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. 9-1 and 9-2). As the disease progresses in severity, the nodules may become confluent (Figs. 9-3 and 9-4). 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 9-1 Silicosis. In this gross specimen, circumscribed areas of nodular fibrosis are slate gray and of firm consistency.

Figure 9-2 Silicosis. At low magnification, silicotic nodules are sharply circumscribed and densely collagenous (Masson trichrome stain).

Figure 9-3 Conglomerate silicosis. A Gough-Wentworth section of lung from a tobacco field worker demonstrates confluent fibrosis in the upper lobe (arrowhead).

Figure 9-4 Conglomerate silicosis. Multiple silicotic nodules have coalesced, forming an area of confluent fibrosis.

The histologic hallmark of silicosis is the silicotic nodule.^4,5 This lesion is a sharply circumscribed nodule consisting of dense, whorled hyalinized collagen (Fig. 9-5). 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. Longstanding lesions may be calcified or even ossified (Fig. 9-6). 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. 9-7). There may also be extensive pleural fibrosis⁶ (Fig. 9-8). Nodules are frequently also present within hilar lymph nodes (Fig. 9-9). 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. 9-10). Cholesterol clefts may be prominent within the intra-alveolar material. The granular proteinaceous exudate typically stains strongly positive with periodic acid/Schiff with diastase (D-PAS).

Figure 9-5 Silicosis. This silicotic nodule demonstrates the typical whorled appearance. Macrophages are present at the periphery of the nodule.

Figure 9-6 Silicosis. A mature silicotic nodule exhibits partial ossification.

Figure 9-7 Silicosis. The lung parenchyma underlying the pleura is a common location for silicotic nodules.

Figure 9-8 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 9-9 Silicosis. Silicotic nodules within a lymph node characteristically contain centrally dense, hyalinized collagen surrounded by concentric whorls of more loosely arranged collagen bundles.

Figure 9-10 Acute silicosis. Granular eosinophilic material fills alveoli, imparting an appearance similar to that 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.)

Examination with polarizing microscopy shows faintly birefringent particulates within the fibrotic nodules (Fig. 9-11). Larger, brightly birefringent particles, which represent silicates, may also be seen, but these should not predominate (see later section on silicatosis).⁷ On scanning electron microscopy the particles appear angulated (Fig. 9-12). Analytic electron microscopy with EDXA reveals peaks for silicon only (Fig. 9-13).

Figure 9-11 Silicosis. Partial polarization of a silicotic nodule demonstrates faintly birefringent silica particles.

Figure 9-12 Silicosis. Scanning electron microscopy demonstrates angulated silica particles.

Figure 9-13 Energy-dispersive x-ray analysis (EDXA) spectrum shows a peak for silicon (Si).

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 multinucleate 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. 9-14). These 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.⁸ Both processes may be present simultaneously. Concurrent tuberculosis infection is most likely to occur with conglomerate silicosis.

Figure 9-14 Birefringent particles in sarcoidosis. In contrast to silicosis, this example of sarcoidosis contains large platy birefringent particles, typical for endogenous calcium oxalate.

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.⁹ 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.

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.^10,11

Pathologic Findings

CWP is characterized by increased pigmentation in the lungs resulting from the deposition of coal dust (Figs. 9-15 to 9-17). 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. 9-18). 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 mid-lung zones (Fig. 9-19). These are the lesions of PMF. Cavitation may occur in areas of PMF and, when present, suggests superimposed tuberculosis.¹²

Figure 9-15 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.)

Figure 9-16 Simple coal worker’s 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 9-17 Simple coal worker’s 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 9-18 Simple coal worker’s pneumoconiosis. In addition to diffusely increased pigmentation, the lung parenchyma shows well-demarcated black nodules. Centrilobular emphysematous bullae are also present.

Figure 9-19 Complicated coal worker’s pneumoconiosis. The upper lobe contains a confluent irregular area of fibrosis with the consistency of vulcanized rubber. Central cavitation is present.

The histologic hallmark of CWP is the coal dust macule (Fig. 9-20). 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 collarette of pigmented macrophages often surrounds the nodules, imparting a “Medusa head” appearance (Fig. 9-21). Areas of massive fibrosis (Fig. 9-22) consist of collagen bundles that are arranged in a haphazard distribution and intermixed with abundant pigment (Figs. 9-23 and 9-24). Vascular obliteration is common within areas of PMF, and ischemia may be the cause of cavitation in some cases.

Figure 9-20 Simple coal worker’s 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 9-21 Simple coal worker’s pneumoconiosis. A collarette of pigmented macrophages gives a “Medusa head” appearance to this intraparenchymal silicotic nodule.

Figure 9-22 Complicated coal worker’s 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.)

Figure 9-23 Complicated coal worker’s pneumoconiosis. In this example of progressive massive fibrosis, haphazardly arranged collagen bundles are interspersed with abundant pigment.

Figure 9-24 Complicated coal worker’s pneumoconiosis. A Masson trichrome stain highlights the collagenous composition of a heavily pigmented region of progressive massive fibrosis.

Examination with polarizing microscopy typically shows numerous faintly to brightly birefringent particulates within a background of black pigment (Fig. 9-25). 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.¹³ Ferruginous bodies are sometimes seen in the lungs of coal workers, typically within the alveolar spaces (Fig. 9-26). These may be distinguished from true asbestos bodies by virtue of their black carbonaceous cores¹⁴ (Fig. 9-27). Tuberculosis may also complicate CWP (Fig. 9-28).

Figure 9-25 Coal worker’s pneumoconiosis. Partial polarization shows a mixture of faintly and brightly birefringent particles superimposed on black pigment.

Figure 9-26 Coal worker’s pneumoconiosis. Along with pigmented macrophages, this case demonstrates numerous intra-alveolar ferruginous bodies.

Figure 9-27 Coal worker’s pneumoconiosis. At higher magnification, the black carbonaceous core of this ferruginous body (pseudoasbestos body) is evident.

Figure 9-28 Coal worker’s pneumoconiosis. A caseous granuloma in this case of coal worker’s pneumoconiosis was found to contain acid-fast bacilli.

Differential Diagnosis

CWP must be distinguished from the anthracotic pigment deposition that occurs in urban dwellers and cigarette 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. 9-29). A giant cell reaction to the crystalline carbon of graphite assists in this distinction.³ 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. Therefore, transbronchial biopsy is not useful for assessing disease severity.

Figure 9-29 Graphite worker’s pneumoconiosis. Although somewhat similar in appearance to particulates in coal worker’s pneumoconiosis, graphite particles appear crystalline and elicit a giant cell reaction.

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.

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. 9-30) with evidence of honeycombing.^17,18 Diffuse visceral pleural fibrosis is frequently present and is usually most severe over the lower lung zones. Parietal pleural plaques, which are frequently bilateral (Fig. 9-31), 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.

Figure 9-30 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.)

Figure 9-31 Pleural plaque. The gross appearance has been likened to that of candle wax drippings.

Histologically, asbestosis is characterized by discrete foci of fibrosis in the walls of respiratory bronchioles accompanied by asbestos bodies¹⁷ (Box 9-3 and Fig. 9-32). As the fibrotic process progresses, it extends distally 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. 9-33). In the most advanced cases, honeycomb fibrosis is present (Fig. 9-34), characterized by 0.5- to 1-cm–diameter fibrotic-walled cysts that are lined by bronchiolar epithelium and often contain pools of mucus. Alveolar macrophages are sometimes so prominent as to suggest a diagnosis of desquamative interstitial pneumonia (DIP). In some cases, multinucleate giant cells may be identified, within either the interstitium or the alveolar spaces (Fig. 9-35). Rarely, hyperplastic alveolar type II pneumocytes may contain cytoplasmic hyaline (Fig. 9-36) reminiscent of that found in the cytoplasm of hepatocytes in alcoholic liver disease.

Figure 9-32 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, rod-like, and dumbbell shapes.

Figure 9-33 Asbestosis. Peribronchiolar fibrosis extends into adjacent alveolar septa. Centrilobular emphysema and visceral pleural fibrosis (top) are also seen.

Figure 9-34 Asbestosis. In a more advanced case, honeycombing (arrowhead) is seen, in addition to lower lobe fibrosis.

Figure 9-35 Asbestosis. Within an interstitial giant cell lies a curvilinear asbestos body in this transbronchial biopsy specimen.

Figure 9-36 Asbestosis. Type II pneumocytes demonstrate cytoplasmic hyaline.

The hallmark of asbestos exposure is the asbestos body, a rod-like, beaded, or dumbbell-shaped structure with golden brown coating and a thin, translucent core.¹⁹ Asbestos bodies are typically found in the peribronchiolar interstitium (Fig. 9-37), but, with heavy exposure, may be seen in the alveolar spaces (Fig. 9-38). Detection of asbestos bodies may be facilitated by the use of iron stains, which impart a deep blue color (Fig. 9-39). Asbestos bodies may also be seen in sputum (Fig. 9-40) and in thoracic lymph nodes (Fig. 9-41) of patients with heavy exposure to asbestos. Pleural plaques consist of layers of acellular hyalinized collagen, arranged in a “basketweave” pattern (Fig. 9-42). Visceral pleural fibrosis may show this basketweave pattern or appear as compact layers of collagen. A mild lymphocytic infiltrate sometimes accompanies the fibrosis.

Figure 9-37 Asbestosis. In a transbronchial biopsy, interstitial fibrosis and an asbestos body (upper left) can be seen.

Figure 9-38 Asbestosis. Asbestos bodies are present within an alveolar space in this case of severe asbestosis.

Figure 9-39 Asbestosis. In this iron-stained section of lung, an asbestos body has a characteristic beaded morphology and deep blue color.

Figure 9-40 Asbestosis. Asbestos bodies in a sputum cytology specimen.

Figure 9-41 Asbestosis. A section from a thoracic lymph node from a heavily exposed individual contains numerous asbestos bodies.

Figure 9-42 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. 9-43). 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 microscopy²⁰ (Figs. 9-44 and 9-45). In cases in which asbestos bodies are not identified in histologic sections, the fiber burden is typically always more than 2 standard deviations below the mean value in cases with bona fide (histologically confirmed) asbestosis.²¹ Polarizing microscopy is not useful for the detection of asbestos in histologic sections.

Figure 9-43 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 9-44 Asbestosis. Scanning electron microscopy image of an asbestos body. Note the thin, beaded appearance.

Figure 9-45 Asbestosis. Energy-dispersive x-ray analysis (EDXA) spectra showing characteristic elemental composition of types of asbestos. A, Amosite has a prominent peak for silica (Si), as well as peaks for magnesium (Mg) and iron (Fe). B, Crocidolite shows a peak for sodium (Na) in addition to silica and iron. C, Tremolite demonstrates peaks for silica, magnesium, and calcium (Ca). D, Chrysotile exhibits a prominent peak for magnesium with smaller peaks for silica and iron. 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) and other forms of diffuse pulmonary fibrosis but also from peribronchiolar fibrosis associated with cigarette smoking. UIP is characterized by honeycomb changes, fibroblastic foci, and the absence of asbestos bodies in histologic sections (see Chapter 7). Honeycomb changes are a rarity in asbestosis, and, in our experience, fibroblastic foci are also uncommon. Pleural changes are much more common in individuals with asbestosis than in individuals with UIP. In contrast to asbestosis, the form of small-airway disease known as respiratory bronchiolitis that is seen in cigarette smokers and 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.

Asbestos bodies must be distinguished from non-asbestos ferruginous bodies (“pseudoasbestos bodies”) that instead have broad yellow or black central cores (see Fig. 9-27) (also see “Silicatosis” section). The use of transbronchial biopsy in the diagnosis of asbestosis is controversial.^16,20 In our experience, patients with evidence of diffuse pulmonary fibrosis on plain chest films or HRCT scans 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.

Clinical Presentation

Patients with uncomplicated silicate pneumoconiosis are typically asymptomatic. With extensive fibrosis, patients 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.^5,27 The lungs may be macroscopically normal in mild disease or may be firm and fibrotic (Fig. 9-46). In patients with significant exposure to silica in addition to silicates, silicotic nodules and even massive fibrosis may also be present (Fig. 9-47). Paracicatricial emphysema may sometimes be seen adjacent to areas of fibrosis (Fig. 9-48).

Figure 9-46 Silicatosis. Grossly, this lung from a kaolinite worker shows scattered gray areas of fibrosis in addition to centrilobular emphysema.

Figure 9-47 Silicatosis. Area of massive fibrosis with deposits of dust-laden macrophages.

Figure 9-48 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. 9-49). Interstitial fibrosis may also be present, characterized by irregularly contoured, stellate lesions with variable collagenization. Non-asbestos ferruginous bodies with broad yellow sheet silicate-type cores (Figs. 9-50 and 9-51) may be observed in some cases.^14,27 Examination with polarizing microscopy typically demonstrates numerous brightly birefringent particulates (Fig. 9-52) 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.²⁸

Figure 9-49 Silicatosis. At higher magnification, dust-laden macrophages are apparent.

Figure 9-50 Silicatosis. Pseudoasbestos ferruginous bodies accompany interstitial fibrosis in this transbronchial biopsy specimen from a patient who had silicatosis with exposure to feldspar.

Figure 9-51 Silicatosis. Pseudoasbestos bodies with broad yellow sheet silicate-type cores.

Figure 9-52 Silicatosis. Partial polarization of a fibrotic area demonstrates brightly birefringent silicate particles.

(Courtesy of Dr. Thomas V. Colby, Mayo Clinic, Scottsdale, AZ.)

A special variant of silicatosis is mixed dust pneumoconiosis (MDP), defined as the occurrence of dust macules and stellate lesions producing so-called “mixed dust fibrotic nodules” (Figs. 9-53 and 9-54), with or without accompanying silicotic nodules.²⁹ 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.

Figure 9-53 Mixed dust pneumoconiosis. The peribronchiolar distribution of fibrosis seen in this case is typical of mixed dust pneumoconiosis.

Figure 9-54 Mixed dust pneumoconiosis. Dust deposits are evident in this stellate mixed dust fibrotic nodule.

(Courtesy of Dr. Thomas V. Colby, Mayo Clinic, Scottsdale, AZ.)

Differential Diagnosis

Silicatosis must be distinguished from silicosis, UIP, and nonspecific interstitial pneumonia (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 (see Chapter 7). It is important to keep in mind that a few scattered birefringent particulates may be found in the lungs of members of 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. 9-55).

Figure 9-55 Mixed dust pneumoconiosis. Partially polarized photomicrograph of a mixed dust fibrotic nodule showing particles with variable birefringence.

Clinical Presentation

Patients are often asymptomatic, but fatal pulmonary fibrosis has been reported among talc miners and millers.³⁰ 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.^31,32

Pathologic Findings

Macroscopically, the lungs in talcosis may be normal or firm in consistency.^33,34 Histologically, patchy peribronchiolar and perivascular fibrosis is associated with abundant dust deposits (Fig. 9-56). 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. 9-57), 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.¹⁴ True asbestos bodies may also be observed in cases in which talc is contaminated with substantial amounts of asbestos (anthophyllite or tremolite). Similarly, silicotic nodules may be seen when there is substantial contamination with quartz.

Figure 9-56 Talcosis. In this example, needle-like talc particles are associated with an exuberant giant cell response.

Figure 9-57 Talcosis. Partially polarized view of talc, exhibiting a characteristic needle-like morphology.

Intravenous drug abuse talcosis is characterized by the accumulation of numerous talc granulomas within the pulmonary vasculature and alveolar septal walls (Figs. 9-58 and 9-59). Progressive massive fibrosis has been reported in some cases.³¹ Concomitant paracicatricial emphysema may be pronounced.³² Accumulations of talc can also be seen in talc pleurodesis, which is characterized by deposits of talc (Figs. 9-60 and 9-61) within the pleura that are associated with macrophages and are also accompanied by a giant cell reaction.³⁵

Figure 9-58 Intravenous talcosis. Faintly blue-gray talc particles occupy cleft-like spaces. Note the presence of an asteroid body within a giant cell.

Figure 9-59 Intravenous talcosis. Talc particles appear brightly birefringent under polarized light.

Figure 9-60 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.

Figure 9-61 Talc pleurodesis. Partial polarization of the case in Figure 9-60 shows numerous platy and needle-shaped birefringent talc particles.

Analytic electron microscopy in talcosis demonstrates platy particles composed of magnesium and silicon³⁶ (Figs. 9-62 and 9-63).

Figure 9-62 Talcosis. In this backscatter microscope electron image, talc has a platy appearance.

Figure 9-63 Talcosis. Energy-dispersive x-ray analysis (EDXA) spectrum of a talc particle demonstrating peaks for silica (Si) and magnesium (Mg). The peak for platinum (Pt) represents the coating applied to the specimen before electron microscopic examination.

Differential Diagnosis

Inhalational talcosis must be distinguished from intravenous talcosis and from sarcoidosis. In inhalational talcosis, the deposits are primarily perivascular and peribronchiolar, and intra-alveolar 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 to 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.

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.³⁷ Patients with significant exposures to silica or asbestos in addition to iron may demonstrate clinical features related to the inhalation of such dusts.³⁸

Pathologic Findings

Iron pigment imparts a reddish-brown color to the lung parenchyma.^3,39 Because iron is minimally fibrogenic, there is 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. 9-64).

Figure 9-64 Siderosilicosis. This case demonstrates welder’s pigment, as well as nodular fibrosis typical of siderosilicosis.

The histologic hallmark of siderosis is perivascular and peribronchiolar deposition of iron pigment (Fig. 9-65).⁴⁰ The pigment, which consists predominantly of iron oxide, typically is dark brown to black, often with a distinctive golden brown halo (Fig. 9-66). The pigment may be found in macrophages or the interstitium, or both, with very little fibrous response. As mentioned earlier, the finding of significant amounts of fibrosis should prompt a search for evidence of exposure to asbestos or silica (Figs. 9-67 and 9-68). Ferruginous bodies may be observed in some cases¹⁴ (Figs. 9-69 and 9-70). These may have black iron oxide cores, particularly in iron foundry workers (Fig. 9-71), 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.

Figure 9-65 Siderosis. Perivascular pigment deposition is seen in this histologic section taken from the lung of a welder.

Figure 9-66 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 intra-alveolar and lacks black central cores.

Figure 9-67 Siderosilicosis. A Masson trichrome stain demonstrates the whorled appearance of this heavily pigmented silicotic nodule.

Figure 9-68 Siderosilicosis. The iron pigment appears deep blue in this iron-stained section of the silicotic nodule depicted in Figure 9-67.

Figure 9-69 Siderosis. Pseudoasbestos bodies with broad yellow sheet silicate cores are seen in this case from a welder.

Figure 9-70 Siderosis. Iron-stained section of lung from the same patient as in Figure 9-69 demonstrates numerous pseudoasbestos bodies.

Figure 9-71 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.

Iron oxide pigment is typically nonrefringent when viewed with polarizing microscopy. Analytic electron microscopy demonstrates spherical particles with prominent peaks for iron (Figs. 9-72 and 9-73).

Figure 9-72 Siderosis. Scanning electron micrograph of iron oxide particles from a welder’s lung.

Figure 9-73 Siderosis. Energy-dispersive x-ray analysis (EDXA) spectrum of iron oxide particles, showing predominant peak for iron (Fe).

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 intra-alveolar accumulation of numerous hemosiderin-laden macrophages. Although both hemosiderin and exogenous iron pigment 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.

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.⁴³

Pathologic Findings

Macroscopically, the lung parenchyma in aluminosis ranges from essentially normal to heavy and grayish black with dense fibrotic areas scattered throughout³ (Fig. 9-74). A metallic sheen, resembling tarnished aluminum, has been described in some cases.

Figure 9-74 Aluminosis. Scattered areas of fibrosis are present in the lungs of this aluminum arc welder.

Histologic examination discloses perivascular and peribronchiolar accumulations of dust-laden macrophages (Fig. 9-75). The dust is refractile and gray to brown (Fig. 9-76). Tissue reaction to aluminum ranges in degree from nil to interstitial fibrosis to granulomatous inflammation.^43–46 Cases with a prominent granulomatous response may mimick sarcoidosis. Areas resembling DIP may also be observed.⁴⁷ Rare cases have been described with an alveolar proteinosis–like pattern (Figs. 9-77 and 9-78) similar to that seen in acute silicoproteinosis.⁴⁰

Figure 9-75 Aluminosis. An accumulation of dust-laden macrophages surrounds a pulmonary vessel.

Figure 9-76 Aluminosis. Detail of dust-laden macrophages, showing the gray-brown granular appearance typical of aluminum oxide.

Figure 9-77 Aluminosis. Amorphous eosinophilic material fills the alveoli in a pattern similar to pulmonary alveolar proteinosis. Interstitial accumulations of dust-laden macrophages are also present.

Figure 9-78 Aluminosis. Higher magnification view showing the characteristic granular appearance of aluminum-laden macrophages.

Aluminum dust is nonrefringent when examined by polarizing microscopy. Analytic electron microscopy shows electron-dense spherical particles (Figs. 9-79 and 9-80) composed of aluminum (Fig. 9-81).

Figure 9-79 Aluminosis. Transmission electron micrograph showing an alveolar type II cell overlying a dust-filled interstitial macrophage.

Figure 9-80 Aluminosis. In this transmission electron micrograph of an aluminum-containing macrophage, the aluminum particles appear spherical and electron-dense.

(From Roggli VL. Rare pneunoconioses: metalloconioses. In: Saldana MJ, ed. Pathology of Pulmonary Disease. Philadelphia: Lippincott; 1994:411–422, with permission.)

Figure 9-81 Aluminosis. Energy-dispersive x-ray analysis (EDXA) 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 “Silicatosis” section) 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 primarily within the alveolar spaces and are typically associated with scattered black dot-like carbon particles. Aluminum-induced granulomatosis must be considered in the differential diagnosis for 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.

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.⁵¹

Pathologic Findings

Macroscopically, the lungs in hard metal lung disease are small and fibrotic. Microscopically, hard metal lung disease is synonymous with giant cell interstitial pneumonia (GIP),⁵² 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. 9-82 and 9-83). A moderate chronic inflammatory infiltrate is present. Multinucleate giant cells are a conspicuous feature (Fig. 9-84) 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. 9-85). Occasionally, the overall pattern mimics that of UIP, with areas of microscopic honeycombing (Figs. 9-86 and 9-87). The fibrotic and inflammatory reaction may be accentuated around bronchioles.

Figure 9-82 Hard metal pneumoconiosis. At low magnification, the interstitium appears widened, accompanied by alveolar filling.

Figure 9-83 Hard metal pneumoconiosis. This example demonstrates interstitial pneumonia with hyperplastic type II pneumocytes and multinucleate giant cells in alveolar spaces.

(Courtesy of Dr. Thomas V. Colby, Mayo Clinic, Scottsdale, AZ.)

Figure 9-84 Hard metal pneumoconiosis. 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 9-85 Hard metal pneumoconiosis. Along with multinucleate giant cells, macrophages fill alveolar spaces in a pattern resembling desquamative interstitial pneumonia.

(Courtesy of Dr. Thomas V. Colby, Mayo Clinic, Scottsdale, AZ.)

Figure 9-86 Features reminiscent of usual interstitial pneumonia (UIP) in a case of tungsten carbide pneumoconiosis include server interstitial fibrosis and honeycombing.

Figure 9-87 Hard metal pneumoconiosis. Detail of the case shown in Figure 9-86, demonstrating honeycomb cysts filled with macrophages.

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. 9-88 and 9-89).⁵³ Tungsten particles are most common, followed by titanium and tantalum (Fig. 9-90). Cobalt, the suspected causative agent of the disease, may or may not be identified, because its water solubility makes it susceptible to removal from tissue during fixation and processing.

Figure 9-88 Hard metal pneumoconiosis. Scanning electron microscopy image of alveolar macrophages shows small, electron-dense metal particles.

(Courtesy of Dr. Frank Johnson and Dr. Jose Centano, Armed Forces Institute of Pathology, Washington, DC.)

Figure 9-89 Hard metal pneumoconiosis. The metal particles shown in Figure 9-88 appear as dark dots in this backscatter electron microscopic image.

(Courtesy of Dr. Frank Johnson and Dr. Jose Centano, Armed Forces Institute of Pathology, Washington, DC.)

Figure 9-90 Hard metal pneumoconiosis. Energy-dispersive x-ray analysis (EDXA) spectrum demonstrates a large peak for tungsten, also known as wolfram (W). A small peak for cobalt (Co) is also present.

(Courtesy of Dr. Frank Johnson and Dr. Jose Centano, Armed Forces Institute of Pathology, Washington, DC.)

Differential Diagnosis

Hard metal lung disease must be distinguished from UIP, DIP, and hypersensitivity pneumonitis. The presence of intra-alveolar and alveolar septal giant cells 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 lining of the alveolar septa by 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 intra-alveolar or alveolar septal giant cells of hard metal lung disease.

Transbronchial biopsy and bronchoalveolar lavage may be useful in the diagnosis of hard metal lung disease.⁵⁴ Analytic electron microscopy can be performed on either of these types of specimens and may demonstrate the characteristic profile of metallic elements.

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. Only about 1% of patients at risk develop berylliosis. Beryllium hypersensitivity has therefore 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 workup.⁶⁰

Pathologic Findings

Macroscopically, the lungs in chronic berylliosis are small and fibrotic and may show honeycomb changes.³ Bilateral hilar lymphadenopathy may be present. Microscopically, there are well-formed non-necrotizing granulomas (Figs. 9-91 and 9-92). A chronic interstitial inflammatory infiltrate typically is present (Fig. 9-93). Granulomas may also be found in hilar lymph nodes. Schaumann bodies (Fig. 9-94) and asteroid bodies (Fig. 9-95) within multinucleate giant cells are observed in some cases.^39,40

Figure 9-91 Berylliosis. The presence of numerous granulomas is characteristic of berylliosis.

(Courtesy of Dr. Fred Askin, Johns Hopkins University, Baltimore, MD.)

Figure 9-93 Berylliosis. In addition to granulomatous inflammation, a chronic intersititial inflammatory infiltrate is seen.

(Courtesy of Dr. Thomas V. Colby, Mayo Clinic, Scottsdale, AZ.)

Figure 9-92 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 9-94 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.)

Figure 9-95 Berylliosis. This granuloma features a giant cell containing an asteroid body (upper center).

(From Roggli VL. Rare pneumoconioses: metalloconioses. In: Saldana MJ, ed. Pathology of Pulmonary Disease. Philadelphia: Lippincott; 1994: 411–422, with permission.)

Beryllium is a lightweight metal that has recently become detectable by analytic electron microscopy.⁶¹ 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, so a high index of suspicion for exposure to beryllium and a thorough occupational history are necessary in order 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.

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 a 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.⁶² The fibrosis is similar to that observed with UIP or NSIP (Fig. 9-96). 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. 9-97 and 9-98).

Figure 9-96 Rare earth pneumoconiosis. Diffuse interstitial fibrosis with honeycomb cyst formation in a pattern reminiscent of that seen in usual interstitial pneumonia (UIP).

Figure 9-97 Rare earth pneumoconiosis. Backscatter electron microscopy image of electron-dense cerium oxide particles.

Figure 9-98 Rare earth pneumoconiosis. Energy-dispersive x-ray analysis (EDXA) 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.)

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 detection of rare earth compounds in lung tissue by analytic electron microscopy.