Asbestos and benign pleural diseases: a narrative review

Abstract

The term “asbestos” is used to refer to a group of silicate minerals that often break down into fibres and whose inhalation over time can cause a number of diseases, especially pleuropulmonary diseases. While the most serious complications are malignant diseases, inhalation of these fibres can also cause benign pleural diseases such as round atelectasis, pleural plaques, diffuse pleural thickening and non-malignant asbestos pleural effusion.

Although asbestos is banned in most developed countries (in the European Union, since 2002), it is still used in developing countries. Despite these restrictions, the prevalence of diseases due to inhalation remains high due to the long latency period between the onset of exposure and the onset of disease.

In this paper we review benign pleural diseases induced by asbestos exposure, update the diagnostic criteria for these disorders, and describe the approaches suggested so far to differentiate them from malignant pleural diseases.

Shareable abstract

A review of benign pleural diseases arising from asbestos exposure, updated diagnostics and differentiation from malignancy. Despite bans, asbestos-related diseases remain prevalent due to their long latency and are expected to persist for years. https://bit.ly/43F7waS

Introduction

The term “asbestos” refers to a group of fibrous silicates that usually break into fibres and are characterised by long durability, high tensile strength and heat resistance. These properties made this material of great commercial interest. Asbestos was widely used in the past, having over 3000 different applications in a variety of industrial sectors (thermal insulation products, electrical wiring, construction materials, friction products, and toys, to name just a few).

Asbestos fibres are classified into two groups: amphiboles and serpentines. Each fibre type has different mineralogical and chemical properties. Amphiboles include crocidolite, amosite, anthophyllite and tremolite. These forms of asbestos have a rectilinear and rigid morphology and vary in length. Serpentines are represented by chrysotile, which has a curved shape and accounts for 95% of the asbestos commercially available worldwide [1].

Asbestos is identified by the World Health Organization as a group 1 carcinogen. Crocidolite is recognised as a major cause of mesothelioma; however, the evidence available on its fibrogenic potential is more limited. The fibre with the highest carcinogenic and fibrogenic potential is crocidolite, although chrysotile also plays an important role in carcinogenesis [2]. The iron content of asbestos fibres is also relevant, as it may play a role in the generation of free radicals, genotoxic agents that induce DNA damage. This damage affects gene transcription and protein expression, leading to important changes in inflammation, cell proliferation and cell death [3].

Asbestos is currently being replaced with other products as countries across the world ban its use. In 2002, the European Union banned the use of asbestos in all member states [4]. However, even in these countries, the risk of occupational exposure persists in certain jobs such as building demolition, maintenance, repair and transport of previously installed asbestos-containing structures. Nevertheless, it continues to be used in developing nations, with Russia and China being the main global producers and consumers of asbestos.

Asbestos fibres can act differently at several stages, resulting in a wide spectrum of associated pleuropulmonary diseases. Asbestos-related pleural diseases described to date include round atelectasis (RA), pleural plaques (PPs), diffuse pleural thickening (DPT), non-malignant asbestos pleural effusion (NMAPE) and malignant mesothelioma. All these conditions share the characteristic of having a long latency period [5, 6]. As malignant mesothelioma has been extensively studied and specific guidelines are available for this disease [7, 8], we provide a narrative review on benign pleural diseases (BPD) associated with asbestos exposure (table 1).

TABLE 1.

Clinical characteristics of benign pleural diseases related to asbestos

Disease	Incidence	Symptoms	Pathogeny	Radiological findings	Treatment
Round atelectasis	Not established	Usually asymptomatic	Folding/visceral pleural fibrosis/bronchial distortion	Rounded opacity on the periphery of the lung	None
Pleural plaques	∼60%	Asymptomatic	Unknown	Areas of hyaline fibrosis of the parietal pleura	No effective treatments
Diffuse pleural thickening	5–14%	Dyspnoea	Possible sequelae of non-malignant asbestos pleural effusion	Pleural thickening of at least one quarter of the chest wall and obliteration of at least one of the costophrenic angles	No effective treatments Symptomatic
Non-malignant asbestos pleural effusion	21% of all asbestosis cases	Usually asymptomatic	Mechanical irritation of the visceral pleura by asbestos fibres and/or obstruction of lymphatic drainage of the parietal pleura induced by pleural fibrosis	Usually small or moderate unilateral pleural effusion, although it can be massive or bilateral	Usually resolves spontaneously Drainage, if dyspnoea

Pathogenesis and exposure

The biological activity of asbestos fibres depends on their physical form and durability, rather than their chemical properties. The high penetration power of some fibres enables them to reach the areas of the lungs involved in gas exchange. Thus, the aerodynamic diameter of these fibres allows them to “align” with the laminar flow of inspired air to reach the most distal areas of the airways. Once the fibres reach these areas, they are phagocytosed and cleared by macrophages. Phagocytosis is a slow mechanism whose success depends on several factors. Clearance of longer fibres is more challenging for macrophages, the mucociliary transport system of the airways, and the lymphs of the interstitium and pleura. Long-lasting fibres are also more difficult to digest by immune cells. The longer the fibres persist in tissues, the greater the risk for them causing inflammation and having fibrosing or oncogenic effects [9]. The most common cause of BPD is direct occupational exposure to asbestos. However, BPD can also develop for causes unrelated to occupational exposure, due to contact with building or car maintenance products (these products contain asbestos) [10] or para-occupational exposure [11]. In the building-related setting, the incidence of BPD and malignant mesothelioma has been observed to be higher in inhabitants of buildings constructed with asbestos-rich materials and professionals involved in the rehabilitation of these buildings. It is expected that these diseases will continue to increase in the coming years. In the case of para-occupational exposure, pleuropulmonary diseases related to asbestos exposure have been long and persistently described in cohabitants of exposed workers. This is because cohabitants breathe the dust accumulated on workers’ clothes or hair, especially in workers highly exposed to amphibole fibres.

The mechanism by which asbestos fibres enter the body by inhalation and reach the pleural surface is not yet fully understood. Moreover, the ability of these fibres to damage the parietal pleura differently across individuals while leaving the visceral pleura intact is even more intriguing. Although there is no clear explanation for this, the clue may lie in a combination of different mechanical, biochemical and genetic factors that have not been sufficiently elucidated [12, 13]. The classical theory that PPs are induced by asbestos fibres protruding from the visceral pleura, thereby causing mechanical irritation of the overlying parietal pleura has been ruled out [14]. In the case of PPs, asbestos fibres would reach the parietal pleura via the lymphatic flow and the blood stream (systemic circulation). The characteristics of the different types of asbestos fibres would also explain their different effects on certain cell types. The mechanism may be as follows: either the iron contained in some fibres that remain retained in the lung for a long time, or long thin fibres (>8 µm), which are more difficult to phagocytise, might generate reactive oxygen species; these species cause oxidative lesions leading to genetic mutations. Therefore, long fibres would be more carcinogenic than shorter ones, as the latter can be phagocytosed and incorporated into the lysosome [3, 15]. As all asbestos fibres can cause DNA damage, these fibres may play a major role in reducing apoptosis in target cells such as mesothelial cells. Asbestos induces apoptosis in mesothelial cells via reactive oxygen species. Escaping from this pathway would result in the abnormal survival of mesothelial cells carrying asbestos-induced mutations [16].

Claiming a disease to be induced by exposure to asbestos, as is the case for some BPDs, has legal and economic implications, as some are recognised as occupational diseases. Furthermore, their diagnosis entails previous follow-up controls. Although asbestos is known to cause respiratory diseases, for a case of asbestos-induced disease to be demonstrated, sufficient evidence must be provided of a long intensive exposure to this material, together with supportive clinical and imaging studies. Finally, other causes have to be reasonably ruled out. In the case of BPD, at least 10 years of exposure, even if low intensity, are required [17]. If there is doubt about exposure, the most objective proof is demonstrating the presence of asbestos in a tissue sample. However, in many cases, this is unrealistic as, in the case of the pleura, the amount of asbestos will always be low. If exposure was domestic or environmental, establishing causality is even more challenging.

Round atelectasis

Round atelectasis is a rare form of peripheral lung collapse that develops adjacent to previously-thickened areas of the visceral pleura [18]. Radiologically, it manifests as a round opacity (mass-like lesion) in the peripheral lung adhered to the thickened pleura, with curvilinear opacities extending from the atelectasis towards the hilum (“comet tail” sign) [19]. However, it is sometimes difficult to distinguish round atelectasis from malignant tumours. In these cases, computed tomography (CT) and magnetic resonance imaging of the chest are very helpful [20]. They are usually seen in people exposed to asbestos, although traumatic rib fractures and haemorrhagic pleural effusion, as well as previous pleural exudates, can also cause round atelectasis [18].

In a review of 100 cases, 95% of RAs were located in the middle lobe, lingula and lower lobes [18]. The mechanism by which they form is still under debate and is the subject of several theories. According to the lung folding theory, the pathogenesis of RA is mediated by lung compression by a loculated accumulation of pleural fluid that subsequently invaginates (figure 1a). In accordance with the fibrosing theory, the primary lesion is a local inflammation of the visceral pleura leading to fibrosis. Contraction of this fibrotic focus would lead to RA of the underlying lung (figure 1b). Both situations could be complementary [22, 23]. A third option would be the distortion of the small airways, resulting in absorption of the air contained therein and consequent localised atelectasis (figure 1c). The retracted lung engulfs its airways and adjacent blood vessels, giving rise to a characteristic, almost diagnostic radiological image called the “comet tail” sign [19, 20].

FIGURE 1.

Mechanism of formation of round atelectasis. a) Folding. Increasing pressure of accumulating pleural fluid (black arrow) causes inward bulging of visceral pleura and atelectasis of the underlying lung parenchyma (white arrows). b) Fibrosis. Contraction of a focus of visceral pleural fibrosis (vertical arrows) causes shrinkage of underlying parenchyma (curved and horizontal arrows). c) Microbronchial distortion. Increasing pleural fluid pressure (black arrow), and/or visceral pleural fibrotic plaque contraction (long white arrow), cause displacement of underlying pulmonary parenchyma (short white arrow), and distortion of small bronchi (black arrowhead) with subsequent peripheral gas absorption. Reproduced from [21] with permission.

Patients with RA usually remain asymptomatic. However, if atelectatic lung volume is high enough to compromise lung function, patients may develop dyspnoea [24]. An insufficiently understood question is whether RA related to asbestos exposure predisposes to malignancy. The only study on the subject suggests that patients with RA and coexisting diffuse pleural thickening and/or interstitial fibrosis should be considered to be at an increased risk for lung cancer and should therefore be followed up [25]. Currently, checking the stability of the lesions over time using imaging studies (CT) every 6 months for 2 years is currently recommended. If the patient is symptomatic, other techniques (positron emission tomography, positron emission tomography-CT or fine needle aspiration) should be considered to exclude malignancy [26]. RAs are not treated, except when there is significant deterioration of lung function or cancer is suspected [21].

Pleural plaques

PPs are the most frequent radiological manifestation of asbestos exposure [27] and are considered a marker of exposure. Individuals with PPs have an increased risk of developing more serious asbestos-related diseases in the future. PPs are observed in more than 50% of directly exposed workers and also (although to a lesser extent) in environmentally-exposed individuals (i.e., cohabitants and neighbours), provided that a long latency period (20–30 years) is considered. PPs are a clinically relevant marker of asbestos exposure. When calcification turns evident, PPs are pathognomonic of asbestos-related pleural fibrosis [28]. PPs are usually present in varying numbers and sizes and are distributed over the posterolateral chest wall, the dome of the diaphragm and the mediastinal pleura [29]. Their presence is confirmed by CT scanning. The CT scan also may reveal non-calcified plaques, diffuse pleural thickening or interstitial lung disease (asbestosis). This imaging study is also useful for differential diagnosis from other diseases that may also manifest with PPs (previous tuberculosis, haemothorax, pleurodesis, early mesothelioma, myeloma and rib fractures).

The development of PPs depends on the duration and level of exposure, requiring a high level of cumulative dose of inhaled asbestos fibres (continuous exposure for ≥1 year or discontinuous exposure for ≥10 years) [30]. Its pathogenesis is unclear, and several hypotheses have been posited, some of which are hardly plausible, such as that of Meurman [31], who proposed that PPs are formed as a result of the inflammation of the parietal pleura by asbestos fibres protruding from the visceral pleura; or that microfibrils gain access to the pleural space and from there to the parietal pleura. The most widely accepted theory is that asbestos fibres reach the parietal pleura via retrograde lymphatic drainage, which implies their flow from the mediastinal, retrosternal and intercostal lymph nodes. Another possibility is that they do so via the blood stream [28, 32].

PPs do not cause symptoms. Occasionally, and if extensive, they have been associated with non-specific chest pain not attributable to other cause [33] or angina-like chest pain [34]. If patients develop other asbestos-related disease inducing lung restriction, they may develop dyspnoea [35]. Some authors correlate the volume of PPs with the presence of a restrictive pattern on lung function tests. Although a direct correlation has not been proven, there is evidence of a tendency of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV₁) and diffusing capacity of the lung for carbon monoxide (D_LCO) values to be lower [36, 37]. In another study, the presence of PPs was associated with a small but statistically significant difference in FVC and FEV₁ values compared to individuals exposed to asbestos but without PPs or other radiological changes [38].

Diagnosis is established on the basis of radiological findings and a history of exposure. Sometimes a thorough occupational history will be necessary to confirm past exposure [32]. After diagnosis, follow-up may be terminated [39], but if the patient is concerned and wishes to discuss the risk for future complications, follow-up can be offered [40]. In Spain, it is recommended to perform a checkup including a chest radiograph and a forced spirometry test every 1–3 years. If forced spirometry is abnormal, a D_LCO test is recommended [26]. However, the probability that patients with PPs develop respiratory complications in the future is low, as is the risk for disease progression (5–10% probability that plaques extend; 2–5% probability of developing diffuse pleural thickening; 1–2% probability of developing mesothelioma) [33]. However, in certain occupations associated with a higher risk for mesothelioma, the chances of developing this disease are higher [41].

Diffuse pleural thickening

Asbestos exposure can cause chronic pleuritis leading to DPT. It involves an extensive area of the visceral pleura, often with adhesions to the parietal pleura, radiologically characterised by obliteration of the costophrenic sinus [42] and often causes restrictive impairment on lung function tests [43, 44]. The incidence of DPT will depend on whether the definition of DPT includes involvement of both the pleura and the underlying lung or only the pleura. If both are included, lung restriction will be more frequently diagnosed by pulmonary function tests, but its incidence will be lower. If only pleural lesions are considered, the opposite would occur [28].

Whether DPT develops depends on the duration of exposure and the cumulative dose of asbestos [45]. Jeebun et al. [46] show that in 40% of cases, DPT took more than 40 years to manifest from onset of exposure. The mean latency of the entire series was 34 years.

DPT is interpreted as an effect of either exudative pleural effusion or repeated episodes of pleuritis related to asbestos, which creates a fibrous structure [47, 48]. Unlike PPs, which are located in the parietal pleura, DPT affects the visceral pleura [47, 48]. DPT diagnosis can be established based on radiograph finding of obliteration of the costophrenic angle in continuity with pleural thickening ≥3 mm [49]. Chest CT is more sensitive in establishing diagnosis [50, 51] and is useful for differential diagnosis between DPT and extrapleural fat.

Unlike PPs, which are usually asymptomatic, DPT varies from the absence of symptoms to chest pain or dyspnoea, with a restrictive pattern on pulmonary function tests (reduced FVC, static lung volumes and D_LCO). A classic study on the International Labour Office profusion score confirmed the parallel occurrence of lung function reduction (except for intermediate scores). This study also revealed the additional effects of DPT on lung function [52]. Chest wall restriction induced by asbestos-related DPT may cause ventilatory failure and carbon dioxide retention in patients with minimal or no pulmonary fibrosis [33, 35, 53].

Diagnosis is established by occupational history and radiological imaging. Biopsy is rarely necessary. However, differential diagnosis is needed to exclude other causes of DPT or discard malignant pleural effusion as the cause of rapidly progressive chest pain [40].

Treatment is usually limited to monitoring the course of symptoms, as DPT may progress over time [54]. If this happens and there is no progressive pulmonary fibrosis, decortication may be useful, although it is rarely performed [28]. Although the evidence available is insufficient, these patients are at a higher risk of developing lung cancer or malignant mesothelioma; therefore, follow-up is advisable [55]. In Spain, an annual check-up involving a chest radiograph and a complete functional study including lung volumes and D_LCO is recommended [26].

Non-malignant asbestos pleural effusion

All asbestos fibres have the potential to cause pleural effusion [35, 40]. In contrast to other benign asbestos-related diseases, NMAPE usually presents early after the onset of exposure (<10 years) [55] and may overlap with other asbestos-related diseases. Although its prevalence is unknown, as many cases remain asymptomatic (incidental radiological finding), an old study established that 21% of patients with asbestosis develop NMAPE [24]. However, some patients may present with fever or severe pleuritic pain [56, 57].

The pathogenic mechanism that causes NMAPE is unknown. Some authors suggest it to be caused by mechanical irritation of the visceral pleura either by asbestos fibres or by obstruction of the lymphatic drainage of the parietal pleura induced by pleural fibrosis [58, 59].

NMAPE is usually unilateral (80%), most frequently occurring on the left side, and may resolve spontaneously within an average of 3–4 months. However, relapse occurs in one-third of cases [48, 57, 60], and not necessarily on the same side [56].

The fluid is an exudate [61] and has no distinctive biochemical features [59]. It can sometimes be predominantly eosinophilic and have a haemorrhagic appearance [62]. The presence of PPs on imaging studies and fibres in pleural tissue [63], although the latter rarely occurs [20], provide diagnostic guidance. Diagnosis of NMAPE is based on a diagnosis of exclusion and must meet the following criteria: asbestos exposure demonstrated by a detailed clinical history; pleural effusion confirmed by radiography and/or thoracentesis; exclusion of other causes of pleural effusion (mainly parapneumonic, tuberculosis, malignancy, pulmonary embolism, pancreatitis and connective tissue diseases); and no malignant tumour in the previous 3 years [48]. Low concentrations of carcinoembryonic antigen and hyaluronic acid in pleural fluid are not sufficient to exclude a diagnosis of mesothelioma. Additionally, pleural fluid cytology and pleural tissue sampling are required to rule out neoplastic pleural effusion [35]. The role of imaging studies and various biochemical parameters in pleural fluid and blood in differentiating NMAPE from malignant mesotheliomas has been assessed in a range of studies. Kato et al. [64] conducted a study to differentiate the two types of effusions through CT and found that the prevalence of PPs, RA and DPT was significantly higher in the NMAPE group. The authors noted that “low-level” irregularities (regular surface with thickening >3 mm but ≤1 cm) were more frequent in NMAPE (p<0.001), whereas “high-level” irregularities (regular thickening >1 cm) and mediastinal and interlobar fissure locations were more prevalent in the mesothelioma group (p<0.001) (interlobar pleural irregularity: no cases in NMAPE, 55% in mesothelioma group; mediastinal pleural involvement, 74% in mesotheliomas; positive predictive value, 89%). Therefore, the level and location of pleural abnormalities could be useful in differential diagnosis between NMAPE and malignant pleural mesothelioma [64].

Soluble mesothelin-related peptides in blood (area under the curve (AUC) 0.872; cut-off point: 0.93 nM·L⁻¹; sensitivity 80%, specificity 82.6%) and pleural fluid (AUC 0.831; cut-off point: ≥10.4 nM·L⁻¹; sensitivity 76.7%, specificity 76.2%) were effective in differentiating the two types of effusions [65]. Subsequent studies provided similar results [66, 67]. In a recent study, the secretory leukocyte peptidase inhibitor (among other parameters) in pleural fluid was used to differentiate NMAPE from malignant mesothelioma. Peptidase inhibitor is a biomarker present in the respiratory tract that exerts protection against tissue destruction. Values were significantly lower in NMAPE than in malignant mesotheliomas (p<0.001; AUC 0.902; sensitivity 82.4%, specificity 86.5%) and could therefore be useful for diagnosing NMAPE [68].

It is not uncommon for non-specific pleural effusions to precede mesothelioma by several years. However, if a malignant disease has not manifested within 3 years from the onset of effusion, the effusion should be considered benign [40]. NMAPE does not usually have prognostic implications in case mesothelioma occurs (no cases in a series of 22 patients followed for 17 years) [69], although some authors recommend follow-up [57]. NMAPE can leave sequelae such as costophrenic sinus obliteration or DPT [55].

Conclusions

Asbestos was used virtually without restrictions until the mid-1980s in countless sectors of industry. Since then, it has been progressively banned in developed countries. However, even in these nations, the prevalence of asbestos-related diseases continues to be high and is expected to remain so in the coming years due to the long latency of these diseases. This will especially occur in certain occupations related to the maintenance or demolition of asbestos-containing structures.

Asbestos-related BPDs constitute a broad spectrum of diseases that may occasionally cause disabling symptoms and require some type of intervention. For the time being, avoiding asbestos exposure is crucial for the primary prevention of these diseases. It is necessary that tools are developed to differentiate asbestos-related BPD from malignant mesothelioma. Efforts have been made to use imaging studies or biochemical markers in pleural fluid and blood for differential diagnosis. However, a pleural fluid cytology or a pleural tissue biopsy are currently required to conclusively differentiate asbestos-related BPDs from malignant mesothelioma.

Future directions

In the future, cases related to asbestos exposure should be addressed from different approaches. Firstly, it is necessary to avoid exposure by banning the use of asbestos fibres in all countries. However, as we have discussed throughout this article, even though the use of asbestos was forbidden, the number of cases would not decrease significantly, at least in the short to medium term, due to the long latency period of these diseases.

Secondly, the evidence provided in the literature suggesting that some individuals are genetically predisposed to develop the effects of asbestos exposure may help identify population subgroups at risk [70]. Finally, conducting surveillance studies by annually screening (e.g. low-dose radiation CT) [71] asbestos-exposed individuals at increased risk of developing malignant disease should be considered. This would also require the development of cancer risk prediction models based on the history of asbestos exposure.