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Criteria for Attributing Lung Cancer

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					                                                                                                                     AJCP / EDITORIAL




Criteria for Attributing Lung Cancer to Asbestos Exposure
Philip T. Cagle, MD




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      The article by Mollo and coworkers 1 examines the             it is important if one is addressing etiology of a disease. Risk



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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-
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in Italy might be underestimated. Their review of 924 consec-       lation. Any membes of the at-risk population may not
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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
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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
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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
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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
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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
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      The great majority of lung cancers are caused by tobacco            A smoker has a risk of lung cancer because of smoking that
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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-
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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
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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




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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




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workers and/or their asbestos exposures in regard to lung           cancers. There is a synergistic effect of asbestos with tobacco




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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




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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




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     In regard to the first factor, studies indicate that           general population. Specific criteria are needed to separate



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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.
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(nonoccupationally exposed) population have tens of thou-                As noted, no increased risk of asbestos-related lung
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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
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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
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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
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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
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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
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one of the factors that determine lung cancer risk. However,        cancer.12 To put this in perspective, a report from Florida
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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
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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
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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




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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.




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cancer to asbestos exposure on the basis of tissue burden.12          However, in response to the aforementioned reviews




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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




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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




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     Tissue burden analyses and work history analyses tell us    or tissue burden is enough evidence by itself to establish a



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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
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noted, individual susceptibility to the asbestos exposure is     often are based on grounds of intuitive reasoning. Therefore,
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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-
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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
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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
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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
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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
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tobacco smoker could have a purely tobacco-related lung          lung cancers are caused or partly caused by asbestos expo-
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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
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     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-
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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




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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




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cancer, including usual interstitial pneumonia/idiopathic           provides a basis for the simultaneous occurrence of




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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




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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




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demonstrated that scar cancers do not arise from preexisting        changes that can be observed more often in the lung tissue of



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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
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caused by diffuse fibrosis or scarring in the lungs, but rather     pulmonary disease who have the greatest risk of developing
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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
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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
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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-
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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
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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
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tigators have observed for several decades as an increased          markers of tobacco dose and susceptibility to that dose to
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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
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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
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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-




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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




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Since we would expect that some people with excessive             study by Mollo et al1 were smokers, and tobacco smoke can




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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




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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




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Roggli and Sanders39 for whom information was available                Banks et al21 pointed out that traditional epidemiologic



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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
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were smokers.                                                     also are differences in whether traditional studies of various
     The study by Mollo et al1 in this issue of the Journal has
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                                                                  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
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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
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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
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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
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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
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The article by Mollo et al1 raises a question that there may be   studies, these factors must be taken into account, in addition
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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
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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
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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


smoking-related cancers have been reported in lung cancers               8. Churg A. Neoplastic asbestos-induced disease. In: Churg
said to be due to asbestos, but a unique marker for asbestos-               A, Green FHY, eds. Pathology of Occupational Lung
                                                                            Disease. 2nd ed. Baltimore, MD: Williams & Wilkins;
related lung cancer has not been identified.42                              1998:339-391.
     From the point of view of the pathologist, asbestosis is            9. Gaensler EA, McLoud TC, Carrington CB. Thoracic surgical
an unambiguous marker not only of a tissue burden of                        problems in asbestos-related disorders. Ann Thorac Surg.
asbestos sufficient to cause a risk of lung cancer but also of              1985;40:82-96.
individuals whose tissues are susceptible to the effects of             10. Doll R, Peto R. The Causes of Cancer. Oxford, England:
                                                                            Oxford Medical Publications; 1981:1238-1245, 1305-1308.
that tissue burden. Asbestosis is the most consistent marker
                                                                        11. Churg A. Asbestos, asbestosis and lung cancer [editorial]. Mod
of asbestos-related lung cancer in the literature to date and               Pathol. 1993;6:509-511.
has a basis in current molecular theories of disease similar            12. Asbestos, asbestosis and cancer: the Helsinki criteria for
to many other inflammatory or fibrotic diseases associated                  diagnosis and attribution. Scand J Work Environ Health.
with an increased risk of lung cancer, including diseases                   1997;23:311-316.




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caused by tobacco smoke. Tobacco smoke is sufficient by                 13. Tousey PM, Wolfe KW, Mozeleski A, et al. Determinants of
                                                                            the excessive rates of lung cancer in northeast Florida. South
itself to cause the vast majority of lung cancers and is suffi-




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                                                                            Med J. 1999;92:493-501.
cient by itself to cause lung cancers in workers with                   14. Jones RN, Hughes JM, Weil H. Asbestos exposure, asbestosis




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asbestos exposures. Asbestosis establishes the link between                 and asbestos-attributable lung cancer. Thorax.
a lung cancer and asbestos exposure even when the patient                   1996;51(suppl):S9-S15.




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also was a tobacco smoker. Since there is no other marker,              15. Weiss W. Asbestosis: a marker for the increased risk of lung
                                                                            cancer among workers exposed to asbestos. Chest.
for example, a molecular genetic marker, available to link a
                                                                            1999;115:536-549.
lung cancer to asbestos exposure, currently there is no basis




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                                                                        16. Hammond EC, Selikoff IJ, Seidman H. Asbestos exposure,
in the absence of asbestosis for assuming that an individual                cigarette smoking and death rates. Ann N Y Acad Sci.



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lung cancer is caused by asbestos or asbestos and tobacco                   1979;330:473-490.
smoke combined rather than by tobacco smoke alone. This                 17. Kipen HM, Lilis R, Suzuki Y, et al. Pulmonary fibrosis in
                                                                          N asbestos insulation workers with lung cancer: a radiological
also applies to the 0.5% of cases in which Mollo et al1 raise
                                                                            and histopathological evaluation. Br J Ind Med. 1986;43:18-28.
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the issue of occult asbestosis, to which we must add a
                                                                        18. Roggli VL, Hammar SP, Pratt PC, et al. Does asbestos or
debate about the histopathologic definition of asbestosis.                  asbestosis cause carcinoma of the lung [editorial]? Am J Ind
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Unless and until a better marker comes along, the only                      Med. 1994;26:835-838.
consistently reliable marker for an asbestos-related lung               19. Abraham JL. Asbestos inhalation, not asbestosis, causes lung
                                                                            cancer. Am J Ind Med. 1994;26:839-842.
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cancer is asbestosis, especially in asbestos workers who are
                                                                        20. Egilman D, Reinert A. Lung cancer and asbestos exposure:
also tobacco smokers.
                                                                            asbestosis is not necessary. Am J Ind Med. 1996;30:398-406.
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