Kelly J. Butnor, MD, and Victor L. Roggli, MD
Overview and General Considerations
Pneumoconiosis literally means “dust in the lung,” and the term has come to refer to disease of the lung related to the inhalation of dusts. Pneumoconioses are for the most part due to the inhalation of inorganic dusts in the workplace, and the reaction of the lungs to these dusts is generally fibrosis. These diseases typically evolve over several decades, although There are some exceptions to this rule. The pathologic findings in these conditions can resemble those in other fibrotic and granulomatous disorders of the lung, so the pathologist must be familiar with their diagnostic features. Although no specific treatment is available for most of these disorders, proper diagnosis is crucial for accurate determination of prognosis and, when indicated, compensation.
The toxicity and corresponding fibrogenicity of inorganic particulates are related to both the nature of the dust and the nature of the host response.1 One important feature of particle toxicity is the aerodynamic diameter, with particles in the size range of 1 to 5 pm having the highest probability of deposition and retention within the respiratory tract. In addition, the total inhaled dose and intrinsic properties of the dust are important determinants of fibrosis. For example, crystalline silica is highly fibrogenic, whereas carbon is an innocuous nuisance dust. Host factors include the efficiency of clearance mechanisms and individual susceptibility. Many of the dusts have a characteristic reaction pattern or appearance in histologic sections, which permits an accurate diagnosis (Table 10.1). The silicotic nodule and the asbestos body are familiar examples. Others are associated with a reaction pattern that may suggest the diagnosis, but a careful occupational history or use of supplemental analytic techniques may be required to confirm the diagnosis, as with berylliosis, in which the histologic findings closely resemble those in sarcoidosis.
Analytic electron microscopy provides a powerful tool for identifying dusts in lung tissue samples, and these methods are emphasized when appropriate.2 An analytic electron microscope consists of a scanning or transmission electron microscope equipped with an energy-dispersive spectrometer. Electron microscopic techniques may permit the detection of particles too small to be observed by light microscopy. Furthermore, energy-dispersive x-ray analysis (EDXA) identifies the elemental composition of individual particulates, which can be critical to the identification and, in some cases, the source of the inhaled dust. It must be emphasized, however, that the identification of a particular xenobiotic in lung tissue is in and of itself not proof of disease and must be correlated with the pathologic response (if any) to the dust in routine histologic sections.
Types of Pneumoconiosis
Silicosis
Silicosis results from the inhalation of particles of crystalline silica. It is characterized by circumscribed areas of nodular fibrosis that tend to have the greatest profusion in the upper lung zones. Occupations with exposure to crystalline silica are summarized in Box 10.1.3 In the past, very heavy exposures occurred from sandblasting. This type of exposure has been banned in most countries but continues in certain parts of the world, such as Bangladesh, where sandblasting of denim jeans is still an industry.4-6 Soil in the extreme eastern and western portions of the United States is rich in alpha quartz (The most common form of crystalline silica). Silicotic nodules may be found in the thoracic lymph nodes and even within the lung parenchyma in farmers and agricultural laborers working in these regions.
Table 10.1 Histopathologic Patterns of Pneumoconioses
|
Pattern |
Type |
Pneumoconiosis/Exposure |
|
Acute lung injury |
Cadmium |
|
|
Alveolar filling |
Pulmonary alveolar proteinosis |
Silicosis Aluminosis Indium |
|
Macrophages/giant cells |
Hard metal lung disease |
|
|
Nodules |
Fibrotic |
Silicosis Coal workers’ pneumoconiosis Silicatosis/mixed dust pneumoconiosis Silicon carbide (carborundum) Vineyard sprayer’s lung |
|
With nonnecrotizing granulomas |
Aluminosis Berylliosis |
|
|
Cellular infiltrates |
With granulomas With lymphoid hyperplasia ± bronchiolitis |
Vineyard sprayer’s lung Flock worker’s lung |
|
Fibrosis |
With variable involvement |
Conglomerate silicosis Coal workers’ pneumoconiosis (progressive massive fibrosis) Asbestosis Silicatosis/mixed dust pneumoconiosis Talcosis Aluminosis Hard metal lung disease Rare earth pneumoconiosis Silicon carbide (carborundum) Dental technician’s pneumoconiosis Domestically acquired particulate lung disease |
|
With granulomas |
Aluminosis Berylliosis Rare earth pneumoconiosis |
|
|
Minimal changes |
With small airways disease |
Flavorings-related lung disease |
Clinical Presentation
Patients demonstrate a range of clinical presentations, from asymptomatic with simple silicosis to markedly dyspneic with conglomerate silicosis. In conglomerate silicosis, hypoxemia and cor pulmonale may be fatal.
Pathologic Findings
Silicotic nodules are of firm consistency and typically slate gray in appearance, measuring from a few millimeters to approximately 1 cm in diameter (Figs. 10.1 and 10.2). As the disease progresses in severity, the nodules may become confluent (Figs. 10.3 and 10.4). Areas of confluent fibrosis greater than 2 cm in maximum dimension are the defining feature of conglomerate silicosis. Cavitation may occur within areas of confluent fibrosis and, when present, suggests the possibility of superimposed tuberculosis.
Figure 10.1 Silicosis. In this gross specimen, circumscribed areas of nodular fibrosis are slate gray and of firm consistency.
Figure 10.2 Silicosis. At low magnification, silicotic nodules are sharply circumscribed and densely collagenous (Masson trichrome stain).
The histologic hallmark of silicosis is the silicotic nodule.7,8 This lesion is a sharply circumscribed nodule consisting of dense, whorled, hyalinized collagen (Figs. 10.5 and eSlide 10.1). More loosely arranged collagen bundles are typically found at the periphery of the nodule. In recently formed lesions, macrophages form a mantle around the fibrotic center. Long-standing lesions may be calcified or even ossified (Fig. 10.6). The nodules may be present anywhere within the lung parenchyma but typically are most numerous in the upper lung zones. Not uncommonly, they are concentrated beneath the pleura (Fig. 10.7). There may also be extensive pleural fibrosis (Fig. 10.8).9 Nodules are frequently also present within hilar lymph nodes (Fig. 10.9). In patients with extremely high exposures to very fine silica particles, the pattern of resultant lung injury may closely resemble that in pulmonary alveolar proteinosis, characterized by the presence of granular eosinophilic material filling the alveoli, alveolar ducts, and bronchioles (Fig. 10.10). Cholesterol clefts may be prominent within the intraalveolar material. The granular proteinaceous exudate typically stains strongly positive with periodic acid-Schiff with diastase.
Examination with polarizing microscopy shows faintly birefringent particulates within the fibrotic nodules (Fig. 10.11). Larger, brightly birefringent particles, which represent silicates, may also be seen, but these should not predominate (see later section on silicatosis).10 On scanning electron microscopy the particles appear angulated (Fig. 10.12). Analytic electron microscopy with EDXA reveals peaks for silicon only (Fig. 10.13).
Figure 10.3 Conglomerate silicosis. A Gough-Wentworth section of lung from a tobacco field worker demonstrates confluent fibrosis in the upper lobe (arrowhead).
Figure 10.4 Conglomerate silicosis. Multiple silicotic nodules have coalesced, forming an area of confluent fibrosis.
Differential Diagnosis
Silicotic nodules must be distinguished from the fibrotic nodules of healed or burned-out sarcoidosis, as well as healed mycobacterial or fungal infections, a classic example being the so-called histoplasmoma. The presence of multinucleated giant cells and the absence of significant dust deposits favor sarcoidosis. Sarcoid granulomas may contain fine needle-like or large, platy birefringent particles, which represent endogenous calcium carbonate or oxalate, respectively (Fig. 10.14). ’Hiese particles should not be confused with the foreign material of pneumoconiosis. The presence of necrosis in association with giant cells favors an infectious etiology. Patients with silicosis are at increased risk for acquiring tuberculosis.11 Both processes may be present simultaneously. Concurrent tuberculosis infection is most likely to occur with conglomerate silicosis. The occasionally somewhat stellate appearance of the macrophage mantle in recently formed silicotic nodules may simulate Langerhans cell histiocytosis, but the latter does not contain whorled collagen.
Figure 10.5 Silicosis. This silicotic nodule demonstrates the typical whorled appearance. Macrophages are present at the periphery of the nodule.
Figure 10.6 Silicosis. A mature silicotic nodule exhibits partial ossification.
Figure 10.7 Silicosis. The lung parenchyma underlying the pleura is a common location for silicotic nodules.
Figure 10.8 Pleural silicosis. (A) Pleural involvement sometimes manifests as dense fibrosis. (B) At higher magnification, a cellular area consisting of fibroblasts and histiocytes is evident. Polarizing microscopy showed numerous birefringent particulates.
Figure 10.9 Silicosis. Silicotic nodules within a lymph node characteristically contain centrally dense, hyalinized collagen surrounded by concentric whorls of more loosely arranged collagen bundles.
Figure 10.10 Acute silicosis. Granular eosinophilic material fills alveoli, imparting an appearance similar to that seen in pulmonary alveolar proteinosis. Note the presence of a silicotic nodule at left. (From Sporn TA, Roggli VL. Pneumoconioses, mineral and vegetable. In: Tomashefski JF, ed. Dail and Hammar's Pulmonary Pathology. Vol 1. 3rd ed. New York: Springer-Verlag; 2008:911-949, with permission.)
Figure 10.11 Silicosis. Partial polarization of a silicotic nodule demonstrates faintly birefringent silica particles.
Figure 10.12 Silicosis. Scanning electron microscopy demonstrates angulated silica particles.
Figure 10.13 Energy-dispersive x-ray analysis spectrum shows a peak for silicon (Si).
Figure 10.14 Birefringent particles in sarcoidosis. In contrast to silicosis, this example of sarcoidosis contains large platy birefringent particles, typical of endogenous calcium oxalate.
Rheumatoid pneumoconiosis, eponymously termed Caplan syndrome, which was originally described in coal miners with rheumatoid arthritis but can also be seen in individuals exposed to silica or silicates, reflects the presence of rheumatoid nodules in association with pneumoconiosis.12 the nodules demonstrate central necrobiosis with peripheral palisading histiocytes often associated with a rim of dust.
Extrathoracic location does not rule out a silicotic origin of a fibrous nodule, because silicotic nodules have been found in the liver, spleen, bone marrow, and abdominal lymph nodes.13 Extrathoracic involvement, when present, usually occurs in the setting of advanced pulmonary silicosis. The diagnostic yield of transbronchial biopsy in silicosis is low, probably because the firm circumscribed nodules are pushed aside by the biopsy forceps.
Coal Workers' Pneumoconiosis
Coal workers’ pneumoconiosis (CWP), also known as black lung disease, occurs in persons involved in the mining of coal. The nature of the disease is related to the intensity and duration of exposure, host factors, and the specific duties of the miner. Workers involved with drilling in the ceiling of the shaft or constructing communicating shafts are exposed to greater amounts of silica than those working at the coal face. Dust suppression measures greatly reduce the incidence of progressive massive fibrosis (PMF), the advanced form of CWP.
Figure 10.15 Normal lung. A Gough-Wentworth section of normal lung shows scattered minimal accumulations of anthracotic pigment and intact parenchyma. (From Kleinerman J, Green FHY, Laquer W, et al. Pathology standards for coal workers pneumoconiosis. Arch Pathol Lab Med. 1979;103:375-432, with permission.)
Clinical Presentation
Patients exhibit a range of clinical presentations, from asymptomatic with simple CWP to markedly dyspneic with PMF. The latter is associated with hypoxemia and cor pulmonale and may be fatal.14,15
Pathologic Findings
CWP is characterized by increased pigmentation in the lungs resulting from the deposition of coal dust (Figs. 10.15-10.17). Foci of accentuated pigmentation, superimposed on a background of diffusely increased pigment, are present on the pleura and within the lung parenchyma. In some cases, palpable nodules are present within the lung parenchyma and usually are most numerous in the upper lung zones. These nodules are grossly similar to silicotic nodules except for being black rather than slate gray (Fig. 10.18). The most advanced cases of CWP feature greater than 2 cm in maximal dimension confluent areas of irregular fibrosis with the consistency of vulcanized rubber, typically in the upper to middle lung zones (Fig. 10.19). ’Hiese are the lesions of PMF. Cavitation may occur in areas of PMF and, when present, suggests superimposed tuberculosis.16
The histologic hallmark of CWP is the coal dust macule (Fig. 10.20). Coal dust macules consist of discrete collections of interstitial pigment deposition in the vicinity of respiratory bronchioles. Areas of emphysematous destruction, referred to as focal emphysema, are typically present at the periphery of macules. Pigment-laden macrophages may be present within alveolar spaces, and pigment deposits may occur anywhere along the lymphatic routes of the lung including the secondary lobular septa, as well as in the pleura. Lymph nodes frequently contain numerous pigmented macrophages and may also demonstrate silicotic nodules. Silicotic nodules may also be present within the lung parenchyma, but unlike cases of pure silicosis, a collare The of pigmented macrophages often surrounds the nodules, imparting a “Medusa head” appearance (Fig. 10.21). Areas of massive fibrosis (Fig. 10.22) consist of collagen bundles that are arranged in a haphazard distribution and intermixed with abundant pigment (Figs. 10.23 and 10.24). Vascular obliteration is common within areas of PMF, and ischemia may be the cause of cavitation in some cases.
Figure 10.16 Simple coal workers' pneumoconiosis. This thin section of lung demonstrates multiple small, circumscribed black nodules, predominantly in the upper lobe. (From Kleinerman J, Green FHY, Laquer W, et al. Pathology standards for coal workers pneumoconiosis. Arch Pathol Lab Med. 1979;103:375-432, with permission.)
Figure 10.17 Simple coal workers' pneumoconiosis. In contrast to the normal lung, this thin section shows diffusely increased pigment resulting from the deposition of coal dust. (From Kleinerman J, Green FHY, Laquer W, et al. Pathology standards for coal workers pneumoconiosis. Arch Pathol Lab Med. 1979;103:375-432, with permission.)
Figure 10.18 Simple coal workers' pneumoconiosis. In addition to diffusely increased pigmentation, the lung parenchyma shows well-demarcated black nodules. Centrilobular emphysematous bullae are also present.
Figure 10.20 Simple coal workers' pneumoconiosis. The coal dust macule is characterized by focal interstitial pigment deposition. In this example, destruction of the adjacent alveolar septa, termed focal emphysema, is also seen.
Figure 10.19 Complicated coal workers' pneumoconiosis. The upper lobe contains a confluent irregular area of fibrosis with the consistency of vulcanized rubber. Central cavitation is present.
Figure 10.21 Simple coal workers' pneumoconiosis. A collare The of pigmented macrophages gives a "Medusa head” appearance to this intraparenchymal silicotic nodule.
Figure 10.22 Complicated coal workers pneumoconiosis. A large, black, irregular fibrotic lesion has destroyed the perihilar lung parenchyma. (From Kleinerman J, Green FHY, Laquer W, et al. Pathology standards for coal workers pneumoconiosis. Arch Pathol Lab Med. 1979;103:375-432, with permission.)
Examination with polarizing microscopy typically shows numerous faintly to brightly birefringent particulates within a background of black pigment (Fig. 10.25). This appearance reflects the mixed nature of coal dust, which is composed of amorphous carbon, silicates, and silica. The presence of silica in coal dust is responsible for the formation of silicotic nodules and is an important factor in the pathogenesis of PMF.17 Ferruginous bodies are sometimes seen in the lungs of coal workers, typically within the alveolar spaces (Fig. 10.26). These may be distinguished from true asbestos bodies by virtue of their black carbonaceous cores (Fig. 10.27).18 Tuberculosis may also complicate CWP (Fig. 10.28).
Figure 10.23 Complicated coal workers' pneumoconiosis. In this example of progressive massive fibrosis, haphazardly arranged collagen bundles are interspersed with abundant pigment.
Figure 10.24 Complicated coal workers' pneumoconiosis. A Masson trichrome stain highlights the collagenous composition of a heavily pigmented region of progressive massive fibrosis.
Figure 10.25 Coal workers' pneumoconiosis. Partial polarization shows a mixture of faintly and brightly birefringent particles superimposed on black pigment.
Figure 10.26 Coal workers' pneumoconiosis. Along with pigmented macrophages, this case demonstrates numerous intraalveolar ferruginous bodies.
Figure 10.27 Coal workers' pneumoconiosis. At higher magnification, the black carbonaceous core of this ferruginous body (pseudoasbestos body) is evident.
Figure 10.28 Coal workers' pneumoconiosis. A caseous granuloma in this case of coal workers' pneumoconiosis was found to contain acid-fast bacilli.
Figure 10.29 Graphite worker's pneumoconiosis. Although somewhat similar in appearance to particulates in coal workers' pneumoconiosis, graphite particles appear crystalline and elicit a giant cell reaction.
Differential Diagnosis
CWP must be distinguished from the anthracotic pigment deposition that occurs in urban dwellers and cigare The smokers and from graphite worker’s pneumoconiosis. The extent of pigmentation in normal persons is a function of environmental exposure to carbon-containing dust and the natural ability of the lung to rid itself of particulates. Distinction from CWP is somewhat a matter of degree, but the presence of true coal dust macules, as described earlier, is indicative of CWP. The finding of anthracotic pigment-laden macrophages within alveoli is also a useful feature, but such macrophages may be absent in miners who have been retired for many years. Graphite worker’s pneumoconiosis appears similar to CWP, but graphite is crystalline, whereas the carbon present in coal is amorphous (Fig. 10.29). A giant cell reaction to the crystalline carbon of graphite assists in this distinction. Transbronchial biopsy may be useful in the diagnosis of CWP, showing the typical changes described earlier. However, areas of nodular fibrosis or PMF may be missed by such sampling. There fore transbronchial biopsy is not useful for assessing disease severity.
Asbestosis
Asbestosis is defined as pulmonary interstitial fibrosis caused by the inhalation of asbestos fibers.19 Substantial and significant exposures to asbestos can occur in a variety of occupational settings, including the mining and milling of asbestos, the manufacture of asbestos-containing products, and the use of products containing asbestos. Workers who may be involved in the use of asbestos-containing products include insulators, shipyard workers, railroad workers, power plant workers, US Navy or Merchant Marine seamen, oil or chemical refinery workers, construction workers, steel and other molten metal workers, and paper mill workers (Box 10.2). A few cases of asbestosis have also occurred among household contacts of asbestos workers, apparently as a consequence of exposure to asbestos brought home on the workers’ clothing.
Clinical Presentation
In patients with asbestosis, the clinical presentation ranges from asymptomatic to severely dyspneic at rest. Hypoxemia and cor pulmonale may prove fatal in these patients. Pulmonary function testing typically shows restrictive changes, and the diffusion capacity is reduced. Patients with asbestosis who smoke cigarettes have a markedly increased risk for developing lung cancer. Pleural plaques in and of themselves are rarely symptomatic and, when present in isolation, should not be referred to as asbestosis. Although the pleural and parenchymal changes caused by asbestos may be recognized on plain films, high-resolution computed tomography (HRCT) is considered to be a more sensitive and specific modality for the radiographic evaluation of asbestosis.20
Figure 10.30 Asbestosis. The lower lobe parenchyma shows patchy fibrosis. Visceral pleural thickening also is evident (arrowhead). (From Roggli VL, Oury TD, Sporn TA, eds. Pathology of Asbestos-Associated Diseases. 2nd ed. New York: Springer; 2004, with permission.)
Pathologic Findings
The fibrosis in asbestosis demonstrates a fine reticular pattern, and the macroscopic appearance of the lungs ranges from normal to severely scarred and shrunken (Fig. 10.30) with evidence of honeycombing.21,22 Asbestosis is usually most severe in the lower lung zones, and accompanying overlying visceral pleural fibrosis is frequently present. Parietal pleural plaques, which are frequently bilateral (Fig. 10.31), are present in the vast majority of cases and may be calcified. Although diffuse pleural fibrosis and plaques serve as a suggestive indicator of an asbestos etiology of pulmonary fibrosis, the term asbestosis should not be applied to these pleural abnormalities when they occur in the absence of parenchymal disease.
Histologically the earliest manifestation of asbestos-associated parenchymal disease is fibrosis of the walls of respiratory bronchioles accompanied by asbestos bodies, for which the designation asbestosairways disease has been proposed (Box 10.3 and Fig. 10.32).17 As the fibrotic process progresses in asbestosis, it extends distally beyond the bronchiolar walls to the alveolar ducts and proximally to the membranous (terminal) bronchioles. The fibrosis also extends radially to involve alveolar septa distant from the respiratory bronchiole (Fig. 10.33). In the most advanced cases of asbestosis, honeycomb fibrosis is present (Fig. 10.34 and eSlide 10.2), characterized by fibrotic-walled cysts 0.5 to 1 cm in diameter lined by bronchiolar epithelium and often containing pools of mucus. Alveolar macrophages are sometimes so prominent as to suggest a diagnosis of desquamative interstitial pneumonia (DIP). In some cases multinucleated giant cells may be identified within either the interstitium or the alveolar spaces (Fig. 10.35). Rarely hyperplastic alveolar type II pneumocytes may contain cytoplasmic hyaline (Fig. 10.36) reminiscent of that found in the cytoplasm of hepatocytes in alcoholic liver disease.
*An average score is obtained for an individual case by adding the scores for each slide (0-4) and then dividing by the number of slides examined.
From Roggli VL, Gibbs AR, Attanoos R, et al. Pathology of asbestosis—an update of the diagnostic criteria. Report of the Asbestosis Committee of the College of American Pathologists and Pulmonary Pathology Society. Arch Pathol Lab Med. 2010;134:462-480.
Figure 10.31 Pleural plaque. The gross appearance has been likened to that of candle wax drippings.
The hallmark of asbestos exposure is the asbestos body, a rodlike, beaded, or dumbbell-shaped structure with a golden-brown coating and a thin, translucent core.23 Asbestos bodies are typically found in the peribronchiolar interstitium (Fig. 10.37), but with heavy exposure, these may be seen in the alveolar spaces (Fig. 10.38). Detection of asbestos bodies may be facilitated by the use of iron stains, which impart a deep blue color (Fig. 10.39). Asbestos bodies may also be seen in sputum (Fig. 10.40) and thoracic lymph nodes (Fig. 10.41) of patients with heavy exposure to asbestos. Pleural plaques consist of layers of acellular hyalinized collagen arranged in a “basket-weave” pattern (Fig. 10.42). Visceral pleural fibrosis may show this pattern or appear as compact layers of collagen. A mild lymphocytic infiltrate sometimes accompanies the fibrosis.
Figure 10.32 Asbestosis. (A) the histologic hallmarks of asbestosis are peribronchiolar fibrosis accompanied by asbestos bodies. (B) Numerous asbestos bodies are present within a fibrotic alveolar septum in this case with heavy asbestos exposure. Note the variable beaded, rodlike, and dumbbell shapes.
Figure 10.33 Asbestosis. Peribronchiolar fibrosis extends into adjacent alveolar septa.
Centrilobular emphysema and visceral pleural fibrosis (top) are also seen.
Figure 10.34 Asbestosis. In a more advanced case, honeycombing (arrowhead) is seen in addition to lower lobe fibrosis.
Figure 10.35 Asbestosis. A curvilinear asbestos body is seen lying within an interstitial giant cell in this transbronchial biopsy specimen.
Figure 10.36 Asbestosis. Type II pneumocytes demonstrate cytoplasmic hyaline.
Figure 10.37 Asbestosis. In a transbronchial biopsy, interstitial fibrosis and an asbestos body (upper left) can be seen.
Figure 10.38 Asbestosis. Asbestos bodies are present within an alveolar space in this case of severe asbestosis.
Figure 10.39 Asbestosis. In this iron-stained section of lung, an asbestos body has a characteristic beaded morphology and deep blue color.
Figure 10.40 Asbestosis. Asbestos bodies in a sputum cytology specimen.
Figure 10.41 Asbestosis. A section from a thoracic lymph node from a heavily exposed individual contains numerous asbestos bodies.
Figure 10.42 Pleural plaque. Pleural plaque showing the typical composition of layers of acellular hyalinized collagen arranged in a "basket-weave” pattern.
Digestion procedures have been developed for quantifying the content of asbestos in lung tissue (Fig. 10.43). Any of the commercial forms of asbestos (chrysotile and amphiboles) may be identified in lung tissue from patients with asbestosis by means of analytic electron microscopy (Figs. 10.44 and 10.45).24 In cases with diffuse pulmonary fibrosis where asbestos bodies are not identified in histologic sections, the fiber burden is typically more than 2 standard deviations below the mean value.25 Polarizing microscopy is not useful for the detection of asbestos in histologic sections.
Figure 10.43 Asbestosis. Asbestos bodies from a lung tissue digest on a Nuclepore filter. (From Roggli VL, Oury TD, Sporn TA, eds. Pathology of Asbestos-Associated Diseases. 2nd ed. New York: Springer; 2004, with permission.)
Figure 10.44 Asbestosis. Scanning electron microscopy image of an asbestos body. Note the thin, beaded appearance.
Figure 10.45 Asbestosis. Energy-dispersive x-ray analysis spectra showing characteristic elemental composition of types of asbestos. (A) Amosite has a prominent peak for silicon (Si) as well as peaks for magnesium (Mg) and iron (Fe). (B) Crocidolite shows a peak for sodium (Na) in addition to silicon and iron. (C) Tremolite demonstrates peaks for silicon, magnesium, and calcium (Ca). (D) Chrysotile exhibits prominent peaks for magnesium and silicon. The peak for platinum (Pt) represents the coating applied to the specimen prior to electron microscopic examination.
Differential Diagnosis
Asbestosis must be distinguished not only from usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), and other forms of diffuse pulmonary fibrosis but also from peribronchiolar fibrosis associated with cigare The smoking. UIP is characterized by honeycomb changes, fibroblastic foci, and the absence of asbestos bodies in histologic sections (Chapter 8). Honeycomb changes are a rarity in asbestosis; in our experience, fibroblastic foci are also uncommon. Pleural fibrosis is much more common in individuals with asbestosis than in those with UIP the greater temporal uniformity of asbestosis as compared with UIP is reminiscent of NSIP, but the fibrosis in NSIP exhibits a greater degree of spatial uniformity and, in cellular examples, more interstitial inflammation than asbestosis. The early forms of asbestosis (grades 1 to 2) must be distinguished from both mixed dust pneumoconiosis (MDP) and the form of small-airway disease known as respiratory bronchiolitis, which is seen in cigare The smokers. The latter, which is characterized by peribronchiolar fibrosis and pigmented smokers’-type macrophages, tends to involve membranous (terminal) bronchioles and is often accompanied by mucous plugging and goblet cell metaplasia. Asbestos bodies are absent in respiratory bronchiolitis. The peribronchiolar fibrosis in grades 1 to 2 asbestosis can also mimic burned-out Langerhans cell histiocytosis, sarcoidosis, or chronic hypersensitivity pneumonia, but it is distinguished by the presence of asbestos bodies.
Asbestos bodies must be distinguished from nonasbestos ferruginous bodies (pseudoasbestos bodies) that instead have broad yellow or black central cores (Fig. 10.27) (also see the Silicatosis section). The use of transbronchial biopsy in the diagnosis of asbestosis is controversial.19,24 In our experience, patients with evidence of diffuse pulmonary fibrosis on plain chest films or HRCT who have pulmonary fibrosis and asbestos bodies on transbronchial biopsy can be reliably diagnosed as having asbestosis. Conversely, the absence of asbestos bodies on transbronchial biopsy does not exclude the possibility that asbestosis is the cause of pulmonary fibrosis.
Silicatosis (Silicate Pneumoconiosis)
Silicatosis is caused by the inhalation of silicates. A variety of silicate minerals may be encountered in the workplace, usually in the setting of mining and quarry work. Silicates include nonfibrous silicates such as talc (see later section titled Talcosis), vermiculite, mica, and kaolinite as well as fibrous silicates such as fuller’s earth.26-29 MDP occurs among patients exposed to a mixture of silica and nonfibrous silicates. Silicate pneumoconiosis has also been described in farm workers in areas with silicate-rich soil.30
Clinical Presentation
Patients with uncomplicated silicate pneumoconiosis are typically asymptomatic. With extensive fibrosis, they may be short of breath and demonstrate restrictive changes on pulmonary function testing. In the rare case with massive fibrosis, hypoxemia and cor pulmonale may supervene.
Pathologic Findings
Silicatosis is characterized by irregular deposits of collagen, predominantly in a peribronchiolar and perivascular distribution, associated with numerous birefringent particulates.8,31 the lungs may be macroscopically normal in mild disease or may be firm and fibrotic (Fig. 10.46). In patients with significant exposure to silica in addition to silicates, silicotic nodules and even massive fibrosis may also be present (Fig. 10.47). Paracicatricial emphysema may sometimes be seen adjacent to areas of fibrosis (Fig. 10.48).
Figure 10.46 Silicatosis. Grossly, this lung from a kaolinite worker shows scattered gray areas of fibrosis in addition to centrilobular emphysema.
Figure 10.47 Silicatosis. Area of massive fibrosis with deposits of dust-laden macrophages.
Figure 10.48 Silicatosis. A section of lung from a patient with heavy exposure to kaolin dust demonstrates an area of massive fibrosis with paracicatricial emphysema.
The histologic findings in silicatosis include perivascular and peribronchiolar deposits of dust-laden macrophages (dust macules) (Fig. 10.49). Interstitial fibrosis may also be present, characterized by irregularly contoured, stellate lesions with variable collagenization. Nonasbestos ferruginous bodies with broad yellow sheet silicate-type cores (Figs. 10.50 and 10.51) may be observed in some cases.18,31 Examination with polarizing microscopy typically demonstrates numerous brightly birefringent particulates (Fig. 10.52) associated with macrophages or within stellate lesions. Analytic electron microscopy shows numerous particulates, most of which consist of silicon combined with other elements such as magnesium, aluminum, potassium, calcium, or iron.32
Figure 10.49 Silicatosis. At higher magnification, dust-laden macrophages are apparent.
Figure 10.50 Silicatosis. Pseudoasbestos ferruginous bodies accompany interstitial fibrosis in this transbronchial biopsy specimen from a patient who had silicatosis with exposure to feldspar.
Figure 10.51 Silicatosis. Pseudoasbestos bodies with broad yellow sheet silicate-type cores.
Figure 10.52 Silicatosis. Partial polarization of a fibrotic area demonstrates brightly birefringent silicate particles. (Courtesy Dr. Thomas V. Colby, Mayo Clinic, Scottsdale, Arizona.)
Figure 10.53 Mixed dust pneumoconiosis. The peribronchiolar distribution of fibrosis seen in this case is typical of mixed dust pneumoconiosis.
A special variant of silicatosis is MDP, defined as the occurrence of dust macules and stellate (Medusa head) lesions producing so-called mixed dust fibrotic nodules (Figs. 10.53, 10.54, and eSlide 10.3) with or without accompanying silicotic nodules.33 For a diagnosis of MDP, the macules and mixed dust fibrotic nodules should outnumber silicotic nodules. If silicotic nodules predominate, the preferred diagnosis is silicosis. MDP can occur in individuals who have worked in the coal mining industry, most typically those involved in the installation of roof bolts in coal mine shafts. Analytic electron microscopy in MDP shows aluminum silicates with varying numbers of silica (SiO2) particles.
Differential Diagnosis
Silicatosis must be distinguished from silicosis, UIP, and NSIP. In cases with dust macules, mixed dust fibrotic lesions, and silicotic nodules, a diagnosis of silicosis should be made when silicotic nodules predominate. UIP has well-defined features that are not seen in silicate pneumoconiosis (Chapter 8). It is important to keep in mind that a few scattered bire- fringent particulates may be found in the lungs of individuals in the general population, including those with UIP and NSIP. Such findings should not be confused with those in silicate pneumoconiosis, in which numerous brightly birefringent silicate particles are present within dust macules or mixed dust fibrotic lesions (Fig. 10.55).
Figure 10.54 Mixed dust pneumoconiosis. Dust deposits are evident in this stellate mixed dust fibrotic nodule. (Courtesy Dr. Thomas V Colby, Mayo Clinic, Scottsdale, Arizona.)
Figure 10.55 Mixed dust pneumoconiosis. Partially polarized photomicrograph of a mixed dust fibrotic nodule showing particles with variable birefringence.
Talcosis (Talc Pneumoconiosis)
Talcosis, or talc pneumoconiosis, is a type of silicate pneumoconiosis with unique morphologic and clinical features. Talc is used in many industries. Typical exposures include those related to mining and milling as well as the rubber and steel industries. Exposures may also occur among individuals who use excessive amounts of talcum powder. Talc is a filler in many medications intended for oral consumption. It may reach the lungs by the vascular route in individuals who intravenously inject crushed tablets. Talc is also frequently used for pleurodesis and may be observed in radical extrapleural pneumonectomy or autopsy specimens from patients with malignant mesothelioma.
Clinical Presentation
Patients are often asymptomatic, but fatal pulmonary fibrosis has been reported among talc miners and millers.34 Intravenous drug abusers may develop pulmonary hypertension, massive fibrosis, or paracicatricial emphysema with spontaneous pneumothorax as a complication of massive intravascular deposition of talc within the lungs.35,36
Figure 10.56 Talcosis. In this example, needle-like talc particles are associated with an exuberant giant cell response.
Figure 10.57 Talcosis. Partially polarized view of talc, exhibiting a characteristic needlelike morphology.
Pathologic Findings
Macroscopically, the lungs in talcosis may be normal or firm in con- sistency.37 Histologically, patchy peribronchiolar and perivascular fibrosis is associated with abundant dust deposits (Fig. 10.56). The particles within these deposits are needle-like and have a bluish-gray color. Examination by polarizing microscopy shows numerous brightly birefringent, needle-like particles within giant cells (Fig. 10.57), granulomas, or foci of interstitial fibrosis. Multinucleate giant cells are variably present in talcosis, and in some cases a granulomatous reaction resembling sarcoidosis is seen. Ferruginous bodies with broad yellow sheet silicate-type cores may also be seen.18 True asbestos bodies may also be observed in cases where talc is contaminated with substantial amounts of asbestos (anthophyllite or tremolite). Similarly, silicotic nodules may be seen when There is substantial contamination with quartz.
Intravenous drug abuse talcosis is characterized by the accumulation of numerous talc granulomas within the pulmonary vasculature and alveolar septal walls (Figs. 10.58 and 10.59). PMF has been reported in some cases.35 Concomitant paracicatricial emphysema may be pronounced.36 Accumulations of talc can also be seen in talc pleurodesis, which is characterized by deposits of talc (Figs. 10.60 and 10.61) within the pleura that are associated with macrophages and are also accompanied by a giant cell reaction.38
Analytic electron microscopy in talcosis demonstrates platy particles composed of magnesium and silicon (Figs. 10.62 and 10.63).39
Figure 10.58 Intravenous talcosis. Faintly blue-gray talc particles occupy cleftlike spaces. Note the presence of an asteroid body within a giant cell.
Figure 10.59 Intravenous talcosis. Talc particles appear brightly birefringent under polarized light.
Figure 10.60 Talc pleurodesis. Talc instilled into the pleural space for therapeutic purposes elicited a florid fibrohistiocytic response in this case from a patient with recurrent empyema.
Differential Diagnosis
Inhalational talcosis must be distinguished from intravenous talcosis and sarcoidosis. In inhalational talcosis, the deposits are primarily perivascular and peribronchiolar, and intraalveolar ferruginous bodies may be observed. In intravenous talcosis, talc deposits are intravascular and within alveolar capillary walls. The talc particles in intravenous talcosis are on average larger than those observed with inhalational talcosis. Often they are too large to be deposited by inhalation. Inhalational talcosis producing a prominent granulomatous reaction differs from sarcoidosis in the presence of numerous, long, needle-like birefringent crystals as compared with the smaller and sparser needle-like particles of endogenous calcium carbonate that are sometimes seen in sarcoidosis. In difficult cases, analytic electron microscopy may be required to make the distinction. The fibrohistiocytic reaction to talc pleurodesis may superficially resemble areas of sarcomatoid mesothelioma. The distinction can be made by the observation of foreign body giant cells and numerous platy birefringent particles in talc pleurodesis.
Figure 10.61 Talc pleurodesis. Partial polarization of the case in Fig. 10.60 shows numerous platy and needle-shaped birefringent talc particles.
Figure 10.62 Talcosis. In this backscatter electron microscope image, talc has a platy appearance.
Figure 10.63 Talcosis. Energy-dispersive x-ray analysis spectrum of a talc particle demonstrating peaks for silicon (Si) and magnesium (Mg). The peak for platinum (Pt) represents the coating applied to the specimen before electron microscopic examination.
Siderosis
Siderosis refers to the accumulation of exogenous iron particulates within the lung parenchyma. This disease occurs primarily among hematite miners, iron foundry workers, and welders. Miners and foundry workers may be exposed to significant amounts of silica in the workplace, resulting in siderosilicosis, which is characterized by histologic features of both siderosis and silicosis.
Clinical Presentation
Iron is minimally fibrogenic, so even patients with heavy exposures are typically asymptomatic. Chest x-rays may suggest interstitial fibrosis owing to shadows cast by the deposits of iron pigment.40 Patients with significant exposures to silica or asbestos in addition to iron may demonstrate clinical features related to the inhalation of such dusts.41
Pathologic Findings
Iron pigment imparts a reddish-brown color to the lung parenchyma.42 Because iron is minimally fibrogenic, there is typically no increase in firmness in pure siderosis. However, in cases in which There is concomitant exposure to significant amounts of silica or asbestos, excess collagen may be deposited (Fig. 10.64).
Figure 10.64 Siderosilicosis. This case demonstrates welder's pigment (iron oxide) as well as nodular fibrosis typical of siderosilicosis.
Figure 10.65 Siderosis. Perivascular pigment deposition is seen in this histologic section taken from the lung of a welder.
The histologic hallmark of siderosis is perivascular and peribronchiolar deposition of iron pigment (Fig. 10.65).43 This pigment, which consists predominantly of iron oxide, is typically dark brown to black, often with a distinctive golden-brown halo (Fig. 10.66). The pigment may be found in macrophages, in the interstitium, or in both, with very little fibrous response. Although There have been rare examples of nodular fibrosis in the lungs of hematite (iron-containing ore) miners that contained little or no silica, the finding of significant amounts of fibrosis should prompt a search for evidence of exposure to asbestos or silica (Figs. 10.67 and 10.68).42 Ferruginous bodies may be observed in some cases (Figs. 10.69 and 10.70).18 These may have black iron oxide cores, particularly in iron foundry workers (Fig. 10.71), or broad yellow sheet silicate cores in welders. True asbestos bodies may also be observed if There has been significant exposure to asbestos, as with shipyard welders.
Iron oxide pigment is typically nonrefringent when viewed with polarizing microscopy. Analytic electron microscopy demonstrates spherical particles with prominent peaks for iron (Figs. 10.72 and 10.73).
Differential Diagnosis
Siderosis must be distinguished from chronic passive congestion of the lungs and from anthracosis (perivascular and peribronchiolar deposits of anthracotic pigment). Chronic passive congestion manifests as intraalveolar accumulation of numerous hemosiderin-laden macrophages. Although both hemosiderin and exogenous iron pigment that has been ferruginized in vivo stain with Prussian blue, hemosiderin lacks the dark brown to black centers characteristic of iron oxide. At low magnification, iron oxide deposits may resemble anthracotic pigment. However, anthracotic pigment is black throughout, lacking the golden-brown rim characteristic of iron oxide.
Figure 10.66 Siderosis. (A) Detail of iron oxide, or welder's pigment, which appears brown-black with a golden-brown halo. (B) In contrast to welder's pigment, hemosiderin is typically intraalveolar and lacks black central cores.
Figure 10.67 Siderosilicosis. A Masson trichrome stain demonstrates the whorled appearance of this heavily pigmented silicotic nodule.
Figure 10.68 Siderosilicosis. The iron pigment appears deep blue in this iron-stained section of the silicotic nodule depicted in Fig. 10.67.
Figure 10.69 Siderosis. Pseudoasbestos bodies with broad yellow sheet silicate cores are seen in this case from a welder.
Figure 10.70 Siderosis. Iron-stained section of lung from the same patient as in Fig. 10.69 demonstrates numerous pseudoasbestos bodies.
Figure 10.71 Siderosis. Pseudoasbestos body on a tissue digestion filter from the lung of an iron foundry worker. Note the stout, irregularly shaped black iron oxide core.
Figure 10.72 Siderosis. Scanning electron micrograph of iron oxide particles from a welder's lung.
Figure 10.73 Siderosis. Energy-dispersive x-ray analysis spectrum of iron oxide particles showing predominant peak for iron (Fe).
Figure 10.74 Aluminosis. Scattered areas of fibrosis are present in the lungs of this aluminum arc welder.
Aluminosis
Aluminosis is a pneumoconiosis caused by the inhalation of aluminum- containing dusts. Although aluminum is relatively ubiquitous within the environment, aluminosis is a rare disease. Hypersensitivity to aluminum is believed to play a role in the pathogenesis of aluminosis. Substantial exposure to aluminum-containing dust may occur in the setting of aluminum smelting, manufacture of aluminum oxide (corundum) abrasives, aluminum polishing, and aluminum arc welding.44-46
Clinical Presentation
Aluminosis in which interstitial fibrosis is the dominant tissue reaction may manifest as dyspnea on exertion and restrictive changes on pulmonary function testing. Fatal cases with severe interstitial fibrosis have been reported.46
Pathologic Findings
Macroscopically, the lung parenchyma in aluminosis ranges from essentially normal to heavy and grayish black with dense fibrotic areas scattered throughout (Fig. 10.74). A metallic sheen, resembling tarnished aluminum, has been described in some cases.
Histologic examination discloses perivascular and peribronchiolar accumulations of dust-laden macrophages (Fig. 10.75). The dust is refractile and gray to brown (Fig. 10.76). Tissue reaction to aluminum ranges in degree from nil to interstitial fibrosis (eSlide 10.4) to granulomatous inflammation.46-49 Cases with a prominent granulomatous response may mimic sarcoidosis. Areas resembling DIP may also be observed.50 Rare cases have been described with an alveolar proteinosislike pattern (Figs. 10.77 and 10.78) similar to that seen in acute silicoproteinosis.43
Aluminum dust is nonrefringent when examined by polarizing microscopy. Analytic electron microscopy shows electron-dense spherical particles (Figs. 10.79 and 10.80) composed of aluminum (Fig. 10.81).
Figure 10.75 Aluminosis. An accumulation of dust-laden macrophages surrounds a pulmonary vessel.
Figure 10.76 Aluminosis. Detail of dust-laden macrophages, showing the gray-brown granular appearance typical of aluminum oxide.
Figure 10.77 Aluminosis. Amorphous eosinophilic material fills the alveoli in a pattern similar to that of pulmonary alveolar proteinosis. Interstitial accumulations of dust-laden macrophages are also present.
Figure 10.78 Aluminosis. Higher-magnification view showing the characteristic granular appearance of aluminum-laden macrophages.
Figure 10.79 Aluminosis. Transmission electron micrograph showing an alveolar type II cell overlying a dust-filled interstitial macrophage.
Figure 10.80 Aluminosis. In this transmission electron micrograph of an aluminum- containing macrophage, the aluminum particles appear spherical and electron-dense. (From Roggli VL. Rare pneumoconioses: metalloconioses. In: Saldana MJ, ed. Pathology of Pulmonary Disease. Philadelphia: Lippincott; 1994:411-422, with permission.)
Figure 10.81 Aluminosis. Energy-dispersive x-ray analysis spectrum in a case of aluminosis demonstrates a peak for aluminum only (AL).
Differential Diagnosis
Dust deposits of aluminum must be distinguished from kaolinite (a form of aluminum silicate; see earlier section titled Silicatosis) and smoker’s macrophages. The dust deposits in kaolin worker’s pneumoconiosis are fine and tan, whereas aluminum is more refractile and gray to brown in color. In difficult cases, analytic electron microscopy may be required to make the distinction. Smoker’s macrophages are located predominantly within the alveolar spaces rather than the interstitium and are typically associated with scattered black dotlike carbon particles. Aluminum-induced granulomatosis must be considered in the differential diagnosis of sarcoidosis. In addition, aluminum exposure must be considered in cases with a pulmonary alveolar proteinosis pattern. In such cases, the presence of aluminum dust deposits is a useful differentiating feature.
Hard Metal Lung Disease
Tungsten carbide is used in the manufacture of cutting tools, drilling equipment, armaments, alloys, and ceramics (Box 10.4). Cobalt is used as a binder and may constitute up to 25% of the final product by weight. Hard metal lung disease occurs as a consequence of the inhalation of hard metal dust, with cobalt being the suspected causative agent of disease. Exposure may occur during the manufacturing process of hard metal-containing products or during their use.51 Disease has also been reported in diamond polishers who had exposure only to cobalt and no exposure to hard metal dust.52,53
Clinical Presentation
Workers with hard metal lung disease present with dyspnea of insidious onset and restrictive changes, with small lung volumes on pulmonary function testing. Diffusely increased interstitial markings are observed on plain chest films and CT scans. Disease develops in less than 1% of those exposed, suggesting that hypersensitivity to cobalt is the underlying pathogenic mechanism. Workers may also present with asthma that predates interstitial lung disease by months to years. Hard metal lung disease has been reported to recur after lung transplantation without additional exposure.54
Figure 10.82 Hard metal pneumoconiosis. At low magnification, the interstitium appears widened, accompanied by alveolar filling.
Figure 10.83 Hard metal pneumoconiosis. This example demonstrates interstitial pneumonia with hyperplastic type II pneumocytes and multinucleated giant cells in alveolar spaces. (Courtesy Dr. Thomas V Colby, Mayo Clinic, Scottsdale, Arizona.)
Pathologic Findings
Macroscopically, the lungs in hard metal lung disease are small and fibrotic. Microscopically, hard metal lung disease is almost synonymous with giant cell interstitial pneumonia,55 once considered to be one of the idiopathic interstitial pneumonias. In this disorder, the alveolar septa are thickened and fibrotic and lined by hyperplastic type II pneumocytes (Figs. 10.82 and 10.83). A moderate chronic inflammatory infiltrate is present. Multinucleated giant cells are a conspicuous feature (Fig. 10.84) and are found both within the alveolar spaces and lining the alveolar septa. Alveolar macrophages are present in increased numbers, and in some cases a pattern reminiscent of DIP is observed (Fig. 10.85). Occasionally the overall pattern mimics that of UIP, with areas of microscopic honeycombing (Figs. 10.86 and 10.87). The fibrotic and inflammatory reaction may be accentuated around bronchioles.
Figure 10.84 Hard metal pneumoconiosis. This bronchoalveolar lavage fluid from a patient with hard metal pneumoconiosis contains multinucleate giant cells. (From Tabatowski K, Roggli VL, Fulkerson WJ, et al. Giant cell interstitial pneumonia in a hard-metal worker: cytologic, histologic and analytical electron microscopic investigation. Acta Cytol. 1988;32:240-246, with permission.)
Figure 10.85 Hard metal pneumoconiosis. Along with multinucleated giant cells, macrophages fill alveolar spaces in a pattern resembling that of desquamative interstitial pneumonia. (Courtesy Dr. Thomas V Colby, Mayo Clinic, Scottsdale, Arizona.)
Figure 10.86 Features reminiscent of usual interstitial pneumonia in a case of tungsten carbide pneumoconiosis include severe interstitial fibrosis and honeycombing.
Figure 10.87 Hard metal pneumoconiosis. Detail of the case shown in Fig. 10.86, demonstrating honeycomb cysts filled with macrophages.
Figure 10.88 Hard metal pneumoconiosis. Scanning electron microscopy image of alveolar macrophages shows small electron-dense metal particles. (Courtesy Dr. Frank Johnson and Dr. Jose Centano, Armed Forces Institute of Pathology, Washington, DC.)
Dust deposits are not readily identified by either routine or polarizing light microscopy. The individual metal particles can be observed by analytic electron microscopy (Figs. 10.88 and 10.89).56 Tungsten particles are most common, followed by titanium and tantalum (Fig. 10.90). Cobalt may or may not be identified because its water solubility makes it susceptible to removal from tissue during fixation and processing.
Differential Diagnosis
Hard metal lung disease must be distinguished from UIP, DIP, and hypersensitivity pneumonitis. The presence of intraalveolar and alveolar septal giant cells, some of which may have a bizarre appearance, and the absence of honeycomb changes favor hard metal disease. In the absence of giant cells, analytic electron microscopy may be required to confirm the diagnosis. In contrast with hard metal lung disease, DIP has a monotonous pattern with minimal interstitial fibrosis, and although a few giant cells can be seen in DIP, lining of the alveolar septa by frequent giant cells is not a feature of DIP. Hypersensitivity pneumonitis is characterized by an interstitial chronic inflammatory infiltrate associated with small clusters of interstitial giant cells that form ill-defined granulomas, as opposed to the intraalveolar or alveolar septal giant cells of hard metal lung disease. DIP can occur in patients with no identifiable exposure to cobalt.56a
Figure 10.89 Hard metal pneumoconiosis. The metal particles shown in Fig. 10.88 appear as dark dots in this backscatter electron microscopic image. (Courtesy Dr. Frank Johnson and Dr. Jose Centano, Armed Forces Institute of Pathology, Washington, DC.)
Figure 10.90 Hard metal pneumoconiosis. Energy-dispersive x-ray analysis spectrum demonstrates a large peak for tungsten, also known as wolfram (W). Ca, Calcium; Fe, iron. (Reprinted with permission from Sporn TA, Roggli VL: A hard [metal] case: value of analytical scanning electron microscopy. Ultrastruct Pathol. 2016;40:147-150.)
Transbronchial biopsy and bronchoalveolar lavage may be useful in the diagnosis of hard metal lung disease.57 Analytic electron microscopy can be performed on either of these types of specimens and may demonstrate the characteristic profile of metallic elements.
Berylliosis
Berylliosis is a granulomatous lung disease caused by the inhalation of beryllium-containing dust.58,59 Beryllium is used in the aerospace industry in the manufacture of structural materials, guidance systems, optical devices, rocket motor parts, and heat shields. It is also used in the manufacture of ceramic parts, thermal couplings, and crucibles and as a controller in nuclear reactors (Box 10.5). Exposure may occur in any of these industries as well as in the mining or extraction of beryllium ores.60-62 Historically beryllium was used in the manufacture of fluorescent lightbulbs, which accounted for most of the initial reports of berylliosis.63
Clinical Presentation
Patients with berylliosis present with insidiously progressive dyspnea. Pulmonary function testing shows restriction with diminished diffusing capacity. Plain films of the chest show a fibronodular process. In longitudinal studies of exposed individuals, less than 1% to 11% develop berylliosis.64 Beryllium hypersensitivity with the development of a beryllium-specific cell-mediated immune response has There fore been postulated as the likely pathogenic mechanism, as in the diseases caused by exposure to aluminum and hard metal. In vitro reactivity of peripheral blood or bronchoalveolar lavage lymphocytes to beryllium salts has been used as part of the diagnostic work-up.65
Figure 10.91 Berylliosis. The presence of numerous granulomas is characteristic of berylliosis. (Courtesy Dr. Fred Askin, Johns Hopkins University, Baltimore, Maryland.)
Figure 10.92 Berylliosis. The granulomas in berylliosis are compact and lack necrosis. (From Roggli VL, Shelburne JD. Pneumoconioses, mineral and vegetable. In: Dail DH, Hammar SP, eds. Pulmonary Pathology. 2nd ed. New York: Springer-Verlag; 1994:867-900, with permission.)
Figure 10.93 Berylliosis. In addition to granulomatous inflammation, a chronic interstitial inflammatory infiltrate is seen. (Courtesy Dr. Thomas V Colby, Mayo Clinic, Scottsdale, Arizona.)
Figure 10.94 Berylliosis. A Schaumann body, with its characteristic basophilic laminations, is observed within a giant cell (lower left). (From Roggli VL. Rare pneumoconioses: metalloconioses. In: Saldana MJ, ed. Pathology of Pulmonary Disease. Philadelphia: Lippincott; 1994:411-422, with permission.)
Pathologic Findings
Macroscopically, the lungs in chronic berylliosis are small and fibrotic and may show honeycomb changes. Bilateral hilar lymphadenopathy may be present. Microscopically, there are well-formed nonnecrotizing granulomas (Figs. 10.91 and 10.92). A chronic interstitial inflammatory infiltrate typically is present (Fig. 10.93). Granulomas may also be found in hilar lymph nodes. Schaumann bodies (Fig. 10.94) and asteroid bodies (Fig. 10.95) within multinucleated giant cells are observed in some cases.42’43
Beryllium is a lightweight metal that may be detected by analytic electron microscopy.66 Other techniques—such as wet chemical analysis, electron energy loss spectrometry, or ion or laser microprobe mass spectrometry—are also used for detection.2 Polarizing microscopy is not useful in the diagnosis of berylliosis.
Differential Diagnosis
Berylliosis must be distinguished from sarcoidosis and hypersensitivity pneumonitis. Sarcoidosis closely resembles berylliosis histologically; There fore a high index of suspicion for exposure to beryllium and a thorough occupational history are necessary to arrive at the correct diagnosis. Hypersensitivity pneumonitis is associated with a more intense lymphocytic interstitial and peribronchiolar infiltrate and lacks the well-formed granulomas observed in berylliosis.
Figure 10.95 Berylliosis. This granuloma features a giant cell containing an asteroid body (uppercenter). (From Roggli VL. Rare pneumoconioses: metalloconioses. In: Saldana MJ, ed. Pathology of Pulmonary Disease. Philadelphia: Lippincott; 1994:411-422, with permission.)
Rare Earth Pneumoconiosis
Rare earth (or cerium oxide) pneumoconiosis is an uncommon disease caused by the inhalation of rare earth metals, primarily cerium oxide. Only about 20 cases have been reported, and descriptions of the pathologic findings are sparse. Most patients with rare earth pneumoconiosis have been employed in settings in which they were exposed to dust from carbon arc lamps. Two patients were exposed to cerium oxide in an extraction plant, two patients used cerium oxide rouge to polish lenses, and one patient was a producer of glass rubbing polish.67-70
Clinical Presentation
The clinical presentation ranges from no symptoms to insidiously progressive dyspnea. Chest films show a diffuse interstitial pattern. Pulmonary function testing shows a restrictive or mixed restrictive/ obstructive pattern and reduced diffusion capacity. The rarity of this disease suggests hypersensitivity to cerium as the pathogenic mechanism.
Pathologic Findings
The spectrum of histopathologic features includes granulomatous disease and interstitial fibrosis.67 the fibrosis is similar to that observed with UIP or NSIP (Fig. 10.96). Pigmented dust deposits may be observed with light microscopy, although these may be sparse. Cerium oxide is birefringent on polarizing microscopy. Analytic electron microscopy demonstrates rare earth metals, primarily cerium and to a lesser degree lanthanum, samarium, and neodymium (Figs. 10.97 and 10.98).
Differential Diagnosis
Rare earth pneumoconiosis is most readily confused with UIP or NSIP. Sarcoidosis may be considered if There is a prominent granulomatous reaction. The diagnosis can be made on the basis of a thorough occupational history and the detection of rare earth compounds in lung tissue by analytic electron microscopy.
Figure 10.96 Rare earth pneumoconiosis. Diffuse interstitial fibrosis with honeycomb cyst formation in a pattern reminiscent of that seen in usual interstitial pneumonia.
Figure 10.97 Rare earth pneumoconiosis. Backscatter electron microscopy image of electron-dense cerium oxide particles.
Other Pneumoconioses
A myriad of other substances have been implicated as causes of pneumoconiosis. Although an exhaustive list is beyond the scope of this discussion, several uncommon and recently recognized pneumoconioses are presented in this section.
Acute high-intensity exposure to cadmium results in acute respiratory distress syndrome, whereas chronic exposure is purported to cause emphysema.71,72 Most reports on the pulmonary effects of chronic cadmium exposure appear not to have taken smoking as a confounding factor into consideration.73,74 In addition to being a major cause of emphysema, cigare The smoking is itself a source, albeit small, of cadmium exposure (=2 μg per cigarette).75-77 One study that reported an increased rate of emphysema in workers exposed to cadmium did control for smoking but unfortunately included only clinicoradiographic data and no histopathologic descriptions.78
Granulomatous interstitial inflammation and nodular fibrosis reminiscent of silicosis have been reported in some vineyard workers.79,80 Vineyard sprayer’s lung is believed to be caused by chronic exposure to copper sulfate, a main constituent of fungicidal solutions commonly used in viticulture. Histochemical stains for copper reportedly highlight the dust within macrophages and fibrotic nodules.79
Exposure to silicon carbide (carborundum), a synthetic abrasive, has been associated with nodular and diffuse interstitial fibrosis resembling silicosis or MDP.81-83 Abundant dust and ferruginous bodies with black silicon carbide cores have been described.
Figure 10.98 Rare earth pneumoconiosis. Energy-dispersive x-ray analysis spectra demonstrate peaks for rare earth metals, including cerium (Ce) (upper left panel) and cerium and lanthanum (La) (lower left panel). Background is shown in the lower right panel and a tin particle (Sn) in the upper right panel. (From McDonald JW, Ghio AJ, Sheehan CE, et al. Rare earth [cerium oxide] pneumoconiosis: analytical scanning electron microscopy and literature review. Mod Pathol. 1995;8:859-865.)
A variety of pathologic features, which in some cases appear to resemble those of silicosis or MDP, have been reported as dental technician’s pneumoconiosis.82,84-88 the heterogeneity of reported findings is not surprising in view of the plethora of substances that have been used in dental prostheses, including silica, beryllium, chromium, cobalt, and molybdenum.
Exposure to oil mists or fine sprays in certain machining and engineering applications, particularly oils low in viscosity or high in mineral oil content, has been reported to cause exogenous lipoid pneumonia. The histologic features are similar to those of mineral oil aspiration.89-92
Metalworking fluids (MWFs) are used extensively in automotive parts manufacturing and other metalworking industries as coolants, cleaning agents, and anticorrosives that are sprayed onto the fabrication surfaces during the machining process.93 Composed of pure petroleum or a mixture of petroleum or synthetic oils and water, MWFs provide a lipid-rich substrate for the growth of microorganisms. Fungal and bacterial antigens in contaminated MWFs have been implicated in outbreaks of hypersensitivity pneumonia in MWF-exposed workers, with recent outbreaks attributed to nontuberculous mycobacterial antigens (Fig. 10.99).94-96
Although inhalational exposure to certain metals—including tin, barium, and titanium dioxide (rutile)—can produce striking dense nodules on chest imaging, the pneumoconioses they induce are generally considered benign because only macules of birefringent dust particles with little to no fibrosis are usually seen pathologically.42,97,98 One case of pulmonary alveolar proteinosis in a painter who was shown to have a high concentration of titanium in the lungs has been reported.99
Figure 10.99 Metalworking fluid hypersensitivity pneumonia. Collections of peribronchiolar granulomas are evident. In this example, scattered dust particles are present within the granulomas. (Courtesy Dr. Thomas V Colby, Mayo Clinic, Scottsdale, Arizona.)
Figure 10.101 Flavorings-related lung disease. Bronchiolitis obliterans, characterized by mural bronchiolar fibrosis, in a microwave popcorn plant worker. (Courtesy Dr. William Travis, Memorial Sloan-Kettering Cancer Center, New York.)
Figure 10.100 Flock worker's lung. Lymphocytic bronchiolitis and lymphoid hyperplasia, sometimes with germinal center formation, as seen in this case, are among the more frequently reported findings in this condition. (Courtesy Dr. Armando Fraire, University of Massachusetts, Worcester, Massachusetts.)
Flock worker’s lung derives its name from an interstitial lung disease that has been reported in some individuals employed in the flocking industry. Flocking involves the application of short synthetic fibers, frequently nylon, onto an adhesive backing, resulting in a plush material. Respired shards generated in the process of cutting fibers to length with a rotary cutter are believed to cause a restrictive process characterized histologically by lymphoid hyperplasia, lymphocytic bronchiolitis, and peribronchiolar interstitial inflammation (Fig. 10.100).100-103 A spectrum of other histologic features and patterns has been reported, including diffuse lymphocytic interstitial inflammation, interstitial fibrosis, fibroblastic foci, bronchiolitis obliterans organizing pneumonia, and NSIP.102 the typically lymphocyte-rich nature of the pathologic changes in flock worker’s lung raises considerations of Sjogren-related interstitial lung disease, lymphocytic interstitial pneumonia, lymphoma, and chronic hypersensitivity pneumonia, making occupational history essential.
Unlike hypersensitivity pneumonia, granulomatous inflammation is not a feature of flock worker’s lung. Initially recognized in former workers at a microwave popcorn plant and thus dubbed popcorn worker’s lung, a form of lung disease featuring bronchiolitis obliterans and occasionally peribronchiolar granulomas, it has subsequently been reported in workers at food flavorings production plants (Fig. 10.101).104-108 the broader term flavorings-related lung disease has been invoked as a more accurate designation for these types of exposure. Although it is possible that other flavoring agents to which workers at these plants are exposed contribute to the development of this condition, exposure data and animal inhalational studies suggest that diacetyl (2,3-butanedione), a principal component of butter flavoring, plays a causal role.109
Indium, in the form of indium-tin oxide, is used in the manufacture of liquid crystal displays. It has been associated with pulmonary alveolar proteinosis and proliferative peribronchial fibrosis with cholesterol clefts.110-112
Analysis of the lungs of individuals exposed to dust from the 2001 World Trade Center terrorist attack who have developed interstitial fibrosis and/or small airways abnormalities has disclosed a variety of particles such as silicates and asbestos.113,114 A case of acute eosinophilic pneumonia has also been described in association with acute exposure to high levels of World Trade Center dust.115
An increased incidence of respiratory symptoms has been reported in soldiers who served in the Middle East. Some of these individuals, including a number who were exposed to smoke from sulfur mine fires in Iraq, had features of constrictive bronchiolitis and peribronchiolar pigment deposition on lung biopsy.116
Pulmonary disease caused by polluted indoor air is a vastly underrecognized problem.117-125 Cooking indoors with coal or biomass fuels such as wood, peat, crop residues, or dung in open-pit fires or poorly ventilated stoves is commonplace in developing countries. This practice releases numerous particulates, including silicates, into the air. Not surprisingly, most reported cases of this pneumoconiosis, which has been referred to as hut lung or domestically-acquired particulate lung disease (DAPLD), have been seen in women. The rare cases that have come to biopsy exhibit dust macules, nodular fibrosis, or occasionally PMF (Figs. 10.102 and eSlide 10.5). Particle analysis in a case of DAPLD has disclosed silica and silicate particles in addition to carbonaceous dust, supporting this as being a form of MDP.126 Although reported as a distinct entity, bronchial anthracofibrosis appears to be part of a spectrum of findings associated with biomass fuel exposure along with DAPLD. Bronchial anthracofibrosis, which is diagnosed bronchoscopically, refers to anthracotic pigmentation of the bronchial mucosa with associated bronchial stenosis/obstruction (Fig. 10.103).127,128 Histopathology shows submucosal dust deposits with peribronchial mixed dust fibrosis (Fig. 10.104).
Figure 10.102 Domestically-acquired particulate lung disease. Extensive interstitial fibrosis with abundant entrapped dust particles is seen. This biopsy is from a woman who had recently immigrated to the United States from a developing country, where for many years she cooked with a poorly ventilated indoor stove that used biomass fuels. (Courtesy Dr. Thomas V. Colby, Mayo Clinic, Scottsdale, Arizona.)
Figure 10.103 Bronchial anthracofibrosis. Pigmented bronchial mucosa with underlying heavily anthracotic dust-laden fibrosis causing bronchial stenosis.
Self-assessment questions and cases related to this chapter can be found online at ExpertConsult.com.
Figure 10.104 Bronchial anthracofibrosis/domestically-acquired particulate lung disease. Anthracotic submucosal and peribronchial dust deposition accompanied by densely, collagenized mixed dust-type fibrosis of variable density.
References
1. Sporn T, Roggli V Pneumoconioses, mineral and vegetable. In: Tomashefski J Jr, Cagle P, Farver C, Fraire A, eds. Dail and Hammer’s Pulmonary Pathology. New York: Springer; 2008:911-949.
2. Ingram P, Shelburne JD, Roggli VL, LeFurgey EA, eds. Biomedical Applications of Microprobe Analysis. San Diego: Academic Press; 1999.
3. Bang KM, Mazurek JM, Wood JM, et al. Silicosis mortality trends and new exposures to respirable crystalline silica—United States, 2001-2010. MMWR Morb Mortal Wkly Rep. 2015;64(5):117-120.
4. Akgun M, Araz O, Ucar EY, et al. Silicosis appears inevitable among former denim sandblasters: a 4-year follow-up study. Chest. 2015;148(3):647-654.
5. Bayram H, Ghio AJ. Killer jeans and silicosis. Am J Respir Cnt Care Med. 2011;184(12):1322-1324.
6. Bakan ND, Ozkan G, Camsari G, et al. Silicosis in denim sandblasters. Chest. 2011;140(5):1300-1304.
7. Churg A, Green FHY, eds. Pathology of Occupational Lung Disease. 2nd ed. Baltimore: Williams & Wilkins; 1998.
8. Craighead JE. Diseases associated with exposure to silica and nonfibrous silicate minerals. Arch Pathol Lab Med. 1988;112(7):673-720.
9. Zeren EH, Colby TV, Roggli VL. Silica-induced pleural disease—an unusual case mimicking malignant mesothelioma. Chest. 1997;112(5):1436-1438.
10. Mcdonald JW, Roggli VL. Detection of silica particles in lung-tissue by polarizing light-microscopy.
Arch Pathol Lab Med. 1995;119(3):242-246.
11. Cowie RL. The epidemiology of tuberculosis in gold miners with silicosis. Am J Respir Crit Care Med. 1994;150(5):1460-1462.
12. Caplan A, Payne RB, Withey JL. A broader concept of Caplan's syndrome related to rheumatoid factors. Thorax. 1962;17:205-212.
13. Slavin RE, Swedo JL, Brandes D, Gonzalezvitale JC, Osorniovargas A. Extrapulmonary silicosis—a clinical, morphologic, and ultrastructural-study. Hum Pathol. 1985;16(4):393-412.
14. Vallyathan V, Brower PS, Green FHY, Attfield MD. Radiographic and pathologic correlation of coal workers' pneumoconiosis. Am J Respir Crit Care Med. 1996;154(3):741-748.
15. Marine WM, Gurr D, Jacobsen M. Clinically important respiratory effects of dust exposure and smoking in british coal-miners. Am Rev Respir Dis. 1988;137(1):106-112.
16. Kleinerman J, Green F, Harley RA, et al. Pathology standards for coal-workers pneumoconiosis— report of the Pneumoconiosis Committee of the College-of-American-Pathologists to the National-Institute-for-Occupational-Safety-and-Health. Arch Pathol Lab Med. 1979;103:375-432.
17. Pratt PC. Role of silica in progressive massive fibrosis. Arch Environ Health. 1968;16(5):734-737.
18. Roggli V Asbestos bodies and non-asbestos ferruginous bodies. In: Oury TD, Sporn TA, Roggli VL, eds. Pathology of Asbestos-Associated Diseases. Heidelberg: Springer Berlin; 2014:25-51.
19. Oury TD, Sporn TA, Roggli VL, eds. Pathology of Asbestos-Associated Diseases. 3rd ed. Berlin: Springer; 2014.
20. Friedman AC, Fiel SB, Fisher MS, et al. Asbestos-related pleural disease and asbestosis: a comparison of CT and chest radiography. AJR Am J Roentgenol. 1988;150(2):269-275.
21. Roggli VL, Gibbs AR, Attanoos R, et al. Pathology of asbestosis—an update of the diagnostic criteria: report of the asbestosis committee of the college of american pathologists and pulmonary pathology society. Arch Pathol Lab Med. 2010;134(3):462-480.
22. Roggli VL. Pathology of human asbestosis: a critical review. In: Fenoglio-Preiser C, ed. Advances in Pathology. Vol. 2. Chicago: Year Book; 1989:31-60.
23. Roggli VL. The pneumoconioses: asbestosis. In: Saldana MJ, ed. Pathology of Pulmonary Disease. Philadelphia: Lippincott; 1994:395-410.
24. Churg A. Nonneoplastic disease caused by asbestos. In: Churg A, Green FHY, eds. Pathology of Occupational Lung Disease. 2nd ed. Baltimore: Williams & Wilkins; 1998:277-338.
25. Schneider F, Sporn TA, Roggli VL. Asbestos fiber content of lungs with diffuse interstitial fibrosis: an analytical scanning electron microscopic analysis of 249 cases. Arch Pathol Lab Med. 2010;134(3):457-461.
26. Morgan WK, Donner A, Higgins IT, Pearson MG, Rawlings W Jr. The effects of kaolin on the lung. Am Rev Respir Dis. 1988;138(4):813-820.
27. Lapenas D, Gale P, Kennedy T, Rawlings W Jr, Dietrich P. Kaolin pneumoconiosis. Radiologic, pathologic, and mineralogic findings. Am Rev Respir Dis. 1984;130(2):282-288.
28. Wagner JC, Pooley FD, Gibbs A, et al. Inhalation of china stone and china clay dusts: relationship between the mineralogy of dust retained in the lungs and pathological changes. Thorax. 1986;41(3):190-196.
29. Landas SK, Schwartz DA. Mica-associated pulmonary interstitial fibrosis. Am Rev Respir Dis. 1991;144(3 Pt 1):718-721.
30. Sherwin RP, Barman ML, Abraham JL. Silicate pneumoconiosis of farm workers. Lab Invest. 1979;40(5):576-582.
31. Green FHY, Churg A. Diseases due to nonasbestos silicates. In: Churg A, Green FHY, eds. Pathology of Occupational Lung Disease. 2nd ed. Baltimore: Williams & Wilkens; 1998: 235-276.
32. Roub LW, Dekker A, Wagenblast HW, Reece GJ. Pulmonary silicatosis. A case diagnosed by needle-aspiration biopsy and energy-dispersive x-ray analysis. Am J Clin Pathol. 1979;72(5):871-875.
33. Honma K, Abraham JL, Chiyotani K, et al. Proposed criteria for mixed-dust pneumoconiosis: definition, descriptions, and guidelines for pathologic diagnosis and clinical correlation. Hum Pathol. 2004;35(12):1515-1523.
34. Vallyathan NV, Craighead JE. Pulmonary pathology in workers exposed to nonasbestiform talc. Hum Pathol. 1981;12(1):28-35.
35. Crouch E, Churg A. Progressive massive fibrosis of the lung secondary to intravenous injection of talc. A pathologic and mineralogic analysis. Am J Clin Pathol. 1983;80(4):520-526.
36. Pare JP, Cote G, Fraser RS. Long-term follow-up of drug abusers with intravenous talcosis. Am Rev Respir Dis. 1989;139(1):233-241.
37. Berner A, Gylseth B, Levy F. Talc dust pneumoconiosis. Acta Pathol Microbiol Scand [A]. 1981;89(1-6):17-21.
38. Kennedy L, Sahn SA. Talc pleurodesis for the treatment of pneumothorax and pleural effusion. Chest 1994;106(4):1215-1222.
39. Miller A, Teirstein AS, Bader ME, Bader RA, Selikoff IJ. Talc pneumoconiosis. Significance of sublight microscopic mineral particles. Am J Med. 1971;50(3):395-402.
40. Sferlazza SJ, Beckett WS. The respiratory health of welders. Am Rev Respir Dis. 1991;143(5 Pt 1):1134-1148.
41. Stern RM. The assessment of risk: application to the welding industry. Lung cancer. Danish Weld Inst Rep. 1983;83:13.
42. Churg A, Colby TV. Diseases caused by metals and related compounds. In: Churg A, Green FHY, eds. Pathology of Occupational Lung Disease. 2nd ed. Baltimore: Williams & Wilkins; 1998:77-128.
43. Roggli VL. Rare pneumoconioses: metalloconioses. In: Saldana MJ, ed. Pathology of Pulmonary Disease. Philadelphia: Lippincott; 1994:411-422.
44. Abramson MJ, Wlodarczyk JH, Saunders NA, Hensley MJ. Does aluminum smelting cause lung disease? Am Rev Respir Dis. 1989;139(4):1042-1057.
45. Vallyathan V, Bergeron WN, Robichaux PA, Craighead JE. Pulmonary fibrosis in an aluminum arc welder. Chest. 1982;81(3):372-374.
46. Jederlinic PJ, Abraham JL, Churg A, et al. Pulmonary fibrosis in aluminum oxide workers. Investigation of nine workers, with pathologic examination and microanalysis in three of them. Am Rev Respir Dis. 1990;142(5):1179-1184.
47. Gilks B, Churg A. Aluminum-induced pulmonary fibrosis: do fibers play a role? Am Rev Respir Dis. 1987;136(1):176-179.
48. Chen WJ, Monnat RJ Jr, Chen M, Mottet NK. Aluminum induced pulmonary granulomatosis. Hum Pathol. 1978;9(6):705-711.
49. De Vuyst P, Dumortier P, Schandene L, et al. Sarcoidlike lung granulomatosis induced by aluminum dusts. Am Rev Respir Dis. 1987;135(2):493-497.
50. Herbert A, Sterling G, Abraham J, Corrin B. Desquamative interstitial pneumonia in an aluminum welder. Hum Pathol. 1982;13(8):694-699.
51. Sprince NL, Oliver LC, Eisen EA, Greene RE, Chamberlin RI. Cobalt exposure and lung disease in tungsten carbide production. A cross-sectional study of current workers. Am Rev Respir Dis. 1988;138(5):1220-1226.
52. Nemery B, Casier P Roosels D, Lahaye D, Demedts M. Survey of cobalt exposure and respiratory health in diamond polishers. Am Rev Respir Dis. 1992;145(3):610-616.
53. Nemery B, Nagels J, Verbeken E, Dinsdale D, Demedts M. Rapidly fatal progression of cobalt lung in a diamond polisher. Am Rev Respir Dis. 1990;141(5 Pt 1):1373-1378.
54. Frost AE, Keller CA, Brown RW, et al. Giant cell interstitial pneumonitis. Disease recurrence in the transplanted lung. Am Rev Respir Dis. 1993;148(5):1401-1404.
55. Ohori NP Sciurba FC, Owens GR, Hodgson MJ, Yousem SA. Giant-cell interstitial pneumonia and hard-metal pneumoconiosis. A clinicopathologic study of four cases and review of the literature. Am J Surg Pathol. 1989;13(7):581-587.
56. Stettler LE, Groth DH, Platek SF. Automated characterization of particles extracted from human lungs: three cases of tungsten carbide exposure. Scan Electron 1983;(Pt 1):439-448.
56a. Khoor A, Roden AC, Colby TV, et al. Giant cell interstitial pneumonia in patients without hard metal exposure: analysis of three cases and review of the literature. Hum Pathol. 2016;50:176-182.
57. Tabatowski K, Roggli VL, Fulkerson WJ, et al. Giant cell interstitial pneumonia in a hard-metal worker. Cytologic, histologic and analytical electron microscopic investigation. Acta Cytol. 1988;32(2):240-246.
58. Meyer KC. Beryllium and lung disease. Chest. 1994;106(3):942-946.
59. Kriebel D, Brain JD, Sprince NL, Kazemi H. The pulmonary toxicity of beryllium. Am Rev Respir Dis. 1988;137(2):464-473.
60. Cullen MR, Kominsky JR, Rossman MD, et al. Chronic beryllium disease in a precious metal refinery. Clinical epidemiologic and immunologic evidence for continuing risk from exposure to low level beryllium fume. Am Rev Respir Dis. 1987;135(1):201-208.
61. Newman LS, Kreiss K, King TE Jr, Seay S, Campbell PA. Pathologic and immunologic alterations in early stages of beryllium disease. Re-examination of disease definition and natural history. Am Rev Respir Dis. 1989;139(6):1479-1486.
62. Kotloff RM, Richman PS, Greenacre JK, Rossman MD. Chronic beryllium disease in a dental laboratory technician. Am Rev Respir Dis. 1993;147(1):205-207.
63. Hardy HL, Tabershaw IR. Delayed chemical pneumonitis occurring in workers exposed to beryllium compounds. J Ind Hyg Toxicol. 1946;28:197-211.
64. Balmes JR, Abraham JL, Dweik RA, et al. An official American Thoracic Society statement: diagnosis and management of beryllium sensitivity and chronic beryllium disease. Am J Respir
Crit Care Med. 2014;190(10):e34-e59.
65. Newman LS, Kreiss K. Nonoccupational beryllium disease masquerading as sarcoidosis: identification by blood lymphocyte proliferative response to beryllium. Am Rev Respir Dis. 1992;145(5):1212-1214.
66. Butnor KJ, Sporn TA, Ingram P, et al. Beryllium detection in human lung tissue using electron probe X-ray microanalysis. Mod Pathol. 2003;16(11):1171-1177.
67. McDonald JW, Ghio AJ, Sheehan CE, Bernhardt PF, Roggli VL. Rare earth (cerium oxide) pneumoconiosis: analytical scanning electron microscopy and literature review. Mod Pathol. 1995;8(8):859-865.
68. Waring PM, Watling RJ. Rare earth deposits in a deceased movie projectionist. A new case of rare earth pneumoconiosis? Med J Aust. 1990;153(11-12):726-730.
69. Sulotto F, Romano C, Berra A, et al. Rare-earth pneumoconiosis: a new case. Am J Ind Med. 1986;9(6):567-575.
70. Husain MH, Dick JA, Kaplan YS. Rare earth pneumoconiosis. J Occup Med. 1980;30(1):15-19.
71. Beton DC, Andrews GS, Davies HJ, Howells L, Smith GF. Acute cadmium fume poisoning. Five cases with one death from renal necrosis. Br J Ind Med. 1966;23(4):292-301.
72. Yamamoto K, Ueda M, Kikuchi H, Hattori H, Hiraoka Y. An acute fatal occupational cadmium poisoning by inhalation. Z Rechtsmed. 1983;91(2):139-143.
73. Lane RE, Campbell AC. Fatal emphysema in two men making a copper cadmium alloy. Br J Ind Med. 1954;11(2):118-122.
74. Bonnell JA. Emphysema and proteinuria in men casting copper-cadmium alloys. Br J Ind Med. 1955;12(3):181-195.
75. Kelleher P Pacheco K, Newman LS. Inorganic dust pneumonias: the metal-related parenchymal disorders. Environ Health Perspect. 2000;108(suppl 4):685-696.
76. Elinder CG, Kjellstrom T, Lind B, et al. Cadmium exposure from smoking cigarettes: variations with time and country where purchased. Environ Res. 1983;32(1):220-227.
77. Hirst RN Jr, Perry HM Jr, Cruz MG, Pierce JA. Elevated cadmium concentration in emphysematous lungs. Am Rev Respir Dis. 1973;108(1):30-39.
78. Davison AG, Fayers PM, Taylor AJ, et al. Cadmium fume inhalation and emphysema. Lancet. 1988;1(8587):663-667.
79. Pimentel JC, Marques F. "Vineyard sprayer's lung": a new occupational disease. Thorax. 1969;24(6):678-688.
80. Villar TG. Vineyard sprayer's lung. Clinical aspects. Am Rev Respir Dis. 1974;110(5):545-555.
81. Funahashi A, Schlueter DP, Pintar K, et al. Pneumoconiosis in workers exposed to silicon carbide. Am Rev Respir Dis. 1984;129(4):635-640.
82. Loewen GM, Weiner D, McMahan J. Pneumoconiosis in an elderly dentist. Chest. 1988;93(6):1312-1313.
83. Masse S, Begin R, Cantin A. Pathology of silicon carbide pneumoconiosis. Mod Pathol. 1988;1(2):104-108.
84. Centers for Disease Control and Prevention (CDC). Silicosis in dental laboratory technicians—five states, 1994-2000. MMWR Morb Mortal Wkly Rep. 2004;53(9):195-197.
85. De Vuyst P, Vande Weyer R, De Coster A, et al. Dental technician's pneumoconiosis. A report of two cases. Am Rev Respir Dis. 1986;133(2):316-320.
86. Morgenroth K, Kronenberger H, Michalke G, Schnabel R. Morphology and pathogenesis of pneumoconiosis in dental technicians. Pathol Res Pract. 1985;179(4-5):528-536.
87. Rom WN, Lockey JE, Lee JS, et al. Pneumoconiosis and exposures of dental laboratory technicians. Am J Public Heath. 1984;74(11):1252-1257.
88. Selden A, Sahle W, Johansson L, Sorenson S, Persson B. Three cases of dental technician's pneumoconiosis related to cobalt-chromium-molybdenum dust exposure. Chest. 1996;109(3):837-842.
89. Cullen MR, Balmes JR, Robins JM, Smith GJ. Lipoid pneumonia caused by oil mist exposure from a steel rolling tandem mill. Am J Ind Med. 1981;2(1):51-58.
90. Skorodin MS, Chandrasekhar AJ. An occupational cause of exogenous lipoid pneumonia. Arch Pathol Lab Med. 1983;107(11):610-611.
91. Jarvholm B. Cutting oil mist and bronchitis. Eur J Respir Dis Suppl. 1982;118:79-83.
92. Skyberg K, Ronneberg A, Kamoy JI, Dale K, Borgersen A. Pulmonary fibrosis in cable plant workers exposed to mist and vapor of petroleum distillates. Environ Res. 1986;40(2): 261-273.
93. Beckett W, Kallay M, Sood A, Zuo Z, Milton D. Hypersensitivity pneumonitis associated with environmental mycobacteria. Environ Health Perspect. 2005;113(6):767-770.
94. Kreiss K, Cox-Ganser J. Metalworking fluid-associated hypersensitivity pneumonitis: a workshop summary. Am J Ind Med. 1997;32(4):423-432.
95. Bernstein DI, Lummus ZL, Santilli G, Siskosky J, Bernstein IL. Machine operator's lung. A hypersensitivity pneumonitis disorder associated with exposure to metalworking fluid aerosols. Chest 1995;108(3):636-641.
96. Gupta A, Rosenman KD. Hypersensitivity pneumonitis due to metal working fluids: sporadic or under reported? Am J Ind Med. 2006;49(6):423-433.
97. Robertson AJ, Rivers D, Nagelschmidt G, Duncumb P. Stannosis: benign pneumoconiosis due to tin dioxide. Lancet. 1961;1(7186):1089-1093.
98. Rode LE, Ophus EM, Gylseth B. Massive pulmonary deposition of rutile after titanium dioxide exposure: light-microscopical and physico-analytical methods in pigment identification. Acta Pathol Microbiol Scand [A]. 1981;89(6):455-461.
99. Keller CA, Frost A, Cagle PT, Abraham JL. Pulmonary alveolar proteinosis in a painter with elevated pulmonary concentrations of titanium. Chest. 1995;108(1):277-280.
100. Eschenbacher WL, Kreiss K, Lougheed MD, et al. Nylon flock-associated interstitial lung disease. Am J Respir Crit Care Med. 1999;159(6):2003-2008.
101. Kern DG, Crausman RS, Durand KT, Nayer A, Kuhn C 3rd. Flock worker's lung: chronic interstitial lung disease in the nylon flocking industry. Ann Intern Med. 1998;129(4):261-272.
102. Kern DG, Kuhn C 3rd, Ely EW, et al. Flock worker's lung: broadening the spectrum of clinicopathol- ogy, narrowing the spectrum of suspected etiologies. Chest. 2000;117(1):251-259.
103. Boag AH, Colby TV, Fraire AE, et al. The pathology of interstitial lung disease in nylon flock workers. Am J Surg Pathol. 1999;23(12):1539-1545.
104. Kanwal R, Kullman G, Piacitelli C, et al. Evaluation of flavorings-related lung disease risk at six microwave popcorn plants. J Occup Environ Med. 2006;48(2):149-157.
105. van Rooy FG, Rooyackers JM, Prokop M, et al. Bronchiolitis obliterans syndrome in chemical workers producing diacetyl for food flavorings. Am J Respir Crit Care Med. 2007; 176(5): 498-504.
106. Kreiss K, Gomaa A, Kullman G, et al. Clinical bronchiolitis obliterans in workers at a microwave- popcorn plant. N Engl J Med. 2002;347(5):330-338.
107. Akpinar-Elci M, Travis WD, Lynch DA, Kreiss K. Bronchiolitis obliterans syndrome in popcorn production plant workers. Eur Respir J. 2004;24(2):298-302.
108. Hendrick DJ. "Popcorn worker's lung" in Britain in a man making potato crisp flavouring. Thorax. 2008;63(3):267-268.
109. Hubbs AF, Battelli LA, Goldsmith WT, et al. Necrosis of nasal and airway epithelium in rats inhaling vapors of artificial butter flavoring. Toxicol Appl Pharmacol. 2002;185(2): 128-135.
110. Cummings KJ, Donat WE, Ettensohn DB, et al. Pulmonary alveolar proteinosis in workers at an indium processing facility. Am J Respir Crit Care Med. 2010;181(5):458-464.
111. Homma S, Miyamoto A, Sakamoto S, et al. Pulmonary fibrosis in an individual occupationally exposed to inhaled indium-tin oxide. Europ Respir J. 2005;25(1):200-204.
112. Homma T, Ueno T, Sekizawa K, Tanaka A, Hirata M. Interstitial pneumonia developed in a worker dealing with particles containing indium-tin oxide. J Occup Health. 2003;45(3):137-139.
113. Wu M, Gordon RE, Herbert R, et al. Case report: Lung disease in World Trade Center responders exposed to dust and smoke: carbon nanotubes found in the lungs of World Trade Center patients and dust samples. Environ Health Perspect. 2010;118(4):499-504.
114. Caplan-Shaw CE, Yee H, Rogers L, et al. Lung pathologic findings in a local residential and working community exposed to World Trade Center dust, gas, and fumes. J Occup Environ Med. 2011;53(9):981-991.
115. Rom WN, Weiden M, Garcia R, et al. Acute eosinophilic pneumonia in a New York City firefighter exposed to World Trade Center dust. Am J Respir Crit Care Med. 2002;166(6):797-800.
116. King MS, Eisenberg R, Newman JH, et al. Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan. N Engl J Med. 2011;365(3):222-230.
117. Balakrishnan K, Sambandam S, Ramaswamy P, Mehta S, Smith KR. Exposure assessment for respirable particulates associated with household fuel use in rural districts of Andhra Pradesh, India. J Expo Anal Environ Epidemiol. 2004;14(suppl 1):S14-S25.
118. Balakrishnan K, Sankar S, Parikh J, et al. Daily average exposures to respirable particulate matter from combustion of biomass fuels in rural households of southern India. Environ Health Perspect. 2002;110(11):1069-1075.
119. Grobbelaar JP, Bateman ED. Hut lung: a domestically acquired pneumoconiosis of mixed aetiology in rural women. Thorax. 1991;46(5):334-340.
120. Gold JA, Jagirdar J, Hay JG, et al. Hut lung. A domestically acquired particulate lung disease. Medicine (Baltimore). 2000;79(5):310-317.
121. Dennis RJ, Maldonado D, Norman S, Baena E, Martinez G. Woodsmoke exposure and risk for obstructive airways disease among women. Chest. 1996;109(1):115-119.
122. Bruce N, Perez-Padilla R, Albalak R. Indoor air pollution in developing countries: a major environmental and public health challenge. Bull World Heath Organ. 2000;78(9):1078-1092.
123. Perez-Padilla R, Regalado J, Vedal S, et al. Exposure to biomass smoke and chronic airway disease in Mexican women. A case-control study. Am J Respir Crit Care Med. 1996;154(3 Pt 1):701-706.
124. Ramirez-Venegas A, Sansores RH, Perez-Padilla R, et al. Survival of patients with chronic obstructive pulmonary disease due to biomass smoke and tobacco. Am J Respir Crit Care Med. 2006;173(4):393-397.
125. Diaz JV, Koff J, Gotway MB, Nishimura S, Balmes JR. Case report: a case of wood-smoke-related pulmonary disease. Environ Health Perspect. 2006;114(5):759-762.
126. Mukhopadhyay S, Gujral M, Abraham JL, Scalzetti EM, Iannuzzi MC. A case of hut lung: scanning electron microscopy with energy dispersive x-ray spectroscopy analysis of a domestically acquired form of pneumoconiosis. Chest. 2013;144(1):323-327.
127. Chung MP, Lee KS, Han J, et al. Bronchial stenosis due to anthracofibrosis. Chest. 1998;113(2):344-350.
128. Gupta A, Shah A. Bronchial anthracofibrosis: an emerging pulmonary disease due to biomass fuel exposure. Int J Tuberc Lung Dis. 2011;15(5):602-612.
1. Which ONE of the following statements regarding silicosis is FALSE?
A. It can be seen in farmers in the extreme eastern portions of the United States.
B. The disease predominates in the upper lung fields.
C. It is caused by inhalation of crystalline silica.
D. It spares the pleura.
E. Pathologic findings include both nodular and diffuse interstitial fibrosis.
ANSWER: D
2. Secondary alveolar abnormalities in silicosis show a histologic similarity to:
A. Alveolar proteinosis
B. Alveolar microlithiasis
C. Alveolar sarcoidosis
D. Alpha-1-antitrypsin deficiency
E. None of the above
ANSWER: A
3. Which ONE of the following statements regarding silicosis is TRUE?
A. Scanning electron microscopy shows angulated particles in the lesions.
B. Caseation necrosis is a common finding in silicotic nodules.
C. The presence of numerous Langhans cells supports this diagnosis.
D. Brightly birefringent particles are numerous in polarization microscopy.
E. Associated alveolar exudates are nonreactive with the periodic acid-Schiff stain.
ANSWER: A
4. Which ONE of the following statements regarding coal worker’s pneumoconiosis (CWP; “black lung” disease) is FALSE?
A. Its development depends partly on idiosyncratic host factors.
B. It may feature the development of small intrapulmonary nodules.
C. Particular job types in mines do not correlate with the risk of CWP.
D. Patients with CWP may be asymptomatic.
E. The pleural surface shows foci of accentuated pigmentation.
ANSWER: C
5. Which ONE of the following statements regarding coal worker’s pneumoconiosis (CWP) is TRUE?
A. The disease predominates in the lower lobes of both lungs.
B. Nodular lesions in CWP are slate-gray on gross inspection.
C. Lesions of progressive massive fibrosis (PMF) are rock-hard.
D. Individual lesions of PMF measure no more than 1.5 cm in diameter.
E. Cavitation in nodular CWP lesions may suggest secondary tuberculosis.
ANSWER: E
6. Fibrotic nodules in coal worker’s pneumoconiosis differ from those of silicosis by showing:
A. A potential for cavitation
B. A complete absence of silica particles
C. An exclusively subpleural localization
D. A “Medusa head”-like microscopic configuration
E. A tendency to regress after inhalation of coal dust ceases
ANSWER: D
7. Intrapulmonary ferruginous bodies with a dematiaceous core may be seen in:
A. Asbestosis
B. Silicosis
C. Coal worker’s pneumoconiosis
D. Silicatosis
E. All of the above
ANSWER: C
8. Which ONE of the following statements regarding asbestosis is FALSE?
A. Pleural plaques alone, in an exposed individual, are diagnostically sufficient.
B. “Bystander” (household) exposures can rarely cause the disease.
C. Pulmonary function testing usually shows a “restrictive” pulmonopathy.
D. High-resolution computed tomography may be necessary for diagnosis.
E. Cor pulmonale can be seen clinically in advanced stages of the disease.
ANSWER: A
9. Which of the following pathologic findings is commonly seen concomitantly in patients with parenchymal asbestosis?
A. Bilateral fibrohyaline pleural plaques
B. Peripherolobular calcification of alveolar walls
C. Alveolar-proteinosis-like alveolar exudates
D. Nodular lymphocytic bronchiolitis
E. All of the above
ANSWER: A
10. Histopathologic findings in asbestosis may include:
A. Peribronchiolar fibrosis
B. Numerous intraalveolar histiocytes
C. Type II pneumocytic hyperplasia
D. Visceral pleural fibrosis
E. All of the above
ANSWER: E
11. Which of the following is least likely to manifest as a granulomatous reaction?
A. Sarcoidosis
B. Aluminosis
C. Silicosis
D. Talcosis
E. Berylliosis
ANSWER: C
12. Pseudoasbestos ferruginous bodies may form on which of the following?
A. Talc
B. Iron oxides
C. Feldspar
D. Coal particles
E. All of the above
ANSWER: E
13. Exposure to aluminum dust may result in all of the following EXCEPT:
A. Parietal pleural plaques
B. Peribronchiolar accumulation of dust laden macrophages
C. Interstitial pulmonary fibrosis
D. Granuloma formation
E. Alveolar-proteinosis-like reaction
ANSWER: A
14. True or false: Talc in histologic sections may derive from inhalation of talc dust, intravenous drug abuse, or talc pleurodesis.
A. True
B. False
ANSWER: A
15. Which of the following statements is TRUE?
A. It is not possible to distinguish welder’s pigment from hemosiderin in histologic sections.
B. Iron oxides from arc welding typically result in an exuberant fibrous reaction in the lungs.
C. Exposure to iron oxide particles may occur from mining hematite or working in a foundry.
D. Iron oxides are brightly birefringent when viewed with polarizing microscopy.
E. None of the above
ANSWER: C
16. Which of the following statements concerning hard metal lung disease is/are TRUE?
A. Disease develops in greater than 90% of individuals exposed to hard metals.
B. It is thought to be due to hypersensitivity to cobalt.
C. It is characterized by abundant dust deposits on routine microscopy.
D. It features interstitial giant cells.
E. All of the above
ANSWER: B
17. Which of the following statements about berylliosis is FALSE?
A. Well-formed non-necrotizing granulomas are present.
B. Polarizing microscopy is not useful for the diagnosis.
C. It develops in less than 5% of individuals exposed to beryllium.
D. Chronic interstitial inflammatory is typically absent.
E. It resembles sarcoidosis histologically.
ANSWER: D
18. All of the following statements about rare earth pneumoconiosis are correct EXCEPT:
A. It is also known as cerium oxide pneumoconiosis.
B. The believed causative agent is birefringent on polarizing microscopy.
C. The histopathologic features are similar to desquamative interstitial pneumonitis.
D. Granulomas may be present.
E. All of the above
ANSWER: C
19. True or false: Flock worker’s lung is characterized by sarcoid-like granulomas.
A. True
B. False
ANSWER: B
20. True or false: Hut lung has been reported to occur predominantly in males.
A. True
B. False
ANSWER: B
Case 1
eSlide 10.1
Sharply circumscribed silicotic nodule characterized by densely hyalinized collagen and dust-containing macrophages at the periphery.
a. History: Granite quarry worker with nodule detected on imaging.
b. Pathologic Findings: Sharply circumscribed nodule of hyalinized collagen with dust-containing macrophages at the periphery.
c. Diagnosis: Silicosis.
d. Discussion: Silicotic nodules are the histologic hallmark of silicosis, a disease caused by the inhalation of crystalline silica.
Case 2
eSlide 10.2
Extensive peribronchiolar fibrosis with subpleural honeycombing accompanied by numerous asbestos bodies.
a. History: Retired insulator with severe progressive dyspnea and reticulonodular infiltrates in the lower lung zones on radiography.
b. Pathologic Findings: Severe peribronchiolar interstitial fibrosis with focal honeycombing accompanied by beaded and rodlike asbestos bodies.
c. Diagnosis: Grades 3 to 4 asbestosis.
d. Discussion: Asbestosis is caused by the inhalation of asbestos fibers, resulting in pulmonary interstitial fibrosis.
Case 3
eSlide 10.3
Stellate mixed dust fibrotic lesions featuring abundant dust-laden macrophages.
a. History: Former coal miner with irregular opacities on imaging.
b. Pathologic Findings: Stellate fibrotic lesions with dust-laden macrophages.
c. Diagnosis: Mixed dust pneumoconiosis.
d. Discussion: Mixed dust pneumoconiosis is a variant of silicatosis defined by the presence of dust macules and stellate mixed dust fibrotic nodules.
Case 4
eSlide 10.4
Copious macrophages filled with gray-brown granular particulates are associated with diffuse interstitial fibrosis in an individual with a history of aluminum arc welding.
a. History: Male with a history of aluminum arc welding presented with progressive dyspnea.
b. Pathologic Findings: Diffuse interstitial fibrosis accompanied by abundant macrophages with granular gray-brown particulate material.
c. Diagnosis: Pulmonary interstitial fibrosis associated with aluminum arc welding.
d. Discussion: Aluminosis can produce a variety of tissue reactions in the lung, sometimes including interstitial fibrosis.
Case 5
eSlide 10.5
Massive peribronchial fibrosis and heavily pigmented mixed dust and silicotic nodules characterize domestically-acquired particulate lung disease.
a. History: 65-year-old Chinese female never-smoker who had immigrated to the United States 20 years prior presented with life- threatening hemoptysis.
b. Pathologic Findings: Extensive peribronchial fibrosis with numerous mixed dust and silicotic nodules with resultant bronchial stenosis.
c. Diagnosis: Domestically-acquired particulate lung disease (hut lung).
d. Discussion: Domestically-acquired particulate lung disease is an underrecognized pneumoconiosis associated with exposure to cooking/heating with biomass fuels in poorly ventilated spaces.