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Asbestos-Related Benign Pleural Disease
Clinical Radiology (2000) 55, 422–432 doi:10.1053/crad.1999.0450, available online at http://www.idealibrary.com on
Review Asbestos-Related Benign Pleural Disease C. PE ACOCK, S. J. COPL E Y, D . M . HA NSE L L Department of Radiology, Royal Brompton Hospital, Sydney St, London SW3 6NP, U.K. Received: 6 September 1999
Accepted: 8 November 1999
Benign pleural disease is the commonest manifestation of asbestos exposure encountered by radiologists. Benign pleural thickening can appear as circumscribed parietal pleural plaques or as more diffuse thickening of the visceral pleura. Benign-asbestos induced pleural effusions are a significant and under-recognized manifestation of asbestos exposure with important sequelae, such as diffuse pleural thickening which may be associated with functional impairment and for which compensation may be sought. This review concentrates on the strengths and weaknesses of chest radiography and computed tomography for the detection and characterization of benign asbestosrelated pleural disease and the relevance of imaging abnormalities to compensation and functional impairment. Peacock, C. et al. (2000). Clinical Radiology 55, 422–432. q 2000 The Royal College of Radiologists Key words: asbestos, pleura, diseases, chest radiography, computed tomography, occupational disease, thorax.
EPIDEMIOLOGY AND PATHOPHYSIOLOGY
‘Asbestos’ encompasses two main groups of silicates: amphibole fibres and serpentine fibres. The amphiboles are characterized by their straight, rigid, needle-like fibres; the major types being crocidolite (blue asbestos), amosite (brown asbestos), and anthophyllite. Chrysotile (white asbestos), the only serpentine of commercial importance commonly used today, has curly, pliable fibres, that readily decompose into finer particles. The disease-inducing role of the various physical characteristics of fibres [length, diameter and length to width (aspect) ratio] is controversial because of conflicting evidence from experimental and human studies. That fine fibres are more pathogenic seems widely accepted [1,2], but the effect of fibre length is less certain. Experimentally long straight fibres (5– 20 mm) are not cleared from the lungs and have a potential to cause an intense inflammatory reaction, particularly crocidolite fibres, which are the longest and thinnest of the amphiboles [3]. A small proportion of fibres interact with macrophages and become inert as they are coated with iron and protein (ferritin or haemosiderin) and these are termed ‘asbestos bodies’ or ‘ferruginous bodies’ as they are not entirely specific for asbestos fibres [4]. This is different to the curly chrysotile fibres that tend to fragment and penetrate less deeply into the lung and which are also chemically more soluble. Chrysotile fibres have been identified in at least 50% of pleural plaques [1,5]. However, it Author for correspondence and guarantor of study: D. M. Hansell. 0009-9260/00/060422+11 $35.00/0
may be that chrysotile is virtually always contaminated with amphibole fibres [6]. Anthophyllite fibres (the thickest of the amphiboles) have been shown to have a strong association with hyaline pleural plaques but not in the development of mesothelioma [4]. A fibre gradient in terms of potential carcinogenicity has been suggested, with crocidolite having a greater carcinogenic effect than amosite and chrysotile [4]. It may be the greater biological longevity of crocidolite fibres in tissues that, with time, induces malignancy [6]. The pleura appears to be more sensitive than the lung parenchyma to the effects of asbestos fibres: pleural plaques occur with lower inhaled fibre burdens, whereas asbestosis is associated with a higher fibre burden [7]. Thus pleural plaques can result from small temporally remote dust exposures. No correlation between fibre counts in the lung parenchyma and the parietal pleura associated with plaques has been established [5]. Copes et al. studied the exposure characteristics of chrysotileexposed workers and compared lung vs pleural fibrosis. They showed that interstitial fibrosis was associated with cumulative, continuous exposure, whereas pleural plaques tended to be associated with intermittent exposures [8]. It has been postulated that the intermittent exposure allows time for clearance of fibres from the lung with consequent accumulation in the pleura [9]. The prevalence of pleural plaques in non-asbestos-exposed populations is very low. The prevalence among environmentally exposed populations ranges from 0.53 to 8% [10] and studies of occupationally exposed individuals show frequencies of 3 to 14% in dockyard workers and up to 58% q 2000 The Royal College of Radiologists
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among insulation workers [10,11]. However, figures about prevalence must be regarded as approximate because much depends on the method employed to detect pleural plaques [12]. There is a long latency period of between 20 and 30 years between asbestos exposure and the development of pleural plaques. The presence of pleural plaques has been found to depend on the length of exposure or time from first exposure, rather than a threshold dose, which is the case with parenchymal fibrosis [3,13–15]. From a post-mortem study a direct relationship was found between the intensity of asbestos exposure and total area of pleura involved by the plaques [12]. The prevalence of diffuse pleural thickening is unknown, even though it is a common post-mortem finding in both individuals with pleural plaques and those with parenchymal asbestosis [4]. In the series reported by McLoud et al. in 1985, parietal pleural plaques and diffuse pleural thickening occurred with almost equal frequency in the 1373 asbestos exposed individuals studied by serial chest radiographs [16]. The authors also suggested that the prevalence of diffuse thickening was increasing. If diffuse pleural thickening is searched for on every chest radiograph it is likely to be discovered with increasing frequency and may be a more reliable indicator of the prevalence of asbestos dust exposure [17]. The exposure– response relationship for diffuse pleural thickening is considered to be similar to pleural plaques in that it is related to time since first exposure [13], but this impression may be partly due to the difficulty in distinguishing between the two on chest radiography alone [18]. The latent period is approximately 15 years and the progression of diffuse pleural thickening is slow as cessation of exposure slows progression [1]. A point of practical importance is that individuals with diffuse pleural thickening more commonly have radiographically evident parenchymal fibrosis compared to those with localized pleural plaques [10]. Epidemiological studies of mesothelioma indicate that the peak incidence in the U.S.A. will be in the year 2000 [19], whereas in the U.K. it is forecast to be in the year 2020, due to a later peak of asbestos use in the 1970s [20]. Men older than 75 years will be mostly affected. This forecast is probably true for pleural plaques too, as the latency period is similar. Eventually the incidence will subside to a steady background level, presumably the result of natural environmental exposures [9]. The number of individuals recognized as suffering from an asbestos-related disease has been slowly increasing [21] and whether this is an actual increase or due to increased recognition because of altered criteria for diagnosis remains contentious. Since 1989, a programme has been set up in the U.K. for surveillance of work-related and occupational respiratory disease (known by the acronym SWORD) [21]. This group found that at least half the cases reported were attributable to asbestos exposure, most having benign pleural disease [22]. Due to the long latency period, asbestos-related benign pleural disease has yet to reach its peak incidence in the U.K. and is therefore likely to be encountered for many years to come. Legislation is variable in different countries regarding the use of asbestos and whilst some fibres, in particular crocidolite, are rarely used nowadays, chrysotile is, and its long-term biological effects are not yet known [9].
MEDICOLEGAL ASPECTS
In assessing occupationally exposed individuals for compensation, it is important to differentiate between the existing impairment of respiratory function and the resulting disability [23]. The World Health Organization defines respiratory disability as a reduction in exercise capacity secondary to impaired lung function; the resulting social and occupational disadvantage being designated a handicap [24]. Traditionally, the assessment of respiratory disability relies on a combination of static pulmonary function tests and clinical assessment (including questionnaires), although more objective methods would be preferable. In the U.K., eligibility for compensation for asbestos-related disease comes from three sources [21,25]: (1) a claim for Industrial Injuries Disablement benefit from the Department of Social Security; (2) a Common Law claim for damages from the firm where exposure to asbestos occurred; (3) a lump sum compensation claim from the Department of Environment, Transport and the Regions under the Pneumoconioses etc. (Workers Compensation) Act, 1979. Claiming for Industrial Injuries Disablement benefit requires certain criteria to be met in that an individual must be suffering from a ‘prescribed disease’ due to employment in a ‘prescribed occupation’ [26]. With respect to asbestos related disease in the U.K., compensation is given for bilateral diffuse pleural thickening, asbestosis, mesothelioma and lung cancer in the presence of asbestosis. Only diffuse pleural thickening will be discussed here. It is now accepted that diffuse pleural thickening can cause significant lung restriction [27–30] and bilateral diffuse pleural thickening became a prescribed disease in 1985 [21]. Pleural plaques alone, however extensive, are not recognized as being associated with significant respiratory disability and are therefore not considered a prescribed disease in the U.K. In claiming for common law compensation through the courts, the onus is on the claimant to show the condition has been caused by exposure to asbestos and has resulted in some disability. The lump sum compensation available from the Department of Environment, Transport and the Regions under the Pneumoconioses etc. (Workers Compensation) Act 1979 is designed for individuals or dependents of individuals who have died, who do not have a realistic prospect of bringing a claim against a previous employer (for example if the employer is no longer in business) providing the individual has not already received damages or out of court settlement from an employer [25].
PLEURAL PLAQUES
Pleural plaques are the commonest manifestation of asbestos exposure and bilateral scattered calcified pleural plaques can be regarded as virtually pathognomonic of asbestos exposure [9,31]. Pleural plaques are discrete elevated areas of hyaline fibrosis almost invariably arising from the parietal pleura. At thoracoscopy the striking smooth whiteness of the plaques has been
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(a)
(a)
(b) Fig. 1 – HRCT images showing the areas commonly affected by pleural plaques: behind the anterior ends of the uppermost ribs (a), in the paravertebral regions and on the diaphragmatic surface (b). Small pleural plaques behind anterior ribs and in paravertebral regions are likely to be overlooked on PA chest radiography.
likened to the appearance of icing on a cake. Pleural plaques tend to lie adjacent to relatively rigid structures such as the ribs, vertebral column and the tendinous portion of the diaphragm. According to radiographic studies, the characteristic sites are on the posterolateral chest wall between the seventh and tenth ribs, on the lateral wall between sixth and ninth ribs on the dome of the diaphragm and the mediastinal pleura particularly over the pericardium [32]. This distribution is largely borne out by computed tomography (CT) studies, although on CT plaques seem to be more profuse beneath the anterior aspects of the upper ribs (an area poorly demonstrated by standard radiographic views) (Fig. 1). Typically, plaques are not seen at the apices or in the costophrenic angles. Plaques that arise from the visceral pleura are very rare and are usually found in the lower aspects of the interlobar fissures; they may calcify and are usually associated with extensive parietal pleural plaque disease [13] (Fig. 2). The size and number of pleural plaques are extremely variable: plaques can occasionally be solitary but are most often multiple and bilateral. The idea that pleural plaques
(b) Fig. 2 – Conventional CT images on lung (a) and mediastinal windows (b) showing bilateral calcified pleural plaques. Note the partly calcified pleural plaque involving the right oblique fissure.
are almost invariably calcified is not confirmed by imaging studies. On plain chest radiography the reported prevalence of calcification in plaques is variable: one study reported less than 10% [33] and another 15% [34]. The conspicuity of calcification clearly depends on radiographic factors such as the kilovoltage used and the views obtained. Nevertheless, a CT study has also shown relatively low prevalence: Gamsu et al. demonstrated calcification in about 5% more patients with CT or HRCT than by chest radiography [33]. Conversely, about 5% of the calcifications thought to be present in pleural plaques on chest radiography were not corroborated by CT [33].
Pathogenesis Microscopically pleural plaques consist of relatively acellular bundles of collagen in an undulating ‘basketweave’ pattern and may contain abundant numbers of asbestos fibres,
ASBESTOS-RELATED PLEURAL DISEASE
almost exclusively chrysotile fibres, but asbestos bodies are absent [1,35]. The inner side is covered by normal mesothelial cells and on the costal side there may be signs of low-grade inflammation [36]. Despite much speculation, the pathogenesis of pleural plaques remains uncertain. In the past it was believed that the fibres caused direct mechanical irritation of the parietal pleura, (the so-called ‘scratching theory’) [37]. It is now thought that short asbestos fibres reach the parietal pleura by passage through lymphatic channels where they excite an inflammatory reaction, whereas the largest fibres, amphiboles, are retained in the lung parenchyma [5,37]. Alternative explanations for the presence of fibres in the parietal pleura are via the blood supply or by direct migration of fibres through the visceral pleura [5]. Pleural plaques slowly progress in size and amount of calcification with time, independent of any further exposure [2]. There is no evidence that pleural plaques undergo malignant degeneration into mesothelioma [9,10]. Asbestosis rarely occurs in the absence of pleural plaques [33]; although there is a significant correlation between severity of pleural disease and presence and severity of asbestosis, most plaques usually occur in isolation [38,39].
Chest Radiography vs CT The International Labour Office (ILO) classification of pneumoconioses assesses asbestos-induced pleural disease on chest radiography, using the posteroanterior projection [40]. The detection rate of pleural plaques on the chest radiograph is dependent on their size, position, shape, degree of calcification and technical quality of the radiograph. Autopsy studies report a high false negative rate for the radiographic detection of pleural plaques [14,31]. Digital storage phosphor radiography does not appear to improve the demonstration of pleural disease compared with conventional radiography [41]. Conversely, normal anatomic structures, such as extrapleural muscle and fat, may lead to false positive diagnoses in up to 20% of cases [10]. Oblique radiographs provide additional views of the pleural surface; in particular, permitting the detection of pleural thickening located in the posterolateral parts of the chest, which are not well visualized on frontal views. The addition of bilateral oblique projections has been reported to increase the radiographic detection of pleural disease by 50% [17], in particular of plaques more than of diffuse pleural thickening. However, in the ILO scoring system there is no scheme for the assessment of oblique views. Furthermore, the interpretation of oblique views is becoming a lost art, probably because of the increased use of CT. As early as 1976, Kreel described the use of CT for assessing asbestos-related disease [42]. He noted that regions of pleural thickening in the posterior sulci and mediastinum could be detected by CT when the chest radiograph appeared normal. On CT, plaques are readily recognized as circumscribed areas of pleural thickening with well-demarcated edges and are commonly located in the posterolateral and paraspinal regions of the thorax. Computed tomography is able to detect small foci of calcification within plaques [10]. Many subsequent studies have shown that CT is more sensitive for the detection of pleural disease [3,38,43,44], especially for plaques located in the paravertebral area. Al Jarad et al. compared chest
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radiographs with CT and demonstrated discrete pleural plaques in 95% of patients compared to 59% on chest radiography [27]. Friedman et al. compared high-resolution CT (HRCT) with a four-view radiograph series (PA, lateral and two obliques) [43]. The positive predictive value for detecting pleural disease was increased by HRCT, but HRCT was particularly useful in eliminating false positive diagnoses caused by subpleural fat found in 10–29% of patients thought to have non-calcified pleural plaques [43]. On HRCT pleural plaques appear focal with well demarcated edges, separated from the underlying rib and adjacent extrapleural soft tissues by a thin layer of fat. Intercostal vessels may cause the extrapleural soft tissues to appear thicker in the paravertebral regions (Fig. 3). It has therefore been suggested that paraspinal pleural plaques be diagnosed only if (a) thickening is visible on multiple levels, (b) extrapleural fat is visible between the pleura and intercostal vessels, (c) the thickened pleura can be seen to indent the subjacent lung, or (d) there is dystrophic calcification within the plaque [45]. Several studies have now compared the efficacy of HRCT with conventional CT [3,33,38]. Aberle et al. showed that HRCT was more sensitive than conventional CT for the detection of pleural disease, even though images were obtained at interspaced levels; the authors felt that the increased resolution of HRCT compensated for any sampling deficiencies and that when plaques were present, they were invariably extensive enough not to be missed on interspaced sections [3]. However, Gevenois et al. compared conventional CT with HRCT and concluded that in cases with known asbestos exposure and no plaques demonstrated on HRCT, then conventional CT should be performed as plaques may be detected in the skip areas [46]. Neri et al. have also shown that HRCT can demonstrate pleural plaques and early lung involvement in asymptomatic amosite exposed workers with apparently normal chest radiographs [47]. High resolution CT may also be useful in detecting other lung abnormalities, particularly emphysema, that may be responsible for symptoms in asbestos-exposed individuals. Pleural plaques are not usually associated with impairment
Fig. 3 – HRCT images on mediastinal windows showing how intercostal vessels may mimic pleural thickening and make extrapleural fat thicker in the paravertebral regions (arrows). Immediately adjacent sections did not reveal any pleural thickening.
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of lung function [14] and it has been suggested that in those cases where there is a restrictive impairment it is more likely to be due to subclinical interstitial fibrosis [48]. Some plaques demonstrate abnormality in the immediately adjacent lung parenchyma suggesting localized fibrosis; this consists of short (<1 cm) interstitial lines giving rise to the term ‘hairy plaques’ (Fig. 4). Such localized parenchymal changes related to pleural plaques should be distinguished from the generalized interstitial fibrosis of asbestosis, seen away from pleural disease on CT. However, the significance of ‘hairy plaques’ in terms of whether they herald the development of asbestosis has not been clarified.
BENIGN ASBESTOS-INDUCED PLEURAL EFFUSION
Benign pleural effusion ascribable to previous asbestos exposure was first described by Eisenstadt in 1964 [49]. Epler et al. reported 34 (3.1%) benign effusions among 1135 asbestos-exposed workers compared with no unexplained effusions among 717 controls [11]. This figure may, however, be an underestimate as many cases are probably subclinical, as judged by two studies in which between 46 and 66% of individuals with benign asbestos pleural effusion were asymptomatic [11,50]. In another study by Epler et al. the frequency
of benign asbestos pleural effusion was 3.7% in indirectly exposed workers and 7% in heavily exposed workers [11].
Pathogenesis Benign asbestos pleural effusions are exudative [50,51], but have a variable composition: the fluid is often macroscopically haemorrhagic, of mixed cellularity, or with an increased eosinophil cell count [50]. Epler et al. reported that there was a dose-response relationship with an increased incidence of effusions in those with the most severe exposure [11]. However, even slight exposure may be enough to cause a benign effusion [50]. Epler et al. also suggested a relationship with the type of occupation; in this series, asbestos effusion was most common among asbestos pipe coverers and least common among shipfitters, maintenance personnel and welders [11]. Such effusions usually spontaneously resolve with a mean duration of 3–4 months [35,39,50], but can persist or recur over several years. As these effusions resolve, many individuals develop diffuse pleural thickening, in particular blunting of the costophrenic angle [11]. Lilis et al. surveyed 2815 insulation workers and found that in the 20 cases with a positive history of pleural effusion, most had diffuse pleural thickening with blunting of the costophrenic angle [52].
Problems in Differential Diagnosis
Fig. 4 – Prone HRCT image of a ‘hairy plaque’ (arrowheads) showing short interstitial lines adjacent to the plaque. There are also features of interstitial fibrosis posteriorly.
The development of a pleural effusion is probably the earliest manifestation of previous asbestos exposure, it usually occurs within 10 years of exposure, and remains the commonest complication of asbestos exposure for the succeeding 10 years. However, a benign asbestos pleural effusion can occur much later [53], at which time the important differential diagnosis is malignant mesothelioma. The diagnosis of benign asbestos pleural effusion may be difficult, as the symptoms and character of the effusion are extremely variable; it is unlikely to be considered unless a history of occupational exposure to asbestos is elicited. The clinical picture varies from no symptoms to an acute illness with fever, pain, and elevated white cell count [10]. Computed tomography may be able to distinguish the sanguinous content of the pleural fluid by the higher attenuation number [39]. Certain criteria have been stipulated before the diagnosis of benign asbestos pleural effusion can be made [11,52]. These include: (1) history of direct or indirect exposure to asbestos, (2) exclusion of other causes of effusion, particularly TB and malignancy, (some authors advocate treatment of effusions with antituberculous therapy as TB cannot always be excluded [50]), and (3) no malignancy detected within 3 years after the onset of the effusion [54]. Contrary to what might be expected, asbestos fibres are not usually found in the effusion, whilst they can be found in the lungs and sputum [11]. Solomon has suggested that the presence of pleural plaques helps to distinguish asbestos-related effusions from other idiopathic effusions [39]; but given that plaques occur after a much longer latency period this is probably unhelpful in the majority of cases. The presence of linear structures converging on the pleura (so called ‘crow’s feet’) and folded lung are features which occur less frequently in association with exudative pleural effusion of
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other known cause [54]. Computed tomography is often indicated to exclude an underlying pulmonary cause, or the presence of an obvious pleural soft tissue mass. At present there is no definite evidence to suggest a relationship between benign asbestos pleural effusion and the subsequent development of malignant pleural mesothelioma. Although mesotheliomas have been reported in patients with a previous history of benign pleural effusions [11], another study followed-up 22 cases of benign asbestos pleural effusion for a mean of 23 years with no subsequent development of a mesothelioma [51]. Both conditions are associated with asbestos exposure; however, benign effusions occur within 10 years of asbestos exposure whereas malignant mesothelioma usually has a latent period of 20–40 years after initial exposure. Nevertheless, these differences in latent period are not absolute and it has been speculated, however tentatively, that the pleural drift of asbestos fibres causes mechanical irritation, resulting first in effusion and ultimately in mesothelioma [11]. Larger long-term studies are needed to determine whether there is a relationship between benign asbestos pleural effusion and mesothelioma.
DIFFUSE PLEURAL THICKENING
Diffuse pleural thickening as a sequel of asbestos exposure has only more recently been recognized as a separate entity. The revised edition of the ILO classification has partially addressed the issue of distinguishing plaques from diffuse pleural thickening [40]. However, there is still potential for confusion as the distinction is made solely on a single standard chest radiograph [16]. Diffuse pleural thickening is less specific to asbestos exposure than pleural plaques, given that many causes of exudative pleural effusions can give rise to diffuse pleural fibrosis, including previous inflammatory episodes (such as a parapneumonic effusion), haemothorax or connective tissue disease. Diffuse pleural thickening results from thickening and fibrosis of the visceral pleura, with fusion to the parietal pleura, often over a wide area [39]. This is in contrast to pleural plaques that tend to be discrete localized lesions arising from the parietal pleura, and are rarely adherent. Many studies have confirmed that diffuse pleural thickening is preceded by a benign asbestos pleural effusion [11,16,52,53].
Pathogenesis Microscopically there are similarities between diffuse pleural thickening and plaques, including the typical basket weave fibrous structure and scant cellular fibroblastic activity. However, with diffuse pleural thickening there is fusion of the two pleural layers with obliteration of the submesothelial elastic tissue, suggesting that a severe inflammatory reaction has occurred [55]. Moreover, Stephens et al. also showed pathologically that in a series of seven cases with diffuse pleural thickening there was subpleural honeycombing without appreciable diffuse parenchymal disease in every case [55]. The pathogenesis of diffuse pleural thickening, although not precisely known, is thought to be secondary to the inflammation and fibrosis of the superficial or visceral pleural lymphatic
pathways and has been considered as a direct extension of parenchymal lung fibrosis [56]. Diffuse pleural thickening is a frequent concomitant finding to asbestosis with a reported associated incidence of 10%. This is probably an underestimate. Asbestos bodies are profuse and easily recovered from pleuroparenchymal tissue, particularly adjacent to areas of pleural thickening [9,56]. In a study by Rockoff et al. there was a strong association between even early pulmonary interstitial fibrosis and fissural visceral pleural thickening [13]. Other studies, however, have shown only a weak association between these two features [16].
Chest Radiography vs CT McLoud et al. defined diffuse pleural thickening on a chest radiograph as a smooth non-interrupted pleural density extending over at least one-quarter of the chest wall, with or without costophrenic angle obliteration [16]. Lynch et al. defined it on CT criteria as a continuous sheet of pleural thickening more than 5 cm wide, more than 8 cm in craniocaudal extent, and more than 3 mm thick [57]. Diffuse pleural thickening which is less than 3 mm thick or less extensive may still be functionally significant, however, and a less rigorous definition is probably more appropriate. Differentiation from pleural plaques can sometimes be difficult. Fletcher et al. made the following observations from chest radiographs [32]: (1) plaques generally spare the costophrenic angles and apices; (2) diffuse pleural thickening due to asbestos exposure rarely calcifies; (3) diffuse pleural thickening is ill-defined and irregular from all angles whereas plaques are often well defined; and (4) plaques rarely extend over more than four rib interspaces unless multiple and confluent. Radiographically, diffuse pleural thickening can be difficult to diagnose but involvement of the interlobar fissures, by definition visceral pleural involvement, is the rule [13]. Involvement of the minor fissure on the lateral radiograph occurs with sufficient frequency that a separate classification symbol, ‘pi’, has been added to the ILO-1980 classification [40]. Ameille et al. compared oblique chest radiographs with high-resolution CT as the ‘gold standard’ for the detection of diffuse pleural thickening and found that the positive predictive value for diffuse pleural thickening with the addition of the right anterior oblique film was only 13–26% [58]. Most of the false-positive diagnoses of pleural fibrosis were due to abundant extrapleural fat. As with discrete pleural plaques, CT is more sensitive and specific for the detection of diffuse pleural thickening than chest radiography [27,38,43], in particular for differentiating extrapleural fat from pleural thickening (Fig. 5a, b). Al Jarad et al. found that there was greater inter-observer agreement regarding the type of pleural disease present with CT compared with chest radiography [27]. On CT diffuse thickening appears continuous, commonly involving the posterior and lateral surfaces of the lower thorax [35,39] (Fig. 6). Frequently there is an accompanying increase in extrapleural fat, presumably drawn inwards by pleural retraction [35]. The advantage of HRCT over conventional CT is more controversial: Aberle et
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Fig. 6 – Prone HRCT image of a patient with bilateral diffuse pleural thickening due to asbestos exposure predominantly affecting the posterobasal regions. Note the coexisting calcified right pleural plaque.
(a)
(b) Fig. 5 – Chest radiograph (a) of an individual showing a linear opacity paralleling the innermost aspect of the ribs in the mid and upper zones, mimicking pleural thickening. HRCT image (b) using mediastinal windows demonstrates fat attenuation adjacent to the ribs on the right (arrows), confirming the cause as extrapleural fat.
al. found HRCT to be less sensitive compared to CT for detecting diffuse pleural thickening than pleural plaques [38], whereas Friedman et al. found, as with pleural plaques, that HRCT was a better discriminator of extrapleural fat and of fissural pleural thickening from intrafissural fat [59]. Even on HRCT, however, subpleural oedema may occasionally mimic diffuse pleural thickening, but such cases are rare. Computed tomography may be particularly helpful in distinguishing malignant from benign pleural disease. Leung et al. suggested that the presence of pleural rind, pleural nodularity, pleural thickening greater than 1 cm and mediastinal pleural involvement were most discriminatory as they are all more frequent in malignant disease [60]. Many studies have shown that diffuse pleural thickening, in the absence of parenchymal fibrosis, results in impaired lung function [27–29,61]. Typically, there is a restrictive ventilatory defect with a decrease in lung volumes, decreased inspiratory capacity, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and preserved gas diffusing capacity [14]. Cotes et al. found that in the presence of thickening, obliteration of either or both costophrenic angles was associated with an additional deleterious effect on lung function [28]. Al Jarad et al. reported a tendency for the gas transfer coefficient to increase with more extensive pleural disease, reflecting a proportionately greater reduction in lung volumes than in gas transfer [27]. This can be explained by the normal lung being encased in a ‘cuirasse’ of fibrous tissue. These observations have led to the adoption of the ILO scoring system for pleural thickening [28]. Al Jarad et al. have proposed an HRCT scoring system analogous to the ILO for the quantification of pulmonary fibrosis, pleural disease and emphysema in patients with asbestos-related disease and found that HRCT and chest radiography correlated with indices of lung function to a similar extent [62]. Whether stronger correlations are possible using more precise visual CT estimation of the extent of pleural disease has not been established.
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(a)
Fig. 7 – Chest radiograph of a patient with unilateral diffuse pleural thickening post-thoracotomy. The 3.5 cm rounded opacity at the left costophrenic angle was thought to represent a possible bronchial neoplasm, but proved to represent an area of folded lung on CT.
FOLDED LUNG
Folded lung refers to peripheral atelectatic lung adjacent to an area of pleural thickening with characteristic drawing in of the bronchi and vessels into the atelectatic lung [63–65]. Synonyms for folded lung include Blesovsky’s syndrome, rounded atelectasis, atelectatic pseudotumour and pulmonary pseudotumour. Blesovsky first reported three cases in 1966 in which there was unusually extensive lung folding due to a fibrous membrane on the costal surface of the visceral pleura of the lower lobe, and termed it ‘folded lung’ [66]. There is a strong association with previous asbestos exposure [67,68] but any cause of an organizing pleural exudate such as tuberculosis, histoplasmosis, Dressler’s syndrome following cardiac surgery and haemothorax may be responsible [68,69] (Fig.7). In Hillerdal’s review of 74 cases the commonest site was in the lingula, followed by the middle lobe and then the lower lobes [68] but any lobe can be affected and bilateral involvement is not uncommon [63].
Pathogenesis Two theories about the pathogenesis of folded lung have been proposed. Hanke and Kretzschmar suggested that the infolding is preceded by a pleural effusion that causes the lung to collapse and fold on itself, resulting in localized invagination of visceral pleura [65]. As the effusion recedes adhesions between the invaginated visceral pleura prevent full re-expansion, resulting in a mass of folded lung adjacent to a residual area of pleural thickening [65]. The second, more widely accepted theory was originally suggested by Blesovsky [66] and recently revisited by Menzies et al. [64]. These authors proposed that the primary event is an injury that leads to an
(b) Fig. 8 – Folded lung on HRCT. On the superior section (a) the area of folded lung could be mistaken for a pulmonary neoplasm, whereas a lower section (b) shows the typical features of folded lung described in the text.
inflammatory reaction and subsequent fibrosis in the most superficial layer of the pleura. As the fibrous tissue matures it contracts causing the pleura to buckle into the lung, resulting in atelectasis at this point.
Chest Radiography vs CT On chest radiography, folded lung appears as a rounded peripheral pulmonary mass; distortion of the adjacent lung may or may not be obvious and pleural thickening is usually evident (Fig. 7). Conventional CT is most helpful in making the diagnosis and McHugh and Blaquiere described three major features: (1) rounded or oval mass (2.5–7 cm) abutting a peripheral pleural surface; (2) the curving ‘comet tail’ of bronchovascular structures passing into the mass, resulting in a blurred central margin; and (3) thickening of the adjacent
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(a)
(b) Fig. 9 – Chest radiograph of an individual exposed to asbestos (a) with bilateral pleural thickening and blunting of both costophrenic angles. Parenchymal strands are seen radiating from the pleura on the left. Conventional CT (b) of the same patient shows the parenchymal bands converging on point at the pleural surface resembling ‘crows’ feet’.
pleura with or without calcification, which is usually, but not always, thickest adjacent to the mass [63] (Fig. 8). Lynch et al. included the further feature of evidence of volume loss in the adjacent lung [67]. Dynamic contrast-medicine enhanced CT does not reliably differentiate folded lung from malignancy in equivocal cases. It has been suggested by Marchbank et al. [69] that ultrasound may be helpful in confirming the diagnosis by the demonstration of a highly echogenic line within the mass that is seen adjacent to pleural and extrapleural fat layer thickening. The visceral pleura may be thickened and have single or multiple pleuroparenchymal fibrous bands radiating from it [39]. They are usually seen in addition to (or rather in
Fig. 10 – HRCT of an individual exposed to asbestos showing limited ‘crow’s feet’ adjacent to right-sided diffuse pleural thickening: an example of the difficulty in differentiating limited parenchymal fibrosis due to underlying pleural disease from interstitial fibrosis.
connection with) diffuse pleural thickening [6,70] and may be considered analogous to a forme fruste of folded lung. On a chest radiograph these may be seen as fine or coarse densities partially or completely traversing the lung field, usually converging on a single point on the pleura, creating a likeness to ‘crows’ feet’ [6] (Fig. 9a). Computed tomography demonstrates this phenomenon to advantage and shows strands penetrating the underlying lung parenchyma from an area of thickened pleura, sometimes producing a blurred demarcation line between the pleura and the lung [70] (Fig. 9b). These strands are thought to represent thickening of adjacent interlobular septa due to a fibrotic reaction [39]. Gevenois et al. have suggested from a CT series that ‘crow’s feet’, pleural tags and parenchymal bands are predominantly related to the fibrosis of the visceral pleura and should be differentiated from HRCT features more suggestive of diffuse interstitial fibrosis [71]. Nevertheless, this distinction is not always easy and, paradoxically, may be particularly difficult in cases showing limited changes on HRCT (Fig. 10). An association with mesothelioma has recently been reported with involvement of the ipsilateral thorax in all cases [72,73]. From these cases it was suggested that mesothelioma should be considered if there is either an associated large pleural effusion, a pleural mass with or without chest wall invasion, or thickened pleura not adjacent to the folded lung [72]. SUMMARY X X X X X X
Benign pleural effusion is the earliest manifestation of asbestos exposure. Diffuse visceral pleural thickening follows benign asbestos pleural effusion. Diffuse pleural thickening is more commonly found in association with asbestosis than pleural plaques. ‘Crow’s feet’ and folded lung are related to diffuse visceral pleural thickening. Thickening of the interlobar fissures reflects involvement of the visceral pleura. Diffuse pleural thickening may result in a restrictive functional lung impairment and affected individuals are eligible for compensation.
ASBESTOS-RELATED PLEURAL DISEASE
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52 Lilis R, Lerman Y, Selikoff IJ. Symptomatic benign pleural effusions among asbestos insulation workers: residual radiographic abnormalities. Br J Ind Med 1988;45:443–449. 53 Fridriksson HV, Hedenstrom H, Hillerdal G, Malmberg P. Increased lung stiffness of persons with pleural plaques. Eur J Respir Dis 1981;62:412–424. 54 Ma˚rtensson G, Hagberg S, Pettersson K, Thiringer G. Asbestos pleural effusion: a clinical entity. Thorax 1987;42:646–651. 55 Stephens M, Gibbs AR, Pooley FD, Wagner JC. Asbestos induced diffuse pleural fibrosis: pathology and mineralogy. Thorax 1987; 42:583–588. 56 Frank W, Loddenkemper R. Fiber-associated pleural disease. Semin Respir Crit Care Med 1995;16:315–323. 57 Lynch DA, Gamsu G, Aberle DR. Conventional and high resolution tomography in the diagnosis of asbestos-related diseases. Radiographics 1989;9:523–551. 58 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 asbestos pollution. Int Arch Occup Environ Health 1993;64:545–548. 59 Friedman AC, Fiel SB, Radecki PD, Lev-Toaff AS. Computed tomography of benign pleural and pulmonary parenchymal abnormalities related to asbestos exposure. Semin Ultrasound CT MR 1990;11:393– 408. 60 Leung AN, Mu¨ller NL, Miller RR. CT in differential diagnosis of diffuse pleural disease. Am J Roentgenol 1990;154:487–492. 61 Becklake MR. Asbestos and other fiber-related diseases of the lungs and pleura. Distribution and determinants in exposed populations. Chest 1991;100:248–254. 62 Al Jarad N, Wilkinson P, Pearson MC, Rudd RM. A new high
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resolution computed tomography scoring system for pulmonary fibrosis, pleural disease, and emphysema in patients with asbestos related disease. Br J Ind Med 1992;49:73–84. McHugh K, Blaquiere RM. CT features of rounded atelectasis. Am J Roentgenol 1989;257–260. Menzies R, Fraser R. Round atelectasis. Pathologic and pathogenetic features. Am J Surg Pathol 1987;11:674–681. Hanke R, Kretzschmar R. Round atelectasis. Semin Roentgenol 1980;15:174–182. Blesovsky A. The folded lung. Br J Dis Chest 1966;60:19–22. Lynch DA, Gamsu G, Ray CS, Aberle DR. Asbestos-related focal lung masses: manifestations on conventional and high-resolution CT scans. Radiology 1988;169:603–607. Hillerdal G. Rounded atelectasis. Clinical experience with 74 patients. Chest 1989;95:836–841. Marchbank ND, Wilson AG, Joseph AE. Ultrasound features of folded lung. Clin Radiol 1996;51:433–437. Hillerdal G, Malmberg P, Hemmingsson A. Asbestos-related lesions of the pleura: parietal plaques compared to diffuse thickening studied with chest roentgenography, computed tomography, lung function, and gas exchange. Am J Ind Med 1990;18:627–639. Gevenois PA, de Maertelaer V, Madani A, Winant C, Sergent G, De Vuyst P. Asbestosis, pleural plaques and diffuse pleural thickening: three distinct benign responses to asbestos exposure. Eur Respir J 1998; 11:1021–1027. Munden RF, Libshitz HI. Rounded atelectasis and mesothelioma. Am J Roentgenol 1998;1519–1522. Ng CS, Munden RF, Libshitz HI. Malignant pleural mesothelioma: the spectrum of manifestations on CT in 70 cases. Clin Radiol 1999; 54:415–421.
Review Asbestos-Related Benign Pleural Disease C. PE ACOCK, S. J. COPL E Y, D . M . HA NSE L L Department of Radiology, Royal Brompton Hospital, Sydney St, London SW3 6NP, U.K. Received: 6 September 1999
Accepted: 8 November 1999
Benign pleural disease is the commonest manifestation of asbestos exposure encountered by radiologists. Benign pleural thickening can appear as circumscribed parietal pleural plaques or as more diffuse thickening of the visceral pleura. Benign-asbestos induced pleural effusions are a significant and under-recognized manifestation of asbestos exposure with important sequelae, such as diffuse pleural thickening which may be associated with functional impairment and for which compensation may be sought. This review concentrates on the strengths and weaknesses of chest radiography and computed tomography for the detection and characterization of benign asbestosrelated pleural disease and the relevance of imaging abnormalities to compensation and functional impairment. Peacock, C. et al. (2000). Clinical Radiology 55, 422–432. q 2000 The Royal College of Radiologists Key words: asbestos, pleura, diseases, chest radiography, computed tomography, occupational disease, thorax.
EPIDEMIOLOGY AND PATHOPHYSIOLOGY
‘Asbestos’ encompasses two main groups of silicates: amphibole fibres and serpentine fibres. The amphiboles are characterized by their straight, rigid, needle-like fibres; the major types being crocidolite (blue asbestos), amosite (brown asbestos), and anthophyllite. Chrysotile (white asbestos), the only serpentine of commercial importance commonly used today, has curly, pliable fibres, that readily decompose into finer particles. The disease-inducing role of the various physical characteristics of fibres [length, diameter and length to width (aspect) ratio] is controversial because of conflicting evidence from experimental and human studies. That fine fibres are more pathogenic seems widely accepted [1,2], but the effect of fibre length is less certain. Experimentally long straight fibres (5– 20 mm) are not cleared from the lungs and have a potential to cause an intense inflammatory reaction, particularly crocidolite fibres, which are the longest and thinnest of the amphiboles [3]. A small proportion of fibres interact with macrophages and become inert as they are coated with iron and protein (ferritin or haemosiderin) and these are termed ‘asbestos bodies’ or ‘ferruginous bodies’ as they are not entirely specific for asbestos fibres [4]. This is different to the curly chrysotile fibres that tend to fragment and penetrate less deeply into the lung and which are also chemically more soluble. Chrysotile fibres have been identified in at least 50% of pleural plaques [1,5]. However, it Author for correspondence and guarantor of study: D. M. Hansell. 0009-9260/00/060422+11 $35.00/0
may be that chrysotile is virtually always contaminated with amphibole fibres [6]. Anthophyllite fibres (the thickest of the amphiboles) have been shown to have a strong association with hyaline pleural plaques but not in the development of mesothelioma [4]. A fibre gradient in terms of potential carcinogenicity has been suggested, with crocidolite having a greater carcinogenic effect than amosite and chrysotile [4]. It may be the greater biological longevity of crocidolite fibres in tissues that, with time, induces malignancy [6]. The pleura appears to be more sensitive than the lung parenchyma to the effects of asbestos fibres: pleural plaques occur with lower inhaled fibre burdens, whereas asbestosis is associated with a higher fibre burden [7]. Thus pleural plaques can result from small temporally remote dust exposures. No correlation between fibre counts in the lung parenchyma and the parietal pleura associated with plaques has been established [5]. Copes et al. studied the exposure characteristics of chrysotileexposed workers and compared lung vs pleural fibrosis. They showed that interstitial fibrosis was associated with cumulative, continuous exposure, whereas pleural plaques tended to be associated with intermittent exposures [8]. It has been postulated that the intermittent exposure allows time for clearance of fibres from the lung with consequent accumulation in the pleura [9]. The prevalence of pleural plaques in non-asbestos-exposed populations is very low. The prevalence among environmentally exposed populations ranges from 0.53 to 8% [10] and studies of occupationally exposed individuals show frequencies of 3 to 14% in dockyard workers and up to 58% q 2000 The Royal College of Radiologists
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among insulation workers [10,11]. However, figures about prevalence must be regarded as approximate because much depends on the method employed to detect pleural plaques [12]. There is a long latency period of between 20 and 30 years between asbestos exposure and the development of pleural plaques. The presence of pleural plaques has been found to depend on the length of exposure or time from first exposure, rather than a threshold dose, which is the case with parenchymal fibrosis [3,13–15]. From a post-mortem study a direct relationship was found between the intensity of asbestos exposure and total area of pleura involved by the plaques [12]. The prevalence of diffuse pleural thickening is unknown, even though it is a common post-mortem finding in both individuals with pleural plaques and those with parenchymal asbestosis [4]. In the series reported by McLoud et al. in 1985, parietal pleural plaques and diffuse pleural thickening occurred with almost equal frequency in the 1373 asbestos exposed individuals studied by serial chest radiographs [16]. The authors also suggested that the prevalence of diffuse thickening was increasing. If diffuse pleural thickening is searched for on every chest radiograph it is likely to be discovered with increasing frequency and may be a more reliable indicator of the prevalence of asbestos dust exposure [17]. The exposure– response relationship for diffuse pleural thickening is considered to be similar to pleural plaques in that it is related to time since first exposure [13], but this impression may be partly due to the difficulty in distinguishing between the two on chest radiography alone [18]. The latent period is approximately 15 years and the progression of diffuse pleural thickening is slow as cessation of exposure slows progression [1]. A point of practical importance is that individuals with diffuse pleural thickening more commonly have radiographically evident parenchymal fibrosis compared to those with localized pleural plaques [10]. Epidemiological studies of mesothelioma indicate that the peak incidence in the U.S.A. will be in the year 2000 [19], whereas in the U.K. it is forecast to be in the year 2020, due to a later peak of asbestos use in the 1970s [20]. Men older than 75 years will be mostly affected. This forecast is probably true for pleural plaques too, as the latency period is similar. Eventually the incidence will subside to a steady background level, presumably the result of natural environmental exposures [9]. The number of individuals recognized as suffering from an asbestos-related disease has been slowly increasing [21] and whether this is an actual increase or due to increased recognition because of altered criteria for diagnosis remains contentious. Since 1989, a programme has been set up in the U.K. for surveillance of work-related and occupational respiratory disease (known by the acronym SWORD) [21]. This group found that at least half the cases reported were attributable to asbestos exposure, most having benign pleural disease [22]. Due to the long latency period, asbestos-related benign pleural disease has yet to reach its peak incidence in the U.K. and is therefore likely to be encountered for many years to come. Legislation is variable in different countries regarding the use of asbestos and whilst some fibres, in particular crocidolite, are rarely used nowadays, chrysotile is, and its long-term biological effects are not yet known [9].
MEDICOLEGAL ASPECTS
In assessing occupationally exposed individuals for compensation, it is important to differentiate between the existing impairment of respiratory function and the resulting disability [23]. The World Health Organization defines respiratory disability as a reduction in exercise capacity secondary to impaired lung function; the resulting social and occupational disadvantage being designated a handicap [24]. Traditionally, the assessment of respiratory disability relies on a combination of static pulmonary function tests and clinical assessment (including questionnaires), although more objective methods would be preferable. In the U.K., eligibility for compensation for asbestos-related disease comes from three sources [21,25]: (1) a claim for Industrial Injuries Disablement benefit from the Department of Social Security; (2) a Common Law claim for damages from the firm where exposure to asbestos occurred; (3) a lump sum compensation claim from the Department of Environment, Transport and the Regions under the Pneumoconioses etc. (Workers Compensation) Act, 1979. Claiming for Industrial Injuries Disablement benefit requires certain criteria to be met in that an individual must be suffering from a ‘prescribed disease’ due to employment in a ‘prescribed occupation’ [26]. With respect to asbestos related disease in the U.K., compensation is given for bilateral diffuse pleural thickening, asbestosis, mesothelioma and lung cancer in the presence of asbestosis. Only diffuse pleural thickening will be discussed here. It is now accepted that diffuse pleural thickening can cause significant lung restriction [27–30] and bilateral diffuse pleural thickening became a prescribed disease in 1985 [21]. Pleural plaques alone, however extensive, are not recognized as being associated with significant respiratory disability and are therefore not considered a prescribed disease in the U.K. In claiming for common law compensation through the courts, the onus is on the claimant to show the condition has been caused by exposure to asbestos and has resulted in some disability. The lump sum compensation available from the Department of Environment, Transport and the Regions under the Pneumoconioses etc. (Workers Compensation) Act 1979 is designed for individuals or dependents of individuals who have died, who do not have a realistic prospect of bringing a claim against a previous employer (for example if the employer is no longer in business) providing the individual has not already received damages or out of court settlement from an employer [25].
PLEURAL PLAQUES
Pleural plaques are the commonest manifestation of asbestos exposure and bilateral scattered calcified pleural plaques can be regarded as virtually pathognomonic of asbestos exposure [9,31]. Pleural plaques are discrete elevated areas of hyaline fibrosis almost invariably arising from the parietal pleura. At thoracoscopy the striking smooth whiteness of the plaques has been
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(a)
(a)
(b) Fig. 1 – HRCT images showing the areas commonly affected by pleural plaques: behind the anterior ends of the uppermost ribs (a), in the paravertebral regions and on the diaphragmatic surface (b). Small pleural plaques behind anterior ribs and in paravertebral regions are likely to be overlooked on PA chest radiography.
likened to the appearance of icing on a cake. Pleural plaques tend to lie adjacent to relatively rigid structures such as the ribs, vertebral column and the tendinous portion of the diaphragm. According to radiographic studies, the characteristic sites are on the posterolateral chest wall between the seventh and tenth ribs, on the lateral wall between sixth and ninth ribs on the dome of the diaphragm and the mediastinal pleura particularly over the pericardium [32]. This distribution is largely borne out by computed tomography (CT) studies, although on CT plaques seem to be more profuse beneath the anterior aspects of the upper ribs (an area poorly demonstrated by standard radiographic views) (Fig. 1). Typically, plaques are not seen at the apices or in the costophrenic angles. Plaques that arise from the visceral pleura are very rare and are usually found in the lower aspects of the interlobar fissures; they may calcify and are usually associated with extensive parietal pleural plaque disease [13] (Fig. 2). The size and number of pleural plaques are extremely variable: plaques can occasionally be solitary but are most often multiple and bilateral. The idea that pleural plaques
(b) Fig. 2 – Conventional CT images on lung (a) and mediastinal windows (b) showing bilateral calcified pleural plaques. Note the partly calcified pleural plaque involving the right oblique fissure.
are almost invariably calcified is not confirmed by imaging studies. On plain chest radiography the reported prevalence of calcification in plaques is variable: one study reported less than 10% [33] and another 15% [34]. The conspicuity of calcification clearly depends on radiographic factors such as the kilovoltage used and the views obtained. Nevertheless, a CT study has also shown relatively low prevalence: Gamsu et al. demonstrated calcification in about 5% more patients with CT or HRCT than by chest radiography [33]. Conversely, about 5% of the calcifications thought to be present in pleural plaques on chest radiography were not corroborated by CT [33].
Pathogenesis Microscopically pleural plaques consist of relatively acellular bundles of collagen in an undulating ‘basketweave’ pattern and may contain abundant numbers of asbestos fibres,
ASBESTOS-RELATED PLEURAL DISEASE
almost exclusively chrysotile fibres, but asbestos bodies are absent [1,35]. The inner side is covered by normal mesothelial cells and on the costal side there may be signs of low-grade inflammation [36]. Despite much speculation, the pathogenesis of pleural plaques remains uncertain. In the past it was believed that the fibres caused direct mechanical irritation of the parietal pleura, (the so-called ‘scratching theory’) [37]. It is now thought that short asbestos fibres reach the parietal pleura by passage through lymphatic channels where they excite an inflammatory reaction, whereas the largest fibres, amphiboles, are retained in the lung parenchyma [5,37]. Alternative explanations for the presence of fibres in the parietal pleura are via the blood supply or by direct migration of fibres through the visceral pleura [5]. Pleural plaques slowly progress in size and amount of calcification with time, independent of any further exposure [2]. There is no evidence that pleural plaques undergo malignant degeneration into mesothelioma [9,10]. Asbestosis rarely occurs in the absence of pleural plaques [33]; although there is a significant correlation between severity of pleural disease and presence and severity of asbestosis, most plaques usually occur in isolation [38,39].
Chest Radiography vs CT The International Labour Office (ILO) classification of pneumoconioses assesses asbestos-induced pleural disease on chest radiography, using the posteroanterior projection [40]. The detection rate of pleural plaques on the chest radiograph is dependent on their size, position, shape, degree of calcification and technical quality of the radiograph. Autopsy studies report a high false negative rate for the radiographic detection of pleural plaques [14,31]. Digital storage phosphor radiography does not appear to improve the demonstration of pleural disease compared with conventional radiography [41]. Conversely, normal anatomic structures, such as extrapleural muscle and fat, may lead to false positive diagnoses in up to 20% of cases [10]. Oblique radiographs provide additional views of the pleural surface; in particular, permitting the detection of pleural thickening located in the posterolateral parts of the chest, which are not well visualized on frontal views. The addition of bilateral oblique projections has been reported to increase the radiographic detection of pleural disease by 50% [17], in particular of plaques more than of diffuse pleural thickening. However, in the ILO scoring system there is no scheme for the assessment of oblique views. Furthermore, the interpretation of oblique views is becoming a lost art, probably because of the increased use of CT. As early as 1976, Kreel described the use of CT for assessing asbestos-related disease [42]. He noted that regions of pleural thickening in the posterior sulci and mediastinum could be detected by CT when the chest radiograph appeared normal. On CT, plaques are readily recognized as circumscribed areas of pleural thickening with well-demarcated edges and are commonly located in the posterolateral and paraspinal regions of the thorax. Computed tomography is able to detect small foci of calcification within plaques [10]. Many subsequent studies have shown that CT is more sensitive for the detection of pleural disease [3,38,43,44], especially for plaques located in the paravertebral area. Al Jarad et al. compared chest
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radiographs with CT and demonstrated discrete pleural plaques in 95% of patients compared to 59% on chest radiography [27]. Friedman et al. compared high-resolution CT (HRCT) with a four-view radiograph series (PA, lateral and two obliques) [43]. The positive predictive value for detecting pleural disease was increased by HRCT, but HRCT was particularly useful in eliminating false positive diagnoses caused by subpleural fat found in 10–29% of patients thought to have non-calcified pleural plaques [43]. On HRCT pleural plaques appear focal with well demarcated edges, separated from the underlying rib and adjacent extrapleural soft tissues by a thin layer of fat. Intercostal vessels may cause the extrapleural soft tissues to appear thicker in the paravertebral regions (Fig. 3). It has therefore been suggested that paraspinal pleural plaques be diagnosed only if (a) thickening is visible on multiple levels, (b) extrapleural fat is visible between the pleura and intercostal vessels, (c) the thickened pleura can be seen to indent the subjacent lung, or (d) there is dystrophic calcification within the plaque [45]. Several studies have now compared the efficacy of HRCT with conventional CT [3,33,38]. Aberle et al. showed that HRCT was more sensitive than conventional CT for the detection of pleural disease, even though images were obtained at interspaced levels; the authors felt that the increased resolution of HRCT compensated for any sampling deficiencies and that when plaques were present, they were invariably extensive enough not to be missed on interspaced sections [3]. However, Gevenois et al. compared conventional CT with HRCT and concluded that in cases with known asbestos exposure and no plaques demonstrated on HRCT, then conventional CT should be performed as plaques may be detected in the skip areas [46]. Neri et al. have also shown that HRCT can demonstrate pleural plaques and early lung involvement in asymptomatic amosite exposed workers with apparently normal chest radiographs [47]. High resolution CT may also be useful in detecting other lung abnormalities, particularly emphysema, that may be responsible for symptoms in asbestos-exposed individuals. Pleural plaques are not usually associated with impairment
Fig. 3 – HRCT images on mediastinal windows showing how intercostal vessels may mimic pleural thickening and make extrapleural fat thicker in the paravertebral regions (arrows). Immediately adjacent sections did not reveal any pleural thickening.
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of lung function [14] and it has been suggested that in those cases where there is a restrictive impairment it is more likely to be due to subclinical interstitial fibrosis [48]. Some plaques demonstrate abnormality in the immediately adjacent lung parenchyma suggesting localized fibrosis; this consists of short (<1 cm) interstitial lines giving rise to the term ‘hairy plaques’ (Fig. 4). Such localized parenchymal changes related to pleural plaques should be distinguished from the generalized interstitial fibrosis of asbestosis, seen away from pleural disease on CT. However, the significance of ‘hairy plaques’ in terms of whether they herald the development of asbestosis has not been clarified.
BENIGN ASBESTOS-INDUCED PLEURAL EFFUSION
Benign pleural effusion ascribable to previous asbestos exposure was first described by Eisenstadt in 1964 [49]. Epler et al. reported 34 (3.1%) benign effusions among 1135 asbestos-exposed workers compared with no unexplained effusions among 717 controls [11]. This figure may, however, be an underestimate as many cases are probably subclinical, as judged by two studies in which between 46 and 66% of individuals with benign asbestos pleural effusion were asymptomatic [11,50]. In another study by Epler et al. the frequency
of benign asbestos pleural effusion was 3.7% in indirectly exposed workers and 7% in heavily exposed workers [11].
Pathogenesis Benign asbestos pleural effusions are exudative [50,51], but have a variable composition: the fluid is often macroscopically haemorrhagic, of mixed cellularity, or with an increased eosinophil cell count [50]. Epler et al. reported that there was a dose-response relationship with an increased incidence of effusions in those with the most severe exposure [11]. However, even slight exposure may be enough to cause a benign effusion [50]. Epler et al. also suggested a relationship with the type of occupation; in this series, asbestos effusion was most common among asbestos pipe coverers and least common among shipfitters, maintenance personnel and welders [11]. Such effusions usually spontaneously resolve with a mean duration of 3–4 months [35,39,50], but can persist or recur over several years. As these effusions resolve, many individuals develop diffuse pleural thickening, in particular blunting of the costophrenic angle [11]. Lilis et al. surveyed 2815 insulation workers and found that in the 20 cases with a positive history of pleural effusion, most had diffuse pleural thickening with blunting of the costophrenic angle [52].
Problems in Differential Diagnosis
Fig. 4 – Prone HRCT image of a ‘hairy plaque’ (arrowheads) showing short interstitial lines adjacent to the plaque. There are also features of interstitial fibrosis posteriorly.
The development of a pleural effusion is probably the earliest manifestation of previous asbestos exposure, it usually occurs within 10 years of exposure, and remains the commonest complication of asbestos exposure for the succeeding 10 years. However, a benign asbestos pleural effusion can occur much later [53], at which time the important differential diagnosis is malignant mesothelioma. The diagnosis of benign asbestos pleural effusion may be difficult, as the symptoms and character of the effusion are extremely variable; it is unlikely to be considered unless a history of occupational exposure to asbestos is elicited. The clinical picture varies from no symptoms to an acute illness with fever, pain, and elevated white cell count [10]. Computed tomography may be able to distinguish the sanguinous content of the pleural fluid by the higher attenuation number [39]. Certain criteria have been stipulated before the diagnosis of benign asbestos pleural effusion can be made [11,52]. These include: (1) history of direct or indirect exposure to asbestos, (2) exclusion of other causes of effusion, particularly TB and malignancy, (some authors advocate treatment of effusions with antituberculous therapy as TB cannot always be excluded [50]), and (3) no malignancy detected within 3 years after the onset of the effusion [54]. Contrary to what might be expected, asbestos fibres are not usually found in the effusion, whilst they can be found in the lungs and sputum [11]. Solomon has suggested that the presence of pleural plaques helps to distinguish asbestos-related effusions from other idiopathic effusions [39]; but given that plaques occur after a much longer latency period this is probably unhelpful in the majority of cases. The presence of linear structures converging on the pleura (so called ‘crow’s feet’) and folded lung are features which occur less frequently in association with exudative pleural effusion of
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other known cause [54]. Computed tomography is often indicated to exclude an underlying pulmonary cause, or the presence of an obvious pleural soft tissue mass. At present there is no definite evidence to suggest a relationship between benign asbestos pleural effusion and the subsequent development of malignant pleural mesothelioma. Although mesotheliomas have been reported in patients with a previous history of benign pleural effusions [11], another study followed-up 22 cases of benign asbestos pleural effusion for a mean of 23 years with no subsequent development of a mesothelioma [51]. Both conditions are associated with asbestos exposure; however, benign effusions occur within 10 years of asbestos exposure whereas malignant mesothelioma usually has a latent period of 20–40 years after initial exposure. Nevertheless, these differences in latent period are not absolute and it has been speculated, however tentatively, that the pleural drift of asbestos fibres causes mechanical irritation, resulting first in effusion and ultimately in mesothelioma [11]. Larger long-term studies are needed to determine whether there is a relationship between benign asbestos pleural effusion and mesothelioma.
DIFFUSE PLEURAL THICKENING
Diffuse pleural thickening as a sequel of asbestos exposure has only more recently been recognized as a separate entity. The revised edition of the ILO classification has partially addressed the issue of distinguishing plaques from diffuse pleural thickening [40]. However, there is still potential for confusion as the distinction is made solely on a single standard chest radiograph [16]. Diffuse pleural thickening is less specific to asbestos exposure than pleural plaques, given that many causes of exudative pleural effusions can give rise to diffuse pleural fibrosis, including previous inflammatory episodes (such as a parapneumonic effusion), haemothorax or connective tissue disease. Diffuse pleural thickening results from thickening and fibrosis of the visceral pleura, with fusion to the parietal pleura, often over a wide area [39]. This is in contrast to pleural plaques that tend to be discrete localized lesions arising from the parietal pleura, and are rarely adherent. Many studies have confirmed that diffuse pleural thickening is preceded by a benign asbestos pleural effusion [11,16,52,53].
Pathogenesis Microscopically there are similarities between diffuse pleural thickening and plaques, including the typical basket weave fibrous structure and scant cellular fibroblastic activity. However, with diffuse pleural thickening there is fusion of the two pleural layers with obliteration of the submesothelial elastic tissue, suggesting that a severe inflammatory reaction has occurred [55]. Moreover, Stephens et al. also showed pathologically that in a series of seven cases with diffuse pleural thickening there was subpleural honeycombing without appreciable diffuse parenchymal disease in every case [55]. The pathogenesis of diffuse pleural thickening, although not precisely known, is thought to be secondary to the inflammation and fibrosis of the superficial or visceral pleural lymphatic
pathways and has been considered as a direct extension of parenchymal lung fibrosis [56]. Diffuse pleural thickening is a frequent concomitant finding to asbestosis with a reported associated incidence of 10%. This is probably an underestimate. Asbestos bodies are profuse and easily recovered from pleuroparenchymal tissue, particularly adjacent to areas of pleural thickening [9,56]. In a study by Rockoff et al. there was a strong association between even early pulmonary interstitial fibrosis and fissural visceral pleural thickening [13]. Other studies, however, have shown only a weak association between these two features [16].
Chest Radiography vs CT McLoud et al. defined diffuse pleural thickening on a chest radiograph as a smooth non-interrupted pleural density extending over at least one-quarter of the chest wall, with or without costophrenic angle obliteration [16]. Lynch et al. defined it on CT criteria as a continuous sheet of pleural thickening more than 5 cm wide, more than 8 cm in craniocaudal extent, and more than 3 mm thick [57]. Diffuse pleural thickening which is less than 3 mm thick or less extensive may still be functionally significant, however, and a less rigorous definition is probably more appropriate. Differentiation from pleural plaques can sometimes be difficult. Fletcher et al. made the following observations from chest radiographs [32]: (1) plaques generally spare the costophrenic angles and apices; (2) diffuse pleural thickening due to asbestos exposure rarely calcifies; (3) diffuse pleural thickening is ill-defined and irregular from all angles whereas plaques are often well defined; and (4) plaques rarely extend over more than four rib interspaces unless multiple and confluent. Radiographically, diffuse pleural thickening can be difficult to diagnose but involvement of the interlobar fissures, by definition visceral pleural involvement, is the rule [13]. Involvement of the minor fissure on the lateral radiograph occurs with sufficient frequency that a separate classification symbol, ‘pi’, has been added to the ILO-1980 classification [40]. Ameille et al. compared oblique chest radiographs with high-resolution CT as the ‘gold standard’ for the detection of diffuse pleural thickening and found that the positive predictive value for diffuse pleural thickening with the addition of the right anterior oblique film was only 13–26% [58]. Most of the false-positive diagnoses of pleural fibrosis were due to abundant extrapleural fat. As with discrete pleural plaques, CT is more sensitive and specific for the detection of diffuse pleural thickening than chest radiography [27,38,43], in particular for differentiating extrapleural fat from pleural thickening (Fig. 5a, b). Al Jarad et al. found that there was greater inter-observer agreement regarding the type of pleural disease present with CT compared with chest radiography [27]. On CT diffuse thickening appears continuous, commonly involving the posterior and lateral surfaces of the lower thorax [35,39] (Fig. 6). Frequently there is an accompanying increase in extrapleural fat, presumably drawn inwards by pleural retraction [35]. The advantage of HRCT over conventional CT is more controversial: Aberle et
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Fig. 6 – Prone HRCT image of a patient with bilateral diffuse pleural thickening due to asbestos exposure predominantly affecting the posterobasal regions. Note the coexisting calcified right pleural plaque.
(a)
(b) Fig. 5 – Chest radiograph (a) of an individual showing a linear opacity paralleling the innermost aspect of the ribs in the mid and upper zones, mimicking pleural thickening. HRCT image (b) using mediastinal windows demonstrates fat attenuation adjacent to the ribs on the right (arrows), confirming the cause as extrapleural fat.
al. found HRCT to be less sensitive compared to CT for detecting diffuse pleural thickening than pleural plaques [38], whereas Friedman et al. found, as with pleural plaques, that HRCT was a better discriminator of extrapleural fat and of fissural pleural thickening from intrafissural fat [59]. Even on HRCT, however, subpleural oedema may occasionally mimic diffuse pleural thickening, but such cases are rare. Computed tomography may be particularly helpful in distinguishing malignant from benign pleural disease. Leung et al. suggested that the presence of pleural rind, pleural nodularity, pleural thickening greater than 1 cm and mediastinal pleural involvement were most discriminatory as they are all more frequent in malignant disease [60]. Many studies have shown that diffuse pleural thickening, in the absence of parenchymal fibrosis, results in impaired lung function [27–29,61]. Typically, there is a restrictive ventilatory defect with a decrease in lung volumes, decreased inspiratory capacity, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and preserved gas diffusing capacity [14]. Cotes et al. found that in the presence of thickening, obliteration of either or both costophrenic angles was associated with an additional deleterious effect on lung function [28]. Al Jarad et al. reported a tendency for the gas transfer coefficient to increase with more extensive pleural disease, reflecting a proportionately greater reduction in lung volumes than in gas transfer [27]. This can be explained by the normal lung being encased in a ‘cuirasse’ of fibrous tissue. These observations have led to the adoption of the ILO scoring system for pleural thickening [28]. Al Jarad et al. have proposed an HRCT scoring system analogous to the ILO for the quantification of pulmonary fibrosis, pleural disease and emphysema in patients with asbestos-related disease and found that HRCT and chest radiography correlated with indices of lung function to a similar extent [62]. Whether stronger correlations are possible using more precise visual CT estimation of the extent of pleural disease has not been established.
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(a)
Fig. 7 – Chest radiograph of a patient with unilateral diffuse pleural thickening post-thoracotomy. The 3.5 cm rounded opacity at the left costophrenic angle was thought to represent a possible bronchial neoplasm, but proved to represent an area of folded lung on CT.
FOLDED LUNG
Folded lung refers to peripheral atelectatic lung adjacent to an area of pleural thickening with characteristic drawing in of the bronchi and vessels into the atelectatic lung [63–65]. Synonyms for folded lung include Blesovsky’s syndrome, rounded atelectasis, atelectatic pseudotumour and pulmonary pseudotumour. Blesovsky first reported three cases in 1966 in which there was unusually extensive lung folding due to a fibrous membrane on the costal surface of the visceral pleura of the lower lobe, and termed it ‘folded lung’ [66]. There is a strong association with previous asbestos exposure [67,68] but any cause of an organizing pleural exudate such as tuberculosis, histoplasmosis, Dressler’s syndrome following cardiac surgery and haemothorax may be responsible [68,69] (Fig.7). In Hillerdal’s review of 74 cases the commonest site was in the lingula, followed by the middle lobe and then the lower lobes [68] but any lobe can be affected and bilateral involvement is not uncommon [63].
Pathogenesis Two theories about the pathogenesis of folded lung have been proposed. Hanke and Kretzschmar suggested that the infolding is preceded by a pleural effusion that causes the lung to collapse and fold on itself, resulting in localized invagination of visceral pleura [65]. As the effusion recedes adhesions between the invaginated visceral pleura prevent full re-expansion, resulting in a mass of folded lung adjacent to a residual area of pleural thickening [65]. The second, more widely accepted theory was originally suggested by Blesovsky [66] and recently revisited by Menzies et al. [64]. These authors proposed that the primary event is an injury that leads to an
(b) Fig. 8 – Folded lung on HRCT. On the superior section (a) the area of folded lung could be mistaken for a pulmonary neoplasm, whereas a lower section (b) shows the typical features of folded lung described in the text.
inflammatory reaction and subsequent fibrosis in the most superficial layer of the pleura. As the fibrous tissue matures it contracts causing the pleura to buckle into the lung, resulting in atelectasis at this point.
Chest Radiography vs CT On chest radiography, folded lung appears as a rounded peripheral pulmonary mass; distortion of the adjacent lung may or may not be obvious and pleural thickening is usually evident (Fig. 7). Conventional CT is most helpful in making the diagnosis and McHugh and Blaquiere described three major features: (1) rounded or oval mass (2.5–7 cm) abutting a peripheral pleural surface; (2) the curving ‘comet tail’ of bronchovascular structures passing into the mass, resulting in a blurred central margin; and (3) thickening of the adjacent
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(a)
(b) Fig. 9 – Chest radiograph of an individual exposed to asbestos (a) with bilateral pleural thickening and blunting of both costophrenic angles. Parenchymal strands are seen radiating from the pleura on the left. Conventional CT (b) of the same patient shows the parenchymal bands converging on point at the pleural surface resembling ‘crows’ feet’.
pleura with or without calcification, which is usually, but not always, thickest adjacent to the mass [63] (Fig. 8). Lynch et al. included the further feature of evidence of volume loss in the adjacent lung [67]. Dynamic contrast-medicine enhanced CT does not reliably differentiate folded lung from malignancy in equivocal cases. It has been suggested by Marchbank et al. [69] that ultrasound may be helpful in confirming the diagnosis by the demonstration of a highly echogenic line within the mass that is seen adjacent to pleural and extrapleural fat layer thickening. The visceral pleura may be thickened and have single or multiple pleuroparenchymal fibrous bands radiating from it [39]. They are usually seen in addition to (or rather in
Fig. 10 – HRCT of an individual exposed to asbestos showing limited ‘crow’s feet’ adjacent to right-sided diffuse pleural thickening: an example of the difficulty in differentiating limited parenchymal fibrosis due to underlying pleural disease from interstitial fibrosis.
connection with) diffuse pleural thickening [6,70] and may be considered analogous to a forme fruste of folded lung. On a chest radiograph these may be seen as fine or coarse densities partially or completely traversing the lung field, usually converging on a single point on the pleura, creating a likeness to ‘crows’ feet’ [6] (Fig. 9a). Computed tomography demonstrates this phenomenon to advantage and shows strands penetrating the underlying lung parenchyma from an area of thickened pleura, sometimes producing a blurred demarcation line between the pleura and the lung [70] (Fig. 9b). These strands are thought to represent thickening of adjacent interlobular septa due to a fibrotic reaction [39]. Gevenois et al. have suggested from a CT series that ‘crow’s feet’, pleural tags and parenchymal bands are predominantly related to the fibrosis of the visceral pleura and should be differentiated from HRCT features more suggestive of diffuse interstitial fibrosis [71]. Nevertheless, this distinction is not always easy and, paradoxically, may be particularly difficult in cases showing limited changes on HRCT (Fig. 10). An association with mesothelioma has recently been reported with involvement of the ipsilateral thorax in all cases [72,73]. From these cases it was suggested that mesothelioma should be considered if there is either an associated large pleural effusion, a pleural mass with or without chest wall invasion, or thickened pleura not adjacent to the folded lung [72]. SUMMARY X X X X X X
Benign pleural effusion is the earliest manifestation of asbestos exposure. Diffuse visceral pleural thickening follows benign asbestos pleural effusion. Diffuse pleural thickening is more commonly found in association with asbestosis than pleural plaques. ‘Crow’s feet’ and folded lung are related to diffuse visceral pleural thickening. Thickening of the interlobar fissures reflects involvement of the visceral pleura. Diffuse pleural thickening may result in a restrictive functional lung impairment and affected individuals are eligible for compensation.
ASBESTOS-RELATED PLEURAL DISEASE
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