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MINI-SYMPOSIUM: PATHOLOGY OF NON-NEOPLASTIC LUNG DISEASE

The pathology of asbestosis are straight and rigid with long biopersistence in tissues (years to
decades) whereas chrysotile fibres are curled, pliable with short
biopersistence in tissues (weeks to months) (Figures 1e3). The
Richard L Attanoos
persistence of respirable bio-active fibres is the single most
Allen R Gibbs important factor in the development of asbestos-related diseases
whether neoplastic or non-neoplastic. Because of its physico-
chemical properties, chrysotile asbestos is most suitable for
making fabrics, other flexible items and also used in friction
Abstract product manufacture. The amphiboles with superior chemical
The term asbestosis refers to diffuse interstitial pulmonary fibrosis conse-
and physical stability were used often with chrysotile to make
quent to the excess inhalation of asbestos fibres. It is a disease associ-
various asbestos-cement products, insulation pipes and boards,
ated with heavy cumulative asbestos dose and the latent period, from
roofing and fire-proofing materials.
initial exposure to disease manifestation, is long usually 20 years or
Historically, asbestosis was the first asbestos-related disease
more, with an inverse correlation with dose. Because heavy industrial ex-
recognized. Dr. Montague Murray, has been generally credited as
posures have diminished the incidence of asbestosis has decreased.
the first person to report the disease in 1899, with the term
Asbestosis is a divisible disease with the frequency and severity of dis-
asbestosis coined in 1925 by Oliver and again used in 1927 by
ease correlating with cumulative asbestos dose. Disease severity also cor-
Cooke.2 The links between asbestos and lung cancer in the
relates with asbestos fibre type (amphiboles more potent than
presence of asbestosis were suggested and disputed a decade
commercial chrysotile), immune and genetic factors. Pathologically,
later and firmly established in 1955 by Doll.3,4 For mesothelioma
there are two components to the diagnostic criteria which must be met:
the association with asbestos was suggested in 1960 by Wagner
first, the presence of diffuse interstitial lung fibrosis of an appropriate
and co-workers in his case series of persons in the crocidolite
pattern; and second, some tissue marker of excess asbestos inhalation
mining district of Griqualand West in the North West Province of
either requisite numbers of asbestos bodies (as determined by light mi-
South Africa.5
croscopy) or elevated asbestos fibres (as determined by mineral anal-
The adverse risks of asbestosis have been effectively
ysis). The clinical picture is not specific although in contrast to
controlled by the workplace changes introduced by the 1931
idiopathic pulmonary fibrosis, which is the most frequent diagnostic prob-
Asbestos regulations and again by the more stringent 1969
lem, asbestosis has a slowly progressive course over decades. Lung can-
Asbestos regulations. These allowed the continued use of
cer occurs at cumulative asbestos doses similar to that necessary to
asbestos only if maximum allowable concentrations of dust were
cause lung fibrosis (asbestosis). The main differential diagnoses with
not exceeded and if other precautions were maintained. In the
asbestosis are idiopathic pulmonary fibrosis, pulmonary fibrosis associ-
1970s, 1980s, and 1990s further restrictions, both voluntary and
ated with connective tissue disorders, chronic phase hypersensitivity
statutory, were placed on the importation and use of asbestos.
pneumonitis and silicate (mica, talc, kaolin) pneumoconiosis.
This has resulted in a dramatic decrease in the number of
symptomatic cases of asbestosis in the developed countries. In
Keywords asbestos; asbestosis; interstitial lung disease; pathology July 1999, the European Commission announced a European
Union ban on all remaining chrysotile use by 1 January 2005. In
the United States, Occupational Safety and Health Administration
(OHSA) introduced a range of controls for asbestos. The current
Introduction OSHA airborne permissible exposure limit (PEL) (introduced in
1994) is set at 0.1 fibre/ml (for all fibre types). Life-long exposure
Asbestos is a general term applied to certain fibrous forms of
to asbestos at these permissible levels is considered sufficient to
various silicate minerals which have crystallized in nature pro-
prevent the manifestation of asbestosis.
ducing fibres of high tensile strength and flexibility, a feature
It has long been known that amphibole asbestos dust expo-
which is important in its commercial applications.1 Asbestos
sure constitutes a significant danger to health. However, some
occurs in one of two forms: serpentine and amphibole. Chrysotile
critical issues still remain in scientific dispute, including the
is the only serpentine form of asbestos and comprises 90% of all
relative hazards of different types of asbestos and whether there
asbestos used in most countries. The major amphiboles that have
is a safe level of exposure to any of them. Nowadays, the major
been used commercially are amosite, crocidolite, anddto a much
adverse health effects of asbestos are related to increased risk of
lesser degreedanthophyllite. Non-commercial amphiboles
cancer especially malignant pleural mesothelioma following low
include tremolite and actinolite. The physicochemical differences
dose exposures from brief, intermittent sources to amphibole
between amphiboles and chrysotile are distinct and underpin
asbestos in populations of persons previously not considered ‘at
their significant different biological toxicities. Amphibole fibres
risk’ of developing fatal asbestos-related diseases.

Clinico-radiological features
Richard L Attanoos BSc MB BS FRCPath is a Consultant Histopathologist at The clinical presentation of asbestosis is typically insidious with
University Hospital, Llandough, Cardiff, UK. Conflicts of interest: none shortness of breath on exertion and a dry cough. Auscultation
declared. may reveal late inspiratory crackles initially in the postero-lateral
regions of the lower zones but later becoming more widespread
Allen R Gibbs MB BCH FRCPath is a Consultant Histopathologist at University as the disease progresses. In advanced stages cyanosis and
Hospital, Llandough, Cardiff, UK. Conflicts of interest: none declared. cardiorespiratory failure may occur.

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MINI-SYMPOSIUM: PATHOLOGY OF NON-NEOPLASTIC LUNG DISEASE

Figure 1 Chrysotile asbestos fibres (TEM). Figure 3 Crocidolite asbestos fibres (TEM).

Lung function tests show a restrictive pattern with impair- causation of the lung fibrosis because the pleura is far more
ment of gas transfer but there may be an element of airflow sensitive to the injurious effects of asbestos than the lung pa-
limitation. renchyma. Accordingly, the same lack of significance may be
Generally asbestosis is characterized by lower lobe involve- stated for exposed persons with lung cancer and pleural changes.
ment and small irregular opacities. Progression will result in The light microscopic findings of asbestosis are now well
thickening of the linear opacities and the development of hon- established and defined by the recent 2010 College of Patholo-
eycombing particularly in the sub-pleural region of the lower gists e Pulmonary Pathology Society (CAP-PPS) Asbestosis
lobes. Pleural abnormalities such as diffuse pleural fibrosis or Guidelines committee.6 First there is a requirement to confirm
plaques may be present. the presence of diffuse interstitial fibrosis of an appropriate
pattern described as ‘always acellular and collagenous rather
Pathology than fibroblastic and inflammatory’. The second component is
the presence of a necessary minimum number of either asbestos
Asbestosis is characterized by diffuse interstitial fibrosis of the
bodies or fibres (see below). The aforementioned asbestosis
lungs, particularly with involvement of the lower zones and with
sub-pleural accentuation (Figures 4). In advanced cased the
lungs have a firm consistency with a bosselated surface and have
a greyewhite cut surface with areas of honeycombing. Purulent
secretions may be seen indicating complicating pneumonia. Firm
mass lesions may suggest complicating neoplasia. There may or
may not be associated pleural thickening and/or plaques. The
presence of pleural changes is a neutral factor in determining the

Figure 4 Lung showing fibrosis and honeycombing (asbestosis) most


Figure 2 Amosite asbestos fibres (TEM). marked in the lower zones and sub-pleurally.

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MINI-SYMPOSIUM: PATHOLOGY OF NON-NEOPLASTIC LUNG DISEASE

pattern translates, in effect to a fibrotic phase non-specific


interstitial pneumonia-like (N.S.I.P.-like) morphology and this Asbestosis (fibrosis) grades
consideration is useful as it contrasts with other common dif-
ferentials e.g. Usual Interstitial Pneumonia (U.I.P) and hyper- Grade 1 Fibrosis involving the bronchiolar wall and
sensitivity pneumonitis, both of which are fibroblastic and first layer of alveoli
inflammatory in nature, notwithstanding other significant dif- Grade 2 Fibrosis involving bronchioles and more
ferences.7,8 The presence of fibroblastic ‘buds’ and cellular distant alveolar walls but not linking up with
interstitial infiltrates are so uncommon in asbestosis as to suggest each other
an alternate diagnosis, namely U.I.P. There is medical debate Grade 3 Fibrosis involving all alveoli between two
whether the pattern of fibrosis alone is sufficiently robust a adjacent bronchioles but with little
feature to indicate an alternate diagnosis to asbestosis, irre- architectural distortion
spective of asbestos biomarkers (asbestos body counts and fi- Grade 4 Widespread fibrosis usually with
bres) or whether U.I.P. asbestosis exists in certain persons honeycombing
exposed to asbestos. It would seem logical that U.I.P. could
Table 1
sometimes occur in heavily exposed asbestos workers unrelated
to asbestos exposure since they have a similar risk to the general
population of developing U.I.P. tobacco smoking in the presence of focal interstitial fibrosis
The assessment of ‘diffuse interstitial fibrosis’ is not simple associated with numerous intra-alveolar pigment laden macro-
and prompts the requirement to examine multiple tissue blocks, phages and respiratory bronchiolitis (RBILD). This smoking
in general at least 10 samples should be examined (central and related interstitial lung disease is a common pitfall because the
peripheral from each lobe) although there is a recognition that fibrosis is not fibroblastic and not inflammatory (in the inter-
this may not be possible in resection specimens. Small biopsies stitium). Smoking is also likely to induce more advanced fibrosis,
(transbronchial and even open lung wedge specimens) are very possibly honeycombing, in a proportion of cases. A U.I.P.
limited in predicting pneumoconiosis and unsuitable for mineral morphology has been described, distinct from that described in
analyses (see later). The presence of cancer, atelectasis and the vast majority of asbestosis cases. Langerhans cell histiocy-
bronchopneumonia may all hinder the assessment of back- tosis may produce chronic stellate fibrotic lesions with pauci-
ground interstitial fibrosis. Extensive areas of organizing diffuse cellular infiltrates of Langerhans cells (CD1aþ, S100þ,
alveolar damage in post mortem lungs cause problems in Langerinþ). We have seen occasional cases of Langerhans His-
assessing how much chronic interstitial fibrosis is present e this tiocytosis mis-diagnosed as asbestosis, particularly when there is
can often be resolved by correlation with sequential radiological extensive fibrosis and the focal collections of Langerhans cells
findings if available. Collagen stains may assist but are often and eosinophils have been largely lost. Close attention to the
inconclusive in problematic cases. pattern of fibrosis will make it unlikely to be confused with that
In the early stages of asbestosis, the fibrosis appears airway- seen in asbestosis but may mimic that of mixed dust fibrosis
centric only with early alveolar duct fibrosis (grade 1 fibrosis). (mixed silica and less fibrogenic mineral agents e see later)
Bronchiolar wall fibrosis alone is now not regarded as bonafide (Figures 5e8).
asbestosis, a new development departing from the previous 1982 The second essential component to allow for a diagnosis of
College of Pathologists e National Institute Occupational Safety asbestosis is the presence of necessary numbers of either
and Health (CAP-NIOSH) Asbestosis committee report.9 As with asbestos bodies (assessed by light microscopy) or fibres
many pneumoconioses the disease distribution is actually lym- (assessed by mineral analysis). With respect to asbestos body
phangiocentric in nature, around broncho-vascular bundles, counts, their assessment may be enhanced by Perls stained
septa and pleura and this explains the accentuation of disease in
these regions. Asbestosis is a true dose dependent disease. With
increasing cumulative asbestos dose so the interstitial fibrosis
(grade) advances and this is accompanied by increased numbers
of asbestos bodies and amphibole fibres in lung. Grade 3 fibrosis
shows true ‘bridging fibrosis’ and grade 4 fibrosis represents
honeycomb lung (Table 1). It is at these pathological levels of
fibrosis (grades 3 and 4) that clinical manifestations of disease
exist. It has been estimated that persons with clinical asbestosis
have prior cumulative exposures of at least 25 fibre/ml years.
This cumulative dose is regarded as the same necessary to double
the relative risk of lung cancer in exposed persons (even in the
absence of asbestosis). Grade 1 and 2 fibrosis is sub-clinical
(pathological) asbestosis which may manifest at lower cumula-
tive exposures. However grade 1 and 2 fibrosis is more difficult to
assess, being subtle and common in the lungs of urban dwellers
and in tobacco smokers. Considerable caution should be exer-
cised by the pathologist in making a diagnosis of early/mild
asbestosis in an asbestos exposed person with a history of Figure 5 Moderate interstitial fibrosis and numerous asbestos bodies.

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MINI-SYMPOSIUM: PATHOLOGY OF NON-NEOPLASTIC LUNG DISEASE

transparent cores. A range of non-asbestos minerals may form


similar ferruginous bodies; some may mimic asbestos bodies with
transparent cores (erionite) whereas others are platy-form with
brown cores (silicates such asmica, talc, kaolin), some have black
cores (coal, metals) and some are wavy (elastin). In some com-
plex exposures (e.g. welders, foundry workers), mixed ferrugi-
nous bodies may occur and this necessitates mineral analysis to
allow for an accurate diagnosis because it is not possible to count
the true asbestos bodies accurately using light microscopic means.
In general, interstitial fibrosis is not marked in persons
following silicate exposures but so-called silicatoses e kaoli-
nosis, talcosis and mica pneumoconiosis e have been reported
in association with very heavy exposures.10 The presence of
interstitial fibrosis and ferruginous bodies (albeit qualitatively
different from true asbestos bodies) may represent a pitfall to the
unwary pathologist. Silicatoses may show varying degrees of
lung and pleural fibrosis. Exposures to other minerals such as
Figure 6 Same as Figure 5 but at higher power.
quartz and feldspar may also occur and histologically be asso-
ciated with prominent refractile particulates and granulomatous
routine thickness (5 micron) sections. The average (arithmetic reactions. Talc is a mineral widely used in the ceramic, paper,
mean) number is calculated by counting all present within the plastics, rubber, paint, and cosmetic industries. The distinct
available lung section area. For bonafide asbestosis, an average forms of pulmonary disease caused by talc have been defined
rate of >2 asbestos bodies/cm2 section area is necessary (in the according to route of administration.11 Talcosis may follow pure
presence of diffuse interstitial fibrosis). Most persons with industrial exposure or seen in association with asbestos and sil-
bonafide asbestosis meet these morphological criteria set by the ica exposures. The particle size is finer than that observed with
2010 CAP-PPS Asbestosis committee. In most persons there is a ‘mainline’ talc granulomatosis following intravenous drug abuse,
correlation between inhaled and retained amphibole asbestos although the condition has been reported as a radiological mimic
fibres and asbestos body counts. However, very rare cases, so- of asbestosis. Ferruginous bodies have been detected in persons
called occult asbestosis, do arise in which persons with significant following talc pleurodesis for the management of chronic effu-
asbestos exposure have diffuse interstitial fibrosis but with sions, a consideration of importance in persons with mesotheli-
inadequate numbers or no asbestos bodies. Due to an immune oma as there may be false ascription to asbestos.
lysosomal dysfunction the host has an innate inability to form Mineralizing pulmonary elastosis (endogenous pneumoconi-
asbestos bodies. The mineralogical demonstration of an elevated osis) seen in persons with chronic haemorrhagic disorders,
amphibole asbestos fibre count is necessary to prove significant chronic cardiac failure and obesity/chronic sleep apnoea may
asbestos exposure in these rare individuals. develop lung fibrosis, encrustation of elastic fibres with the for-
Care must be taken when interpreting ferruginous body counts mation of pseudoasbestos bodies, and may be a pitfall in the
because the Perls stain will identify a wide range of iron staining diagnosis of asbestosis.12,13 Mineral analysis is useful in con-
material and small fragments (without asbestiform morphology) firming the fibre content.
should not be counted. Strict adherence should be attained to Mineral analysis plays a central role in the diagnosis of
counting only those dumbbell, beaded bodies formed on asbestosis. Numerous studies have shown a correlation between

Figure 8 Mica ferruginous bodies from a case of mica induced pneumo-


Figure 7 Classical asbestos bodies with straight clear fibrous cores. coniosis showing platy cores.

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MINI-SYMPOSIUM: PATHOLOGY OF NON-NEOPLASTIC LUNG DISEASE

grade of lung fibrosis and retained amphibole asbestos fibre count. airway-centric granulomas and areas of organizing pneumonia
There is no correlation with chrysotile asbestos fibre counts may suggest the diagnosis. Allergen testing is important.
because the fibres are not biopersistent. Fibre deposition does vary Pleuro-pulmonary manifestations of collagen vascular disease
across the lung so ‘pooled’ samples comprising three 2e3 cm3 may mimic asbestos-related disease, not only by inducing lung
samples of lung or 2e3 standard lung paraffin lung blocks are fibrosis (directly or via treatments such as methotrexate) (either
optimal for the analytical process. By this process the intra- indistinguishable N.S.I.P. less often U.I.P.) but also by inducing
laboratory variation is no more than 2e3 fold. All laboratories diffuse pleural fibrosis. Serological tests are important in estab-
must establish control reference ranges for non-occupational lishing these diagnoses. Pathologists are minded to look for spe-
exposed persons and for subjects with asbestosis. The latter con- cific features which may indicate a connective tissue disease. For
stitutes the laboratory ‘asbestosis range’, a value now regarded of rheumatoid arthritis: rheumatoid necrobiotic nodules, vasculitis,
important diagnostic and medico-legal interest with regard to the follicular bronchiectasis/bronchioloectasis. For ankylosing spon-
causation of lung cancer in the absence of asbestosis. The range dylitis, the disease has an upper zone predilection. For Sjo €gren’s
has to be established for each laboratory because preparation, syndrome, the disease typically manifests as lymphocytic inter-
instrumentation and counting protocols vary between laboratories. stitial pneumonia. The history of connective tissue disease makes
The asbestosis range represents the total retained amphibole the confirmation of asbestosis problematic in an exposed person.
asbestos fibre count collated amongst all persons (all grades) There is the basic requirement to consider the pattern of fibrosis
with morphological degrees of asbestosis (according to the 2010 and doseeresponse profile observed in asbestosis in association
CAP-PPS criteria e listed above). Chrysotile fibre counts are with the known biomarkers (asbestos bodies and fibres). Funda-
excluded. As qualitative fibre typing is necessary and such in- mentally, is the degree of fibrosis commensurate with the expo-
formation is only available in electron microscopic mineral sure, asbestos body and fibre counts? If so, the condition is likely
analytical methods, the asbestosis range cannot be effectively asbestosis. If there is an atypical fibrotic process or fibrosis is in
established by using phase contrast light microscopy. The latter excess of that expected then it is likely that a significant contri-
method is too blunt a tool to identify the majority of asbestos bution from a non-asbestos factor is present.
fibres in the respirable bio-active fraction. Some fibrosing lung conditions have an upper zone predilection,
for example sarcoidosis, Langerhans cell histiocytosis and anky-
Differential diagnoses losing spondylitis; this is in contradistinction to asbestosis. Focal
The clinical factors in asbestosis offer little to allow for a specific interstitial fibrosis and scars as seen in apical fibroelastosis, tuber-
diagnosis. Typically there is a slow tempo of disease over de- culosis, healed organized pneumonia, healed infarct, rounded
cades. The exposure history is important but this may be difficult atelectasis, pulmonary hyalinized granuloma should similarly be
to quantify even in experienced hands. Clinical assessments discounted and are wholly inconsistent with asbestosis. In a person
require history taking and recollection of exposures many de- with a history of prior irradiation, radiation pneumonitis/fibrosis
cades prior to the onset of disease. However, because of the may show central zone predilection of disease. A
relatively high exposures to asbestos required to produce clinical
asbestosis it is unlikely that an individual would struggle to recall
a substantial exposure to asbestos. Indeed if there is such a
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MINI-SYMPOSIUM: PATHOLOGY OF NON-NEOPLASTIC LUNG DISEASE

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