mesothelioma cancer

The determination of whether an abnormal asbestos exposure took place is
important in mesothelioma cases because of the potential for financial
compensation and for the assessment of the likelihood of further cases occurring
from similar occupational, paraoccupational, or environmental circumstances. One
should be aware that not all mesotheliomas are associated with asbestos
exposure. Spirtas et al (1) found after careful systematic inquiry that 88% of
pleural and 54% of peritoneal mesotheliomas could be attributed to asbestos
exposure in men in the United States but only 23% of pleural and peritoneal
mesotheliomas could be attributed to asbestos in women in the United States. An
earlier study of mesotheliomas in North America showed lower figures—50% in men
and 5% in women (2).

There are several ways whereby a reasonable determination can be made of whether
abnormal asbestos exposure has occurred in an indi¬vidual. These include (1) a
detailed and reliable occupational history; (2) identification of clinical
markers of exposure such as pleural plaques, diffuse pleural fibrosis, rounded
atelectasis, and asbestosis; (3) histopathologic features, such as pleural
plaques and asbestos bodies; and (4) mineral analyses of digested lung tissues.

In most, if not all, parts of the world, there are background exposures to
asbestos both inside and outside of buildings. These have arisen from natural
outcrops and from industrial activity. These are at very low levels, usually
less than 0.001F/mL (F stands for the degree of fine¬ness of abrasive particles)
but in some countries there are higher envi¬ronmental exposures, for example,
Turkey, Corsica, Cyprus, Russia, Czechoslovakia, Austria, Bulgaria, Greece, and
New Caledonia, which have given rise to asbestos-related diseases such as
pleural plaques and mesotheliomas. Asbestos fibers have been found in the air
and water supplies. Airborne levels of asbetos fibers are generally higher in
urban than in rural areas but this has not been accompanied by a detectable
increase in nonoccupational mesotheliomas (3). Interestingly, a study of
airborne asbestos levels in 12 buildings where friable amosite was used as
fireproofing material and generally was in poor condition, found indoor
concentrations indistinguishable from outdoor levels,

and no evidence of episodic asbestos release was found (4). However, if the
fireproofing was knocked out of the ceiling and allowed to fall to the ground,
airborne asbestos fiber levels increased for a brief period of time but did not
exceed the United States Occupational Safety and Health Administration (OSHA)
occupational exposure level for asbestos.

There is a continuum from background exposure to industrially derived exposures
to asbestos, and there is no sharp boundary between them. This can give rise to
difficulties in determining the background ranges of asbestos for various
populations. Indeed, much debate centers on what constitutes a realistic set of
controls. Another impor¬tant point is that when mineral fiber concentrations are
determined in the lungs of subjects with mesothelioma in order to determine the
like¬lihood of it being asbestos related, it is important to be aware that
background levels of asbestos fibers do exist in the lungs of the gen¬eral
population not occupationally or paraoccupationally exposed to asbestos. These
background levels should be determined for the labo¬ratory carrying out the
analysis in the individual case because there are technical differences in the
way the analyses are carried out by differ¬ent laboratories, and therefore one
cannot use the background range for one laboratory and extrapolate it to another
(5).

One should be aware also that asbestos is not a homogeneous entity. There are
two main families of asbestos fibers: serpentine and amphi-bole. These have
important physical, chemical, and pathobiologic dif¬ferences. The sole
constituent fiber of the serpentine asbestos group is chrysotile (white), while
the amphibole group includes amosite (brown), crocidolite (blue), tremolite,
actinolite, and anthophyllite. When assessing a prior asbestos exposure it is
useful to determine the fiber type(s) involved because there is a much lower
potential for causing mesothelioma from chrysotile exposure than there is from
the amphiboles; a study by Hodgson and Darnton (6) estimated a risk ratio for
mesothelioma of chrysotile/amosite/crocidolite of 1:100:500.

Clinical History

It continues to disappoint that inquiries into possible exposures to mineral
dust, particularly asbestos, are poorly carried out in hospitals that deal
frequently with pulmonary diseases. A reliable occupational history is crucial
to assessing the risks of occupational disease in a worker and in attribution of
a particular disease to an occupational exposure. With respect to mesothelioma,
an appropriate latency period from first exposure to asbestos to onset or death
from the tumor is nec¬essary for attribution. A review by Lanphear and Buncher
(7) of 1690 cases of mesothelioma found that 99% had a latency period of more
than 15 years; 96% had a latency period of at least 20 years, and the median
latency period was 32 years. In fact, in the series of cases where there was a
well-defined period of asbestos exposure, the latency period was almost always
in excess of 20 years and averaged 30 to 40 years.

In any individual case a careful inquiry should be made commenc¬ing with the
individual’s first employment and working completely through chronologically
until the current or final employment, noting for each the dates of commencement
and termination. Careful details of the nature of the various employments should
be made because it may not be immediately apparent that there was a potential
for asbestos exposure. The reliability of the history varies since in some
sit¬uations, for example, work as an insulator or in shipbuilding, exposure to
asbestos is clear-cut, whereas in other situations, such as the con¬struction
industry, the amount and frequency of exposure is variable and depends on the
precise work carried out. Direct regular exposure to asbestos is easier to
evaluate than indirect intermittent exposures. Sometimes exposures are
exaggerated because there is a tendency to assume all visible dust was asbestos,
whereas it might have contained other types of mineral dust, particularly where
a disease, such as mesothelioma, which is strongly associated with asbestos
exposure, is the subject of the inquiry (so-called recall bias) or where there
are pending medicolegal proceedings. The recollections of relatives who provide
the occupational history of a deceased patient are generally less accurate than
if the occupational history had been obtained directly from the patient.

Sometimes exposures to asbestos, particularly tremolite or antho-phyllite, have
occurred environmentally from birth, for example, in Turkey, Greece, Corsica,
New Caledonia, Russia, Czechoslovakia, Austria, Bulgaria, and Finland.

Mesotheliomas have also resulted from exposures to asbestos brought home on the
clothes of other family members who worked in a facility using asbestos.
Exposures to asbestos in females are more commonly through the paraoccupational
than the direct occupational route and these can be equivalent to occupational
exposures, which has been confirmed by lung fiber burden analyses in some cases
(8). There¬fore, it is necessary to make inquiries as to the occupational
activities of other family members and whether, if they were occupationally
exposed, they wore their dirty workplace clothes home for laundering during the
period appropriate for the latency of the tumor.

Accurate, comprehensive, and detailed histories of exposure to agents such as
asbestos can be facilitated by the use of questionnaires.

Clinical and Radiologic Markers of Exposure

The clinical and radiologic markers of exposure include pleural plaques, diffuse
pleural fibrosis, rounded atelectasis, and asbestosis.

Pleural Plaques

Plaques are pearl gray, smooth, raised nodules, often calcified, which are
situated on the parietal pleura, most commonly on the posterolat-eral and basal
parts of the chest wall and diaphragm (Fig. 16.1). They are frequently
associated with asbestos exposure especially when large,

numerous, and bilateral, but there are other causes such as trauma, old
tuberculosis, exposures to talc or mica, and idiopathic causes.

Pleural plaques are benign, and the great majority of individuals with plaques
alone have no symptoms or changes detectable by lung function studies. They
appear to be related more to amphibole than to chrysotile asbestos exposure. The
study by Gibbs (9) of the Quebec chrysotile miners and millers showed that the
incidence correlated with tremolite better than with chrysotile concentrations.
Pleural plaques can occur with brief, intermittent, low-level exposure, and they
have been found in individuals exposed indirectly to asbestos (paraoccupational,
neighborhood, environmental). Plaques related to environmental exposure have
been associated with the tremolite or anthophyllite types of fiber.

Less than 10% of pleural plaques found at postmortem have been detected in life.
This proportion may alter with the increasing use of computed tomography (CT)
scanning. Identification of pleural plaques by chest radiographs has a
significant error rate, particularly in obese individuals where fat pads can be
mistaken for pleural plaques.

Pleural plaques do not begin to show themselves until 15 to 20 years after the
first exposure and they may take 30 years for calcification. Their incidence in
an asbestos-exposed population increases with time since first exposure. Pleural
plaques are a marker of asbestos exposure only and do not indicate an increased
risk of malignancy (10). For instance, a shipyard worker with plaques is no more
likely to develop mesothelioma or lung cancer than a shipyard worker without
plaques.

Knowledge of their presence is less informative than an accurate occu¬pational
history.

Diffuse Pleural Fibrosis

Diffuse pleural fibrosis predominantly affects the visceral pleura and it can
surround the lung completely (11,12). When bilateral and exten¬sive it can be
associated with a decrease in vital capacity. It can be associated with quite
low exposures to asbestos. The changes are not specific to asbestos and require
evidence of an elevated asbestos fiber burden in the lungs to attribute it to
asbestos (vide infra).

Rounded Atelectasis

Rounded atelectasis refers to an asymptomatic, peripheral, rounded pulmonary
mass 2 to 7cm in diameter that is attached to the pleura. It can mimic lung
cancer on radiologic investigations, but a typical “comet’s tail” of vessels and
bronchi may be evident linking into the lateral aspect of the mass, which
distinguishes it from neoplasia (13,14). Pathologically it consists of dense
pleural fibrosis, which is drawn into atelectatic lung parenchyma. Although most
closely associated with exposures to asbestos, because of the latter’s tendency
to induce pleural fibrosis, it has also been described in association with
trauma, infec¬tion, and other agents such as silica, which can result in pleural
thickening (15).

Asbestosis

Asbestosis is defined as diffuse interstitial fibrosis of the lung that has been
caused by inhalation of asbestos fibers. Clinically evident and radiologic
changes of asbestosis are usually associated with prolonged heavy exposures to
asbestos, which are far higher than necessary to produce mesothelioma. Changes
of asbestosis are frequently absent in cases of mesothelioma. If they are
present, then there is usually a strong and convincing history of asbestos
exposure.

Histopathologic Evaluation of Cases

Examination of the pleura at autopsy may reveal the presence of pari¬etal
pleural plaques that were not detected during life and it is impor¬tant that the
examiner note their presence, number, and location.

Asbestos Bodies

The main histopathologic evidence for asbestos exposure is dependent on the
finding of asbestos bodies in light microscopic sections of lung tissue either
by conventional or iron stains. Asbestos bodies are golden, brown, club-shaped,
often beaded structures that contain a clear pale transparent straight
needle-like core. They are formed by the coating of the asbestos fiber with
ferritin and protein and take months or years

to develop after deposition of the fiber in the lung. If the morphologic
criteria are carefully adhered to the majority (greater then 95%) of the
asbestos bodies are found on examination by electron microscopy with energy
dispersive x-ray spectrometry to contain commercial amphibole (crocidolite or
amosite) cores. In some areas of the world with environ¬mental exposures to
asbestos they contain tremolite or anthophyllite. Asbestos bodies formed from
chrysotile are rare. The finding of one convincing asbestos body by light
microscopy in a standard histo-logic section nearly always signifies an
above-background exposure. However, ferruginous bodies that are not formed on
asbestos fibers can occur, for example, on talc, mica, kaolin, coal, carbon,
rutile, and iron (16). These are distinguished by having cores that are yellow
or black or platy rather than fibrous. Particular care has to be exercised by
the histopathologist when evaluating cases with mixed dust exposures where
substantial amounts of sheet silicates (talc, mica, kaolin, etc.) are present;
these silicates can be coated to form ferruginous bodies and although these are
platy, they can be cut at such an angle as to appear to be fibrous and can be
incorrectly identified as asbestos. If the histopathologist finds clusters of
asbestos bodies, this usually signifies very high levels of commercial asbestos
fibers.

Tissue Digests and Bronchoalveolar Lavage Examinations

When conventional light microscopic examination of tissue sections fails to
demonstrate the presence of asbestos bodies, other quantitative approaches can
be utilized to demonstrate an elevated fiber burden such as counting asbestos
bodies or fibers on lung tissue digests or bronchoalveolar lavage (BAL) samples
(5,17–19). The former can be done using light microscopy and the latter
necessitates phase-contrast microscopy or electron microscopy. For both
approaches the standard reference ranges for the normal population should be
determined by the laboratory carrying out the analysis since numerous studies
have been published from many countries that have demonstrated the presence of
asbestos bodies and fibers in digestates of lung from individuals without
occupational exposure to asbestos. Asbestos bodies constitute only about 0.01%
to 1% of fibers visible by electron microscopy. Further the proportion of
asbestos fibers that become coated to form asbestos bodies varies with a number
of factors including fiber type, fiber length, fiber number, and the amount of
iron in the tissue, and therefore one cannot calculate a precise fiber load by
quantifying the number of asbestos bodies. Analyses using electron microscopic
techniques are more time-consuming and costly but are much more sensitive and
can provide a precise breakdown of the different fiber types present (20). They
should certainly be employed where the light microscopic techniques fail to
demonstrate an elevated fiber burden.

Samples of sputum can also be evaluated for the presence of asbestos bodies.
Their detection indicates heavy occupational exposure to asbestos even years
after cessation of exposure (21). However, the examinations are of little
practical use in subjects exposed to relatively light or moderate amounts of
asbestos.

References

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Health Effects of Chrysotile Asbestos. The Canadian Mineralogist Special
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