Pneumoconioses

Clinical presentation

The clinical presentation of silicosis ranges from asymptomatic in simple silicosis to markedly dyspneic with conglomerate silicosis. In conglomerate silicosis, hypoxemia and cor pulmonale may be fatal. The length of time required for symptoms to manifest is dependent on the concentration of respirable crystalline silica to which an individual is exposed. Symptoms developing after 10 or more years of relatively low-level exposure are designated as chronic silicosis. Accelerated silicosis refers to symptoms that manifest within 3 to 10 years of high concentration exposure. Individuals who have extremely high concentration exposures to very fine silica particles may develop acute silicosis with symptoms arising within a few weeks to less than 5 years from initial exposure.

Pathologic findings

The hallmark feature of silicosis is the silicotic nodule. Silicotic nodules are typically slate gray and firm, ranging from a few millimeters to 1 cm in diameter ( Figs. 10.1 and 10.2 ). The presence of discrete silicotic nodules in this size range are designated as chronic simple silicosis. As disease progresses in severity, the nodules may become confluent ( Figs. 10.3 and 10.4 ). These areas of confluent fibrosis, termed progressive massive fibrosis (PMF), are the defining feature of conglomerate silicosis, which is also known as complicated silicosis. The minimum pathologic size criterion some have proposed for PMF is 2 cm in any single dimension, while others define it as at least 1 cm. ^, Cavitation may occur within areas of confluent fibrosis and is a finding that suggests superimposed tuberculosis.

Histologically, silicotic nodules appear as sharply circumscribed nodules consisting of whorled, densely hyalinized collagen ( Fig. 10.5 ). More loosely arranged collagen bundles are typically found at the periphery of silicotic nodules. In recently formed lesions, macrophages form a mantle around the fibrotic center. Long-standing lesions may be calcified or even ossified ( Fig. 10.6 ). Silicotic nodules may develop anywhere in the lungs but typically are most numerous in the upper lung zones. Not uncommonly, they are concentrated beneath the pleura ( Fig. 10.7 ). Silicotic nodules can also protrude through the visceral pleura to its surface where they may macroscopically resemble drops of candle wax. Rarely, they appear as “pleural pearls” dangling into the pleural cavity by a fibrous strand attached to the pleural surface. There may also be extensive pleural fibrosis associated with macrophages that can simulate malignant mesothelioma at first glance ( Figs. 10.8 and 10.9 ). Regional lymph node involvement by silicotic nodules is common and can occur in the absence of parenchymal lung disease ( Fig. 10.10 ). Involved nodes occasionally undergo peripheral calcification, which has a characteristic eggshell appearance on radiography. The general consensus is that isolated nodal involvement, while indicative of silica exposure, should not be categorized as silicosis. Rarely, the mediastinum and/or peribronchial lymph nodes become engulfed by destructive silica dust-laden proliferative fibrosis, which has been referred to as silicotic fibrous pseudotumor. Acute silicosis typically resembles pulmonary alveolar proteinosis and is characterized by the presence of granular eosinophilic material filling the alveoli, alveolar ducts, and bronchioles ( Fig. 10.11 ). The granular proteinaceous exudate, which may show prominent cholesterol clefts, typically stains strongly positive with periodic acid-Schiff with diastase (PAS-D).

Examination with polarizing microscopy shows faintly birefringent particulates within the fibrotic nodules ( Fig. 10.12 ). Larger brightly birefringent particles, which represent silicates, may also be seen, but should not predominate (see Silicatosis section). On scanning electron microscopy, the particles appear angulated ( Fig. 10.13 ). Analytic electron microscopy with EDXA shows peaks solely for silicon ( Fig. 10.14 ).

Differential diagnosis

Silicotic nodules must be distinguished from the fibrotic nodules of burned out (healed) sarcoidosis, as well as healed mycobacterial and fungal infections, a classic example of which is so-called histoplasmoma. The presence of multinucleated giant cells and the absence of significant dust deposits favor sarcoidosis. Giant cells in sarcoidosis and other granulomatous processes sometimes contain variably shaped birefringent particles that represent endogenous calcium salts, such as calcium oxalate ( Fig. 10.15 ). ^, 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. Healed infectious granulomas are often solitary, in contrast to silicosis. Individuals with silicosis are at increased risk for acquiring tuberculosis and 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.

Rheumatoid pneumoconiosis, eponymously termed Caplan syndrome, was originally described in coal miners with rheumatoid arthritis. It can also be seen in individuals exposed to silica or silicates and reflects the presence of rheumatoid nodules in association with pneumoconiosis. The nodules demonstrate central necrosis with peripheral palisading of histiocytes, often in association with a rim of dust.

An extrathoracic location does not exclude silica as the etiology of fibrous nodules, as silicotic nodules have been reported in the liver, spleen, bone marrow, and abdominal lymph nodes. Extrathoracic involvement usually occurs in the setting of advanced pulmonary silicosis. The diagnostic yield of transbronchial biopsy in silicosis is low, which is likely explained by the firm nodules being pushed aside by the biopsy forceps.

Clinical presentation

Individuals range from asymptomatic with simple CWP to markedly dyspneic with PMF. The latter is associated with hypoxemia and cor pulmonale and may be fatal. ^,

Pathologic findings

In comparison to normal lungs, CWP is characterized by increased pigmentation resulting from the deposition of coal dust ( Figs. 10.16–10.18 ). Superimposed on a background of diffusely increased pigment are foci of accentuated pigmentation on the pleural surface 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 that they are black rather than slate gray ( Fig. 10.19 ). The most advanced cases of CWP feature PMF. Macroscopically, PMF in CWP features confluent areas of irregular fibrosis, typically in the upper to middle lung zones that have the consistency of vulcanized rubber ( Fig. 10.20 ). Cavitation may occur in areas of PMF, and its presence suggests superimposed tuberculosis.

The histologic hallmark of CWP is the coal dust macule ( Fig. 10.21 ). Coal dust macules consist of discrete 1 to 4 mm collections of interstitial pigment in the vicinity of respiratory bronchioles that have minimal to no associated collagen deposition and are generally nonpalpable. Areas of emphysematous destruction, referred to as focal emphysema, are typically present at the periphery of macules. Coal nodules may also be present within the lung parenchyma. They are larger (usually >4 mm) and have more fibrosis than macules and are not confined to the respiratory bronchioles. ^{, ,} Although reminiscent of silicotic nodules, coal nodules have a collarette of pigmented macrophages that imparts a “Medusa head” appearance ( Fig. 10.22 ). Dust-laden macrophages may also be present within alveolar spaces and pigment deposits can occur anywhere along the lymphatic routes of the lung including the secondary lobular septa and in the pleura. Lymph nodes frequently contain numerous pigmented macrophages and may also demonstrate coal nodules.

The term simple CWP is used for cases that show coal dust macules in combination with focal emphysema. In complicated CWP, there is coalescence of coal dust macules along with areas of PMF ( Fig. 10.23 ) consisting of collagen bundles arranged in a haphazard distribution intermixed with abundant pigment ( Figs. 10.24 and 10.25 ). As discussed in the preceding section on silicosis, differing minimum pathologic size criteria have been proposed for PMF. ^, Although some authors define it as 2 cm, others argue that 1 cm or greater better aligns with the International Labour Office (ILO) Classification of Radiographs of Pneumoconiosis definition of large opacities. ^, Features of simple CWP are usually present in the background in cases with PMF. PMF may transgress anatomic boundaries, such as blood vessels, and may cross interlobar fissures. Vascular obliteration is common within areas of PMF and ischemia may be the cause of cavitation in some cases.

Examination with polarizing microscopy typically shows numerous faintly to brightly birefringent particulates within a background of black pigment ( Fig. 10.26 ). This appearance reflects the mixed nature of coal dust, which is composed of amorphous carbon, silicates, and silica. Carbon in and of itself is not considered fibrogenic. 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. The outsize role of silica in disease development is reflected in a contemporary study of lung tissue from coal miners in which silicotic nodules predominated and classic lesions of simple CWP were seen in only a minority of cases. Ferruginous bodies are sometimes seen in the lungs of coal workers, typically within the alveolar spaces ( Fig. 10.27 ). These may be distinguished from true asbestos bodies by virtue of their black carbonaceous cores ( Fig. 10.28 ). Tuberculosis may also complicate CWP ( Fig. 10.29 ).

Differential diagnosis

CWP must be distinguished from the black carbonaceous pigment deposition that occurs in urban dwellers and cigarette smokers and from graphite 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 bona fide coal dust macules is indicative of CWP. Perivascular and peribronchiolar deposition of black carbonaceous pigment is often referred to as anthracosis. However, use of this term is discouraged outside of the setting of evaluating cases for the purposes of determining disability or death due to coal mining. Under the Black Lung Benefits Act, anthracosis is included in the US federal regulatory definition of pneumoconiosis. Graphite pneumoconiosis appears similar to CWP, but graphite is crystalline, whereas the carbon present in coal is amorphous ( Fig. 10.30 ). A giant cell reaction to the crystalline carbon of graphite assists in this distinction. Increased deposition of black carbonaceous pigment accompanied by interstitial fibrosis has also been reported in an individual with indoor woodstove exposure. Transbronchial biopsy may be useful in the diagnosis of CWP, but as areas of nodular fibrosis or PMF can be missed by such sampling, it is not useful for assessing disease severity.

Clinical presentation

Individuals with asbestosis range from asymptomatic to severely dyspneic at rest with cor pulmonale that may prove fatal. The time between initial exposure to asbestos and the development of symptoms in individuals with long-term exposure (latency period) is typically decades. However, there are rare reports of disease manifesting after short latency and/or brief intense asbestos exposure. Pulmonary function testing typically shows restrictive changes with reduced diffusion capacity. Individuals with asbestosis who smoke cigarettes have a markedly increased risk for developing lung cancer. 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 typically demonstrates a fine reticular pattern that can be seen macroscopically. However, the lungs can range from normal in gross appearance to severely scarred and shrunken ( Fig. 10.31 ) with evidence of honeycombing. Asbestosis is usually most severe in the lower lung zones and is frequently accompanied by overlying visceral pleural fibrosis. Pleural plaques are also present in the vast majority of cases. Like silicotic lesions involving the pleura, pleural plaques often resemble candle wax drippings macroscopically ( Fig. 10.32 ). However, whereas silicotic lesions are situated on the visceral pleura in a distribution that corresponds to anatomic lobules of the underlying lung, pleural plaques commonly involve the parietal pleura, as well as the diaphragm. Although the presence of diffuse pleural fibrosis and pleural plaques suggests asbestos is the etiology of pulmonary fibrosis, the term asbestosis should not be applied to cases in which these pleural abnormalities 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 asbestos airways disease has been proposed ( Box 10.3 and Figs. 10.33 and 10.34 ). As the fibrosis 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. 10.35 ). In the most advanced cases of asbestosis, honeycomb fibrosis is present ( Fig. 10.36 ), characterized by 0.5 to 1 cm in diameter fibrous-walled cysts lined by bronchiolar-type epithelium that often contain pools of mucus. However, some investigators have reported a disconnect between diffuse fibrosis with honeycomb changes and peribronchiolar fibrosis, hence questioning this sequence of fibrosis progression. 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. 10.37 ). Rarely, hyperplastic alveolar type 2 pneumocytes may contain cytoplasmic hyaline ( Fig. 10.38 ) reminiscent of that found in the cytoplasm of hepatocytes in alcoholic liver disease. This finding is not specific for asbestosis.

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. Asbestos bodies are typically found in the peribronchiolar interstitium ( Fig. 10.39 ), but with heavy exposure they also may be seen in alveolar spaces ( Fig. 10.40 ). Polarizing microscopy is not useful for the detection of asbestos in histologic sections. A minimum of two asbestos bodies per cm ² , in conjunction with an appropriate pattern of alveolar septal fibrosis, in well-inflated lung tissue away from lung carcinoma or mass lesions, is required for a histologic diagnosis of asbestosis. ^, Detection of asbestos bodies may be facilitated by the use of iron stains, which impart a deep blue color ( Fig. 10.41 ). Asbestos bodies may also be seen in sputum ( Fig. 10.42 ) and thoracic lymph nodes ( Fig. 10.43 ) of individuals with heavy exposure to asbestos. Pleural plaques consist of layers of acellular hyalinized collagen arranged in a “basket-weave” pattern that sometimes show areas of calcification ( Fig. 10.44 ). Asbestos-related diffuse pleural fibrosis may also show this pattern or appear as compact layers of collagen. A mild lymphocytic infiltrate sometimes accompanies the fibrosis.

Digestion procedures have been developed for quantifying the content of asbestos in lung tissue ( Fig. 10.45 ). Any of the commercial forms of asbestos (chrysotile and amphiboles) may be identified in lung tissue from individuals with asbestosis by means of analytic electron microscopy ( Figs. 10.46 and 10.47 ). Performing lung asbestos fiber burden analysis in cases of diffuse interstitial fibrosis in which fewer than two asbestos bodies per cm ² of lung tissue are identified in histologic sections is generally unnecessary, as the vast majority do not represent asbestosis. Such cases typically have lung asbestos fiber counts well below the range seen in asbestosis. However, this technique may be informative in cases of interstitial fibrosis with a compelling exposure history that lack the requisite concentration of asbestos bodies on histologic sections, particularly if pleural plaques are present. Occasional individuals are poor asbestos body formers whose lung asbestos fiber concentration is in the asbestosis range despite not meeting the minimum concentration of asbestos bodies on histologic sections.

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 cigarette smoking. UIP, which is the pattern of pulmonary fibrosis seen in idiopathic pulmonary fibrosis (IPF), is characterized by honeycomb changes, fibroblast foci, and the absence of asbestos bodies in histologic sections. Although asbestosis has a basilar subpleural distribution that is similar to UIP, honeycomb changes are rare and fibroblast foci are uncommon in asbestosis. Pleural fibrosis is far commoner in individuals with asbestosis than in those with UIP. The greater temporal uniformity of asbestosis as compared with UIP is reminiscent of NSIP. However, the fibrosis in NSIP exhibits a greater degree of spatial uniformity, lacks subpleural accentuation, and in cellular examples, shows more interstitial inflammation than asbestosis. Early asbestosis (grades 1-2) must be distinguished from both mixed dust pneumoconiosis (MDP) and respiratory bronchiolitis (RB), a form of small airway disease seen in cigarette smokers that is characterized by peribronchiolar fibrosis and pigmented smoker’s macrophages. Asbestos bodies are absent in RB. The peribronchiolar fibrosis in grades 1–2 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 non-asbestos ferruginous bodies (pseudoasbestos bodies) that instead have broad yellow or black central cores ( Figs. 10.28 and 10.53 ) (also see Silicatosis section).

It is controversial whether the presence of fibrosis accompanied by one or more asbestos bodies on transbronchial biopsy is sufficient to diagnose asbestosis in individuals who have evidence of diffuse pulmonary fibrosis on radiography. ^, On the contrary, the absence of asbestos bodies on transbronchial biopsy does not exclude the possibility that asbestosis is the cause of pulmonary fibrosis.