers have reported various percentages (i.e.,
0-87%) of cases for which asbestos exposure was not
documented-11 In our earlier report,1 we evaluated
asbestos body counts in the lungs of 27 malignant
mesothelioma cases, and approximately one-half of
mesothelioma cases had counts of more than 151
asbestos bodies per 5 gram;wet lung: tissue; thus indi
cating occupational asbestos exposure. In the current
study, the frequency of the patients who were clearly
identified as having asbestos exposure was not very'
high- However, we note, that all occupational records
related to asbestos exposure have not been described in
87
the Annuals. In addition, the Absence of proof of asbestos exposure does not constitute a lack of proba bility that die epidemic, of mesothelioma in Japan has resulted from asbestos. One must consider that asbestos-induced malignant mesotheliomas may result from nonoccupationaf exposure to asbestos. It is report ed that bystander and consumer exposures ate the "thi rd wave" of Asbestos di sease playing out now,,s
Three main hlstologitat types are recognized in mesothelioma: (1) epithelial, (2) sarcomatous, and (3) biphssic. Hiflerdaf6 reported that the epithelial type (50%) was die most common in 829 pleural mesothe lioma cases; the next most-frequent type was biphasic (34%), followed by sarcomatous (76%). Roggli et a!.17 sported thO following:histologlcal cell types from-200 cases of malignant pleural mesothelioma: epithelial (40%), biphaslc (37%), and sarcomatous (23%), In our: survey, the histological type that occurred most fre quently (41,0%) was epithelial; however, the frequency of btphasic 28.1%) and sarcomatous (30,9%) cell types was the opposite of that reported by Roggli et aL17
Whether specific histological cell types of mesothe-
iiomas are related to asbestos exposure remains uncer tain. Magner and McDonald1 suggested that mixed mesothclial tumors were specifically associated with
asbestos exposure, Leigh et ah19 reported there was a significant correlation in iung fiber content with celt type from epithelial (i.e., low fiber content} through mixed to sarcomatous (i.e., high fibercontent), Howev er, Hirsh et al,jB reported that the proportion of epithe lial mesothelioma: type in the group with definite past asbestos exposure was higher than that in the group that was unexposed to asbestos. On the other hand, Wright and Sherwin71 concluded that their data did not support the hypothesis that any specific histological type qf
mesothelioma is especially related to asbestos expo sure. Although only mesotheliomas with asbestosis were selected in this study, our data support the-con clusion posited by Wright and Sherwin.71
i * *' *. *':*"* *; :
.
vf:. The authors: thank all of those who contributed to the Annual of lhe lithological Autopsy Casas Ih Japan. . - ... . Submitted far publ Icatjon July 21, .1999; revised; accepted for publicatipn March 29, 2000. Requests for reprints should be sent to Or. Yoshihiro Murai; Departmerit of fethology, Faculty of:Medlcine,::Toyama: Medical and PharmaceuUcat University, 2630 Sugitani, Toyama, 930-0194 Japan.
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M. Arcidves of Environmental Health-