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The pathology of some familiar pneumoconioses
The Pathology
of Some Familiar By JEROME KLEINERMAN,
Pneumoconioses M.D.
W
HILE NEW pneumoconioses are being observed with advances of industry and technology, the detailed observations on at least one pneumoconiotic disease, silicosis, dates back to the mid-nineteenth century. As regards the other diseases to be discussed in this review, asbestosis, coalworkers’ pneumoconiosis and berylliosis, our recognition and understanding have occurred only within the last 50 years. The pathologic picture of all of these entities are fully described and understood; however, it is well to keep in mind that the classical pathological lesions seen at autopsy usually represent an exaggerated and therefore simplified aspect of the disease state. The clinician and radiologist more frequently observe the patient in an earlier stage. The period of latency may extend over fifteen or twenty years, dependent to a great extent on the ambient concentration and size of the offending particulate materials. This long latent period is also related to efficient lung cleansing of inhaled dust by the mucociliary escalator and pulmonary macrophages as well as to the fact that the lesion must be at least around 3 mm. in size before it is distinctly visible on the roentgenogram. *4,33Considerably smaller lesions can, of course, be seen pathologically. sILIcosIs
The mature lesion of simple silicosis is the hyalinized nodule. These vary in diameter from 3 to 12 mm. and are roughly spherical. They are usually distributed diffusely throughout the lung and are present in all lobes and subpleurally (Fig. 1A). The hilar lymph nodes are usually enlarged, firm and nodular.6 Both the lymph nodes and parenchymal nodules may be heavily pigmented, depending upon the material admixed with the crystalline silica (Fig. 1C). Microscopically, the nodular lesion is composed of laminated masses of acellular hyaline tissue arranged to form a nodule (Fig. 1D). The nodules are frequently present in the perivenous or peribronchiolar locale, although they may appear anywhere in the parenchyma. Not infrequently, when the process is still active, the periphery of the lesion shows serpiginous borders composed of pigmented and cellular connective tissue extending into the surrounding parenchyma. A few chronic inflammatory cells may be present, and these are frequently plasmacytes or lymphocytes (Fig. 1D). When viewed by polarizing light, doubly refractive particles of crystalline silica can be seen within the nodule and at its periphery. As the process progresses, the nodules tend to enlarge and coalesce, forming larger dense hyalinized masses (Figs. 1E and 2B). In this way, large areas of JEROME KLEINERMAN, M.D.: Department of Pathology Research and Clinical St. Luke’s Hospital and Western Reserve Uniuersity, Department of Pathology, Ohio.
Pathology, Cleueland,
244 SEMINARS IN ROENTGENOLOGY, Vo~.2,No.3
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lung tissue may be replaced and obliterated. This usually occurs chiefly in the upper lobes (Fig. 1B) and is unimaginatively distinguished as the COW glomerate phase.8 Not infrequently the phase of massive conglomeration is associated with or complicated by a tuberculous infection. la,11 It has been variously estimated that from 40 to 60 per cent of cases of conglomerate silicosis show some pathological evidence of a previous or continuing infection with tubercle bacilli. When this occurs, caseation necrosis and cavitation may ensue in the conglomerate lesion as in any tuberculous process. Diffuse miliary or disseminated systemic tuberculosis are also potential complications. On the other hand, cavitation may occur in the massive conglomerate lesion from ischemic, nontuberculous causes (Fig. 2A).41 Thus, the exact etiologic nature of a large cavitation on the roentgenogram may be difficult to define. Clinical observation and study of the sputum for tubercle bacilli may distinguish the cause. Histologic study of the tissue lining the cavity will readily differentiate the ischemic lesion from the tuberculous one. The pigmentation of the nodular silicotic lesions will depend on the associated mineral substances which may be present in the ore along with the free crystalline silica (Fig. 1C). There is evidence that certain minerals, such as iron and aluminum, may have a retarding influence on the temporal course of the nodular fibrosis associated with silicosis. While much has been written concerning the development of carcinoma in scars, there appears to be no increased incidence of pulmonary carcinoma in silicotic patients. The only other complication worthy of note is obstructive airway disease or emphysema Breathlessness and the characteristic physiologic alterations of obstructive disease generally appear only in the advanced stages of conglomerate disease. The lung is frequently involved with emphysema of the panlobular type in areas adjacent to massive silicotic fibrosis. Cor pulmonale and clinical heart failure may ensue. Experimental silicosis provides some understanding of the pathogenesis of this disease ( Figs. 2C, D and E ) . The inhaled quartz dust particles are ingested by alveolar phagocytes which either ascend the mucociliary escalator and are swallowed, or migrate to efferent lymphatic channels in the interstitial tissue. From there they move to the lymph nodes proper, where they are arrested and form a granuloma-like lesion which, in its earliest phase, does not undergo necrosis7 The silica-containing macrophages become arrested or degenerate and stimulate the formation of reticulum and collagen. Gross et a1.14 have recently challenged this thesis and have suggested that silica particles can penetrate the pulmonary interstitium without the aid of phagocytic cells. Regardless of the method, however, silica crystals are transported to regional lymph nodes, where silica granulomas and fibrosis occur. The experimental production of the complicated or conglomerate stage requires still another factor, the presence of tubercle bacilli, alive or dead, virulent or avirulent.27~2x In the human it is possible that other factors, such as bronchial occlusion with resultant atelectasis or vascular occlusion with local scar formation, may also play a part in the development of the massive fibrosis. Theories regarding the mechanism of action of silicosis have undergone a
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Fig. 2.-Silicosis. (A) Section of lung ( x 2/5), showing ischemic cavitation in a zone of conglomerate silicosis in the upper lobe. (B) High power photomicrograph (x 120) of conglomerate silicosis. Note the dark wavy elastic fibers outlining the blood vessels, which are completely obliterated. ( Weigert’s elastic stain). (C) Low power (x 12 ) photomicrograph of early experimental silicosis in a rat. Note the cellular granulomas in perivascular and bronchiolar regions. (D) High power (x 120) view of noncaseating cellular granuloma in early experimental silicosis. (E) High power (x 140) view of later stage of experimental silicosis, showing hyaline fibrosis.
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profound change in recent years. Chemical theories16,28 have immunological theories,3”,3g which more readily explain many and experimental findings in silicosis, such as the long latent development of the hyaline collagenous lesions and the definite the lesions following removal of the offending quartz dust.
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given way to of the clinical period in the progression of
ASBESTOSIS
While the mineral, abestos, has been known and used as a woven cloth as far back as the Greek and Roman civilizations, its study as a fibrogenic dust dates back only to the turn of the twentieth century. It became a compensible disease by law in Great Britain in 1931. The characteristic pathological features of a well-developed case of pulmonary asbestosis are a diffuse non-nodular fibrosis involving particularly the lateral and basal portions of both lungs and a dense fibrous pleural thickening, often in the form of plaques (Fig. 3A) which may calcify.‘g The alveolar septa arc thickened by deposition of collagen and reticulin fibers and the overlying alveolar epithelium is hypertrophic and cuboidal ( Fig. 3B and C ) . Frequently, asbestos bodies can be seen within the thickened septa as brown or orange, baton-like structures 20-50 micra in length and 3-10 micra in width which characteristically stain positive for iron by the Perls’ stain (Figs. 3C and D). They are more or less symmetrically haustrated. The extent of the fibrosis varies from a severe degree, in which the alveolar spaces are hardly visible, to a more mild form in which the airspace pattern is coarsened by the diffusely thickened walls. The fibrosis extends irregularly into the lung and is characterized by the predominance in the lower lobes, the diffuse pattern, the presence of asbestos bodies, and the history of prolonged exposure to asbestos dust. The major and medium-sized bronchi appear relatively normal. The tracheobronchial lymph nodes are usually only slightly involved. They frequently contain asbestos bodies, most of which are engulfed in giant cells or macrophages, but, however, fibrosis is minimal. An interesting gross finding in some cases of asbestosis is the so-called honeycomb lung. Asbestosis is one of the many causes of this lesion. Honeycomb lung is characterized by enlarged airspaces resembling small cysts, usually about 1 cm. in diameter, with fibrous walls. The normal alveolar and capillary structures are destroyed. The cyst-like structures may involve an entire lung, a lobe, or any portion of a lobe. Microscopically, these cysts are lined by hyperplastic bronchiolar epithelium and their walls contain hypertrophic smooth muscle bundles and fibrous connective tissue. Chronic inflammatory cells and asbestos bodies are found in the thickened septal walls. While tuberculosis does not appear to be a frequent complication of asbestosis,g.4Z an increased incidence at necropsy has been reported in South Africa.4”,“0 Bronchiectasis has also been reported as a complication by early workers and more recently by Leathart from bronchographic studies? For many years sporadic reports of primary lung cancer associated with asbestosis have appeared in the literature,5 with an occasional dissenting voice.2 The recent studies of Selikoff, Churg, and Hammond35 provide strong evidence
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that there is a significant increased incidence of bronchogenic carcinoma in asbestosis. In a study of 632 insulation workers exposed to asbestos for 20 years or more, 45 died of cancer of the lung or pleura, which is approximately seven times the predicted figure. They also reported an increase in cancer of the stomach and colon among these workers. Malignancy arising in other organs were not found to be increased. Others have reported similar findings.2”,47,50 in 1960 reported 33 patients with diffuse Wagner, Sleggs and Marchand” pleural mesothelioma in South Africa, in all but one of whom there had been a probable exposure to crocidolite asbestos. The increased incidence of mesotheliomas in asbestos workers has been confirmed by others35,5oand the tumor has been produced experimentally in rodents by the intrapleural inoculation of asbestos fibers.3”,4g Reports of peritoneal mesothelioma as a complication of asbestos exposure are also appearing.23Jo Our understanding of the pathogenesis of asbestosis is undergoing a change. Until about 5 years ago; it was held that the long fibers of asbestos, in the range of 20 microns, were of paramount importance in the development of the disease. However, early experimental studies did not produce a florid lesion similar to that of human asbestosis.g~4’ More recent reports suggest that the small particles may be of greater importance than previously thought. The degree of fibrosis appears related more to the lapse of time after exposure than to the amount of dust to which the animals were exposed.1,22,47 The asbestos body has been considered to be the most characteristic sign of inhalation of asbestos. It must be noted, however, that the mere presence of these bodies is not diagnostic of asbestosis. They indicate only that exposure to asbestos has occurred, and that the host has reacted to the fibers by the formation of asbestos bodies. These structures are believed to be formed by the condensation of protein materials upon the native asbestos fiber; these are then mEltrated by iron-containing ferritin. Native asbestos fibers may also be seen in the tissue. There is considerable question as to the pathogenicity of the asbestos body. Vorwald et a1.42suggest that after the asbestos fiber has been converted to the “body,” it is no longer capable of eliciting tissue reaction. However, the asbestos bodies are sometimes surrounded by giant cells of the foreign body type, indicating that some reaction has occurred. Perhaps they are not capable of stimulating fibrous tissue reaction. Sinoe it has been observed that fibrous minerals other than asbestos can stimulate the production of structures identical to the asbestos body, the less specific term ferruginous body, indicating only iron content, is being advocated. The mechanism of action of asbestos in tissue remains unknown. There are suggestions that a slow process of solubilization of the native fiber occurs.1j.53 The functional abnormalities associated with asbestosis are those of a restrictive or small lung and the so-called “alveolar-capillary block” or diffusion effect.“l Functional evidence of obstructive pulmonary disease (emphysema and/or bronchitis) appears to be uncommon. Ventilation perfusion ratio inequalities are also frequently present. Gross30 recently has questioned the implication of the thickened collagenized alveolar septum as the anatomic basis for the alveolar-capillary block. He demonstrated many areas in which the free
Fig. 3.-Asbesto sis. (A) Low power micrograph of pleura and underlying lung. Note the thickened plet na on the left and bottom and the infiltrated parenchyma with loss of alveolar spaces (x 1.7). (B) Medium power photomicrograph of interstitial fibrosis with thickening of alvet alar walls and epithelialization of alveolar spaces. Some asbestos bodies are present (x 60 ) ( C) High power view of same (x 180).
Fig. 3-(Cont’d). (II) High power photomicrograph of typical asbestos bodies with bulbof experimental asous end and hnustrated shaft (x 1200). (E ) L ow power micrograph bestos exposure showing typical peribronchial fibrosis without extensive interstitial disease (x 12).
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surface of capillaries show no suggestion of mural thickening. While such loci may occur, it would appear that many capillaries are obliterated, contributing greatly to the loss of capillary surface. When the disease has existed in moderate or severe form for many years, right ventricular enlargement and failure may develop. This may ultimately cause the patient’s demise. BERYLLIOSIS
The diseases caused by beryllium inhalation are the most recent to be recognized of the pneumoconioses under discussion. One of the earliest cases reported in this country was that of a 29 year old white female who died in a tuberculosis sanatorium in Massachusetts, diagnosed as military tuberculosis from a roentgenogram. Litigation for compensation ensued and an autopsy was ordered. The medical examiner’s report was Boeck’s sarcoid and the compensation claim was dropped. In the ensuing three years, 17 similar cases were observed in workers from the same plant. Six of these died. Many did not become ill until after leaving the plant.l? The late Dr. Leroy Gardner of Saranac Lake was consulted; by chance he was in the process of reviewing cases of pulmonary insufficiency in brass foundrymen and had noted that the afIected workers had been exposed to 4 per cent beryllium master alloy. It soon become evident that the pathological changes were similar and beryllium was exposed as the noxioas agent. Even prior to these incidents, reports of a more “acute” form of pulmonary disease in beryllium workers were to be found in the German, Italian, and Russian literature. Van Ordstrand et al. in this country reported their experience with the acute form of the disease.3’,38 More recently chronic berylliosis has been observed in persons living in the vicinity of beryllium industries, without direct occupational exposures. The serious acute respiratory tract involvement induced by beryllium is a chemical pneumonitis. It has been noted after inhalation of metallic beryllium, or its salts. Symptoms may appear within 72 hours of a heavy exposure, or the disease may be insidious if the dose is slight. These include nonproductive cough, dyspnea, blood-streaked sputum and weakness. The duration of the disease varies from one to four months and may end in complete recovery or death.“” Roentgenographic changes usually occur within weeks and consist of bilateral and often symmetrical patchy densities. These may become more diffuse and irregular. With clinical recovery, the lungs become clear. While human autopsy material of acute berylliosis is meager, the lungs that have been studied have the characteristic appearance of an acute chemical pneumonia, Grossly they are large, heavy and do not collapse on opening the thorax. The cut surface is usually moist, dark red, firm and granular and the airspaces are frequently obscured by exudate. Microscopically, the alveolar spaces are filled in the affected areas by a variegated exudate. In some, a deeply staining eosinophilic, granular, acellular material is seen while in others an exudate composed of macrophages, red blood cells, lymphocytes and plasmacytes is present. If the course has been
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prolonged intra-alveolar fibroblastic proliferation and organization is present. Central necrosis in the liver and focal myocarditis have been reported.ls Thus, in the acute form of the disease, there is an acute or subacute pneumonitis, sometimes with evidence of organization and fibrosis. The gross picture of the lungs in chronic berylliosis is not striking. The pleural surfaces may show evidence of the diffuse granularity existing in the lung substance, but are rarely directly involved. The trachea and bronchi are usually not involved. The lymph nodes may be slightly to moderately enlarged and firm; they may reveal areas of infiltration which represent the lymphatic involvement by the ganulomatous process. The pulmonary parenchyma is firmer and less resilient than normal owing to the interstitial disease. Histologically, the interstitial substance and alveolar walls may be considered more coarse than normal. In some areas, the alveolar spaces are obliterated, and a trabecular pattern of fibrosis may infiltrate the parenchyma (Fig. 4A). The characteristic microscopic lesion is the noncaseating granuloma.43+” It is composed of discrete collections of epithelioid cells and foreign body giant cells of the Langhans type. These are usually ringed by lymphocytes and plasma cells. The granulomas are present in the interstitial tissue and frequently replace al.veolar walls. The surrounding alveolar septa may be thickened and the alveolar epithelium hypertrophied and cuboidal. Intraalveolar collections of mononuclear cells may be present. These granulomas may be subpleural, peribronchial, perivascular or distributed through the interstitial tissue (Figs. 4B and C). Several types of inclusions may be observed in the giant cells and rarely in the epithelioid cells. These are the asteroid bodies, the conchoidal or Schaumann bodies, and crystals. The Schaumann bodies are shell-like, concentrically laminated, deeply basophilic bodies, and measure up to 50 micra in diameter. They are found with reasonable regularity in berylliosis.52 The crystals may be of two types: cholesterol, seen as empty slits in the tissue after paraffin embedding, and brilliant, plate-like, birefringent, irregularly-shaped structures, 3 to 10 micra in diameter which always have a sharp edge. The latter are frequently found in association with Schaumann bodies. None of these inclusions are diagnostically specific and they are frequently found in other granulomatous diseases, such as tuberculosis, histoplasmosis, sarcoidosis, etc. In older lesions or where steroid therapy has been used, the cellular structure may be replaced by fibrous tissue. In addition, there is usually some degree of diffuse interstitial fibrosis. Emphysema is not a frequent complication. While primary carcinoma of the lung has been reported as a late complication of berylliosis, there has not been sufficient experience to consider neoplasia as a common complication. Perhaps this is due in part to the fact that patients with chronic berylliosis have not survived for a sufficiently long period. It is obvious that pathologically and clinically berylliosis mimics Boeck’s sarcoid to the point that differentiation is frequently impossible. Hardy,‘” after study of many cases in the Beryllium Disease Registry, has suggested the following points of differentiation: berylliosis has little, if any hilar adenopathy, no ocular involvement, no uveoparotid fever, no cystic bone changes, a low
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Fig. 4-Berylliosis. (A) Low power photomicrograph of chronic pulmonary berylliosis showing interstitial infiltration and fibrosis (x 1.25). (B) Medium power view showing the typical interstitial noncaseating granuloma with giant cells (x 80). (C) High power photomicrograph of a granulomatous lesion (x 120).
rate of complicating tuberculosis, no change in the tuberculin skin test with the onset of disease, a slower response to steroid therapy, and a less favorable prognosis.
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The finding of beryllium in the urine and in lung tissue by chemical or spectrographic analysis at one time was suggested as a means of differentiating the granuloma of beryllium from other similar lesions. However, beryllium is present in small concentrations in soil and water and in the vicinity o,f beryllium industries, and many healthy persons with no occupational exposure have evidence of beryllium in their tissues or body fluids. In addition, beryllium may be excreated in the urine for periods up to ten years after industrial exposure, by workers who give every evidence of good health. Chemical analysis of necropsy tissues from beryllium workers who died of unrelated causes and with no histologic evidence of berylliosis, demonstrated as much beryllium in the normal pulmonary tissues as has been observed in the pulmonary tissues of persons with confined berylliosis. Much experimental work has been performed in an attempt to produce the histological pictures of berylliosis, but a satisfactory model has not been found. Administration of several forms of beryllium on the lung of a variety of animal species has produced lesions which superficially resemble those of chronic berylliosis, but they are few in number, limited in extent, and show no progression following cessation of the exposure.43+ However, malignant neoplastic changes have been found with reasonable consistency after prolonged experimental exposures. COAL
WORKERS’
PNEUMOCONISIS
‘Coal workers pneumoconiosis is the name which has evolved to describe the pulmonary manisfestations in workers specifically exposed to dust from coal mines, and formerly categorized under the less specific terms anthracosis or anthracosilicosis. Observations concerning the black lungs of coal miners date back 130 years in Scotland. At the turn of the century, however, the disease of coal workers was thought to have disappeared because of improved working conditions in the mines. The application of chest roentgenography revealed evidence of pulmonary abnormalities in South Wales coal miners in the early 1930’s and the great number of men applying for compensation stimulated an extensive survey. It was observed that the radiological changes were not typically those of silicosis. Gough12J3 and Heppleston 21 described the characteristic pathology of the pulmonary lesion in the simple and complicated forms and today it is widely accepted that coal dust alone is capable of causing a distinctive lesion. Coal miners may have widely varying jobs in the mine and may receive vastly different, exposures. Those who work on the coal face, drilling rock, cutting strata or sanding tracks may develop lesions typical of silicosis. Other coal miners working on the coal seams, cutting or loading the coal, present a lesion distinctly different from silicosis and one typical for coal dust. The gross appearance of the lung in simple coal workers’ pneumoconisis varies with the duration of exposure. In general, the lung is fairly normal in external appearance and is unusual only because of the deep black pigmentation on the pleural surface. The trachea and bronchi are usually normal. The lymph nodes are
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enlarged, firm but not fibrotic, and homogeneously pigmented. The cut surface of the lung reveals numerous pigmented foci 5 mm. or more in diameter. These black dust foci are located in the vicinity of the terminal and respiratory bronchioles. No nodular lesion is present unless there are manifestations of both diseases, silicosis and coalworkers’ pneumoconiosis. This is a frequent occurrence since every coal bed contains varying amounts of free crystalline silica. The pigmented lesions are called coal macules (Fig. 5A and B ). They are characteristic regardless of the type of coal mine or character of the bed rock. Microscopically, the dust appears to be contained within cells, probably macrophages, which are enmeshed in a collection of reticulin fibers (Fig. 5C ) . Collagen deposition is usually not. present, This dust mantle surrounds the respiratory bronchiole and extends into the surrounding alveolar structures (Fig. SD). Frequently the air spaces immediately surrounding the collections of dust are enlarged (Fig, 5C). This is called focal emphysema and should not be confused with other incapacitating forms of emphysema. Hepplestonzl considers the focal emphysema to be caused by a shrinkage of reticulin tissue in the coal focus and dilatation of the surrounded air space or bronchiole. Our observations suggest that there is some destruction of the alveolar walls and capillaries in the zone affected by the dust and reticulin deposition; however, the extent of the tissue loss is very limited and local. Persons affected with the simple form of coal workers’ pneumoconiosis show minimal or no physiological abnormalities unless there is associated disease. The radiologic picture in the simple form was previously described as a reticulation; now, however, it is recognized as minute opacities which may be as small as 1 mm. in diameter. They may increase in number and size and density until both lungs are more or less uniformly involved by opacities 3 to 4 mm. in diameter; these correspond to the coal macules seen pathologically. The complicated form of coal workers’ pneumoconiosis is characterized by the presence of relatively large confluent zones of dense fibrosis, usually presenting in one or both upper lobes (Fig. 5B). These masses may be small in the earlier lesion, measuring 1 to 2 cm. in diameter, but can replace an entire upper lobe and extend across lobar divisions into the adjacent lobe as well. The masses are darkly pigmented, firm and rubbery. Microscopically, they are dense, acellular fibrous tissue which contains much pigment. The lung parenchyma has been completely replaced and the vessels in the region frequently show an obliterative endarteritis. A few chronic inflammatory cells, including plasmacytes, lymphocytes and macrophages, may be present. In approximately 40 per cent of cases of progressive massive fibrosis encountered at autopsy, tubercle bacilli can be demonstrated by culture or animal inoculation.Z5 Gough’l believes that this progressive massive fibrosis is the result of a combination of infection superimposed on simple coal wo8rkers’ pneumoconiosis. Caseous necrosis is not seen unless floridly active tuberculosis occurs; but ischemic cavitation of the type described in conglomerate silicosis may occur, and mimic tuberculosis. In the progressive massive fibrosis of coal
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workers, right heart enlargement and ultimately failure commonly causes death. Pulmonary embolism or thrombosis is another common terminal complication. Primary pulmonary cancer has not been observed in increased incidence. Extensive and severe fibrosis can be produced in experimental animals by intratracheal inoculation of coal dust with or without small concentrations of free crystalline silica, coupled with living or dead tubercle bacilh5’ These observations fortify the contention that a tuberculous infection is necessary for the occurrence of progressive massive fibrosis of coal workers. Other investigators feel that progressive massive fibrosis may be the result of factors other than tuberculosis, such as vascular obstruction, bronchial occlusion, previous pulmonary disease with residual scar, and perhaps even a rheumatoid diathesis.” It may be justifiable to end this discussion with a word concerning the socalled benign pneumoconioses. On occasion, inhalation of dense metallic materials, such as iron, tin, barium or bismuth, may result in the widespread deposition of these materials in the lung. These substances are not fibrogeni@ and are imbibed by macrophages and remain focalized in some of the alveolar spaces adjacent to respiratory bronchioles. The alveolar epithelium in these zones is frequently hypertrophic but reticulin or collagen deposition is absent (Fig. 6). These zones will appear radiopaque in a chest roentgenogram and may be confused with silicosis or other nodule-producing disease. It is obvious that the density seen is produced by the collection of heavy metal in macrophages and not to fibrogenic tissue reaction. These lesions are not progressive or symptomatic, and contribute one more red herring to the radiologist’s barrel. SUMMARY
AND
CONCLUSIONS
This brief and incomplete review of the pathology of some of the pneumoconioses does not lend itself well to summary. However, the following may bear repetition: Silicosis in its simple form is a nodule-producing disease which may progress to the conglomerate or massive fibrosis state. Asbestosis and chronic berylliosis are interstitial diseases. Prolonged exposure to asbestos is probably associated with an increased incidence of primary lung cancer. This complication is rarely seen in chronic berylliosis although experimental work points to it as a possibility. Simple coal workers’ pneumoconiosis is characterized by small opacities not large enough to be considered nodules, which are related to the formation of the coal macule and focal emphysema. Progressive massive fibrosis may occur after prolonged exposure to coal dust and is frequently associated with some evidence of a tuberculous infection. The benign pneumoconioses may mimic nodular disease but are nonfibrogenic and not progressive. While these pneumoconioses are among the best studied, much still remains to be learned concerning pathogenesis and tissue reactions. The future of pneumoconiosis study promises even more exciting new experiences as our industrial research and technology respond to the needs and challenges of the era of the space adventure.
260 Fig. 5-Coalworkers’ pneumoconiosis. (A) Large paper section of simple coalworkers’ pneumoconiosis (x 2/5) showing the small coal macules and surrounding zones of focal emphysema. (B ) Large paper section of relatively early lesion of massive fibrosis in the upper lobe of a coal worker (x 2/5). (C) Low power photomicrograph (x 12) of a typical coal macule with surrounding zone of focal emphysema. (D) Medium power photomicrograph (x 80) of a coal macule cut in the plane of the long axis of the respiratory bronchiole to show the peribronchiolar location of the deposit.
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Fig. 5-Cont’d
REFERENCES 1. Beattie, J., and Knox, J. F.: Studies of mineral content and particle size distribution in the lungs of asbestos workers. In Davies, C. N. (Ed. ) : International symposium on inhaled particles and vapours. London, Pergamon Press, 1961, pp. 419-433. 2. Braun, D. C., and Truan, T. D.: An epidemiological study of lung cancer in asbestos miners. A.M.A. Arch. Indust. Health 17:634-653, 1938. 3. Caplan, A.: Certain unusual radiological appearances in the chest of coal miners
suffering from rheumatoid arthritis. Thorax 8:29-37, 1953. 4. DiNardi, J. M., Van Ordstrand, H. S., Curtis, G. H., and Zielinski, J.: Ber) dliosis: summary and survey of all clinical 1 types observed in 12-year period. A.M.A. Indust. Hyg. 8: l-24, 19.53. 3. Doll, R.: Mortality from lung cancer in asbestos workers. Brit. J. Indust . Med. 12:81-86, 1953. 6. Gardner, L. I.J.: Pneumoconiosir i. Med. Clin. N. Amer. 26:1239-1260, 1942.
Fig. 6-(A) Low power view of lung (x 1.5) f rom an experimental animal with siderosis, a benign pneumoconiosis. (B) High power photomicrogrnph of lung (x 125) showing the intra-alveolar collection of iron-containing macrophages, without evidence of fibrosis or other tissue reaction. 7. Gardner, L. U.: Studies on experimental pneumoconiosis. VIII. Inhalation of quartz dust. J. Indust. Hyg. 14:18-38, 1932. 8. Gardner, L. U.: Pathology and roentgenologic manifestations of pneumoconiosis. J.A.M.A. 114:535-545, 1940. 9. Gardner, L. U., and Cummings, D. E.: Studies on experimental pneumoconioses. VI. Inhalation of asbestos dust: its effect upon primary tuberculous infection. J. In-
dust. Hyg. 13:65-81, 1931. 10. Gough, J.: Pathology of pneumoconiosis. Postgrad. Med. J. 25:611-617, 1949. 11. Gough, J.: Patterns in pneumoconiosis. Proceedings of the 4th Conference of McIntyre Research Foundation on Silicosis, 1952, pp. l-15. 12. Gough, J.: Pneumoconiosis in coal trimmers. J. Path. Bact. 51:277-285, 1940. 13. Gough, J.: Pnemnoconiosis in coal
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workers in Wales. Occup. Med. 4:86-97, 1947. 14. Gross, P., Westrick, M. L., and McNerney, J. M.: Experimental silicosis. The morphogenesis of the silicotic nodule. A.M.A. Arch. Indust. Health 18:374-388, 1958. 15. Gross, P., and Smith, K.: The topographic distribution of mineral dusts in some pneumoconiotic lungs. Dis. Chest 35: 140154, 1959. 16. Gye, W. E., and Kettle, E. H.: Silicosis and miners’ phthisis. Brit. J. Exper. Path. 3:241-251, 1922 17. Hardy, H. L., and Tabershaw, I. R.: Delayed chemical pneumonitis occurring in workers exposed to beryllium compounds. J. Indust. Hyg. & Toxicol. 28:197-211, 1946. 18. Hardy, H. L.: Differential diagnosis between beryllium poisoning and sarcoidosis. Amer. Rev. Tuberc. 7~885-896, 1956. 19. Hazard, J. B.: Pathologic changes of beryllium disease. A.M.A. Arch. Indust. Health 19: 179-183, 1959. 20. Heard, B. E., and Williams, R.: Pathology of asbestosis with reference to lung function. Thorax 10:264-281, 1961. 21. Heppleston, A. G.: The pathogenesis of simple pneumoconiosis in coal workers. J. Path. Bact. 67:51-63, 1954. 22. Holt, P. F., Mills, J., and Young, D. K.: The early effects of chrysotile asbestos dust on the rat lung. J. Path. Bact. 87:15-23, 1964. 2.3. Hourihane, D. L.: The pathology of mesotheliomata and an analysis of their association with asbestos exposure. Thorax 19:268-278, 1964. 24. James, D. G., and Carstairs, L. S.: ?;Iilitary diseases of the lungs. Disease-aMonth, pp l-8, July, 1962. 25. James, W. R. L.: The relationship of tuberculosis to the development of massive ?neumoconiosis in coal workers. Brit. J. Tuberc. 48:89-96, 1954. 26. Keal, E. E.: Asbestosis and abdominal neoplasms. Lancet 2: 1211-1216, 1960. 27. King, E. J.: Recent research in infective pneumoconiosis. Internat. Cong. Occup. Health 1:283-302, 1957. 28. King, E. J.: Experimental infective pneumoconiosis. In Proceedings of the Pneumoconiosis Conference, Johannesburg, 1959. 29. Kiviluoto, R.: Pleural calcification as roentgenologic sign of non-occupational en-
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demic anthrophyllite asbestosis. Acta Radiol. ( Stockhl. ) Suppl. 194: l-67, 1960. 30. Lanza, A. (Ed.) : The Pneumoconioses. New York, Gnme & Stratton, 1963 (chapter by P. Gross, pp. 34-54). 31. Lanza, A. (Ed) : The Pneumoconioses. New York, Grune & Stratton, 1963 (chapter by H. S. Van Ordstrand, pp. 73-102). 32. Leathart, G. L.: Clinical, bronchographic, radiological and physiological observations in 10 cases of asbestosis. Brit. J. Indust. Med. 17:213-227, 1960. 33. Newell, R. R., and Barneau, R.: Threshold visibility of pulmonary shadows. Radiology 56:409-415, 1951. 34. Schcel, L. D., Smith, B., Van Riper, J., and Fleisher, E.: Toxicity of silica: Characteristics of protein films absorbed by quartz. A.M.A. Arch. Indust. Hyg. 9:29-36, 1954. 35. Selikoff, I. J., Churg, J., and Hammond, E. C.: Asbestos exposure and neoplasia. J.A.M.A. 188:142-146, 1964. 36. Smith, W. E., Miller, L., Churg. J., and Selikoff, I. J.: Mesotheliomas in hamsters following intrapleural injection of asbestos. J. Mt. Sinai Hosp. 32:1-8, 1965. 37. Van Ordstrand, H. S., Hughes, R., and Carmody, >I. G.: Chemical pneumonia in workers extracting beryllium oxide. Cleve. Clin. Quart. 10: 10-18, 1943. 38. Van Ordstrand, H. S., Hughes, R., DiNardi, J. M., and Carmody, M. G.: Beryllium poisoning. J.A.M.A. 129: 1084-1090, 1945. 39. Vigliani, E. C., and Per&, B.: Immunological factors in the pathogenesis of the hyaline tissue of silicosis. Brit. J. Indust. Med. 15:8-14, 1958. 40. Vorwald, A. J. and Carr, W.: Pneumoconiosis and pulmonary carcinoma. Amer. J. Path. 14:49-58, 1938. 41. Vorwald, A. J.: Cavities in sihcotic lungs. Amer. J. Path. 17:709-718, 1941. 42. Vorwald, A., Durkan, T. M., and studies of asPratt, P. C.: Experimental bestosis. A.M.A. Arch. Indust. Hyg. 3:1-43, 1951. 43. Vorwald, A. J. (Ed. ) : Pneumoconiosis. New York, Hoeber hledical Division, Harper & Row, 1950 (chapters by A. J. Vorwald, pp. 190-207 and 393-425). 44. Vorwald, A. J., and Reeves, A. L.: Pathological changes induced by beryllium compounds. Experimental studies. A.M.A. Arch. Indust. Health 19: 190-199, 1954.
264 45. Vorwald, A. J., Pratt, P. C., Durkan, T. M., Delahant, A. B., and Bailey, D. A.: Siderosis. An experimental study. Indust. Med. Surg. 19:22-32, 1950. 46. Wagner, J. C.: The pathology of asbestosis in South Africa, pp. 66-67. Thesis, University of the Witwaterstrand. 1962. 47. Wagner, J. C.: The sequelae of exposure to asbestos dust. Ann. N. Y. Acad. Sci. 132-691-695, 1965. 48. Wagner, J. C., Sleggs, C. A., and Marchand, P. : Diffuse pleural mesothelioma and asbestos exposure in the North West Cape Province. Brit. J. Indust. Med. 17:260271, 1960. 49. Wagner, J. C.: Experimental production of mesothelial tumors of the pleura by implantation of dusts in laboratory animals. Nature 196:180-181, 1962.
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56.. Webster, I.: Asbestosis. S. Afr. Med. J. 30:870-872, 1964. 51. Williams, R., and Hugh-Jones, P.: Significance of lung function changes in asbestosis. Thorax 15: 109-119, 1960. 52. Williams, W. J.: A histological study of the lungs in 52 cases of chronic beryllium Med. 15:84-91, disease. Brit. J. Indust. 1958. 53. Wyers, H.: Asbestosis. Postgrad. Med. J. 25:631-638, 1949. 54. Zaidi, S. H., Harrison, C. V., King, E. T., and Mitchison, D. A.: Experimental infective pneumoconiosis. IV. Massive pulmonary fibrosis produced by coal mine dust and isoniazid resistant tubercle bacilli of low virulence. Brit. J. Exper. Path. 36:553559, 1955.
of Some Familiar By JEROME KLEINERMAN,
Pneumoconioses M.D.
W
HILE NEW pneumoconioses are being observed with advances of industry and technology, the detailed observations on at least one pneumoconiotic disease, silicosis, dates back to the mid-nineteenth century. As regards the other diseases to be discussed in this review, asbestosis, coalworkers’ pneumoconiosis and berylliosis, our recognition and understanding have occurred only within the last 50 years. The pathologic picture of all of these entities are fully described and understood; however, it is well to keep in mind that the classical pathological lesions seen at autopsy usually represent an exaggerated and therefore simplified aspect of the disease state. The clinician and radiologist more frequently observe the patient in an earlier stage. The period of latency may extend over fifteen or twenty years, dependent to a great extent on the ambient concentration and size of the offending particulate materials. This long latent period is also related to efficient lung cleansing of inhaled dust by the mucociliary escalator and pulmonary macrophages as well as to the fact that the lesion must be at least around 3 mm. in size before it is distinctly visible on the roentgenogram. *4,33Considerably smaller lesions can, of course, be seen pathologically. sILIcosIs
The mature lesion of simple silicosis is the hyalinized nodule. These vary in diameter from 3 to 12 mm. and are roughly spherical. They are usually distributed diffusely throughout the lung and are present in all lobes and subpleurally (Fig. 1A). The hilar lymph nodes are usually enlarged, firm and nodular.6 Both the lymph nodes and parenchymal nodules may be heavily pigmented, depending upon the material admixed with the crystalline silica (Fig. 1C). Microscopically, the nodular lesion is composed of laminated masses of acellular hyaline tissue arranged to form a nodule (Fig. 1D). The nodules are frequently present in the perivenous or peribronchiolar locale, although they may appear anywhere in the parenchyma. Not infrequently, when the process is still active, the periphery of the lesion shows serpiginous borders composed of pigmented and cellular connective tissue extending into the surrounding parenchyma. A few chronic inflammatory cells may be present, and these are frequently plasmacytes or lymphocytes (Fig. 1D). When viewed by polarizing light, doubly refractive particles of crystalline silica can be seen within the nodule and at its periphery. As the process progresses, the nodules tend to enlarge and coalesce, forming larger dense hyalinized masses (Figs. 1E and 2B). In this way, large areas of JEROME KLEINERMAN, M.D.: Department of Pathology Research and Clinical St. Luke’s Hospital and Western Reserve Uniuersity, Department of Pathology, Ohio.
Pathology, Cleueland,
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lung tissue may be replaced and obliterated. This usually occurs chiefly in the upper lobes (Fig. 1B) and is unimaginatively distinguished as the COW glomerate phase.8 Not infrequently the phase of massive conglomeration is associated with or complicated by a tuberculous infection. la,11 It has been variously estimated that from 40 to 60 per cent of cases of conglomerate silicosis show some pathological evidence of a previous or continuing infection with tubercle bacilli. When this occurs, caseation necrosis and cavitation may ensue in the conglomerate lesion as in any tuberculous process. Diffuse miliary or disseminated systemic tuberculosis are also potential complications. On the other hand, cavitation may occur in the massive conglomerate lesion from ischemic, nontuberculous causes (Fig. 2A).41 Thus, the exact etiologic nature of a large cavitation on the roentgenogram may be difficult to define. Clinical observation and study of the sputum for tubercle bacilli may distinguish the cause. Histologic study of the tissue lining the cavity will readily differentiate the ischemic lesion from the tuberculous one. The pigmentation of the nodular silicotic lesions will depend on the associated mineral substances which may be present in the ore along with the free crystalline silica (Fig. 1C). There is evidence that certain minerals, such as iron and aluminum, may have a retarding influence on the temporal course of the nodular fibrosis associated with silicosis. While much has been written concerning the development of carcinoma in scars, there appears to be no increased incidence of pulmonary carcinoma in silicotic patients. The only other complication worthy of note is obstructive airway disease or emphysema Breathlessness and the characteristic physiologic alterations of obstructive disease generally appear only in the advanced stages of conglomerate disease. The lung is frequently involved with emphysema of the panlobular type in areas adjacent to massive silicotic fibrosis. Cor pulmonale and clinical heart failure may ensue. Experimental silicosis provides some understanding of the pathogenesis of this disease ( Figs. 2C, D and E ) . The inhaled quartz dust particles are ingested by alveolar phagocytes which either ascend the mucociliary escalator and are swallowed, or migrate to efferent lymphatic channels in the interstitial tissue. From there they move to the lymph nodes proper, where they are arrested and form a granuloma-like lesion which, in its earliest phase, does not undergo necrosis7 The silica-containing macrophages become arrested or degenerate and stimulate the formation of reticulum and collagen. Gross et a1.14 have recently challenged this thesis and have suggested that silica particles can penetrate the pulmonary interstitium without the aid of phagocytic cells. Regardless of the method, however, silica crystals are transported to regional lymph nodes, where silica granulomas and fibrosis occur. The experimental production of the complicated or conglomerate stage requires still another factor, the presence of tubercle bacilli, alive or dead, virulent or avirulent.27~2x In the human it is possible that other factors, such as bronchial occlusion with resultant atelectasis or vascular occlusion with local scar formation, may also play a part in the development of the massive fibrosis. Theories regarding the mechanism of action of silicosis have undergone a
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Fig. 2.-Silicosis. (A) Section of lung ( x 2/5), showing ischemic cavitation in a zone of conglomerate silicosis in the upper lobe. (B) High power photomicrograph (x 120) of conglomerate silicosis. Note the dark wavy elastic fibers outlining the blood vessels, which are completely obliterated. ( Weigert’s elastic stain). (C) Low power (x 12 ) photomicrograph of early experimental silicosis in a rat. Note the cellular granulomas in perivascular and bronchiolar regions. (D) High power (x 120) view of noncaseating cellular granuloma in early experimental silicosis. (E) High power (x 140) view of later stage of experimental silicosis, showing hyaline fibrosis.
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profound change in recent years. Chemical theories16,28 have immunological theories,3”,3g which more readily explain many and experimental findings in silicosis, such as the long latent development of the hyaline collagenous lesions and the definite the lesions following removal of the offending quartz dust.
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given way to of the clinical period in the progression of
ASBESTOSIS
While the mineral, abestos, has been known and used as a woven cloth as far back as the Greek and Roman civilizations, its study as a fibrogenic dust dates back only to the turn of the twentieth century. It became a compensible disease by law in Great Britain in 1931. The characteristic pathological features of a well-developed case of pulmonary asbestosis are a diffuse non-nodular fibrosis involving particularly the lateral and basal portions of both lungs and a dense fibrous pleural thickening, often in the form of plaques (Fig. 3A) which may calcify.‘g The alveolar septa arc thickened by deposition of collagen and reticulin fibers and the overlying alveolar epithelium is hypertrophic and cuboidal ( Fig. 3B and C ) . Frequently, asbestos bodies can be seen within the thickened septa as brown or orange, baton-like structures 20-50 micra in length and 3-10 micra in width which characteristically stain positive for iron by the Perls’ stain (Figs. 3C and D). They are more or less symmetrically haustrated. The extent of the fibrosis varies from a severe degree, in which the alveolar spaces are hardly visible, to a more mild form in which the airspace pattern is coarsened by the diffusely thickened walls. The fibrosis extends irregularly into the lung and is characterized by the predominance in the lower lobes, the diffuse pattern, the presence of asbestos bodies, and the history of prolonged exposure to asbestos dust. The major and medium-sized bronchi appear relatively normal. The tracheobronchial lymph nodes are usually only slightly involved. They frequently contain asbestos bodies, most of which are engulfed in giant cells or macrophages, but, however, fibrosis is minimal. An interesting gross finding in some cases of asbestosis is the so-called honeycomb lung. Asbestosis is one of the many causes of this lesion. Honeycomb lung is characterized by enlarged airspaces resembling small cysts, usually about 1 cm. in diameter, with fibrous walls. The normal alveolar and capillary structures are destroyed. The cyst-like structures may involve an entire lung, a lobe, or any portion of a lobe. Microscopically, these cysts are lined by hyperplastic bronchiolar epithelium and their walls contain hypertrophic smooth muscle bundles and fibrous connective tissue. Chronic inflammatory cells and asbestos bodies are found in the thickened septal walls. While tuberculosis does not appear to be a frequent complication of asbestosis,g.4Z an increased incidence at necropsy has been reported in South Africa.4”,“0 Bronchiectasis has also been reported as a complication by early workers and more recently by Leathart from bronchographic studies? For many years sporadic reports of primary lung cancer associated with asbestosis have appeared in the literature,5 with an occasional dissenting voice.2 The recent studies of Selikoff, Churg, and Hammond35 provide strong evidence
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that there is a significant increased incidence of bronchogenic carcinoma in asbestosis. In a study of 632 insulation workers exposed to asbestos for 20 years or more, 45 died of cancer of the lung or pleura, which is approximately seven times the predicted figure. They also reported an increase in cancer of the stomach and colon among these workers. Malignancy arising in other organs were not found to be increased. Others have reported similar findings.2”,47,50 in 1960 reported 33 patients with diffuse Wagner, Sleggs and Marchand” pleural mesothelioma in South Africa, in all but one of whom there had been a probable exposure to crocidolite asbestos. The increased incidence of mesotheliomas in asbestos workers has been confirmed by others35,5oand the tumor has been produced experimentally in rodents by the intrapleural inoculation of asbestos fibers.3”,4g Reports of peritoneal mesothelioma as a complication of asbestos exposure are also appearing.23Jo Our understanding of the pathogenesis of asbestosis is undergoing a change. Until about 5 years ago; it was held that the long fibers of asbestos, in the range of 20 microns, were of paramount importance in the development of the disease. However, early experimental studies did not produce a florid lesion similar to that of human asbestosis.g~4’ More recent reports suggest that the small particles may be of greater importance than previously thought. The degree of fibrosis appears related more to the lapse of time after exposure than to the amount of dust to which the animals were exposed.1,22,47 The asbestos body has been considered to be the most characteristic sign of inhalation of asbestos. It must be noted, however, that the mere presence of these bodies is not diagnostic of asbestosis. They indicate only that exposure to asbestos has occurred, and that the host has reacted to the fibers by the formation of asbestos bodies. These structures are believed to be formed by the condensation of protein materials upon the native asbestos fiber; these are then mEltrated by iron-containing ferritin. Native asbestos fibers may also be seen in the tissue. There is considerable question as to the pathogenicity of the asbestos body. Vorwald et a1.42suggest that after the asbestos fiber has been converted to the “body,” it is no longer capable of eliciting tissue reaction. However, the asbestos bodies are sometimes surrounded by giant cells of the foreign body type, indicating that some reaction has occurred. Perhaps they are not capable of stimulating fibrous tissue reaction. Sinoe it has been observed that fibrous minerals other than asbestos can stimulate the production of structures identical to the asbestos body, the less specific term ferruginous body, indicating only iron content, is being advocated. The mechanism of action of asbestos in tissue remains unknown. There are suggestions that a slow process of solubilization of the native fiber occurs.1j.53 The functional abnormalities associated with asbestosis are those of a restrictive or small lung and the so-called “alveolar-capillary block” or diffusion effect.“l Functional evidence of obstructive pulmonary disease (emphysema and/or bronchitis) appears to be uncommon. Ventilation perfusion ratio inequalities are also frequently present. Gross30 recently has questioned the implication of the thickened collagenized alveolar septum as the anatomic basis for the alveolar-capillary block. He demonstrated many areas in which the free
Fig. 3.-Asbesto sis. (A) Low power micrograph of pleura and underlying lung. Note the thickened plet na on the left and bottom and the infiltrated parenchyma with loss of alveolar spaces (x 1.7). (B) Medium power photomicrograph of interstitial fibrosis with thickening of alvet alar walls and epithelialization of alveolar spaces. Some asbestos bodies are present (x 60 ) ( C) High power view of same (x 180).
Fig. 3-(Cont’d). (II) High power photomicrograph of typical asbestos bodies with bulbof experimental asous end and hnustrated shaft (x 1200). (E ) L ow power micrograph bestos exposure showing typical peribronchial fibrosis without extensive interstitial disease (x 12).
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surface of capillaries show no suggestion of mural thickening. While such loci may occur, it would appear that many capillaries are obliterated, contributing greatly to the loss of capillary surface. When the disease has existed in moderate or severe form for many years, right ventricular enlargement and failure may develop. This may ultimately cause the patient’s demise. BERYLLIOSIS
The diseases caused by beryllium inhalation are the most recent to be recognized of the pneumoconioses under discussion. One of the earliest cases reported in this country was that of a 29 year old white female who died in a tuberculosis sanatorium in Massachusetts, diagnosed as military tuberculosis from a roentgenogram. Litigation for compensation ensued and an autopsy was ordered. The medical examiner’s report was Boeck’s sarcoid and the compensation claim was dropped. In the ensuing three years, 17 similar cases were observed in workers from the same plant. Six of these died. Many did not become ill until after leaving the plant.l? The late Dr. Leroy Gardner of Saranac Lake was consulted; by chance he was in the process of reviewing cases of pulmonary insufficiency in brass foundrymen and had noted that the afIected workers had been exposed to 4 per cent beryllium master alloy. It soon become evident that the pathological changes were similar and beryllium was exposed as the noxioas agent. Even prior to these incidents, reports of a more “acute” form of pulmonary disease in beryllium workers were to be found in the German, Italian, and Russian literature. Van Ordstrand et al. in this country reported their experience with the acute form of the disease.3’,38 More recently chronic berylliosis has been observed in persons living in the vicinity of beryllium industries, without direct occupational exposures. The serious acute respiratory tract involvement induced by beryllium is a chemical pneumonitis. It has been noted after inhalation of metallic beryllium, or its salts. Symptoms may appear within 72 hours of a heavy exposure, or the disease may be insidious if the dose is slight. These include nonproductive cough, dyspnea, blood-streaked sputum and weakness. The duration of the disease varies from one to four months and may end in complete recovery or death.“” Roentgenographic changes usually occur within weeks and consist of bilateral and often symmetrical patchy densities. These may become more diffuse and irregular. With clinical recovery, the lungs become clear. While human autopsy material of acute berylliosis is meager, the lungs that have been studied have the characteristic appearance of an acute chemical pneumonia, Grossly they are large, heavy and do not collapse on opening the thorax. The cut surface is usually moist, dark red, firm and granular and the airspaces are frequently obscured by exudate. Microscopically, the alveolar spaces are filled in the affected areas by a variegated exudate. In some, a deeply staining eosinophilic, granular, acellular material is seen while in others an exudate composed of macrophages, red blood cells, lymphocytes and plasmacytes is present. If the course has been
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prolonged intra-alveolar fibroblastic proliferation and organization is present. Central necrosis in the liver and focal myocarditis have been reported.ls Thus, in the acute form of the disease, there is an acute or subacute pneumonitis, sometimes with evidence of organization and fibrosis. The gross picture of the lungs in chronic berylliosis is not striking. The pleural surfaces may show evidence of the diffuse granularity existing in the lung substance, but are rarely directly involved. The trachea and bronchi are usually not involved. The lymph nodes may be slightly to moderately enlarged and firm; they may reveal areas of infiltration which represent the lymphatic involvement by the ganulomatous process. The pulmonary parenchyma is firmer and less resilient than normal owing to the interstitial disease. Histologically, the interstitial substance and alveolar walls may be considered more coarse than normal. In some areas, the alveolar spaces are obliterated, and a trabecular pattern of fibrosis may infiltrate the parenchyma (Fig. 4A). The characteristic microscopic lesion is the noncaseating granuloma.43+” It is composed of discrete collections of epithelioid cells and foreign body giant cells of the Langhans type. These are usually ringed by lymphocytes and plasma cells. The granulomas are present in the interstitial tissue and frequently replace al.veolar walls. The surrounding alveolar septa may be thickened and the alveolar epithelium hypertrophied and cuboidal. Intraalveolar collections of mononuclear cells may be present. These granulomas may be subpleural, peribronchial, perivascular or distributed through the interstitial tissue (Figs. 4B and C). Several types of inclusions may be observed in the giant cells and rarely in the epithelioid cells. These are the asteroid bodies, the conchoidal or Schaumann bodies, and crystals. The Schaumann bodies are shell-like, concentrically laminated, deeply basophilic bodies, and measure up to 50 micra in diameter. They are found with reasonable regularity in berylliosis.52 The crystals may be of two types: cholesterol, seen as empty slits in the tissue after paraffin embedding, and brilliant, plate-like, birefringent, irregularly-shaped structures, 3 to 10 micra in diameter which always have a sharp edge. The latter are frequently found in association with Schaumann bodies. None of these inclusions are diagnostically specific and they are frequently found in other granulomatous diseases, such as tuberculosis, histoplasmosis, sarcoidosis, etc. In older lesions or where steroid therapy has been used, the cellular structure may be replaced by fibrous tissue. In addition, there is usually some degree of diffuse interstitial fibrosis. Emphysema is not a frequent complication. While primary carcinoma of the lung has been reported as a late complication of berylliosis, there has not been sufficient experience to consider neoplasia as a common complication. Perhaps this is due in part to the fact that patients with chronic berylliosis have not survived for a sufficiently long period. It is obvious that pathologically and clinically berylliosis mimics Boeck’s sarcoid to the point that differentiation is frequently impossible. Hardy,‘” after study of many cases in the Beryllium Disease Registry, has suggested the following points of differentiation: berylliosis has little, if any hilar adenopathy, no ocular involvement, no uveoparotid fever, no cystic bone changes, a low
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Fig. 4-Berylliosis. (A) Low power photomicrograph of chronic pulmonary berylliosis showing interstitial infiltration and fibrosis (x 1.25). (B) Medium power view showing the typical interstitial noncaseating granuloma with giant cells (x 80). (C) High power photomicrograph of a granulomatous lesion (x 120).
rate of complicating tuberculosis, no change in the tuberculin skin test with the onset of disease, a slower response to steroid therapy, and a less favorable prognosis.
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The finding of beryllium in the urine and in lung tissue by chemical or spectrographic analysis at one time was suggested as a means of differentiating the granuloma of beryllium from other similar lesions. However, beryllium is present in small concentrations in soil and water and in the vicinity o,f beryllium industries, and many healthy persons with no occupational exposure have evidence of beryllium in their tissues or body fluids. In addition, beryllium may be excreated in the urine for periods up to ten years after industrial exposure, by workers who give every evidence of good health. Chemical analysis of necropsy tissues from beryllium workers who died of unrelated causes and with no histologic evidence of berylliosis, demonstrated as much beryllium in the normal pulmonary tissues as has been observed in the pulmonary tissues of persons with confined berylliosis. Much experimental work has been performed in an attempt to produce the histological pictures of berylliosis, but a satisfactory model has not been found. Administration of several forms of beryllium on the lung of a variety of animal species has produced lesions which superficially resemble those of chronic berylliosis, but they are few in number, limited in extent, and show no progression following cessation of the exposure.43+ However, malignant neoplastic changes have been found with reasonable consistency after prolonged experimental exposures. COAL
WORKERS’
PNEUMOCONISIS
‘Coal workers pneumoconiosis is the name which has evolved to describe the pulmonary manisfestations in workers specifically exposed to dust from coal mines, and formerly categorized under the less specific terms anthracosis or anthracosilicosis. Observations concerning the black lungs of coal miners date back 130 years in Scotland. At the turn of the century, however, the disease of coal workers was thought to have disappeared because of improved working conditions in the mines. The application of chest roentgenography revealed evidence of pulmonary abnormalities in South Wales coal miners in the early 1930’s and the great number of men applying for compensation stimulated an extensive survey. It was observed that the radiological changes were not typically those of silicosis. Gough12J3 and Heppleston 21 described the characteristic pathology of the pulmonary lesion in the simple and complicated forms and today it is widely accepted that coal dust alone is capable of causing a distinctive lesion. Coal miners may have widely varying jobs in the mine and may receive vastly different, exposures. Those who work on the coal face, drilling rock, cutting strata or sanding tracks may develop lesions typical of silicosis. Other coal miners working on the coal seams, cutting or loading the coal, present a lesion distinctly different from silicosis and one typical for coal dust. The gross appearance of the lung in simple coal workers’ pneumoconisis varies with the duration of exposure. In general, the lung is fairly normal in external appearance and is unusual only because of the deep black pigmentation on the pleural surface. The trachea and bronchi are usually normal. The lymph nodes are
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enlarged, firm but not fibrotic, and homogeneously pigmented. The cut surface of the lung reveals numerous pigmented foci 5 mm. or more in diameter. These black dust foci are located in the vicinity of the terminal and respiratory bronchioles. No nodular lesion is present unless there are manifestations of both diseases, silicosis and coalworkers’ pneumoconiosis. This is a frequent occurrence since every coal bed contains varying amounts of free crystalline silica. The pigmented lesions are called coal macules (Fig. 5A and B ). They are characteristic regardless of the type of coal mine or character of the bed rock. Microscopically, the dust appears to be contained within cells, probably macrophages, which are enmeshed in a collection of reticulin fibers (Fig. 5C ) . Collagen deposition is usually not. present, This dust mantle surrounds the respiratory bronchiole and extends into the surrounding alveolar structures (Fig. SD). Frequently the air spaces immediately surrounding the collections of dust are enlarged (Fig, 5C). This is called focal emphysema and should not be confused with other incapacitating forms of emphysema. Hepplestonzl considers the focal emphysema to be caused by a shrinkage of reticulin tissue in the coal focus and dilatation of the surrounded air space or bronchiole. Our observations suggest that there is some destruction of the alveolar walls and capillaries in the zone affected by the dust and reticulin deposition; however, the extent of the tissue loss is very limited and local. Persons affected with the simple form of coal workers’ pneumoconiosis show minimal or no physiological abnormalities unless there is associated disease. The radiologic picture in the simple form was previously described as a reticulation; now, however, it is recognized as minute opacities which may be as small as 1 mm. in diameter. They may increase in number and size and density until both lungs are more or less uniformly involved by opacities 3 to 4 mm. in diameter; these correspond to the coal macules seen pathologically. The complicated form of coal workers’ pneumoconiosis is characterized by the presence of relatively large confluent zones of dense fibrosis, usually presenting in one or both upper lobes (Fig. 5B). These masses may be small in the earlier lesion, measuring 1 to 2 cm. in diameter, but can replace an entire upper lobe and extend across lobar divisions into the adjacent lobe as well. The masses are darkly pigmented, firm and rubbery. Microscopically, they are dense, acellular fibrous tissue which contains much pigment. The lung parenchyma has been completely replaced and the vessels in the region frequently show an obliterative endarteritis. A few chronic inflammatory cells, including plasmacytes, lymphocytes and macrophages, may be present. In approximately 40 per cent of cases of progressive massive fibrosis encountered at autopsy, tubercle bacilli can be demonstrated by culture or animal inoculation.Z5 Gough’l believes that this progressive massive fibrosis is the result of a combination of infection superimposed on simple coal wo8rkers’ pneumoconiosis. Caseous necrosis is not seen unless floridly active tuberculosis occurs; but ischemic cavitation of the type described in conglomerate silicosis may occur, and mimic tuberculosis. In the progressive massive fibrosis of coal
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workers, right heart enlargement and ultimately failure commonly causes death. Pulmonary embolism or thrombosis is another common terminal complication. Primary pulmonary cancer has not been observed in increased incidence. Extensive and severe fibrosis can be produced in experimental animals by intratracheal inoculation of coal dust with or without small concentrations of free crystalline silica, coupled with living or dead tubercle bacilh5’ These observations fortify the contention that a tuberculous infection is necessary for the occurrence of progressive massive fibrosis of coal workers. Other investigators feel that progressive massive fibrosis may be the result of factors other than tuberculosis, such as vascular obstruction, bronchial occlusion, previous pulmonary disease with residual scar, and perhaps even a rheumatoid diathesis.” It may be justifiable to end this discussion with a word concerning the socalled benign pneumoconioses. On occasion, inhalation of dense metallic materials, such as iron, tin, barium or bismuth, may result in the widespread deposition of these materials in the lung. These substances are not fibrogeni@ and are imbibed by macrophages and remain focalized in some of the alveolar spaces adjacent to respiratory bronchioles. The alveolar epithelium in these zones is frequently hypertrophic but reticulin or collagen deposition is absent (Fig. 6). These zones will appear radiopaque in a chest roentgenogram and may be confused with silicosis or other nodule-producing disease. It is obvious that the density seen is produced by the collection of heavy metal in macrophages and not to fibrogenic tissue reaction. These lesions are not progressive or symptomatic, and contribute one more red herring to the radiologist’s barrel. SUMMARY
AND
CONCLUSIONS
This brief and incomplete review of the pathology of some of the pneumoconioses does not lend itself well to summary. However, the following may bear repetition: Silicosis in its simple form is a nodule-producing disease which may progress to the conglomerate or massive fibrosis state. Asbestosis and chronic berylliosis are interstitial diseases. Prolonged exposure to asbestos is probably associated with an increased incidence of primary lung cancer. This complication is rarely seen in chronic berylliosis although experimental work points to it as a possibility. Simple coal workers’ pneumoconiosis is characterized by small opacities not large enough to be considered nodules, which are related to the formation of the coal macule and focal emphysema. Progressive massive fibrosis may occur after prolonged exposure to coal dust and is frequently associated with some evidence of a tuberculous infection. The benign pneumoconioses may mimic nodular disease but are nonfibrogenic and not progressive. While these pneumoconioses are among the best studied, much still remains to be learned concerning pathogenesis and tissue reactions. The future of pneumoconiosis study promises even more exciting new experiences as our industrial research and technology respond to the needs and challenges of the era of the space adventure.
260 Fig. 5-Coalworkers’ pneumoconiosis. (A) Large paper section of simple coalworkers’ pneumoconiosis (x 2/5) showing the small coal macules and surrounding zones of focal emphysema. (B ) Large paper section of relatively early lesion of massive fibrosis in the upper lobe of a coal worker (x 2/5). (C) Low power photomicrograph (x 12) of a typical coal macule with surrounding zone of focal emphysema. (D) Medium power photomicrograph (x 80) of a coal macule cut in the plane of the long axis of the respiratory bronchiole to show the peribronchiolar location of the deposit.
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Fig. 5-Cont’d
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