Content uploaded by Edward James Arthur Harris
Author content
All content in this area was uploaded by Edward James Arthur Harris on Feb 14, 2019
Content may be subject to copyright.
Content uploaded by Edward James Arthur Harris
Author content
All content in this area was uploaded by Edward James Arthur Harris on Jan 17, 2019
Content may be subject to copyright.
Full Terms & Conditions of access and use can be found at
https://www.tandfonline.com/action/journalInformation?journalCode=ierx20
Expert Review of Respiratory Medicine
ISSN: 1747-6348 (Print) 1747-6356 (Online) Journal homepage: https://www.tandfonline.com/loi/ierx20
Diagnosis of asbestos-related lung diseases
Edward J. A. Harris, Arthur Musk, Nicholas de Klerk, Alison Reid, Peter
Franklin & Fraser J. H. Brims
To cite this article: Edward J. A. Harris, Arthur Musk, Nicholas de Klerk, Alison Reid, Peter
Franklin & Fraser J. H. Brims (2019) Diagnosis of asbestos-related lung diseases, Expert Review of
Respiratory Medicine, 13:3, 241-249, DOI: 10.1080/17476348.2019.1568875
To link to this article: https://doi.org/10.1080/17476348.2019.1568875
Accepted author version posted online: 16
Jan 2019.
Published online: 25 Jan 2019.
Submit your article to this journal
Article views: 34
View Crossmark data
REVIEW
Diagnosis of asbestos-related lung diseases
Edward J. A. Harris
a,b
, Arthur Musk
a,c
, Nicholas de Klerk
c,d
, Alison Reid
b
, Peter Franklin
c
and Fraser J. H. Brims
a,b
a
Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia;
b
School of Public Health, Curtin University, Perth, WA,
Australia;
c
School of Population and Global Health, University of Western Australia, Perth, WA, Australia;
d
Telethon Kids Institute, University of
Western Australia, Perth, WA, Australia
ABSTRACT
Introduction: The diagnosis of lung disease in asbestos-exposed individuals is a process that not only
requires a detailed occupational and tobacco smoking history, but the correlation with physical signs,
appropriate imaging, detailed lung function assessment and histology/cytology when required.
Worldwide, the total quantity of asbestos mined is static, having decreased dramatically in devel-
oped countries but increased in countries where there is no restriction on mining: for example, Russia,
China, Brazil, and Kazakhstan.
The predominant diagnostic challenge in most cases of possible asbestos-related disease is the
significant interval between exposure and development of the disease. Also challenging is the estima-
tion of an individual’s risk of disease, not least because asbestos-induced malignancy can be rapidly
fatal, and, in the case of lung cancer, early detection can lead to treatment with curative intent.
Areas covered: Discussion of quantitative asbestos exposure estimation and risk assessment, selection
of the most appropriate imaging modality and frequency of imaging.
Expert commentary: Consideration of the future for asbestos-related lung disease includes screening
those at highest risk particularly in relation to ongoing mining operations and the management of in-
situ asbestos.
In the future, screening programs designed with estimation of risk of malignancy, based on
quantitative estimates of asbestos exposure, and smoking history are indicated.
ARTICLE HISTORY
Received 14 February 2018
Accepted 9 January 2019
KEYWORDS
Asbestos; cancer; diagnosis;
disease; lung; mesothelioma;
future; asbestosis; screening;
pleura; pleural disease
1. Introduction
1.1. Asbestos-related lung disease
Asbestos has been used worldwide because of its physical proper-
ties perhaps for as long as 5,000 years [1], however it was the onset
of commercial mining in the mid-19th century that led to a large
number of significant exposures and subsequent illnesses that
raised suspicions regarding toxicity. Suspicion of diseases caused
by inhalation of asbestos fibers was first raised by an Austrian
doctor in 1897 and first described in the scientific literature in
1899 [2]byDrMontagueMurrayofCharingCrossHospital,who
described the post-mortem findings of asbestos fibers in the fibro-
tic lungs of a young asbestos-textile worker [2]. In 1908 an Italian
physician also described the poor response and hasty demise of
asbestos workers when treated for presumed tuberculosis [3].
Asbestos was listed as a ‘harmful industrial substance’in the
UK in 1902. In 1911 ventilation laws were introduced in
Australia after the discovery of widespread lung disease in
miners. From 1918, US life insurance companies stopped insur-
ing asbestos workers after their studies recognized premature
death. However, it took until 1924 for the first death to be
ascribed solely to asbestos exposure by pathologist Dr William
Cooke. He described extensive lung fibrosis containing ‘parti-
cles of mineral matter’in a young woman who had been
employed as a spinner of asbestos into yarn. Shortly after this
came the first use of the term ‘asbestosis’and further case
reports eventually led to a UK parliamentary inquiry in 1930
[4]. This inquiry, conducted by Merewether and Price concluded
that there was irrefutable proof of a link between asbestos dust
exposure and the development of asbestosis: in fact, two-thirds
of the workers x-rayed demonstrated signs of pulmonary fibro-
sis, with increasing incidence in those with longer duration of
exposure. As a result, dust control regulations were established
in the United Kingdom in 1931 and in 1938 a ‘safe’dust con-
centration limit was established in the United States [5].
A link between asbestos exposure and increasing incidence
of lung cancer was first considered in the 1930s and evidence
was presented in 1955 which indicated excess deaths caused
by lung cancer in the asbestos-exposed [6]. Originally called
‘pleural endothelioma’[6], mesothelioma as a disease entity
separate from lung cancer was first mentioned in the medical
literature in 1931. Wagner et al. in 1960 [7] first described
a case series of 30 patients with significant blue asbestos
exposure in South Africa who had developed pleural or peri-
toneal malignant mesothelioma.
Hyaline pleural plaque formation related to asbestos expo-
sure has been described in radiological and subsequently in
postmortem series since the 1960s [8,9] and has been shown
to have little effect on lung function, gas exchange, and
exercise capacity. Benign asbestos-related pleural effusion
(BAPE) was first described in 1965 by Eisenstadt [10]. In
a crocidolite-exposed population, BAPE was described as
CONTACT Fraser J. H. Brims fraser.brims@curtin.edu.au Sir Charles Gairdner Hospital, Perth, WA
EXPERT REVIEW OF RESPIRATORY MEDICINE
2019, VOL. 13, NO. 3, 241–249
https://doi.org/10.1080/17476348.2019.1568875
© 2019 Informa UK Limited, trading as Taylor & Francis Group
being an ‘unexplained’effusion in an asbestos-exposed per-
son, despite investigation for alternative causes. It has been
hypothesized as a precursor of Diffuse Pleural Thickening
(DPT), first described in 1966 by Elmes [11]. Due to DPT having
a number of possible different etiologies including most com-
monly, pleural infection, this condition is not specifically
related to asbestos-fiber inhalation.
The findings of asbestos-related diseases in US insulation
workers who were not directly employed in the asbestos
industry in 1964 lead to greater understanding of the devel-
opment of asbestos-related diseases in anyone who came into
contact with asbestos [12].
1.2. Types of asbestos exposure
Exposure to asbestos may be both occupational or environ-
mental and all asbestos exposure confers some risk of asbes-
tos-related disease. However, the risk of disease is known to
relate in part to the type of asbestos to which the individual
has been exposed [13]. This depends on occupation, geogra-
phical location and the types of asbestos or other minerals
which have been mined or imported locally [14].
The commercial amphiboles (Crocidolite, Amosite,
Anthophyllite) have sharp, needle-shaped fibers, which pene-
trate deeply into the lung parenchyma and to the pleural
cavity. Serpentine asbestos (chrysotile) fibers are more pliable,
with a feathered, curved appearance and penetrate less into
the lung parenchyma and have lower bio-persistence (i.e.
shorter half-life) in the lung [15]. The longer, thinner amphi-
bole fibers are associated with more asbestos-related disease
for a given exposure, when compared to chrysotile fibers [16].
Amphibole fibers persist in the lung, leading to a prolonged
immune reaction in surrounding tissue resulting in inflamma-
tion, scarring and the formation of asbestos bodies [16,17].
If exposure has been to a single type of asbestos, then
quantification of risk is simplified, as groups exposed to
a single form of asbestos have been well described, for exam-
ple, the Wittenoom miners were exposed almost exclusively to
crocidolite (‘blue’asbestos) and disease in this group can be
attributed to this exposure [18]. Mixed fiber exposures lead to
a more difficult risk estimation as risk estimates will vary
depending on the quantity and proportion of amphibole or
serpentine asbestos to which an individual has been exposed
[19]. Most manufacturing plants worldwide have used multiple
varieties of asbestos depending on their relative market price
over the decades, so that accurate estimation of exposure(s)
can be variable and challenging.
Studies have demonstrated that different fiber types induce
different patterns of pulmonary diseases [20]: for example
exposure to crocidolite has been demonstrated to be asso-
ciated with the highest incidence of BAPE, DPT and malignant
mesothelioma, but lower rates of pleural plaques when com-
pared with individuals with similar exposure to a different
amphibole (anthophyllite) [21]. It is therefore important to be
aware of the nature of an individual’s occupation and location
of working, in order to have an awareness of the spectrum and
possible time frame of asbestos-related diseases that may
manifest in an exposed worker.
Amphibole varieties of asbestos are more carcinogenic to
the pleura than serpentine asbestos [20] and there is evidence
of a much lower incidence of mesothelioma in those purely
exposed to chrysotile (when compared to amphibole expo-
sure) [22]. However, the levels of impurity from contamination
with amphiboles in most chrysotile mines [22] mean that it is
difficult to define precisely the excess risk according to specific
fiber type, although suggested estimates of exposure-specific
risk for mesothelioma are approximately 500:100:1 for croci-
dolite, amosite, and chrysotile, respectively, [20].
A detailed occupational and environmental exposure his-
tory is important in order to help assess an individual’s risk of
developing an asbestos-related disease [23,24]. This is impor-
tant when it comes to selecting appropriate radiological inves-
tigations and for calculating the probability of disease.
Information on the exact job type, the tasks performed,
employing company and whether respiratory protection was
used are needed, as well as the duration and location of these
tasks: there is a proven link between amount and type of
exposure and development of lung diseases. However, esti-
mating this exposure is often difficult due to variable exposure
levels, different types of asbestos used over time and absence
of dust exposure measurement. Where quantitative exposure
estimates are available, a link between increased duration and
intensity of exposure, time since exposure and development
of disease may be demonstrated [18,25,26]. Many estimates of
disease risk have been calculated from data that are not
locality specific, therefore are generalizable at a population
level, but less so for individuals [27].
Time since first (asbestos) exposure is an important variable
in addition to the duration, intensity, and type of asbestos
fiber exposure [23]. The latency period associated with the
development of different asbestos-associated lung diseases
varies, and a short but intense exposure at an early age may
have a stronger association with disease development than
exposures later in life [28].
Attempts have been made to improve the standardization
of occupational exposure estimations using a ‘job exposure
matrix’. An asbestos job exposure matrix (asbJEM) [29]in
Western Australia was developed to estimate exposure,
based on extensive occupational exposure data from 224
occupations from 60 industries in Australia. A group of expert
industrial hygienists assessed these data, including likely fre-
quency and intensity of exposure of different job categories at
different time periods in order to quantify exposure estimates
based on occupation and duration. Similar matrices have been
developed elsewhere [30], however, they are inherently incon-
sistent when applied to an individual, due to the wide varia-
tion of exposures within a single occupation group. These
measures are likely to be best applied to selected populations
which are being considered for screening for asbestos-related
disease. They may also not be applicable to populations other
than those in which they were developed, due to differences
in occupational practices and types of asbestos that have been
used around the world.
A further limitation of occupational exposure matrices
relates to exposures experienced outside the occupation. It is
important to enquire about environmental and non-
occupational exposures which may have occurred earlier in
242 E. J. A. HARRIS ET AL.
life; perhaps relating to place of residence, parents’occupa-
tions or dwellings or home handyman activities: exposures of
these types and subsequent development of an asbestos-
related disease have been demonstrated in the so-called ‘chil-
dren of Wittenoom’[31]. Evidence of other environmental
exposures that it is important to seek include those that
occur from ‘Do it yourself’tasks that involve removing/dril-
ling/cutting asbestos-containing products at home [32].
Occupational pulmonary diseases are screened for using
chest x-ray worldwide. Since 1950 International Labour
Organization (ILO) readings have been used to standardize
interpretation and description of chest x-ray abnormalities
found in occupational exposure [33]. High-resolution
Computed Tomography (HRCT) has a higher sensitivity for
pneumoconiosis, in particular, early stages of the disease.
The International Classification of HRCT for Occupational
and Environmental Respiratory Diseases [34]wasdeveloped
in an attempt to correlate chest x-ray and CT findings of
occupational lung diseases, following the recommendations
laid out in the Helsinki Criteria [35]. This classification was
developed with a scale corresponding to the ILO readings
for chest x-ray and have been used in a similar fashion to
provide a semi-quantitative assessment of occupational
lung disease which can be used for research and compar-
ison between groups [36].
2. Asbestos-related lung diseases
2.1. ‘Benign’disease
Circumscribed pleural plaques (CPP), first described by Sparks in
1931 [37], are the most common asbestos-related finding
identified and are often first incidentally detected on plain
CXR or CT scan in those with prior exposure [8,38]. Mainly
occurring after amphibole exposure they become increasingly
visible on cross-sectional imaging approximately 10 years after
first exposure [8,38], although may not become visible on
a plain chest x-ray until they have become calcified (which
occurred at median 17.5 years in a group exposed predomi-
nantly to Libby amphibole –or Tremolite) [39]. Only 15% of
CPP are diagnosed on plain posteroanterior (PA) chest films
when compared to post mortem/thoracotomy and therefore
their absence on plain CXR does not exclude their presence.
Lateral plain films increase detection, however, more recently
computed tomography (CT) scanning (including low-dose CT
(LDCT)) [40] has been demonstrated to be more sensitive for
the detection of CPP [41].
CPP are typically found incidentally. There are generally
regarded as painless, although there is a reported association
with angina-like pain [42–44]. Lung function in patients with
CPP demonstrates a minimal reduction in Total Lung Capacity
(TLC) and Vital Capacity (VC), unlikely to be of clinical signifi-
cance. Therefore, an alternative cause for breathlessness
should be sought when CPP are the only finding, as they are
not considered to have sufficient physiological impact to
cause shortness of breath [45]. Physical examination in
patients with CPP is usually normal. A pleural rub may be
present in a minority and is usually transient. The presence
of other signs, for example, crackles on chest auscultation,
should lead to an additional disease process being considered
(especially asbestosis).
At thoracoscopy, plaques are usually multiple, raised, white
areas on the parietal pleura, parallel to the ribs in the mid to
lower zones. Microscopically they are described as areas of
hyaline pleural fibrosis with a ‘basket weave’of collagen fibers
in parallel [46]. It is not advised to search for asbestos bodies
in pleural plaques as this is nearly always unsuccessful
although they are occasionally found [47]. It is rarely necessary
to biopsy pleural plaques unless there is suspicion regarding
mesothelioma (see below).
Benign asbestos-related pleural effusion (BAPE) is usually the
earliest disease seen after exposure to asbestos. This usually
occurs between 10 and 20 years after first exposure and is rare
after 25 years [48]. It is often found after investigation for
shortness of breath and pleuritic type pain. Many patients
are concerned and understandably anxious regarding the
possibility of MPM.
The aim of radiological imaging should be to identify pos-
sible malignancy.
Helical–multislice CT scanning (performed with contrast
enhancement in order to attempt differentiation of the under-
lying pleura from fluid), as well as ultrasound scanning to
characterize the fluid and pleura, should be undertaken.
Fluorodeoxyglucose Positive Emission Tomography (FDG-PET)
scanning is also helpful and can aid differentiation from malig-
nant pleural disease [49]. Clinical examination is usually con-
sistent with the imaging findings of a pleural effusion with
dullness to percussion and reduced intensity of breath and
voice sounds and vocal fremitus on the affected side.
Lung function tests vary depending on the size of the
effusion and should not delay further imaging as part of
investigation into an asbestos-exposed individual with an
undiagnosed pleural effusion. Examination of the pleural
fluid in BAPE will reveal an exudative effusion with negative
cytology for malignant cells. A diagnosis of BAPE usually
involves further investigation with thoracoscopy and biopsy
to exclude malignancy, followed by a period of observation
when the effusion may either resolve or not reoccur.
Diffuse pleural thickening (DPT) occurs in approximately
5–14% of asbestos-exposed workers, depending on their
exposure levels. Pleural thickening is not exclusively related
to asbestos exposure and other causes (such as old hae-
mothorax, tuberculosis, and empyema) should be considered
in the absence of an asbestos exposure history. A study from
the United Kingdom reported that 40% of subjects with DPT
had BAPE prior to a presentation [50]. It is usually differen-
tiated from CPP on plain CXR by the obliteration of the costo-
phrenic angles. On CT imaging it is easier to differentiate it
from extensive CPP by its involvement of both parietal and
visceral pleura and is generally a more continuous area of
thickening compared to CPP. DPT may be associated with
round (rolled) atelectasis and parenchymal bands or ‘crows
feet’on x-ray imaging. On pulmonary function testing, lung
volumes are usually found to be reduced and gas transfer
(DLCO) is usually normal with a high value when corrected
for alveolar volume (KCO) [45], reflecting extra-pulmonary
restriction. Progressive exertional shortness of breath is the
most common presentation. Physical examination may be
EXPERT REVIEW OF RESPIRATORY MEDICINE 243
normal and the presence of pain should lead to consideration
of pleural malignancy. Biopsy of DPT (either CT or ultrasound
guided) is non-specific, demonstrating architectural distortion
and extracellular protein deposition with findings similar to
pleural fibrosis from other causes.
Asbestosis (parenchymal fibrosis) demonstrates a significant
dose-response relationship with exposure to asbestos [38,51].
Those with lower exposures can still develop milder forms of
the disease, often with relative stability over time [52], how-
ever, those with greater exposure can develop more extensive
and progressive disease. Differences in host genetic suscept-
ibility to the development of disease is likely, but has not been
defined to date. Symptoms include progressive shortness of
breath, initially on exertion and dry cough (a cough typically
occurs in the later stages of the disease). Clinical examination
is typically characterized by late inspiratory crackles particu-
larly in the lower zones (although these are non-specific and
not required to make the diagnosis). Clubbing of the fingers
can also be present particularly later in the disease process.
On plain chest x-ray, asbestosis is characterized by small
irregular, linear interstitial shadowing, particularly in the lower
zones. High-Resolution CT scan is more sensitive to early
parenchymal and pleural changes [53–55]. Characteristic CT
findings are indistinguishable from those of usual interstitial
pneumonitis (UIP) and therefore idiopathic pulmonary fibrosis
(IPF). In the early stages of the disease, the changes are of
reticular, subpleural, curvilinear opacifications in the lower
zones and these progress to the middle and upper zones
with honeycomb formation and traction bronchial dilatation
in the latter stages of the disease (less commonly than in UIP
[56]) with subsequent loss of volume. More recently it has
been demonstrated that subtle changes consistent with asbes-
tosis can be reliably described on ultra-low dose CT [57],
increasing the utility of LDCT in screening for asbestos-
related diseases.
As with any undifferentiated interstitial lung disease, it is
important to consider alternative causes of parenchymal fibrosis
such as connective tissue diseases and adverse drug reactions.
As the parenchymal changes of asbestosis cannot be reliably
distinguished radiologically from IPF [56] this can lead to diag-
nostic dilemmas if there is any doubt surrounding the asbestos
exposure history, especially as anti-fibrotic therapy has been
proven to slow progression of IPF but has not been explored
in patients with asbestosis [58,59]. The coexistence of pleural
plaques is most helpful for identifying past asbestos exposure
but their absence does not exclude the diagnosis of asbestosis.
The most sensitive lung function test for asbestosis is the
measurement of gas transfer (DLCO) which can be abnormal
before the disease is visible on plain CXR or CT scan [60].
Spirometry demonstrates a progressive restrictive pattern
with a predominant reduction in FVC as well as a reduction
in total lung capacity. These changes may be altered by the
presence of other lung diseases, especially in cigarette smo-
kers and should be interpreted in the context of the history
and imaging findings.
Asbestosis is typically diagnosed on a clinico-radiological
basis without the need for lung biopsy as there is little to
differentiate asbestosis from IPF histologically, apart from the
presence of asbestos bodies (or fibers on electron microscopy).
Thoracoscopic lung biopsy may become useful in an atypical
presentation or if there are doubts surrounding the diagnosis,
however, a biopsy is not indicated to prove disease as part of
a claim for compensation (where an adequate history of expo-
sure is required). Histologically, changes of asbestosis are graded
between 1 and 4, as fibrosis progresses from the respiratory
bronchioles (1), to the alveoli (2). Destruction of the alveoli with
more widespread involvement is considered grade 3, with hon-
eycombing defining grade 4. The presence of asbestos bodies
and fibers, if found, can be helpful; however, these findings vary
between laboratories and there is (legal) disagreement surround-
ing the number of asbestos bodies that must be found per cubic
centimeter to define an adequate exposure and therefore asbes-
tos body counts are limited in their usefulness as part of the
diagnosis. Electron microscopy is required to find uncoated
fibers although this is seldom used in practice.
Round (rolled) atelectasis is commonly found associated
with diffuse pleural thickening and is thought to be related
to an indrawing of the lung parenchyma as a result of the
progressive fibrosis and contraction of the visceral pleura [61].
The invagination causes a characteristic ‘comets tail’appear-
ance. If appearances are not characteristic, investigation for an
indeterminate peripheral lung mass is indicated, usually
requiring FDG-PET scanning and/or CT guided biopsy.
2.2. Malignant disease
Malignant Pleural Mesothelioma (MPM) is often the major con-
cern of asbestos-exposed individuals: particularly those heavily
exposed in industries such as mining or construction, who
have seen former colleagues diagnosed and subsequently
die with this condition. Thus, it remains a major source of
anxiety due to the paucity of effective therapeutic options,
there being no evidence to support screening of those at-risk
[62]. Palliative chemotherapy has been shown to improve
survival by 2–3 months with similar results from a recent
study of immunotherapy [63]. Genetic analysis has not demon-
strated a single mesothelioma specific gene alteration that
alone would confirm a diagnosis, however has demonstrated
repeated occurrence of molecular alterations, most commonly
seen in BRCA1 associated protein 1 gene (BAP1), neurofibro-
min 2(NF2) and CDKN2A tumour suppressor genes, which has
led to hope of novel treatment targets and pathways [64].
The clinical presentation of MPM is often non-specific,
including progressive shortness of breath, weight loss, and
chest wall pain; the presence of chest wall pain in the pre-
sence of a pleural effusion should lead to prompt investigation
in an asbestos-exposed individual (even one with minimal
exposure to asbestos as there is no level of exposure below
which there is no risk and no other exposure which has been
demonstrated to cause MPM).
Spirometry is usually impaired but is not specific for MPM
compared to other causes of pleural effusion/pleural thickening,
e.g., BAPE/DPT. Plain CXR performed as part of investigation
most frequently demonstrates a pleural effusion or pleural
thickening. Contrast CT (with delayed contrast administration
to enhance the pleura) may demonstrate a pleural effusion and/
or nodular pleural thickening, particularly involving the
244 E. J. A. HARRIS ET AL.
mediastinal pleura. MRI scanning has not been shown to confer
any additional benefit in differentiating malignant from benign
pleural disease when compared to contrast CT, although it is
sometimes used in some centers where surgical therapy is still
practised for mesothelioma. MPM demonstrates hyperintensity
on T2 weighted imaging and enhances following intravenous
gadolinium contrast on T1 weighted images [65]. Therefore, as
part of a diagnostic workup, it is rare that MRI adds further
information to CT with contrast.
FDG-PET scanning can be helpful in the diagnosis of MPM,
particularly in differentiation between benign and malignant
pleural disease. A Standardized Uptake Value (SUV) below 2.2
has a high predictive value for benign disease [66]. Dual-time-
point (60 and 120 min) FDG-PET has been demonstrated to
differentiate malignant from benign pleural disease [67,68].
FDG avidity in malignant disease typically increased between
the time-points whereas in benign disease avidity typically
remained stable or decreases. It may also be used to monitor
response to treatment. A study is currently assessing the use
of FDG-PET, targeting areas of high uptake in order to increase
biopsy yield [69] if pleural fluid cytology is unhelpful or pleural
fluid aspiration is not possible.
Ultimately, in order to make a firm diagnosis of primary or
metastatic malignant pleural disease histological/cytological
sampling is required. Pleural aspiration or fine needle biopsy
of the pleura, with cytological examination, is the most com-
mon initial investigation. Differentiation of MPM (particularly
epithelioid containing) from reactive mesothelial hyperplasia,
adenocarcinoma, and poorly differentiated squamous cell car-
cinoma is required. In an experienced, specialized laboratory,
cytology alone is sufficient for a diagnosis of MPM [70,71], with
the formation of a cell block using cytocentrifugation, with
paraffin-embedded material available for immunohistochem-
ical and molecular studies.
Cytological examination of pleural fluid will only identify
the epithelioid subtype of mesothelioma [71], and therefore
an initial ‘negative’cytological investigation will require
a solid tissue biopsy for the sarcomatoid and most biphasic
variants, usually with thoracoscopy or an ultrasound or CT
guided approach. MPM specimens may have heterogeneity
of cellular subtype [72], but this is unlikely to affect
a diagnosis of malignancy.
One of the major challenges in the histopathological diag-
nosis of MPM is that all subtypes can be difficult to differentiate
from other tumors with similar histological appearances.
Advances in immunohistochemical markers in the last
20 years have significantly changed the confidence and mod-
ality in diagnosing MPM, with the use of an electron micro-
graph now extremely rare. Markers such as calretinin, CK5/6,
D240, mesothelin, and WT1, as well as more specific glandular
markers, for example, TTF1 (lung), PAX8 (gynecological tract,
kidney, thyroid) can reliably distinguish between adenocarci-
noma and mesothelioma.
The most promising biomarkers for MPM found in serum
include mesothelin and its related peptides (also secreted by
pancreatic, lung and ovarian tumors) as well as osteopontin
and fibulin-3. However, these markers demonstrate relatively
poor sensitivity and specificity and further work is required,
likely in combination with newer biomarkers including
microRNA and proteomics in order to build a panel to allow
early diagnosis accurately.
Lung Cancer risk has been shown to be increased following
exposure to all asbestos fiber types and risk has been shown
to increase with increased exposure [18,73]. It has been esti-
mated that as many die from asbestos-related lung cancer as
die from MPM [74]. In some studies the number of deaths is
estimated to be up to twice that of MPM [75–77], however,
this ratio has proven difficult to estimate due to the associa-
tion with tobacco smoke and other carcinogens, and any
increased risk from asbestos exposure is difficult to estimate
due to lack of precise estimates of exposure and different
relative amounts of amphibole and chrysotile exposure. The
increased relative risk of lung cancer after asbestos exposure
in a never smoker is estimated between 1.18 and 2.8. When
this is combined with tobacco smoking the risk estimate
increases to between 5.6 and 25.2 times, demonstrating
a synergistic effect which is greater than the addition of
their risks, up to a multiplicative increase in risk [78–80].
The clinical presentation of lung cancer in asbestos-
exposed individuals is the same as for non-exposed individuals
although there may be a greater awareness of potential symp-
toms and signs if other asbestos-related lung disease has been
identified from previous imaging. Symptoms vary depending
on the anatomical location of the disease and the subsequent
progression. Histologically asbestos exposure causes all types
of lung cancer [35,81]. Relatively more cases of adenocarci-
noma have been detected in recent studies although this
appears to be a worldwide observation. There is no alteration
of anatomical lung cancer distribution in the asbestos-
exposed [76,81,82]. Clinical evaluation and investigation are
the same as for any suspected lung cancer or indeterminate
pulmonary nodule.
The 2015 Helsinki consensus encouraged further investi-
gation into low-dose computed tomography (LDCT) screen-
ing for lung cancer in asbestos-exposed individuals,
following the reduction in mortality demonstrated in high-
risk subjects taking part in the US national lung screening
trial (NLST). It recommended screening if their risk was similar
to that of those in the NLST, however establishing the level of
risk in these individuals is complex due to the relationship
between asbestos exposure and tobacco smoking history
[52]. Ongoing research is looking to establish an appropriate
level of asbestos exposure, which when combined with
smoking history would lead to criteria for inclusion in
a lung cancer screening program.
3. Conclusion
Exposure to asbestos causes a range of lung diseases which
are often challenging to diagnose, especially due to the delay
between exposure and development of disease as well as the
mimicry of benign pleural disease when MPM can present in
a similar fashion. Attention to detail in the clinical and occupa-
tional history as well as appropriate and timely imaging is
important as well as considering that an alternative disease
process other than one due to asbestos exposure may be
responsible for the clinical presentation.
EXPERT REVIEW OF RESPIRATORY MEDICINE 245
Many individuals who have been exposed to asbestos will
be aware of their increased risk of asbestos-related lung
diseases, particularly mesothelioma, and therefore any
abnormal symptoms may generate a great deal of anxiety
for them and it is important to address these concerns as
part of specialist assessment.
4. Expert commentary
There are several areas where further work is required to
address limitations in current management. With Asbestosis
having a similar histological appearance to idiopathic pulmon-
ary fibrosis (IPF) and with the recent trials of anti-fibrotic
therapy, now licenced for IPF, slowing decline in FVC and
6-min walk distance after treatment with pirfenidone and
nintedanib [83,84], there is an unmet need for these novel
agents to be trialed in those with progressive asbestosis.
Clinicians dealing with potential asbestos-related diseases
need to have a clear awareness of possible sources of asbestos
exposure, in particular ‘para-occupational’exposures such as
exposure in the home from others working in at-risk trades, or
a history of ‘DIY’exposure from renovating old (asbestos con-
taining) houses.
Despite some promising advances in immunotherapy in the
treatment of MPM [63], there is need to develop more effective
agents and define a clear role for immunotherapy in the man-
agement of MPM. Stratification of prognosis in MPM (which is
possible using routinely collected clinical measures [85,86]) may
allow for better, personalized treatment plans including sys-
temic anti-cancer therapy and/or immunotherapy regimes.
MPM has a long latency with clearly defined populations at
risk. Despite this, there is no defined role for screening asbes-
tos-exposed populations as there is still no effective treatment
and at present no effective biomarker of risk, or indicator of
early disease. Despite clear heterogeneity in risk within asbes-
tos-exposed populations for the development of MPM, and
only one known carcinogen, genetic susceptibility/protection
is still poorly understood.
Further research may yield novel chemotherapy agents for
MPM which will offer hope of survival greater than the median
9–12 months currently afforded by standard first-line cisplatin/
permetrexed based chemotherapy regimes [87].
Research could also yield an effective biomarker for
mesothelioma which could facilitate pre-symptomatic diagno-
sis and could aid (and speed) diagnosis of pleural thickening
or undiagnosed pleural effusion and differentiate benign from
malignant disease. The discovery of markers of genetic risk (or
protection) in future will lead to an improved biological under-
standing of the pathobiological processes in the development
of MPM. The major challenge and obstacle is the rarity of the
disease in the general population and the need for very large
datasets to achieve such progress.
The effectiveness of lung cancer screening, in general, relies
on defining an at-risk population and defining the appropriate
group suitable for Lung Cancer screening in this population will
require expert consideration [52]. The US National
Comprehensive Cancer Network (NCCN) guidelines for lung can-
cer screening arbitrarily reduce the smoking requirement for
lung cancer screening from 30 to 20 pack years once exposed
to asbestos [88]. A research cohort of 1751 asbestos-exposed
individuals in Western Australia [89], have been undergoing
annual LDCT screening for the asbestos-related disease since
2012 and only 63% were ever smokers. Five (29%) of the 17
lung cancers detected over a 5-year period were in never smo-
kers. Many of those screened as part of this study would not be
eligible for lung cancer screening under NCCN criteria. This may
be a signal that in those heavily asbestos-exposed, a bespoke risk
calculator will need to be created to better select those at risk.
Ongoing work to better define at-risk asbestos-exposed indivi-
duals with low or no tobacco exposure will help identify addi-
tional cohorts which may benefit from low dose CT screening of
the chest detecting early lung cancer.
From a clinical perspective, the potential role of immu-
notherapy offers most short-term promise for an advance in
clinical care for mesothelioma.
There is increasing interest in tumor microRNA which may
lead to advances in understanding disease mechanisms for
MPM and also lung cancer in asbestos-exposed never smokers.
The potential association of asbestos exposure and autoim-
mune dysfunction remains an interesting area of unmet need.
‘Libby’amphibole cohorts have high levels of autoimmune dis-
ease –systemic lupus erythematosus, scleroderma etc. Lung
disease associated with this amphibole –‘Libby Amphibole
Disease’seems to have an autoimmune component [90].
The use of computer-aided detection (CAD) in CT screening
for pulmonary nodules is also an area of research interest –
the application of this to an asbestos-exposed cohort will be
useful as pleural plaques may well be confused by the soft-
ware for parenchymal abnormalities. A learning algorithm
applied to this detection software may lead to the develop-
ment of automated CT reading software in the future.
5. Five-year view
An asbestos-exposed cohort (described above) is currently
being screened for asbestos-related disease in Western
Australia. This involves performing ultra-low-dose CT scans
on those with a minimum of three months full-time work
exposure to asbestos or the presence of pleural plaques as
evidence of significant asbestos exposure. Currently, all sub-
jects undergo screening including those non-smokers who are
likely to be at a lower risk of lung cancer given the combined
malignant effect of these two exposures.
Further research and development of the screening program
are anticipated, so that those at highest risk of lung cancer are
imaged and followed up more frequently to allow early detec-
tion of primary lung cancer in order to treat with curative
intent. Those at lower risk, i.e., never smokers are still at
increased risk and the program will hopefully give an indication
regarding the optimum frequency of screening for this group.
Important questions that need to be addressed are: who to
screen as part of an asbestos screening programme i.e. at what
level of exposure and at what age should this be instigated? This
becomes more relevant now LDCT scans are delivering radiation
doses similar to that of a chest X-ray series [41].
There should be further population-based education to
increase awareness of the dangers of all types of asbestos, in
246 E. J. A. HARRIS ET AL.
particular, safe asbestos removal and disposal practices, lead-
ing to a reduction in exposure and hence disease.
Targeted therapies will be developed for mesothelioma
and thus make early detection of this disease beneficial clini-
cally instead of simply conferring a lead-time bias in patient
survival. Research is ongoing into immune targets susceptible
to immunotherapy in the future.
The detection of circulating microRNA sequences for use as
a potential biomarker to detect MPM requires further work to
establish its clinical relevance, particularly in asbestos-exposed
never smokers.
There is currently a randomized controlled trial of surgery
for MPM as previous trials have not demonstrated any benefit
from surgery [91]. A definitive answer for this question should
be reached with the completion of this trial as surgery is still
practised in some centers even in the absence of good evi-
dence of survival benefit.
Over the coming decade the peak of those exposed to
asbestos around 40 years ago will pass and with this there
should be an ongoing reduction in the incidence of all asbes-
tos-related diseases.
Key issues
●Asbestos exposure remains a present threat within the built
environment of many developed countries. Although,
intensity and duration of exposure are much higher histori-
cally, (for most individuals) than at current levels.
●Most benign asbestos-related disease can be diagnosed
with an adequate (exposure) history and radiological ima-
ging. There is no treatment required (or available) for most
asbestos-related diseases.
●Cytological examination of pleural fluid can reliably diag-
nose the epithelioid subtype of mesothelioma although
biopsy is required in cases of doubt or with sarcomatoid-
containing tissue.
●The treatment of mesothelioma continues to be
a challenge. Lung cancer is managed in the same way
regardless of underlying exposures. The early detection of
lung cancer through screening with ultra-low-dose CT holds
some promise for asbestos-exposed populations, although
work is required to define a suitably high-risk population, in
order to benefit from screening.
Funding
This paper was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
Reviewers disclosure
Peer reviewers on this manuscript have no relevant financial relationships
or otherwise to disclose.
ORCID
Nicholas de Klerk http://orcid.org/0000-0001-9223-0767
Alison Reid http://orcid.org/0000-0002-1202-7150
References
Papers of special note have been highlighted as either of interest (•)orof
considerable interest (••) to readers.
1. Ross M, Nolan R. History of asbestos discovery and use and
asbestos-related disease in context with the occurrence of asbestos
within ophiolite complexes. Geological Society of America, Special
Paper 373; 2003. p. 447–470.
2. Luus K. Asbestos: mining exposure, health effects and policy
implications. Mcgill J Med. 2007;10:121–126.
3. Scarpa L. The asbestos industry and tuberculosis. Proceedings of
the 18th Conference on Internal Medicine; 1908; Rome. (Ed.^(Eds).
p. 358–359
4. Tweedale G, Hansen P. Protecting the workers: the medical board and
the asbestos industry, 1930s-1960s. Med Hist. 1998;42:439–457.
5. Department GBHO. Report on conferences between employers and
inspectors concerning methods for suppressing dust in asbestos
textile factories. London: H. M. Stationery off.; 1931.
6. Doll R. Mortality from lung cancer in asbestos workers. Br J Ind
Med. 1955;12:81–86.
•Historical epidemiological study of asbestos exposure and its
association with lung cancer.
7. Wagner JC, Sleggs CA, Marchand P. Diffuse pleural mesothelioma
and asbestos exposure in the North Western Cape Province. Br
J Ind Med. 1960;17:260–271.
•Original epidemiological study of malignant mesothelioma by
a pathologist.
8. Hillerdal G, Lindgren A. Pleural plaques: correlation of autopsy
findings to radiographic findings and occupational history. Eur
J Respir Dis. 1980;61:315–319.
9. Churg A. Asbestos fibers and pleural plaques in a general autopsy
population. Am J Pathol. 1982;109:88–96.
10. Eisenstadt HB. Benign asbestos pleurisy. JAMA. 1965;192:419–421.
11. Elmes PC. The epidemiology and clinical features of asbestosis and
related diseases. Postgrad Med J. 1966;42:623–635.
12. Selikoff IJ, Churg J, Hammond E. Asbestos exposure and neoplasia.
JAMA. 1964;188:22–26.
13. Hodgson JT, Darnton A. Mesothelioma risk from chrysotile. Occup
Environ Med. 2010;67:432.
14. Baur X, Schneider J, Woitowitz HJ, et al. Gibt es Unterschiede in den
gesundheitsschädlichen Wirkungen von Chrysotil- und Amphibol-
Asbest? Pneumologie. 2012;66:497–506.
15. Lippmann M. Effects of fiber characteristics on lung deposition,
retention, and disease. Environ Health Perspect. 1990;88:311–317.
16. Berman DW, Crump KS. A meta-analysis of asbestos-related cancer
risk that addresses fiber size and mineral type. Crit Rev Toxicol.
2008;38:49–73.
17. Churg A, Wright JL. Persistence of natural mineral fibers in human
lungs: an overview. Environ Health Perspect. 1994;102(Suppl
5):229–233.
18. Musk AW, de Klerk NH, Reid A, et al. Mortality of former crocidolite
(blue asbestos) miners and millers at Wittenoom. Occup Environ
Med. 2008;65:541–543.
•Epidemiological study of a unique cohort exposed only to
crocidolite.
19. Churg A, Wright JL, Tazelaar HD. Acute exacerbations of fibrotic
interstitial lung disease. Histopathology. 2011;58:525–530.
20. Hodgson JT, Darnton A. The quantitative risks of mesothelioma and
lung cancer in relation to asbestos exposure. Ann Occup Hyg.
2000;44:565–601.
•Describes relative potency of different forms of asbestos in
causing asbestos-related diseases.
21. Hillerdal G, Zitting A, van Assendelft AH, et al. Rarity of mineral
fibre pleurisy among persons exposed to Finnish anthophyllite and
with low risk of mesothelioma. Thorax. 1984;39:608–611.
EXPERT REVIEW OF RESPIRATORY MEDICINE 247
22. Straif K, Benbrahim-Tallaa L, Baan R, et al. A review of human
carcinogens–part C: metals, arsenic, dusts, and fibres. Lancet
Oncol. 2009;10:453–454.
23. Lacourt A, Lévêque E, Guichard E, et al. Dose-time-response asso-
ciation between occupational asbestos exposure and pleural
mesothelioma. Occup Environ Med. 2017;74:691–697.
24. Oddone E, Imbriani M. Pleural mesothelioma: case-report of
uncommon occupational asbestos exposure in a small furniture
industry. Int J Occup Med Environ Health. 2016;29:523–526.
25. Cookson WO, de Klerk NH, Musk AW, et al. The natural history of
asbestosis in former crocidolite workers of Wittenoom Gorge. Amer
Rev Respir Dis. 1986;133:994–998.
•Describes progression of asbestos-related diseases many years
after cessation of exposure.
26. Musk AW, de Klerk NH, Eccles JL, et al. Wittenoom, Western
Australia: a modern industrial disaster. Am J Ind Med.
1992;21:735–747.
27. Hodgson JT, McElvenny DM, Darnton AJ, et al. The expected bur-
den of mesothelioma mortality in Great Britain from 2002 to 2050.
Br J Cancer. 2005;92:587–593.
28. de Klerk N, Armstrong B. The epidemiology of asbestos and
mesothelioma. Henderson D, Shilkin K, Langlois S, et al. editors
New York (NY): Hemisphere; 1992.
29. van Oyen SC, Peters S, Alfonso H, et al. Development of a
Job-Exposure Matrix (AsbJEM) to estimate occupational exposure
to asbestos in Australia. Ann Occup Hyg. 2015;59:737–748.
30. Burdorf A, Swuste P. An expert system for the evaluation of histor-
ical asbestos exposure as diagnostic criterion in asbestos-related
diseases. Ann Occup Hyg. 1999;43:57–66.
31. Reid A, Franklin P, Olsen N, et al. All-cause mortality and cancer
incidence among adults exposed to blue asbestos during
childhood. Am J Ind Med. 2013;56:133–145.
•Demonstrated that childhood asbestos exposure can lead to
malignant mesothelioma later in life.
32. Olsen NJ, Franklin PJ, Reid A, et al. Increasing incidence of malig-
nant mesothelioma after exposure to asbestos during home main-
tenance and renovation. Med J Aust. 2011;195:271–274.
33. ILO. International Labour Office. Guidelines for the use of ILO
international classification of radiographs of pneumoconioses.
Geneva: ILO; 1980.
34. Kusaka Y, Hering KG, Parker JE. International classification of HRCT
for occupational and environmental respiratory diseases. Tokyo:
Springer; 2005.
35. Asbestos, asbestosis, and cancer: the Helsinki criteria for diagnosis
and attribution.Scand J Work Environ Health. 1997;23:311–316.
•• Collaborative opinion of the risks of asbestos-related diseases
and aims of future research.
36. Suganuma N, Kusaka Y, Hering KG, et al. Reliability of the proposed
international classification of high-resolution computed tomogra-
phy for occupational and environmental respiratory diseases.
JOccup Health. 2009;51:210–222.
37. Sparks JV. Pulmonary Asbestosis. Radiology. 1931;17:1249–1257.
38. Paris C, Thierry S, Brochard P, et al. Pleural plaques and asbestosis:
dose- and time-response relationships based on HRCT data. Eur
Respir J. 2009;34:72–79.
39. Larson TC, Meyer CA, Kapil V, et al. Workers with Libby amphibole
exposure: retrospective identification and progression of radio-
graphic changes. Radiology. 2010;255:924–933.
40. Ameille J, Brochard P, Brechot JM, et al. Pleural thickening:
a comparison of oblique chest radiographs and high-resolution
computed tomography in subjects exposed to low levels of asbes-
tos pollution. Int Arch Occ Env Hea. 1993;64:545–548.
41. Brims FJ, Murray CP, de Klerk N, et al. Ultra-low-dose chest com-
puter tomography screening of an asbestos-exposed population in
Western Australia. Am J Respir Crit Care Med. 2015;191:113–116.
42. Mukherjee S, de Klerk N, Palmer LJ, et al. Chest pain in
asbestos-exposed individuals with benign pleural and parenchymal
disease. Am J Respir Crit Care Med. 2000;162:1807–1811.
43. Allen R, Cramond T, Lennon D, et al. A retrospective study of
chest pain in benign asbestos pleural disease. Pain Med.
2011;12:1303–1308.
44. Park EK, Thomas PS, Wilson D, et al. Chest pain in asbestos and
silica-exposed workers. Occup Med (Lond). 2011;61:178–183.
45. Copley SJ, Wells AU, Rubens MB, et al. Functional consequences of
pleural disease evaluated with chest radiography and CT.
Radiology. 2001;220:237–243.
•Documented the effect of pleural disease on lung function.
46. Jones JS. The pleura in health and disease. Lung.
2001;179:397–413.
47. Bignon J, Monchaux G, Sebastien P, et al. Human and experimental
data on translocation of asbestos fibers through the respiratory
system. Ann N Y Acad Sci. 1979;330:745–750.
48. Cookson WO, De Klerk NH, Musk AW, et al. Benign and malignant
pleural effusions in former Wittenoom crocidolite millers and
miners. Aust N Z J Med. 1985;15:731–737.
49. Nakajima R, Abe K, Sakai S. Diagnostic ability of FDG-PET/CT in the
detection of malignant pleural effusion. Medicine (Baltimore).
2015;94:e1010.
50. Jeebun V, Stenton SC. The presentation and natural history of
asbestos-induced diffuse pleural thickening. Occup Med (Lond).
2012;62:266–268.
51. Mastrangelo G, Ballarin MN, Bellini E, et al. Asbestos exposure and
benign asbestos diseases in 772 formerly exposed workers:
dose-response relationships. Am J Ind Med. 2009;52:596–602.
52. Wolff H, Vehmas T, Oksa P, et al. Asbestos, asbestosis, and cancer,
the Helsinki criteria for diagnosis and attribution 2014:
recommendations. Scand J Work Environ Health. 2015;41:5–15.
•• Further collaborative effort, guiding research direction in the
field and highlighting dangers of asbestos-related disease.
53. Mathieson JR, Mayo JR, Staples CA, et al. Chronic diffuse infiltrative
lung disease: comparison of diagnostic accuracy of CT and chest
radiography. Radiology. 1989;171:111–116.
54. Wells AU. High-resolution computed tomography in the diagnosis
of diffuse lung disease: a clinical perspective. Semin Respir Crit Care
Med. 2003;24:347–356.
55. Te K Jr. Clinical advances in the diagnosis and therapy of the inter-
stitial lung diseases. Am J Respir Crit Care Med. 2005;172:268–279.
56. Arakawa H, Kishimoto T, Ashizawa K, et al. Asbestosis and other
pulmonary fibrosis in asbestos-exposed workers: high-resolution
CT features with pathological correlations. Eur Radiol.
2016;26:1485–1492.
•Analysis attempts to distinguish idiopathic pulmonary fibrosis
from asbestosis.
57. Manners D, Wong P, Murray C, et al. Correlation of ultra-low dose
chest CT findings with physiologic measures of asbestosis. Eur
Radiol. 2017;27:3485-3490.
58. McAllister D, Mathur A, Wright P, et al. The natural history of
asbestosis and idiopathic pulmonary fibrosis according to HRCT
phenotype. QJM. 2016;109:S5–S6.
59. Veijola A, Kaarteenaho R, Lehtonen S. Effect of nintedanib, pirfeni-
done, N-acetylcysteine and their combinations on cultured
myofibroblast-type cells derived from patients with asbestosis
and idiopathic pulmonary fibrosis. Eur Respir J. 2015;46 (supp 59):
PA893.
60. Lee YC, Singh B, Pang SC, et al. Radiographic (ILO) readings predict
arterial oxygen desaturation during exercise in subjects with
asbestosis. Occup Environ Med. 2003;60:201–206.
61. Hillerdal G. Rounded atelectasis. Clinical experience with 74
patients. Chest. 1989;95:836–841.
62. Succony L, Blyth KG, Rintoul RC. There is insufficient evidence to
support a screening programme for malignant pleural
mesothelioma. Shanghai Chest. 2018;2.
63. Zalcman G, Mazieres J, Margery J, et al. Bevacizumab for newly
diagnosed pleural mesothelioma in the Mesothelioma Avastin
Cisplatin Pemetrexed Study (MAPS): a randomised, controlled,
open-label, phase 3 trial. Lancet. 2016;387:1405–1414.
248 E. J. A. HARRIS ET AL.
•Chemotherapeutic trial for malignant mesothelioma - poor
response demonstrated.
64. Hylebos M, Van Camp G, van Meerbeeck JP, et al. The genetic
landscape of malignant pleural mesothelioma: results from
massively parallel sequencing. J Thorac Oncol. 2016;11:
1615–1626.
65. Boraschi P, Neri S, Braccini G, et al. Magnetic resonance appearance
of asbestos-related benign and malignant pleural diseases. Scand
J Work Environ Health. 1999;25:18–23.
66. Yildirim H, Metintas M, Entok E, et al. Clinical value of
fluorodeoxyglucose-positron emission tomography/computed
tomography in differentiation of malignant mesothelioma from
asbestos-related benign pleural disease: an observational pilot
study. J Thorac Oncol. 2009;4:1480–1484.
67. Mavi A, Basu S, Cermik TF, et al. Potential of dual time point
FDG-PET imaging in differentiating malignant from benign pleural
disease. Mol Imaging Biol. 2009;11:369–378.
68. Yamamoto Y, Kameyama R, Togami T, et al. Dual time point FDG
PET for evaluation of malignant pleural mesothelioma. Nucl Med
Commun. 2009;30:25–29.
69. de Fonseka D, Underwood W, Stadon L, et al. Randomised con-
trolled trial to compare the diagnostic yield of positron emission
tomography CT (PET-CT) TARGETed pleural biopsy versus
CT-guided pleural biopsy in suspected pleural malignancy
(TARGET trial). BMJ Open Respir Res. 2018;5:e000270.
70. Segal A, Sterrett GF, Frost FA, et al. A diagnosis of malignant pleural
mesothelioma can be made by effusion cytology: results of a 20 year
audit. Pathology. 2013;45:44–48.
71. Muruganandan S, Alfonso H, Franklin P, et al. Comparison of out-
comes following a cytological or histological diagnosis of malig-
nant mesothelioma. Br J Cancer. 2017;116:703–708.
72. Bueno R, Reblando J, Glickman J, et al. Pleural biopsy: a reliable
method for determining the diagnosis but not subtype in
mesothelioma. Ann Thorac Surg. 2004;78:1774–1776.
73. McGuire S. World cancer report 2014. Geneva, Switzerland: World
Health Organization, International Agency for Research on Cancer,
WHO Press, 2015. Adv Nutr. 2016;7:418–419.
74. Darnton AJ, McElvenny DM, Hodgson JT. Estimating the number of
asbestos-related lung cancer deaths in Great Britain from 1980 to
2000. Ann Work Expo Health. 2006;50:29–38.
75. Driscoll T, Nelson DI, Steenland K, et al. The global burden of
disease due to occupational carcinogens. Am J Ind Med.
2005;48:419–431.
76. Henderson DW, Rodelsperger K, Woitowitz HJ, et al. After Helsinki:
a multidisciplinary review of the relationship between asbestos
exposure and lung cancer, with emphasis on studies published
during 1997–2004. Pathology. 2004;36:517–550.
77. McCormack V, Peto J, Byrnes G, et al. Estimating the
asbestos-related lung cancer burden from mesothelioma
mortality. Br J Cancer. 2012;106:575–584.
78. Markowitz SB, Levin SM, Miller A, et al. Asbestos, asbestosis, smok-
ing, and lung cancer. New findings from the North American
insulator cohort. Am J Respir Crit Care Med. 2013;188:90–96.
79. Lee PN. Relation between exposure to asbestos and smoking jointly
and the risk of lung cancer. Occup Environ Med. 2001;58:145–153.
80. de Klerk NH, Musk AW, Armstrong BK, et al. Smoking, exposure to
crocidolite, and the incidence of lung cancer and asbestosis. Br
J Ind Med. 1991;48:412–417.
81. Nielsen LS, Baelum J, Rasmussen J, et al. Occupational asbestos
exposure and lung cancer–a systematic review of the literature.
Arch Environ Occup Health. 2014;69:191–206.
82. Hillerdal G, Henderson DW. Asbestos, asbestosis, pleural plaques
and lung cancer. Scand J Work Environ Health. 1997;23:93–103.
83. Te K Jr., Wz B, Castro-Bernardini S, et al. A phase 3 trial of pirfeni-
done in patients with idiopathic pulmonary fibrosis. N Engl J Med.
2014;370:2083–2092.
84. Richeldi L, Du Bois RM, Raghu G, et al. Efficacy and safety of
nintedanib in idiopathic pulmonary fibrosis. N Engl J Med.
2014;370:2071–2082.
85. Brims FJ, Meniawy TM, Duffus I, et al. A novel clinical prediction
model for prognosis in malignant pleural mesothelioma using
decision tree analysis. J Thorac Oncol. 2016;11:573–582.
86. Harris EJA, Kao S, McCaughan B, et al. Prediction modelling using
routine clinical parameters to stratify survival in malignant pleural
mesothelioma patients undergoing cytoreductive surgery. J Thorac
Oncol. 2019;14:288-293.
87. Nowak AK. Chemotherapy for malignant pleural mesothelioma:
a review of current management and a look to the future. Ann
Cardiothorac Surg. 2012;1:508–515.
88. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mor-
tality with low-dose computed tomographic screening. N Engl
J Med. 2011;365:395–409.
•• First demonstrated a mortality benefit from LDCT screening
for lung cancer in high risk population.
89. Harris E, Murray C, Franklin P, et al. Lung cancer screening in the
Western Australian asbestos review program. Respirology.
2018;23:21–103.
90. Marchand LS, St-Hilaire S, Putnam EA, et al. Mesothelial cell and
anti-nuclear autoantibodies associated with pleural abnormalities
in an asbestos exposed population of Libby MT. Toxicol Lett.
2012;208:168–173.
91. Hayama M, Izumo T, Matsumoto Y, et al. Complications with endo-
bronchial ultrasound with a guide sheath for the diagnosis of
peripheral pulmonary lesions. Respiration. 2015;90:129–135.
EXPERT REVIEW OF RESPIRATORY MEDICINE 249
