Asbestos Related Malignancies
University of British Columbia
Table 1: Malignancies Associated or Claimed to be Associated with Asbestos Exposure
|Association Accepted ||Association Doubtful|
|Carcinoma of the lung|
|Carcinoma of the oropharynx |
Carcinoma of the esophagus, stomach, colon
Carcinoma of the kidney
Carcinoma of the ovary
Carcinoma of the larynx
Asbestos-Induced Lung Cancer
Epidemiologic and experimental analyses of the relationship between asbestos
exposure and lung cancer: A large number of epidemiologic studies have established a definite
relationship between heavy asbestos exposure and an excess risk of lung
. The latency period (time between first exposure and the appearance of disease) is
relatively long: increases in lung cancer incidence do not appear until about 10 years after first
exposure, and the peak incidence occurs around 30 years after first exposure .
At these high occupational exposure levels lung cancer incidence is in general a linear function of
cumulative exposure. Even with high exposures, there are quite marked differences in lung cancer
incidence by type of industry,with the lowest rates seen in chrysotile mining and milling and chrysotile
friction products manufacture; greater rates in cement and mixed products work; and very high rates in
chrysotile textile workers . The latter may reflect use of long fibers and consequently greater
incidences of asbestosis. Additionally there is evidence that exposure to amphiboles (amosite and
crocidolite) increases the risk of lung cancer compared to exposure to chrysotile. A recent statistical
analysis  suggests that the difference between chrysotile and amphiboles is in the range of 10 to 50
fold for a given fiber dose.
Virtually all asbestos-related lung cancers occur in cigarette smokers, although some studies show an
excess risk for nonsmokers as well
. Excess risk appears to be confined to those with heavy
exposure (many of whom have asbestosis), and in this setting most studies show that the combination of
cigarette smoke and asbestos produces a more than additive risk and in some instances a clearly
Table 2: Relative risk of dying of lung cancer in asbestos insulation workers 
|Group ||Relative Risk|
|Nonsmokers, no asbestos exposure || 1.00|
|Nonsmokers with asbestos exposure || 5.17|
|Smokers, no asbestos exposure ||10.85|
|Smokers with asbestos exposure ||53.24|
There is general agreement about the data just discussed, but there is marked disagreement about the
circumstances in which one can associate a lung cancer with asbestos exposure. Broadly speaking, there
are three schools of thought on this issue: 1) Risk of lung cancer is increased with any exposure to
asbestos, no matter how small 2) Risk is only increased with a relatively high level exposure, an
exposure in the range that produces asbestosis, but asbestosis itself is not required; 3) Only asbestosis
Theory one, that any exposure to asbestos increases lung cancer risk, is based in large part on
observations in experimental tissue culture systems, because asbestos is able, under certain conditions,
to damage DNA or to affect cell proliferation. This theory also depends on extrapolations of dose
response curves from the high exposure levels where actual increases in lung cancer risk have actually
been found, to exposure levels several orders of magnitude less; ie, low level exposures where no
increases in rates have actually been demonstrated, and there is considerable doubt that such
extrapolations are valid.
In contrast, several recent studies have shown that quite significant levels of exposure fail to
increase lung cancer risk. Camus et al  examined women who lived in the Quebec chrysotile mining
townships but did not work in the chrysotile mining and milling industry. Because of environmental
contamination these women were estimated to have received cumulative exposures of about 100 fiber/cc-yrs,
(an amount at the bottom of the asbestosis-risk range) but they had no increased risk of lung cancer.
Similarly, Liddell et al  examined lung cancer risk in those employed in the Quebec chrysotile mining
and milling industry and found no increased risk of lung cancer below an exposure of about 800 to 1000
Theory number two states, in effect, that asbestos-induced lung cancers do not appear until a
threshold cumulative exposure has been reached and that this threshold cumulative exposure is in the
range required to produce asbestosis. There is considerable epidemiologic support for this theory
. Since the level of exposure required to produce asbestosis is quite high, these
observations support a requirement for high exposure as a minimum condition for the development of lung
However, various animal and human studies support the idea that it is actually asbestosis and not
just high exposure by itself that increases risk. Animal experiments show that increases in lung cancer
rates require very long high level exposure to asbestos and that tumors only appear when there is
abnormal fibrosis (asbestosis); fibers that do not cause fibrosis do not cause cancers . In humans
there is no doubt that the presence of asbestosis increases the risk of developing lung cancer. In older
series of workers receiving compensation for asbestosis, lung cancers were seen in an average of 30% of
deaths. More recently Weiss  analyzed 38 worker cohorts and demonstrated a strong correlation between
excess (above that expected from smoking) lung cancer rate and asbestosis rate.
There are two retrospective pathology studies which shed light on this issue. Kipen et al  and
Newhouse et al  evaluated the lungs of workers who had heavy asbestos exposure. Cases were selected
because they had lung cancer, and the presence or absence of asbestosis noted. Histologic asbestosis was
documented in 100% and 90% of the cases. Thus these data indicate that the presence of asbestosis
accounts for all the excess lung cancer risk.
Even more interesting are two prospective studies in which data on both the presence or absence of
asbestosis and cumulative exposure exist. Hughes and Weill  examined asbestos cement workers using
chest radiographs and Sluis-Cremer and Bezuidenhout  documented asbestosis in autopsy lungs from
amosite asbestos miners. In both studies increased lung cancer rates were found only in the presence of
asbestosis (Table 3). These studies also provided data on measured cumulative asbestos exposure, but
cumulative exposure did not account for the presence or absence of lung cancer. Thus these data strongly
support the idea that asbestosis is required to link a lung cancer to asbestos exposure.
Table 3: Relationship of Asbestosis and Lung Cancer in Two Prospective Studies
|Report ||Asbestosis ||SMR ||Significant Increase?|
|Hughes & Weill |
Chest x-ray asbestos cement workers
|Sluis-Cremer & Bezuidenhout |
Autopsy pathology - amosite asbestos miners
Practical approach for the pathologist
Pathologists are commonly asked
to determine whether a lung cancer is caused by asbestos exposure. As indicated above, the weight of the
evidence suggests that a lung cancer should be attributed to asbestos exposure only if asbestosis is
present, either radiographically or pathologically (the pathologic features of asbestosis are discussed
by Victor Roggli in this symposium and will not be repeated here).
There is considerable discussion in the literature about whether histologic subtype and tumor
location provide any useful information for attribution. One can find claims in the literature that
asbestos-induced carcinomas are more frequent in the lower lobes, but equal numbers of claims that they
are more frequent in the upper lobes. Similarly, the literature supports and denies the idea that
asbestos-related carcinomas are peripheral rather than central.
The same types of contradictions apply to attempts to use histologic subtype for attribution, with
reports claiming that one or another histologic type of tumor is or is not increased. A number of years
ago I compiled a listing of the frequency of different cell types in asbestos workers with lung cancer
from different reports; overall there was no difference compared to nonexposed individuals . Thus I
do not believe that either tumor location or tumor cell type are of any use in this situation.
A few claims exist in the literature that the presence of k-ras mutations can be used to determine
which lung cancers are caused by asbestos exposure. Given the high frequency of k-ras mutations in
non-small cell lung cancers from ordinary cigarette smokers, this approach does not appear to be useful.
In the United States the current incidence of mesothelioma is
about 20/million in men and 2 to 3/million in women . In men incidence rates have increased steadily
over the last 30 to 40 years, but in women incidence rates are essentially unchanged over this period.
These differences are believed to reflect gender differences in asbestos exposure. Recent data from the
SEER cohort  indicate that the peak incidence rate for mesothelioma was reached in the US in the
early 1990's and that there is now a slow decline, a phenomenon that probably reflects decreasing
amphibole use starting in the 1970's .
Location of Tumors
The majority of mesotheliomas are pleural in origin,
followed by peritoneal primaries; pericardial and tunica vaginalis primaries are rare. For men, the
ratio of pleural:peritoneal tumors in the US is about 9:1, but for women only 2:1 . This difference
probably reflects the additional tumors produced in men in the pleural cavity by asbestos exposure. The
same histologic patterns are seen in all locations, although sarcomatous lesions are relatively uncommon
in the peritoneal cavity.
Asbestos: By far the most
extensively investigated etiology is asbestos exposure. A report by Spirtas et al  using data from
a set of cancer registries in the United States concluded that asbestos exposure was the cause of 90% of
the pleural tumors, and about 60% of the peritoneal tumors in men, but only about 20% of all
mesotheliomas in women. Other countries where amphibole use was extensive have higher rates and a
greater proportion of asbestos associated tumors in women; however, in all studies some proportion of
mesotheliomas are not associated with asbestos exposure.
Mesotheliomas typically are seen in workers who had significant amphibole asbestos exposure,
particularly pipefitters and insulators, shipyard workers, amphibole asbestos miners, and individual
working in factories that used amphibole or mixtures of amphiboles and chrysotile. Construction workers
of many types also have been shown to have an increased risk. Pleural mesotheliomas may occur as a
result of household contact exposure such as washing amphibole-asbestos contaminated workclothes.
Exposure to chrysotile asbestos carries a much lower risk of pleural mesothelioma and enormous doses of
chrysotile are required before mesotheliomas develop. Hodgson and Darnton  estimated that the
relative risk is 1 (chrysotile): 100 (amosite): 500 (crocidolite). Peritoneal mesotheliomas are only
associated with high level amphibole exposure.
The latency period for mesothelioma after asbestos exposure is long, with a mean value of 30 to 40
years ; latencies less than 20 years are uncommon and even with heavy amphibole exposure
mesotheliomas rarely if ever occur within about 15 years of first exposure .
Other causes of mesothelioma
A few cases of mesothelioma have been
reported in persons who received therapeutic radiation as treatment for a malignant neoplasm ,
although a recent epidemiologic survey has challenged the idea that therapeutic radiation actually
increases mesothelioma risk . A handful of cases have been reported after plombage therapy for
tuberculosis. In Turkey a high incidence mesothelioma is seen in villages where the soil and rocks
contain an asbestos-sized (but not asbestos) biopersistent fiber called erionite . It has also been
proposed that Simian Virus 40 (SV40) contamination of polio vaccines in the 1950's might have lead to
widespread infection of the population and a subsequent role for SV40 in human mesotheliomas. While
there is increasing evidence that SV40 genomic sequences can be found in some mesotheliomas,
epidemiologic studies have failed to show an increased risk in individuals believed to have received SV40
contaminated polio vaccines . At this point the association of SV40 and human mesothelioma, if any,
Short summary of pathologic features
The pathologic features of
asbestos-induced malignant mesothelioma and mesothelioma induced by other agents are identical. This
talk will only briefly mention a few important points but considerable detail is provided in the general
references at the beginning of the reference list:
1) Gross findings
Mesothelioma typically surrounds viscera (lung or
bowel) and invades from the external surface. The presence of diffuse tumor on a serosal membrane and
the absence of a solid organ primary are crucial pieces of information for the diagnosis of mesothelioma.
This information can be obtained from radiographic report, operative reports, or surgical specimens.
Although most mesotheliomas have a distinctive appearance, far greater diagnostic accuracy results if the
pathologist has information available on tumor distribution.
2) Microscopic findings
A wide variety of microscopical appearances are
seen in mesotheliomas. In a broad sense they may be divided into epitheial, sarcomatous, and mixed
epithelial and sarcomatous forms, and this distinction is useful because survival is best in the
epithelial forms and worst in the sarcomatous forms.. Within each of these categories there are numerous
morphologic variants but their importance is purely one of recognition for diagnosis; the different
variants have no independant prognostic implications.
3) Immunohistochemical findings
This is a confusing topic because of the
vast number of stains which have been proposed as shown in Table 4. However, the literature needs to be
examined with caution and a certain amount of testing is required to see what stains work in one's own
Table 4: Histochemical and Immunnohistochemical Techniques for the Diagnosis of Mesothelioma
|Digested PAS ||+ || -|
Intermediate Filament Stains
|Cytokeratin ||+ ||+|
|Vimentin ||+/- ||+|
|Cytokeratin 5/6 ||- ||+|
|CEA ||+ ||-|
|B72.3 ||+ ||-|
|LeuM1 ||+ ||-|
|BEREP4 ||+ ||-|
|MOC31 ||+ ||-|
|Thyroid transcription factor ||+ ||-|
|Calretinin ||- ||+|
|WT-1 ||- ||+|
Practical approach for the pathologist
Pathologists often worry about whether a patient has a history of asbestos exposure when dealing
with a case that might be a mesothelioma. As indicated in the foregoing discussion, mesotheliomas occur
in persons who have had asbestos exposure and those who did not; the importance of a history of exposure
to asbestos is in assigning causation to a given tumor. However, a history of
exposure to asbestos is of no importance in diagnosis: diagnosis depends only on the gross, microscopic,
and special technique observations, as it does with any other tumor.
This presentation considers only carcinoma of the lung and malignant mesothelioma. The various
associations listed under the Association Doubtful column in Tabel 1 are generally not accepted, and are
clearly confounded by exposures to other known carcinogens, particularly alcohol and cigarette smoke, and
likely confounded well as by misclassification of mesotheliomas (for intra-abdominal tumors). These
issues are purely epidemiologic and there are no pathologic features in a given case that could be used
to support an association, even if one existed. Reviews of the various topics in Association Doubtful
are listed in references:
(can be consulted for additional references and greater
|Churg A: Neoplastic asbestos induced disease. In, Churg A, Green FHY: Pathology of Occupational Lung Disease, 2nd Edition. Baltimore, Williams and Wilkins, 1998.|
|Churg A, Green FHY: Occupational Lung Disease, in Thurlbeck=s Pathology of the Lung, 3rd Edition. Edited by Churg A, Myers J, Tazelaar H, Wright JL. New York, Thieme Medical Publishers, in press.|
|Battifora H, McCaughey WTE: Tumors of the Serosal Membranes. Atlas of Tumor Pathology, Third Series, Fascicle 15. Washington, DC, Armed Forces Institute of Pathology, 1995.|
|Churg A, Cagle PT, Roggli VL: Tumors of the Serosal Membranes. Atlas of Tumor Pathology, Fourth Series. Washington, DC, Armed Forces Institute of Pathology, in press.|
|Roggli VL, Oury TD, Sporn TA: Pathology of Asbestos-Associated Disease, 2nd Ed. NewYork, Springer, 2004, in press.|
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