AJCP / EDITORIAL
Criteria for Attributing Lung Cancer to Asbestos Exposure
Philip T. Cagle, MD
The article by Mollo and coworkers 1 examines the it is important if one is addressing etiology of a disease. Risk
criteria for attribution of lung cancers to asbestos exposure, has to do with populations studied for relative likelihood of
suggesting that the number of asbestos-related lung cancers disease due to a common factor not present in a control popu-
in Italy might be underestimated. Their review of 924 consec- lation. Any membes of the at-risk population may not
utive lobectomies and pneumonectomies for lung cancer in develop the disease under investigation and may have many
northwest Italy included light microscopic asbestos body individual factors that may modify the risk from the studied
counts for asbestos body concentration in addition to histo- factor, be a confounding factor for the risk factor under study,
logic examination for asbestosis and asbestos bodies. Their or put them at risk for other diseases. An example can be
interpretation is that 6% of the lung cancers in their series are found with the relationship of tobacco smoke to lung cancer.
attributable to asbestos exposure because of histologic diag- On the one hand, about 10% of tobacco smokers develop
nosis of asbestosis. However, they also conclude that another lung cancer as a result of their tobacco smoking. This is a
0.5% of their cases had interstitial fibrosis without asbestos considerably greater risk than the population of never
bodies on histologic section but an elevated asbestos body smokers who have a background risk of lung cancer that is
concentration on digestion study. Mollo and coworkers1 raise less than 1%, probably considerably so. On the other hand,
the possibility that these cases also may be asbestos-related even though most smokers do not develop lung cancer, about
lung cancers. 90% of all lung cancers are caused by tobacco smoking.2
The great majority of lung cancers are caused by tobacco A smoker has a risk of lung cancer because of smoking that
smoke, but a minority of lung cancers are caused by asbestos is much greater than that of individuals who have never smoked,
exposure, virtually always in association with tobacco smoke but, even so, that person has a fairly good chance of not devel-
exposure. One reason to identify the lung cancers caused by oping a lung cancer based on the risk seen in the population of
asbestos exposure is for establishing occupational and public all smokers. If that smoker does develop lung cancer, the lung
health policies regarding asbestos or for investigation of lung cancer will be caused by the tobacco smoke and could have been
cancer pathogenesis that, in turn, may provide a basis for new avoided if the person had never smoked. If we look closer at the
lung cancer therapies. In the individual case, the major reason population of smokers with a risk of lung cancer, we can identify
to determine whether asbestos contributed to the development criteria that select those with the most risk of developing lung
of a lung cancer is for purposes of compensation, which, in cancer based on the cumulative dose of tobacco smoke that they
the United States, often is through litigation. Accurate identi- are exposed to and to factors of individual susceptibility.3-5
fication of patients deserving compensation is also a primary However, the causal association between tobacco smoke and
concern of Mollo and coworkers.1 lung cancer is so strong that we seldom do more than obtain a
Before proceeding, we should remind ourselves that risk smoking history and do not require a detailed analysis of corrob-
of a disease and actually having a disease due to that risk are orating evidence to link a smoker’s lung cancer to tobacco
two different things. This is a rather simple observation, but smoke in the vast majority of cases.
© American Society for Clinical Pathology Am J Clin Pathol 2002;117:9-15 9
Cagle / CRITERIA FOR ATTRIBUTING LUNG CANCER TO ASBESTOS EXPOSURE
As rightly pointed out by Mollo et al,1 many studies cancers in the United States each year due to tobacco
examine only the risk of lung cancer for asbestos-exposed smoke.2 In contrast, asbestos is estimated to account for 2%
populations and do not investigate the criteria for ascribing to 5%, or about 3,400 to 8,500 new lung cancers in the
an individual’s lung cancer to asbestos exposure. Studies United States each year.9,10 Thus, there are anywhere from
have demonstrated that certain occupations and populations 20 to 50 tobacco-related lung cancers for every asbestos-
of workers commonly have higher asbestos exposures and related lung cancer. Tobacco smoke contains some 4,000 to
greater risks of asbestos-related diseases than others.6,7 For 5,000 chemicals, including many known and suspected
compensation, however, a worker must substantiate the indi- carcinogens, both initiators and promoters. As a result,
vidual claim. tobacco smoke is sufficient by itself to cause the great
Unlike the situation with tobacco smoke and lung majority of lung cancers without the additional contribution
cancer, at least 2 factors necessitate clearly defined criteria of any other agent.
for linking a lung cancer to asbestos in the individual case. Virtually all workers with lung cancers and asbestos
First, most workers with asbestos exposures will not develop exposure also are tobacco smokers or former smokers and,
lung cancers, indicating that there are differences between therefore, have 2 potential etiologic agents for their lung
workers and/or their asbestos exposures in regard to lung cancers. There is a synergistic effect of asbestos with tobacco
cancer risk. Second, as already noted, tobacco smoke is the smoke, and both of these potential etiologic agents are
primary cause of lung cancers and is sufficient by itself to responsible for lung cancers in some workers. Other workers
cause the great majority of lung cancers. As a result, tobacco may have had asbestos exposure, but their lung cancers are
smoke exposure is a powerful confounding factor in most due exclusively to their tobacco smoke exposure, like the
cases of lung cancers in workers with asbestos exposures. overwhelming majority of patients with lung cancer in the
In regard to the first factor, studies indicate that general population. Specific criteria are needed to separate
everyone is exposed to background levels of asbestos in the workers with purely tobacco-related lung cancers from those
ambient air. Studies have shown that members of the general with lung cancers attributable to both tobacco and asbestos.
(nonoccupationally exposed) population have tens of thou- As noted, no increased risk of asbestos-related lung
sands to hundreds of thousands of asbestos fibers in each cancer from background levels of asbestos has been demon-
gram of dry lung tissue, which translates into millions of strated in the general population, and a number of studies
fibers and tens of thousands of asbestos bodies in every have failed to demonstrate an increased risk of lung cancer in
person’s lungs.6,7 However, the general population does not populations with increased but comparatively low levels of
have an increased risk of asbestos-related lung cancers asbestos exposure.6-8 Various tissue burden studies report
despite these background levels. Individuals with occupa- thousands of asbestos bodies and millions of asbestos fibers
tional exposures to asbestos have tissue burdens of asbestos per gram of dried lung tissue in asbestos workers with lung
that are higher than background levels. A number of studies cancer. In industrial hygiene terms, cumulative asbestos
have failed to show an increased risk of lung cancer in popu- exposure of 25 fibers per cubic centimeter year is recognized
lations with comparatively low levels of asbestos exposure.8 by many authorities as a minimal dose for increased risk of
Therefore, the level of cumulative asbestos exposure, lung cancer.8,11 Some investigators estimate that the 25 fibers
reported as asbestos dose or asbestos tissue burden, must be per cubic centimeter year dose doubles the risk of lung
one of the factors that determine lung cancer risk. However, cancer.12 To put this in perspective, a report from Florida
considering that millions of workers have had occupational indicated that increased intake of dietary fat doubles the risk
exposure to asbestos and that only some of these individuals of lung cancer (in multiple studies there is emerging
develop lung cancer, there must be other factors that separate evidence that dietary fat consumption increases the risk of
those who develop asbestos-related lung cancer from those lung cancer). 13 However, it should be noted that most
who do not. As with other types of exposures that carry risk workers with asbestos-related lung cancer have much more
of disease, including tobacco smoke, factors related to indi- than the minimal asbestos dose or tissue burden and, there-
vidual susceptibility also must have a role in whether an fore, potentially will have more than a doubling of risk. For
asbestos-related lung cancer develops in an individual once purposes of establishing causation criteria, however, the
the requisite asbestos tissue burden is present. diminishing risk with lower levels of exposure means that a
The second factor creating a need for attribution criteria worker may have had occupational exposure to asbestos but
is the confounding factor of tobacco smoke. As previously that exposure may be less than the minimal levels of asbestos
stated, current or former active tobacco smoking accounts for required to produce an increased risk of lung cancer.
90% of all lung cancers in the United States. Secondhand This observation has implications for some of the poten-
environmental smoke accounts for a sizable percentage of tial criteria that we might consider for attributing a lung
the remainder, for a total of more than 150,000 new lung cancer to asbestos exposure. Workers with asbestos-related
10 Am J Clin Pathol 2002;117:9-15 © American Society for Clinical Pathology
AJCP / EDITORIAL
lung cancers usually will have histories of asbestos exposure increased risk of lung cancer in insulators. Interestingly,
and are expected to have asbestos bodies on tissue sections when a histopathologic review was performed of the lung
of their lung parenchyma. Many also coincidentally will cancer cases with available lung parenchyma, the insulators
have pleural plaques because of their asbestos exposure. in Selikoff’s series with an increased risk of lung cancer
However, asbestos bodies can be seen in tissue sections from asbestos exposure above that of their smoking showed
when the asbestos tissue burden is less than the minimum for asbestosis in 100% of cases.17 Evaluation of studies said to
lung cancer risk. Pleural plaques also can occur at asbestos support an increased risk for asbestos-related lung cancer in
concentrations less than those required for a lung cancer risk the absence of asbestosis have been criticized for failing to
and in tissue burden studies generally are associated with show an increased risk when cases with asbestosis are
average tissue burdens that are much less than those for lung excluded from their study populations.8,14,15 Overall, there
cancer. As a result, the presence of 1 asbestos body on tissue is a strong association between lung cancer risk and
sections, or even a few asbestos bodies depending on asbestos exposure with asbestosis that can be demonstrated
circumstances, and the presence of pleural plaques are not more readily than an association with asbestos exposure
reliable criteria by themselves for causally linking a lung without asbestosis.
cancer to asbestos exposure on the basis of tissue burden.12 However, in response to the aforementioned reviews
Either of these findings may provide evidence of an asbestos and editorials, reviews and editorials by other authorities in
exposure but neither, by itself, quantitates the exposure. For the field, including Roggli et al,18 Abraham,19 Egilman and
similar reasons, a work history of asbestos exposure must be Reinert,20 and Banks et al,21 have challenged the premise
detailed and comprehensive before it can be used to estimate that asbestosis is necessary to causally link a lung cancer to
the asbestos dose. asbestos exposure, contending that a sufficient asbestos dose
Tissue burden analyses and work history analyses tell us or tissue burden is enough evidence by itself to establish a
that not everyone who has the requisite level of asbestos causal link. Some of their positions are based on different
exposure will develop an asbestos-related lung cancer. As conclusions from portions of the literature, but they also
noted, individual susceptibility to the asbestos exposure is often are based on grounds of intuitive reasoning. Therefore,
necessary before an individual will develop a disease from the primary debate about criteria for attributing a lung
the exposure. Asbestos workers potentially are subject to the cancer to asbestos exposure has centered on whether suffi-
same nonasbestos risk factors and non–asbestos-related cient asbestos tissue burden alone or sufficient asbestos
diseases to which the general population is subject. Since tissue burden with accompanying asbestosis should be the
tobacco smoke is sufficient by itself to cause the majority of criterion. As noted by Abraham,19 litigation has provided
lung cancers, there is no reason that lung cancer in a much of the stimulus for this “debate,” and we already have
tobacco-smoking asbestos worker should not be related observed that criteria for establishing cause of a lung cancer
purely to tobacco smoking. Obviously, if the worker has less are largely for purposes of compensation in the individual
than the minimal asbestos exposure to cause asbestos-related case. The differences between those who require and those
lung cancer, the cause of the lung cancer should not be an who do not require asbestosis may appear exaggerated in the
issue. However, even with sufficient dose or tissue burden of adversarial context of litigation. No one disputes that most
asbestos to create a risk of asbestos-related lung cancer, a lung cancers are caused by tobacco smoking and that some
tobacco smoker could have a purely tobacco-related lung lung cancers are caused or partly caused by asbestos expo-
cancer like most patients with lung cancer if the worker is sure. No one disputes that there must be a basis for
not susceptible to the asbestos exposure. attributing a lung cancer to asbestos exposure, especially if
Do we have any marker for both asbestos tissue burden the patient also is a smoker. No one disputes that a lung
and individual susceptibility to that exposure? Over the cancer in a patient with asbestosis is due to asbestos expo-
years, a number of investigators have concluded that the sure. The debate is what to do with patients with lung cancer
increased risk for lung cancer in asbestos-exposed workers with the requisite asbestos tissue burden who do not have
occurs in workers with asbestosis. Detailed editorials and asbestosis, especially if they also are tobacco smokers or
reviews of the studies supporting this conclusion have been former smokers.
written by several well-known authorities in the field, An intuitive question about the requirement of
including Churg,8,11 Jones et al,14 and Weiss,15 and will not asbestosis for attributing lung cancer causation was raised in
be repeated here. It should be noted that, over the years, a an editorial by Roggli et al18 and then subsequently by other
great many epidemiologic studies of lung cancer risk and editorials: Since asbestos is the cause of the lung cancer,
asbestos exposure do not provide information about pres- why would only patients with asbestosis have the increased
ence or absence of asbestosis in the patients. An example is risk of asbestos-related lung cancer? This question deserves
the classic work by Hammond et al16 demonstrating an further consideration.
© American Society for Clinical Pathology Am J Clin Pathol 2002;117:9-15 11
Cagle / CRITERIA FOR ATTRIBUTING LUNG CANCER TO ASBESTOS EXPOSURE
Part of the relationship between asbestosis and lung Similar to other forms of chronic diffuse pulmonary
cancer risk has to do with the dose or tissue burden of fibrosis or inflammation associated with an increased risk of
asbestos. The risk of asbestosis and the risk of asbestos- lung cancer, asbestosis develops when asbestos fibers stimu-
related lung cancer rise in a parallel manner with increasing late inflammatory cells to produce a variety of mediators of
tissue burden of asbestos.7,8,22 The evidence indicates that the fibrogenesis—eg, growth factors, cytokines, and oxidative
level of asbestos exposure required for a risk of asbestosis is damage.23,28-33 As suggested by Rom et al34 a decade ago
in the same range as that for lung cancer risk. Asbestosis, and observed by subsequent investigators, some of these
thus, is a reliable marker that the patient has been exposed to mediators also can act as similar mediators for the growth of
the asbestos dose or tissue burden necessary to put that carcinomas. A component of the individual susceptibility
patient at risk for asbestos-related lung cancer. that I have referred to would be related, for example, to
Tissue burden alone does not fully explain why whether the individual produces the mediators, how fast or
asbestosis should be the criterion for linking a lung cancer to how much the individual metabolizes the mediators, and how
asbestos exposure. There are a number of forms of diffuse many receptors the individual has for the mediators. The role
lung fibrosis in which there is in an increased risk of lung of these mediators in both fibrogenesis and carcinogenesis
cancer, including usual interstitial pneumonia/idiopathic provides a basis for the simultaneous occurrence of
pulmonary fibrosis (UIP/IPF) and collagen vascular diseases asbestosis and asbestos-related lung cancers in the same indi-
such as scleroderma.23 In earlier decades, the theory was vidual and a basis for the increased risk of lung cancer in
offered that asbestos-related lung cancers were so-called scar patients with asbestosis.
cancers as an explanation for the link between asbestosis and Of course, most tobacco smokers with lung cancer do
lung cancer risk. In regard to local “scars,” Cagle et al24 have not have UIP/IPF. However, there are other tobacco-related
demonstrated that scar cancers do not arise from preexisting changes that can be observed more often in the lung tissue of
focal scars, but rather the cancers produce the so-called scars patients with tobacco-related lung cancers. In particular, it is
as a desmoplastic reaction. Similarly, lung cancer is not the subpopulation of smokers with chronic obstructive
caused by diffuse fibrosis or scarring in the lungs, but rather pulmonary disease who have the greatest risk of developing
lung cancer is caused by the same agent, for example lung cancer, and the association of these diseases with lung
asbestos, that also causes the fibrosis in susceptible patients cancer is so strong that emphysema and other forms of
with sufficient dose. chronic obstructive pulmonary disease have been reported to
There are underlying similarities in the increased risk of be risk factors for lung cancer independent of tobacco
lung cancer in patients with asbestosis and patients with smoking.35-38 In the case of emphysema and other smoking-
other forms of chronic diffuse pulmonary fibrosis. It is now related changes in the lung tissue, we once again have a situ-
thought that tobacco smoking is a likely cause of UIP/IPF.25 ation in which various inflammatory, oxidative, and growth
Tobacco smoke causes a variety of molecular events and factor mediators have a role that might impact carcinogen-
inflammatory responses in the lung tissue with release of esis as well as the changes in other lung tissues, including
substances such as mediators and cytokines, some of which remodeling of tissue in emphysema. However, as noted, the
may have roles in the pathogenesis of both the neoplastic causal association between tobacco smoke and lung cancer is
disease and the nonneoplastic disease producing what inves- so strong that we do not require identification of other tissue
tigators have observed for several decades as an increased markers of tobacco dose and susceptibility to that dose to
risk of lung cancer in patients with UIP/IPF. Interestingly, attribute a lung cancer to tobacco smoking.
there is an increased risk of cancers of both the lung and However, we still have largely been talking about risk in
skin in patients with systemic scleroderma.26 These are the populations and, for assessing individuals, we would like to
same tissues where the fibrosis of scleroderma most often know how often a patient with lung cancer with the requisite
occurs. This, too, is consistent with molecular events and level of asbestos exposure also has asbestosis. This funda-
inflammatory responses that have roles in the pathogenesis mental question has been neglected in most studies, but
of both the neoplastic and nonneoplastic diseases in the Roggli and Sanders39 recently reported on 234 lung cancer
lungs and the skin in scleroderma. As a result, investigators cases with data on asbestos tissue burden from digestion
have observed for decades an increased risk of lung cancer studies. Their cases were mostly medicolegal cases and,
in patients with scleroderma of the lungs. 26 Similar therefore, expected to have at least some asbestos exposure
increases of primary cancers in organs affected by above background. In the series of Roggli and Sanders,39 all
sarcoidosis (lymphoid tissues, skin, liver, and lung during patients with lung cancer with asbestos tissue burdens above
the first decade of follow-up) have been reported with 50,000 amphibole fibers per gram of wet lung tissue by scan-
chronic inflammation as the putative mediator of the ning electron microscopy had histopathologic asbestosis in
increased risk.27 sections of their lung tissue except for 10 patients (based on
12 Am J Clin Pathol 2002;117:9-15 © American Society for Clinical Pathology
AJCP / EDITORIAL
their Table 6), or 6.5%, of the 155 patients without doing the study. The concentration of asbestos bodies per
asbestosis. This finding indicates that the great majority of gram of dry tissue that Mollo et al1 use as their cutoff for a
patients with lung cancer with asbestos tissue burden suffi- level sufficient to produce asbestosis is lower than what
cient to increase lung cancer risk also have asbestosis on others have reported, and Mollo et al1 concur with this in the
tissue sections. This is consistent with asbestosis as a marker article. I wonder if Mollo et al considered that some of the
of asbestos-related lung cancer, both as an indicator of the fibrosis in their cases might be from causes other than occult
requisite tissue burden for increased lung cancer risk and as asbestosis. Churg,8 Roggli and Pratt,40 Egilman and Rein-
verification that the individual is susceptible to the fibro- hart,20 and Hammar41 all have pointed out potential pitfalls
genic-carcinogenic effects of that asbestos exposure. in the histopathologic diagnosis of asbestosis. There are
There are some patients in the series of Roggli and many causes of lung fibrosis, and patients with lung cancer
Sanders39 that have the requisite asbestos burdens for lung are subject to fibrosis from a variety of reasons related to
cancer risk but who do not have asbestosis. Do these their lung cancer. Lung cancers, of course, can cause peritu-
patients have asbestos-related lung cancers or not? I do not moral and postobstructive pneumonias or other reactions
think there is any way to really tell from the published data. that result in interstitial fibrosis. Most of the patients in the
Since we would expect that some people with excessive study by Mollo et al1 were smokers, and tobacco smoke can
amphibole burdens would not be susceptible to those tissue cause smoker’s bronchiolitis and fibrosis around bronchioles
burdens, we cannot say whether one, several, or all of these and may even cause respiratory bronchiolitis–associated
patients would have developed a lung cancer anyway. This interstitial lung disease, desquamative interstitial pneu-
is especially problematic in any who may have been tobacco monia, or Langerhans histiocytosis (eosinophilic granu-
smokers. Although 93% of the patients in the study by loma) in some patients. 25
Roggli and Sanders39 for whom information was available Banks et al21 pointed out that traditional epidemiologic
were smokers, it is not clear whether the 10 patients with studies may not convince all authorities that asbestosis is
the excessive amphibole burdens but without asbestosis required to link a lung cancer to asbestos exposure. There
were smokers. also are differences in whether traditional studies of various
The study by Mollo et al1 in this issue of the Journal has
types include all the information one would like to answer
some similarities to the study by Roggli and Sanders,39 but it specific questions. Not only are there differences in reporting
raises a different question of how to diagnose asbestosis. results owing to varying methods within the same discipline,
Generally, the number of asbestos bodies seen on tissue as already noted, there are also differences in what can be
sections is proportionate to the total asbestos tissue burden. determined within different disciplines (radiologic studies
Of course, with relatively low tissue burdens, no asbestos may sometimes not detect the lesions of minimal grade 1
bodies may be seen on tissue sections, even if the levels are asbestosis that can be seen under the light microscope, for
above background. When someone has a tissue burden in the example). If the increased lung cancer risk occurs in workers
range seen with asbestosis and asbestos-related lung cancer, with asbestosis, then any study that includes workers with
asbestos bodies should be readily identifiable in tissue asbestosis is expected to show an increased risk of lung
sections, and, indeed, the presence of asbestos bodies on cancer, even if the parameter studied is asbestos dose or
tissue sections is a component of the definition of asbestosis. tissue burden. When comparing results between asbestos
The article by Mollo et al1 raises a question that there may be studies, these factors must be taken into account, in addition
a number of “occult” asbestosis cases with fibrosis and to usual issues such as cohort size and control of
elevated asbestos burden on digestion study but no asbestos confounding factors. As Banks et al21 point out, a molecular
bodies on tissue sections. The literature indicates that occult marker likely would be a superior tool to link lung cancers to
asbestosis, if it exists, is extremely rare—much less frequent asbestos exposure. In the case of tobacco smoke and lung
than the 0.5% of cases for which Mollo et al1 raised the cancer, the association is so strong that no special criteria are
question. required to link a lung cancer to tobacco smoke. However,
One challenge in interpreting articles on asbestos- many mutations caused by tobacco smoke during the patho-
related diseases is that different investigators use different genesis of lung cancer have been identified, and some of
methods for determining asbestos tissue burden and report these are unique enough and frequent enough that they can
results differently, eg, asbestos bodies vs asbestos fibers, be used as a “fingerprint” to demonstrate the link between a
wet weight vs dry weight, and light microscopy vs electron lung cancer and tobacco smoke. I agree with Banks et al21
microscopy. Some variability in ranges for different condi- that what is needed is a molecular marker that is unique to
tions is to be expected between different laboratories as asbestos, or at least not caused by tobacco smoke, that would
well. Therefore, results must be interpreted for the methods allow us to link a lung cancer to asbestos exposure. So far,
used and the ranges established for the individual laboratory molecular markers like p53 and k-ras seen in patients with
© American Society for Clinical Pathology Am J Clin Pathol 2002;117:9-15 13
Cagle / CRITERIA FOR ATTRIBUTING LUNG CANCER TO ASBESTOS EXPOSURE
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