© 2004 American Thoracic Society
Diagnosis and Initial Management of Nonmalignant Diseases Related to Asbestos
Diagnostic Criteria and Guidelines for Documenting Them Asbestos as a Hazard Asbestos in Lung Tissue Clinical Evaluation and Indicators Symptoms Occupational and Environmental History Physical Examination Conventional Imaging Computed Tomography Bronchoalveolar Lavage Pulmonary Function Tests Nonmalignant Disease Outcomes Asbestosis Nonmalignant Pleural Abnormalities Associated with Asbestos Chronic Airway Obstruction Implications of Diagnosis for Patient Management Actions Required before Disease Is Apparent Actions Required after Diagnosis Conclusions Asbestos is a general term for a heterogeneous group of hydrated magnesium silicate minerals that have in common a tendency to separate into fibers (1). These fibers, inhaled and displaced by various means to lung tissue, can cause a spectrum of diseases including cancer and disorders related to inflammation and fibrosis. Asbestos has been the largest single cause of occupational cancer in the United States and a significant cause of disease and disability from nonmalignant disease. To this demonstrable burden of asbestos-related disease is added the burden of public concern and fear regarding risk after minimal exposure. This statement presents guidance for the diagnosis of nonmalignant asbestos-related disease. Nonmalignant asbestos-related disease refers to the following conditions: asbestosis, pleural thickening or asbestos-related pleural fibrosis (plaques or diffuse fibrosis), "benign" (nonmalignant) pleural effusion, and airflow obstruction. This document is intended to assist the clinician in making a diagnosis that will be the basis for individual management of the patient. It therefore provides overarching criteria for the diagnosis, specific guidelines for satisfying these criteria, and descriptions of the clinical implications of the diagnosis, including the basic management plan that should be triggered by the diagnosis. It is understood that disease may be present at a subclinical level and may not be sufficiently advanced to be apparent on histology, imaging, or functional studies. One of the most important implications of the diagnosis of nonmalignant asbestos-related disease is that there is a close correlation between the presence of nonmalignant disease and the risk of malignancy, which may arise from exposure levels required to produce nonmalignant disease or mechanisms shared with premalignant processes that lead to cancer. The major malignancies associated with asbestos are cancer of the lung (with a complex relationship to cigarette smoking) and mesothelioma (pleural or peritoneal), with excess risk also reported for other sites. There is a strong statistical association between asbestos-related disease and malignancy, but the majority of patients with nonmalignant asbestos-related disease do not develop cancer. On the other hand, the risk of cancer may be elevated in a person exposed to asbestos without obvious signs of nonmalignant asbestos-related disease. However, a diagnosis of nonmalignant asbestos-related disease does imply a lifelong elevated risk for asbestos-related cancer.
People with past exposure to asbestos consult physicians for many relevant reasons: to be screened for asbestos-related disease, for evaluation of specific symptoms that may relate to past asbestos exposure (known or unsuspected), for treatment and advice, and for evaluation of impairment. In 1986, the American Thoracic Society convened a group of experts to review the literature and to present an authoritative consensus view of the current state of knowledge with respect to diagnosis of nonmalignant disease related to asbestos (2). In 2001, a new group was convened to review and to update the 1986 criteria. This statement constitutes that committee's report, completed in 2004. The criteria formulated in this statement are intended for the diagnosis of nonmalignant asbestos-related disease in an individual in a clinical setting for the purpose of managing that person's current condition and future health. These general criteria are slightly modified from those presented in 1986 (Table 1) (2):
The rest of this statement is largely devoted to presenting clinical guidelines required to document that each of these criteria is met. Demonstration of functional impairment is not required for the diagnosis of a nonmalignant asbestos-related disease, but where present should be documented as part of the complete evaluation. Evaluation of impairment has been extensively reviewed elsewhere and is not repeated here (3). Functional impairment may be demonstrated by evidence of symptoms or signs, ventilatory dysfunction, impaired gas exchange, and inflammation. Pulmonary function testing should be conducted in conformity with standards already published by the American Thoracic Society (4, 5), including multiple trials to confirm reproducibility and documentation of all trials attempted. These guidelines are designed for clinical application, not for research, epidemiologic surveillance, screening, litigation, or adjudication. They balance the need to be as accurate as possible with protection of the patient's safety and the yield, cost, and accessibility of the diagnostic procedures available. These guidelines, if they err, err on the side of specificity rather than sensitivity. This is because nonmalignant asbestos-related disorders are difficult to detect in their earliest stages and because there is no early intervention that has been proven to alter the subsequent evolution of the disease. On the other hand, the documentation of causation by asbestos carries important implications for the patient and can be established with reasonable certainty, once the disease is identified.
Asbestos as a Hazard Commercial-grade asbestos is made up of fiber bundles. These bundles, in turn, are composed of extremely long and thin fibers, often with splayed ends, that can easily be separated from one another. Commercial asbestos has high tensile strength, flexibility, resistance to chemical and thermal degradation, and high electrical resistance, and can often be woven. On the basis of these characteristics, asbestos was broadly used in the past in insulation, brake linings, flooring, cement, paint, textiles, and many other products; however, commercial use has declined substantially in more recent years. Asbestos and asbestiform minerals may occur as a natural accessory mineral in other industrial mineral deposits or rocks. These asbestiform amphiboles and some other fibrous minerals may not completely fit the commercial definition of asbestos but may have similar effects, such as the tremolite-like asbestiform mineral found in association with vermiculite in Libby, Montana (7). Although the general criteria still apply, the specific diagnostic guidelines provided in this statement may or may not apply in such situations, depending on the mineral and exposure circumstances. Documentation of health effects in the scientific literature for these minerals is not as extensive as for chrysotile and the common amphiboles. World production and use of asbestos climbed steadily since its commercial introduction in the late nineteenth century and fell rapidly after documentation of its hazards in the 1970s and 1980s. In Western industrialized countries, the widespread use of asbestos in industry and in the built environment in the first seven decades of the twentieth century has resulted in an epidemic of asbestos-related illness that now continues into the twenty-first century, despite decline in global production and use. Its use has now been banned in many Western countries. Asbestos is still mined in Russia and China, mainly for local use, and in Canada, where most of the product is exported to Asia and Africa. Today, with stringent regulation of asbestos use and the disappearance of almost all asbestos-containing products from the market, nonmalignant asbestos-related disease is primarily a concern in four settings in the developed world: (1) the historical legacy of asbestos exposure affecting older workers; (2) the current risk experienced by the workforce engaged in certain occupations managing the remaining hazard, such as building and facility maintenance; (3) asbestos abatement operations, removing insulation and other asbestos-containing products; and (4) renovation and demolition of structures containing asbestos. In the developing world, workers and their families continue to be exposed. In some countries, including industrialized countries formerly belonging to the Eastern bloc and rapidly industrializing countries in Asia, the use of asbestos continues and may even be increasing. Asbestos is still a hazard for an estimated 1.3 million workers in the construction industry in the United States and for workers involved in maintenance of buildings and equipment (8). Most asbestos in the United States today exists in building and machinery insulation and old products, such as appliances, that may be available for resale. New products that may contain asbestos today in the United States include friction surfaces (brake pads), roofing materials, vinyl tile, and imported cement pipe and sheeting. Significant asbestos content may be present as a contaminant in vermiculite insulation often found in homes (7). Historically, occupations at greatest risk for nonmalignant asbestos-related disease have tended to be those engaged in the production and end use of products made from asbestos. These have included a wide assortment of items, including friction pads, brake linings, gas masks, cement water pipe, insulation, and textiles. Occupations engaged in the mining and extraction of asbestos have usually shown lower frequencies of nonmalignant asbestos-related disease. Passive exposure, including workers carrying home asbestos on their clothing, was historically associated with elevated cancer risk, particularly mesothelioma, and risk of nonmalignant asbestos-related disease. Workers in building and equipment maintenance may still encounter asbestos insulation even though asbestos is no longer widely used in commerce. Asbestos abatement activities, including removal and replacement of insulation, provide opportunities for exposure among contemporary workers (8).
Asbestos in Lung Tissue Asbestos fibers are deposited at airway bifurcations and in respiratory bronchioles and alveoli primarily by impaction and interception. Fibers migrate into the interstitium, in part via an uptake process involving Type I alveolar epithelial cells. This causes an alveolar macrophage–dominated alveolitis, as demonstrated in Figure 1 (12, 13). Thereafter, many of the fibers are cleared.
Activated macrophages are stimulated to engulf and remove asbestos fibers. This process is not uniformly successful, however, and many fibers are retained (9, 10). The long fibers cannot be completely engulfed by the macrophage, as demonstrated in Figure 2.
Chrysotile fibers also split longitudinally, creating additional fibrils. These are cleared more efficiently than amphibole asbestos fibers, which may be retained indefinitely (12). The fibers induce apoptosis, a form of controlled cell death, in the macrophage and stimulate inflammation. This effect is reduced once the fiber is coated to create an asbestos body, but the great majority of fibers in the lung remain uncoated. For these reasons, asbestos has a prolonged residence in the lung, penetrates the interstitium of the distal lung, and shows extensive mobility both in the lung and around the body (9). Asbestos fibers, in particular, stimulate macrophages to produce a variety of mediators. Oxygen radicals contribute to tissue injury. Granulocytes are recruited to sites of disease activity and they in turn release mediators that contribute to tissue fibrosis by stimulating fibroblast proliferation and chemotaxis and ultimately promoting collagen synthesis (11–15). The inflammatory processes induced by asbestos include alveolitis, inflammation in the surrounding interstitium, and inflammation followed by fibrotic change in the respiratory bronchioles that extends into adjacent alveolar tissue (11, 14, 16). Studies of the lung tissue of asbestos-exposed workers, including nonsmokers, have demonstrated a form of peribronchiolitis involving the walls of membranous and respiratory bronchioles, that shows characteristics of a more intense fibrotic response than the small airway lesions caused by nonspecific mineral dusts that the lesions otherwise resemble (17, 18). Asbestos fibers and their derivatives, asbestos bodies, can be identified and quantified in lung tissue and bronchoalveolar lavage (BAL) specimens, as demonstrated in Figure 2 (19). Transbronchial lung biopsy is less reliable than BAL or open lung biopsy in recovering sufficient tissue to demonstrate elevated asbestos body or fiber counts when they do occur (20). Asbestos fibers, unlike asbestos bodies, are rarely seen by light microscopy and must be analyzed by scanning/transmission electron microscopy (19, 21, 22). There is considerable variation among laboratories in procedures to quantify asbestos fibers in tissue (18, 23, 24), which has led to efforts to standardize procedures (19). Asbestos mineralogical types can be identified by energy-dispersive X-ray analysis, in which detection of magnesium and silicon is characteristic of most forms of asbestos and the presence of a large iron peak signifies an amphibole (with the exception of tremolite) (25). Fiber analysis can be helpful in assessment of exposure and provides information about intensity, duration, and latency (e.g., uncoated fibers may reflect recent heavy exposure). However, because some fibers dissolve over time, the absence of a high fiber count does not necessarily mean that there has been no exposure, especially when chrysotile is the predominant exposure (22). Mineralogic analysis of asbestos fibers is largely a research technique and is not widely available (26).
ASBESTOS BODIES.
Transbronchial biopsy. These indicators of fiber burden are sufficient but not necessary to identify occupational exposure and to diagnose asbestos-related disease. Beyond clinical research, the method has applications in litigation and exposure assessment for epidemiology.
Bronchoalveolar lavage. BAL in patients with asbestosis has demonstrated an alveolar macrophage alveolitis associated with a modest increase in neutrophils (12, 13). This neutrophilia correlates with the finding of crackles (rales) on physical examination and disturbances in oxygenation (12, 27) and is apt to be more pronounced in patients with advanced disease (13). Clinically apparent asbestosis occurs only after a significant latent period. However, studies using BAL, computed tomography (CT) scanning, and gallium-67 scanning have demonstrated that inflammatory events occur well before the onset of clinical disease. Thus, it is likely that the initial exposure induces inflammation and injury that persist through the latent or subclinical phase and later develop into the clinical disease, which is typically diagnosed by chest imaging (13).
The clinical evaluation of nonmalignant asbestos-related disease should consider subjective symptoms as well as objective findings on physical examination, pulmonary function tests, and chest radiographic studies. In the large majority of patients, the diagnosis of nonmalignant asbestos-related lung disease is based on the clinical findings discussed below, in the context of an appropriate history of exposure to asbestos and a documented latency period sufficient to place an individual at risk.
Symptoms In a study of 64 patients, diffuse pleural thickening or fibrothorax was associated with dyspnea on exertion, usually mild, in 95%, chest pain in more than half, and restrictive defect in one-third. The chest pain was intermittent in most but constant in 9% (31). Rapidly progressive or severe chest pain should raise clinical suspicion of either malignancy or a nonmalignant pleuritis. Subjective symptoms are not easily interpreted in the absence of objective findings but provide important ancillary information. The persistence or new onset of respiratory symptoms is correlated with accelerated loss of lung function in asbestos-exposed workers and therefore may predict future risk (30).
Occupational and Environmental History The diagnosis of asbestosis is ideally based on an accurate exposure history, obtained whenever possible directly from the patient, that defines the duration, intensity, time of onset, and setting of exposure experienced by the patient. Patients may forget short periods of employment, during which intense exposure is possible, or employment early in their lives. In such cases the characteristic radiographic signs of asbestos exposure may be enough to document exposure. The occupational title is not enough, as the names of many occupations and trades are uninformative, such as "millwright" or "fireman" (a misleading title that sometimes refers to furnace workers and stokers) or "mixer." Representative occupational exposures include, but are not limited to, manufacture of asbestos products, asbestos mining and milling, construction trades (including insulators, sheet metal workers, electricians, plumbers, pipefitters, and carpenters), power plant workers, boilermakers, and shipyard workers. Asbestosis is commonly associated with prolonged exposure, usually over 10 to 20 years. However, short, intense exposures to asbestos, lasting from several months to 1 year or more, can be sufficient to cause asbestosis. For example, shipyard workers who applied or removed insulation in confined spaces have developed asbestosis after brief periods of heavy exposure. Insulation workers have had similarly intense exposures during their apprenticeship when they unloaded asbestos-containing sacks into troughs for mixing asbestos cement. Such occupational exposures are now rare but were common in the United States from the years after World War II until the 1970s. Adequate industrial hygiene controls were absent or not widely applied. Protective regulations were inadequate and only partially enforced during much of that period. Workers whose own jobs may not require handling asbestos may still be "bystanders" who worked in close proximity to other users, especially in the construction trades, where workers have experienced exposure from insulation being installed around them. Among sheet metal workers, for example, the prevalence of asbestos-related changes on chest film was 31% (19% pleural only, 7% parenchymal only, and 6% both). Among those who had been in the trade for 40 or more years, 41.5% had radiographic findings (33). These findings established that sheet metal workers, although not working directly with asbestos, had substantial exposure in the work environment. Measures taken to protect workers, or lapses in these measures, may be important in documenting exposure. Although exposure levels are generally low in developed countries today, lapses occur and were more frequent in the past. Some patients who have immigrated may have worked in countries where occupational health regulations have been poorly enforced or where environmental exposure has occurred. Environmental sources of exposure, for example, tailings of asbestos mines or prolonged exposure in buildings with exposed sources of asbestos contamination, may be important in some cases. Passive exposure, for example, of children in the home when asbestos is brought into the house on the clothes of a worker, may cause disease (34). Undisturbed and nonfriable asbestos insulation in buildings, including schools, does not present a hazard. The prevalence of asbestosis among asbestos workers increases with the length of employment, as illustrated in an early report in which investigators analyzed chest films of 1,117 New York and New Jersey asbestos insulation workers. They found asbestosis in 10% of workers who had been employed for 10 to 19 years, 73% among those employed for 20 to 29 years, and in 92% of those employed for 40 or more years (35). A similar exposure–response relationship was found among asbestos cement workers (36). Differences in solubility among the various types of asbestos may affect fiber retention, body burden, and the risk of nonmalignant disease. The clinician is rarely in a position to evaluate this aspect of exposure and there is no validated means to adjust the occupational history to take this factor into account. Solubility is primarily of concern with respect to projecting future risk, particularly of malignant disease, given a history of exposure. It is irrelevant to diagnosis when disease is already present and other indicators of exposure are demonstrable.
Physical Examination
Conventional Imaging The initial radiographic presentation of asbestosis is typically that of bilateral small primarily irregular parenchymal opacities in the lower lobes bilaterally. Over time, the distribution and density or "profusion" of opacities may spread through the middle and upper lung zones. Although irregular opacities are most common from asbestos exposure, mixed irregular and rounded opacities are often present. The ILO classification profusion score correlates strongly with mortality risk (36), reduced diffusing capacity, and diminished ventilatory capacity (37, 39). A critical distinction is made between films that are suggestive but not presumptively diagnostic (0/1) and those that are presumptively diagnostic but not unequivocal (1/0). This dividing point is generally taken to separate films that are considered to be "positive" for asbestosis from those that are considered to be "negative." However, profusion itself is continuous (36, 38). Plain chest radiographs are limited with respect to sensitivity and specificity in cases of mild or early asbestosis. Among individuals with asbestosis confirmed by histopathologic findings, 15–20% had no radiographic evidence of parenchymal fibrosis in one study (40), similar to the proportion of other interstitial lung diseases that present with normal chest films (41). Pleural plaques are frequently documented on plain chest radiographs, but CT is more sensitive for their detection. Only 50 to 80% of cases of documented pleural thickening demonstrated by autopsy, conventional CT, or high-resolution CT (HRCT) are detected by chest radiograph (42, 43). Plain chest radiographs are also limited by specificity in cases of mild pleural disease, which may be difficult to distinguish from extrapleural fat pads (39, 44). Oblique views can enhance both sensitivity and specificity of plain chest radiographs in clinical settings where HRCT is unavailable, but may also fail to distinguish plaques from fat pads (45). CT and HRCT are discussed in the next section.
Computed Tomography In subjects with low profusion categories of asbestosis, CT signs tend to be clustered as follows (47):
HRCT has an important role when experienced readers disagree about the presence or absence of abnormalities on a high-quality chest film, when chest radiographic findings are equivocal, when diminished pulmonary function is identified in association with otherwise normal plain chest radiographic findings, and when extensive overlying pleural abnormalities do not allow a clear interpretation of parenchymal markings. Because HRCT is more sensitive than other techniques for detecting parenchymal changes, it may reveal abnormalities with uncertain prognostic significance. HRCT is more specific than plain chest radiographs, excluding conditions such as emphysema, vessel prominence, overlying pleural disease, and bronchiectasis, which may confound radiographic interpretation. HRCT is much more sensitive in the detection of asbestosis than plain chest radiographs (46, 48), although even a normal HRCT cannot completely exclude asbestosis (49). Among asbestos-exposed individuals with unremarkable chest radiographic findings (ILO score 0/0 or 0/1), 34% were identified by HRCT as having findings suggestive of asbestosis. HRCT findings also correlated with decrements in pulmonary function tests in these cases, with a significantly diminished vital capacity and diffusing capacity (50). HRCT can detect early pleural thickening (i.e., 1–2 mm in thickness) much more sensitively than plain chest radiographs. Pleural thickening is frequently discontinuous and interspersed with normal regions. It is usually bilateral but may be unilateral in a third of cases (48). HRCT also offers an advantage over plain chest radiographs in specificity, being able to distinguish pleural disease from extrapleural fat (51). HRCT should be obtained at 2-cm intervals, to allow a more accurate assessment of pleural abnormalities, as well as other abnormal findings such as pulmonary masses (52). Prone views should always be obtained, as it is essential to distinguish between dependent atelectasis and parenchymal fibrosis in the posterior lung fields. HRCT findings in asbestosis are typically bilateral, and include evidence of fibrosis (e.g., intralobular interstitial thickening and interlobular septal thickening), subpleural "dotlike" opacities, subpleural lines, parenchymal bands, occasionally ground-glass opacity, and honeycombing in advanced disease (47, 52, 53). A proposal has been put forward for a classification system analogous to that of the ILO system for plain chest radiographs (54), but none has been widely adopted. The extent of plaque formation does not correlate with cumulative asbestos exposure and thus cannot be used to estimate exposure (55).
Bronchoalveolar Lavage Asbestos bodies (ABs) in BAL fluid correlate with occupational exposure and asbestosis (10, 19, 56, 57) and with asbestos bodies in the lung (57). Patients with asbestosis consistently have 2 to 5 orders of magnitude more ABs per milliliter than do pleural plaque subjects. Recovery of more than 1 AB/ml indicates a high probability of substantial occupational exposure to asbestos (19, 58). In one large series, patients with asbestosis had a log mean of 120 AB/ml, those with pleural plaques had 5 AB/ml, those exposed to asbestos who had a normal chest X-ray had 4 AB/ml, and those with malignant mesothelioma or lung cancer had 8 AB/ml. Of those with more than 100 AB/ml, 60% had asbestosis; others had pleural plaques, mesothelioma, or lung cancer, and only 6% were exposed but had no evidence of pathology (59). BAL cells can also be digested with bleach and the residue analyzed by electron microscopy, with fibers expressed per 106 alveolar macrophages (58). In U.S. asbestos insulation workers, electron microscopy identified 1 chrysotile fiber in every 35 alveolar macrophages and 1 amosite fiber per 215 macrophages, with no crocidolite detected. BAL performed on asbestos-exposed subjects has recovered 28 x103 fibers compared with 1 x103 in unexposed subjects (60). For every 100 fibers, there is typically 1 asbestos body (61). Clinically, the appearance of fibers or beaded fibers on a single centrifuged BAL sample mounted on a Diff-Quik slide represents an indicator of parenchymal asbestosis (28). Amphibole fiber recovery on BAL correlates well with amphibole fiber burden in the lung, but the relationship does not hold for chrysotile because of translocation, clearance, and dissolution (57, 61–63).
Pulmonary Function Tests As with other interstitial lung diseases, the classic finding in asbestosis is a restrictive impairment. Mixed restrictive and obstructive impairment is frequently seen; isolated obstructive impairment is unusual. Restrictive impairment may also be observed with pleural disease (see section on pleural abnormalities below). In addition to diminished lung volumes, the carbon monoxide diffusing capacity is commonly reduced due to diminished alveolar–capillary gas diffusion, as well as ventilation–perfusion mismatching. Although a low diffusing capacity for carbon monoxide is often reported as the most sensitive indicator of early asbestosis, it is also a relatively nonspecific finding. Exercise testing is generally not required for diagnostic purposes, but may be useful in assessing aerobic work capacity in selected cases, or when the degree of dyspnea correlates poorly with objective pulmonary function measurements.
Asbestosis Asbestosis is the interstitial pneumonitis and fibrosis caused by inhalation of asbestos fibers. After asbestos exposure, asbestosis becomes evident only after an appreciable latent period. The duration and intensity of exposure influence the prevalence of radiographically evident parenchymal pulmonary fibrosis. In work sites around the world that meet recommended control levels, high exposure to asbestos is now uncommon and clinical asbestosis is becoming a less severe disease that manifests itself after a longer latent interval. Asbestosis specifically refers to interstitial fibrosis caused by the deposition of asbestos fibers in the lung (Figure 3). It does not refer to visceral pleural fibrosis, the subpleural extensions of fibrosis into the interlobular septae or lesions of the membranous bronchioles.
The College of American Pathologists has developed histologic criteria for asbestosis and a grading system to describe the severity and extent. The mildest (Grade I) form of asbestosis involves the alveolated walls of respiratory bronchioles and the alveolar ducts (Figures 4 and 5). More severe histologic grades involve greater proportions of the acinus (Grade II) until the whole acinar structure is involved (Grade III asbestosis) and some alveoli are completely obliterated (Figure 5). Alveolar collapse, with fibrosis and honeycomb remodeling resulting in new dilated spaces in the parenchyma, results in the most severe grade of asbestosis (Grade IV) (64, 65) (Figure 6). These patterns of acinar fibrosis together with the demonstration of asbestos bodies in standard histologic sections are diagnostic of asbestosis. Iron stains may facilitate recognition of the asbestos bodies; however, the presence of asbestos bodies alone is not sufficient to establish the diagnosis of asbestosis. Asbestosis is associated with a variable degree (usually mild) of chronic inflammation and increased numbers of alveolar macrophages, including multinucleate giant cells. The grades of asbestosis correlate with counts and frequencies of asbestos fibers and bodies in the lung and estimates of cumulative workplace exposure (12, 66) (Table 2).
Only the more severe grades of asbestosis are detectable by gross examination. In its classic form, there is diffuse, bilateral, pale, firm fibrosis most severe in the peripheral zones of the lower lobes. Honeycomb cysts and areas of confluent fibrosis may be present (Figure 7). Milder forms of asbestosis and asbestos-associated small airway disease may not be apparent to gross inspection or to palpation, hence the importance of adequate sampling for histology. This should include peripheral and central areas of all lung lobes (depending on the specimen) as well as portions of visibly diseased lung. Adequate sampling of lung adjacent to resected tumors is particularly important and frequently overlooked or inadequately sampled by pathologists. It is strongly recommended that, when biopsy is performed, thoracic surgeons specifically request additional sampling of lung parenchyma in resected lung specimens from patients with known or suspected asbestos exposure (64, 65).
Asbestosis is more prevalent and more advanced for a given duration of exposure in cigarette smokers, presumably because of reduced clearance of asbestos fibers in the lung (67). Some studies suggest that smokers without dust exposure may show occasional irregular radiographic opacities on chest film, but if so the profusion is rarely as high as 1/0; smoking alone therefore does not result in a chest film with the characteristics of asbestosis (68). Both smokers and ex-smokers have a higher frequency of asbestos-related irregular opacities on their chest radiographs than do nonsmoking asbestos-exposed workers in all profusion categories (68–70). Smoking does not affect the presentation of asbestos-related pleural fibrosis.
Clinical diagnosis. Asbestosis becomes evident only after an appreciable latency period, often two decades under current conditions in the United States. In one study of former workers from an amosite asbestos insulation factory that had high levels of asbestos dust, employment for as little as 1 month resulted in a prevalence of 20% of parenchymal opacities 20 years after exposure ceased (70). The duration and intensity of exposure probably influence the length of the latency period: relatively short-term, high-intensity exposures may be associated with a shorter latency than prolonged, lower intensity exposures. Asbestosis is usually associated with dyspnea, bibasilar rales, and changes in pulmonary function: a restrictive pattern, mixed restrictive–obstructive pattern, and/or decreased diffusing capacity. The abnormal PA chest film and its interpretation remain the most important factors in establishing the presence of pulmonary fibrosis (Figure 8). Compensation systems may require that the chest radiographs be classified by the ILO system once it is established that the patient has been exposed to asbestos. A profusion of irregular opacities at the level of 1/0 is used as the boundary between normal and abnormal in the evaluation of the film, although the measure of profusion is continuous and there is no clear demarcation between 0/1 and 1/0 (Figure 9). When radiographic or lung function abnormalities are indeterminate, HRCT scanning is often useful in revealing characteristic parenchymal abnormalities as well as correlative pleural changes that are highly suggestive of asbestos exposure, particularly when they are bilateral. The specificity of the diagnosis of asbestosis increases with the number of consistent findings on chest film, the number of clinical features present (e.g., symptoms, signs, and pulmonary function changes), and the significance and strength of the history of exposure.
Although asbestosis is characteristically most advanced and appears earliest in the lower lung fields, there is a rare but well-characterized syndrome of massive bilateral upper lobe fibrosis, in the absence of tuberculosis or lung cancer (71–73). The characteristic change in pulmonary function observed in asbestosis is a restrictive impairment, characterized by reduction in lung volumes (especially the FVC and total lung capacity), decreased diffusing capacity, and arterial hypoxemia (74, 75). Large airway function, as reflected by the FEV1/FVC ratio, is generally well preserved. In one of the earliest studies conducted, about 50% of asbestos workers presented with FVC below 80% predicted. The frequency of abnormal vital capacity increased, and the mean vital capacity decreased by 18% over the subsequent 10 years (33, 75). The frequency and magnitude of the restrictive defect increased with ILO category (i.e., increased profusion of irregular opacities) and the presence of pleural changes. Notwithstanding the predominantly parenchymal and restrictive pattern of the disease, airway obstruction can also be observed and can be seen alone in nonsmokers who have asbestosis. These patients usually have a restrictive pattern of lung function, but clinically they also feature an obstructive component characterized physiologically by increased isoflow volume, and increased upstream resistance at low lung volumes (14, 16). These obstructive findings may be due to asbestos-induced small airway disease. Thus, mixed restrictive and obstructive abnormalities do not rule out asbestosis or necessarily imply that asbestos has not caused an obstructive functional impairment (76). Asbestosis may remain static or progress; regression is rare (77). The factors that determine prognosis and evolution of the disease are poorly understood. Progression, after cessation of exposure or reduction to current permissible exposure levels, is considerably more common in persons who already have radiographic abnormalities and appears to be associated with level and duration of exposure and therefore cumulative exposure (78).
Differential diagnosis. The presence of asbestos bodies in tissue sections should be sufficient to differentiate asbestosis from other forms of interstitial fibrosis. The chance of finding one asbestos body from background exposure alone has been shown to be about 1 per 1,000 (79). Conversely, the presence of interstitial fibrosis in the absence of asbestos bodies is most likely not asbestosis, although rare cases of pulmonary fibrosis with large numbers of uncoated asbestos fibers have been described (80–82). Idiopathic pulmonary fibrosis (IPF in clinical terms or usual interstitial pneumonitis in terms of pathology) has an acinar pattern of fibrosis different from that of asbestosis and is not associated with asbestos bodies in tissue sections. On occasion, asbestosis is seen in conjunction with an unrelated interstitial lung disease (such as sarcoidosis) or in association with another pneumoconiosis, for example, silicosis. In the absence of fibrosis, asbestos bodies are an indication of exposure, not disease. Asbestosis resembles a variety of other diffuse interstitial inflammatory and fibrotic processes in the lung and must be distinguished from other pneumoconioses, IPF, hypersensitivity pneumonitis, sarcoidosis, and other diseases of this class. The clinical features of asbestosis, although characteristic, are not individually unique or pathognomonic, but the characteristic signs of the disease are highly suggestive when they occur together. The presence of pleural plaques provides useful corollary evidence that the parenchymal process is asbestos related. Diagnostic uncertainty is most likely in certain groups of patients. Patients may have a heavy cigarette-smoking history and concurrent emphysema (which also reduces the diffusing capacity). In such cases, one expects a history of asbestos exposure commensurate with the degree of disease. On occasion, a patient with another interstitial lung disease, such as IPF, will have a history of asbestos exposure. Rapid progression, with a visible, year-to-year increase in symptoms, progression of radiographic findings, and loss of pulmonary function in the absence of intense asbestos exposure, suggests the diagnosis of IPF rather than asbestosis. Patients may be exposed at various times in their working life to more than one dust, such as silica and asbestos, or to mixed exposures, such as dusts in combination with fumes and vapors in welding (83). These patients may have combined disease or the effects of one dust or other exposure may dominate. For example, predominantly upper lobe rounded opacities, hilar node enlargement, and progressive massive fibrosis are not features of asbestosis and if present suggest other causes for the lung disease than asbestos, such as silicosis. On occasion, isolated fibrotic lesions associated with asbestos resemble solitary pulmonary nodules. These are sometimes called "asbestomas" and usually occur against a background of irregular opacities; they rarely appear in isolation. They normally require biopsy because they are not distinguishable from lung malignancies otherwise (84).
Nonmalignant Pleural Abnormalities Associated with Asbestos
It is unclear whether the relative frequency of diffuse and circumscribed pleural thickening has changed. The International Classification of Radiographs of Pneumoconioses (38) provides a basis for recording and classifying both types of pleural thickening, allowing correlation with indices of exposure and measurements of lung function. Manifestations of disease of the lung and of the pleura have become less evident and less characteristic on plain films as exposures have decreased. However, CT scan (including high-resolution images) detects pleural thickening not evident on the plain film, and sometimes fails to confirm apparent pleural thickening read on the plain film. Schemes to quantify extent of pleural thickening on CT scan have been published (55, 85). Rarely, interlobar pleural thickening may mimic lung nodules on CT scan (86).
Pleuritis: acute pleural effusion, chronic pleuritic pain. Chronic severe pleuritic pain is rare in patients with asbestos-related pleural disease (92, 93). Vague discomfort appears to be more frequent. Studies examining the frequency of atypical chest pain in asbestos-exposed patients have not been performed. In the few cases described, it was present for many years, disabling, and often bilateral. Radiographic evidence of pleural disease ranged from plaques to extensive diffuse and circumscribed pleural thickening; several cases followed pleural effusions. The diagnosis of acute asbestos-related pleural effusion is by exclusion of other causes of acute pleuritis, and most often is not arrived at until the pleural space is fully explored and biopsied, generally by thoracoscopy. Differentiation from Dressler's syndrome is difficult in asbestos-exposed patients who have undergone recent cardiac surgery. Differentiation from mesothelioma or pleural extension of a pulmonary malignancy is critical, and may be difficult on clinical grounds (including positive gallium and positron emission scan). Pleural fluid cytology is useful for distinguishing benign from malignant effusions. It is not unusual for nonspecific effusions to precede mesothelioma by several years. If a malignancy has not manifested itself within 3 years, the effusion is generally considered benign. The diagnosis of chronic pleuritis manifested by pleuritic pain is reached by excluding malignancies, because most other causes of acute pleuritis do not result in chronic pain. Malignancy is unlikely when pain persists for years with little or no clinical or radiographic change.
Plaques: circumscribed pleural thickening. Calcification is similarly related to duration. Smoking plays no role in the prevalence of pleural plaques (68). Pleural plaques are bilateral, but not symmetric, lesions of the parietal pleura. Characteristically, they are found following the ribs on the lower posterior thoracic wall (Figure 12) and over the central tendons of the diaphragm (Figure 13). They are raised, sharply circumscribed with a smooth or with a rounded knobby surface, and range in color from white to pale yellow. They generally spare the costophrenic angles and apices of the thoracic cavity. Microscopically, they consist of mature collagen fibers arranged in an open basket-weave pattern and are covered by flattened or cuboidal mesothelial cells. They are relatively avascular and acellular and show minimal inflammation. They are sharply demarcated from subpleural tissues and central calcification is common. Asbestos bodies are not seen in or adjacent to the lesions (64). Isolated plaques may be associated with tuberculosis, trauma, and hemothorax; however, multiple lesions having the classic appearances described above are almost invariably associated with asbestos exposure.
The conventional chest film is a sensitive and appropriate imaging method for plaques, although it may identify abnormalities that resemble plaques but are not. In the PA radiograph, they are best seen in profile on the midlateral chest walls and on the diaphragm or face on, and show serrated borders. HRCT is not a practical screening method for demonstrating plaques because of the separation between sections, the high radiation exposure, and the lack of access to the test in some locations. HRCT is useful to identify questionable abnormalities and to resolve questions about structures that resemble plaques. Typical pleural plaques are easily identified on plain films by sharp, often foliate, borders (face on) and by a raised straight surface with clear, cut-off edges when seen face on (Figures 14– 16) and as irregular margins (sometimes almost rectangular) when seen in profile on the chest wall or diaphragm. Apparent pleural thickening with gradually tapering or indistinct edges is often due to subpleural fat or superimposed soft tissue; fat pads below the parietal pleura typically occur in the midthoracic wall, between the fourth and eighth ribs, as do pleural plaques (51). Proper penetration is important on plain film; differentiation of fat from pleural plaques may still be difficult but is readily made by HRCT. Less typical plaques on the diaphragm may be difficult to detect and should be distinguished from atelectatic streaks, visceral folds, or diaphragmatic straightening caused by bullae. Calcification is helpful but may not be apparent in an underpenetrated film (Figure 14). Axial CT scans often fail to image diaphragmatic plaques (96).
The origin of pleural plaques is not clear (97, 98). The burden of asbestos fibers in lung tissue and of asbestos bodies in bronchoalveolar lavage fluid is greatly increased in patients with diffuse pleural thickening or asbestosis and moderately increased in patients with pleural plaques compared with unexposed subjects (99–101). The presence of pleural plaques is correlated with parenchymal disease, in particular fibrotic bands and both peribronchiolar and alveolar fibrosis. However, peribronchiolar fibrosis is absent in many cases with pleural plaques and present in many cases without them (102). Slow progression of plaques is typical. Approximately 85% of heavily exposed workers showed pleural thickening (predominantly plaques) on plain film more than 40 years from first exposure (103), as did up to 17% of environmentally exposed populations (104). More than half the cases were bilateral. The presence of plaques is associated with a greater risk of mesothelioma and of lung cancer compared with subjects with comparable histories of asbestos exposure who do not have plaques (105, 106). This is thought to be due to greater exposure or retained body burden, not malignant degeneration. Therefore, the presence of pleural plaques should be interpreted as a marker for elevated risk of malignancy, which may be higher than the occupational history alone might suggest. Although pleural plaques have long been considered inconsequential markers of asbestos exposure, studies of large cohorts have shown a significant reduction in lung function attributable to the plaques, averaging about 5% of FVC, even when interstitial fibrosis (asbestosis) is absent radiographically (74, 76, 107). The presence of circumscribed plaques can be associated with restrictive impairment and diminished diffusing capacity on pulmonary function testing, even in the absence of radiographic evidence of interstitial fibrosis (108, 109). Taking into account the degree of interstitial fibrosis as measured by ILO profusion score (described below), smoking, and duration of asbestos exposure, significant decrements in vital capacity have been observed: a reduction of up 140 ml or more of FVC associated with circumscribed plaques (76). This has not been a consistent finding (110, 111) and longitudinal studies have not shown a more rapid decrement in pulmonary function in subjects with pleural plaques (112). Decrements, when they occur, are probably related to early subclinical fibrosis. Dyspnea on exertion was reported more often among subjects with circumscribed pleural thickening independent of parenchymal disease and appeared to be proportional to the extent (110). There is a significant but small association between the extent of circumscribed pleural plaques and FVC, which is not seen with diffuse pleural thickening (112, 113). Even so, most people with pleural plaques alone have well preserved lung function (55). It is unclear whether this small effect on lung function is sufficient to contribute to dyspnea but there is evidence that it might. Half of subjects with pleural thickening but normal chest films and normal lung function showed excessive ventilation with exercise, which can contribute to dyspnea (114). Excessive ventilation on exercise could be the result of decreased chest wall and/or lung compliance caused by pleural thickening alone or to decreased lung compliance and ventilation–perfusion imbalance caused by parenchymal fibrosis that was not detected radiographically. Plaques are indicators of increased risk for the future development of asbestosis (94). This may reflect greater exposure or retained body burden. An autopsy study has demonstrated more frequent peribronchiolar fibrosis when plaques are present (90). This finding, as well as derangements in gas exchange (114) and evidence from HRCT, indicate that subradiographic asbestosis may be present in some patients with only pleural plaques. The presence of plaques is therefore an indication to monitor the patient over time for interstitial fibrosis (115).
Diffuse pleural thickening. The frequency of diffuse pleural thickening increases with time from first exposure and is thought to be dose related (104). Diffuse pleural thickening has been observed after acute pleuritis (90). It may also be caused by extension of interstitial fibrosis to the visceral pleura, consistent with the pleural migration of asbestos fibers. The extent of diffuse pleural thickening seems to be more or less uniformly distributed, the different degrees being fairly equally often seen, however, in contradistinction to circumscribed pleural thickening, in which the lowest categories are more frequent (113). Lung burdens of asbestos in these cases are intermediate between asbestosis and pleural plaques (116–118). This condition affects the visceral pleural surface and is quite different in appearance from the parietal pleural plaque. It consists of pale gray diffuse thickening that blends at the edges with the more normal pleura. It may be extensive and cover a whole lobe or whole lung and obliterate lobar fissures. It ranges in thickness from less than 1 mm up to 1 cm or more. Adhesions to the parietal pleura are common, particularly opposite to pleural plaques. The lesion may show a gradient with immature granulation tissue and fibrin at the surface, progressing to mature collagen adjacent to the lung. The fibrosis may extend for a few millimeters into the lung parenchyma and into the lobular septae. The latter features do not constitute asbestosis. Diffuse pleural thickening may have a significantly greater impact on pulmonary function than circumscribed plaques. A reduction of 270 ml of FVC has been associated with diffuse pleural thickening (76, 119). Workers with diffuse pleural thickening have a significantly greater decrement in FVC (by a factor of two or more) than those with circumscribed pleural thickening (76, 113). This effect is unrelated to the radiographic extent of pleural thickening; a similar reduction in FVC was seen with little more than costophrenic angle blunting as with extensive involvement (113). Decrements associated with diffuse pleural thickening reflect pulmonary restriction as a result of adhesions of the parietal with the visceral pleura. Restrictive impairment is characteristic, with relative preservation of diffusing capacity (pattern of entrapped lung). Diffuse pleural fibrosis extends continuously over a portion of the visceral pleura, often causing adhesions to the parietal pleura, involving the fissures and obliterating the costophrenic angle. The newly revised ILO classification (2003) recognizes pleural thickening as diffuse "only in the presence of and in continuity with, an obliterated costophrenic angle" (38). Localized subpleural parenchymal fibrosis is often present without diffuse interstitial fibrosis (117). Calcification of the pleura occurs with the passage of time, and may involve fissures. A rare variant of visceral pleural fibrosis is progressive apical thickening associated with fibrosis of the upper lobe (120, 121). Pachypleuritis is extensive, often bilateral, pleural fibrosis with evidence of active inflammation histologically and by gallium uptake. Extension of fibrosis into the lung is often evident radiographically as irregular pleural and pericardial borders, fibrous streaks, or "crow's feet" and bands. Ventilatory failure leading to CO2 retention, cor pulmonale, and death has been described in four patients with bilateral involvement and little or no parenchymal fibrosis, and in one patient with unilateral pleural thickening. Decortication may be beneficial (122).
Rounded atelectasis.
Rounded atelectasis is important for the diagnostic pathologist to recognize as it is frequently removed surgically as a suspected peripheral lung cancer. Asbestos bodies and/or evidence of asbestosis should be carefully sought.
Differential diagnosis, including rounded atelectasis and apical thickening. The major differential diagnostic consideration with diffuse pleural thickening is mesothelioma, which is progressive and more likely to be symptomatic at the time of detection. On occasion, when fibrosis and mesothelial proliferation are exuberant, the distinction is difficult clinically, radiographically, and histologically. Apical thickening (120, 122) must also be distinguished from mesothelioma and tuberculosis, which may be suggested by history and (previous) bacteriologic findings.
Chronic Airway Obstruction |
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DIAGNOSTIC CRITERIA AND...
