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The Pathology of Asbestos-Associated Diseases of the Lungs and Pleural Cavities: Diagnostic Criteria and Proposed Grading Schema Report of the Pneumoconiosis Committee of the College of American Pathologists and the National Institute for Occupational Safety and Health John E. Craighead, MD, Chairman Jerrold L. Abraham, MD: Andrew Churg, MD; Francis H. Y. Green, MD; Jerome Kleinerman, MD; Philip C. Pratt, MD; Thomas A. Seemayer, MD; Val Vallyathan, PhD; Hans Weill, MD The observations and conclusions summarized herein represent the ture. Thus, considerable attention was given to the histologic features of work of a committee of North Ameriasbestosis at various stages of what is can pathologists that was organized believed to be its evolutionary course. under the auspices of the National Because most published descriptions Institute for Occupational Safety and are concerned with disease that Health (NIOSH) and the College of results from exposure to an undefined American Pathologists to evaluate mixture of different types of asbestos, the pathology of asbestos-associated the lesions associated with the various diseases and to establish standards types of asbestos also were studied for the grading of asbestosis. This comparatively, using collections of effort was undertaken because of the pathologic material from the United need to develop a common basis for States and abroad. communication among pathologists, A grading schema that is functional and between pathologists and radiolo and widely accepted by pathologists gists, clinicians, pulmonary physiolo would have considerable usefulness in gists, occupational hygienists, and future studies of the clinical and epi epidemiologists. demiologic aspects of the disease. During the course of this study, it Because many pathologists are uncer became clear that the detailed mor tain as to the criteria for the diagnosis phologic features of the asbestos- of asbestosis, a generally accepted associated diseases of the pulmonary description of the lesions would assist parenchyma of man have not been in establishing uniformity for pur described fully in the medical liters- poses of diagnosis. Although this monograph ad dresses a variety of topics concerned Accepted for publication Feb 11,1982. with asbestos and asbestos-associated From the Department of Pathology, Universi ty of Vermont College of Medicine, Burlington (Dr Craighead i; the University of California, San Diego tDr Abraham); the University of British Columbia, Vancouver (Dr Churgi; the Appala chian Laboratory for Occupational Safety and Health. Morgantown, WVa (Drs Green and Val lyathan i; Mount Sinai School of Medicine, New York iDr Kleinerman); Duke University, Dur ham. SC (Dr Pratt); McGill University, Montreal (Dr Seemayerr. and Tulane University, Kew Orleans (Dr Weill). Reprint requests to Department of Pathology, Medical Alumni Building, University of Ver mont, Burlington, YT 0&40S (Dr Craighead). diseases, the committee was con cerned primarily with the pathologic features of the pulmonary parenchy mal disease associated with exposure to asbestos. Several outstanding books, conference proceedings, and committee reports that examine in detail the mineralogy and public health aspects of asbestos and the asbestos-associated diseases have been published in recent years. We refer the interested reader to them for more detailed presentations (see the "Bibliography"). HISTORIC BACKGROUND The fire-resistant properties of asbestos have been appreciated by man since ancient times. Although the mineral apparently was used in the fabrication of ceramics and tex tiles before the industrial revolution, it was not until the middle of the 19th century that commercial mining began. At that time, asbestos first was used in roofing materials and cement in the United States. During the next several decades, it was incor porated into commercial textile prod ucts in both North America and Europe. By the turn of the century, the industrial applications of asbestos seemed almost limitless and demand escalated. With the expanding recog nition of asbestos as a commercially extractable mineral, mines were opened in many parts of the world. It is unlikely that asbestosis was recognized as a disease before the term pneumonokoniosis was intro duced by Zenker in 1S67.1 Early in the 20th century, a few case reports from Europe and the United States indi cated a possible association of expo sure to asbestos dust with pulmonary fibrosis; in 1924 the term asbestosis was introduced by Cooke.: By the 1920s and 1930s, the disease was more commonly recognized and series of 544 Arch Pathot Lab Med--Vol 106, Oct 8. 1982 Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006636 ses appeared in the literature. Yet, e industrial use of asbestos creased. As the United States rned to the automobile for trans udation, the use of asbestos in brake Tings became commonplace. In the >30s, the technique of spraying ibestos insulation in construction as developed, and shortly thereafter ibestos began to be used in the manfacture of insulation and pipe. In the United States, the occurrence f bronchogenic carcinoma in a atient with asbestosis was noted by .ynch and Smith in 1935.1 Their bservation was soon confirmed by thers, and over time an association as established. Although worldwide oncern about the health effects of .sbestos mounted, the problem beame more critical during the mobiliation that accompanied World War I. Warfare demanded ships and modrn weaponry, and the war effort irought countless thousands of per sons into industries that used asbesos. Although Klemperer and Rabin lescribed tumors known by the desiglation mesothelioma in 1931/ recogni tion of the association of the neoplasm with asbestos awaited the reports of Weiss' and Leichner* in the 1950s. In 1960, Wagner and his colleagues' noted the relatively common occur rence of this rare neoplasm in persons exposed to South African cape "blue" asbestos, a type composed of unusual ly long and thin fibers. Subsequent experiments documented the induc tion of morphologically similar pleu ral lesions in animals sifter the intra pleural introduction of asbestos and of man-made fibers that had similar physical properties.* Countless re ports since that time have confirmed the etiologic association of asbestos with mesothelioma. Clinical and pathologic evidence accumulated during the past several decades established the role of asbes tos in the pathogenesis of diffuse pul monary fibrosis. Evaluations of popu lation groups by radiologists and epi demiologists documented the common occurrence of pleural plaques in per sons exposed to asbestos. Definition of the role of asbestos in carcinogenesis required the efforts of epidemioio- gists, who established the association of asbestos with bronchogenic carci noma and with neoplasms in other organs. Noteworthy among these studies are the work of Doll in 1955* and the more recent observations of Selikoff and his associates,10 Enter line and Henderson,11 and investiga tors at the National Cancer Institute12 in this country. OCCUPATIONAL AND NONOCCUPATIONAL EXPOSURE TO ASBESTOS Although asbestos has been mined commercially since the turn of the century, it was not used widely in the United States until after 1930. Approximately 30 million tons of asbestos has been incorporated into construction materials and manufac tured products in this country since then. Each year, US industry con sumes more than 800,000 tons of asbestos. About one million firing Americans either work or have worked in industries that manufac ture asbestos products, and countless millions more are exposed to the sev eral thousand asbestos-containing products that are available commer cially. In addition, persons are exposed inadvertently to the break down products of the mineral during the reconstruction and renovation of buildings and because of the deterio ration of manufactured materials that contain asbestos. Because of its heat- and fire-resis tant properties, as well as its high tensile strength and flexibility, asbes tos finds its greatest use in the con struction industry. About one third of the annual US consumption is incor porated into cement and cement prod ucts. Asbestos cement pipe and corrugated sheeting are the major products, among many others. The concentration of asbestos in cement varies considerably, but customarily is about 15% to 20%. Asbestos-con taining products also are used in floor tile, insulation board, plastic, mold ing, and paint, as well as spackle, patching, and taping compounds. In addition, asbestos is used as a filler in the construction of buildings. In the past, asbestos in the form of a suspen sion was applied by spray guns in the construction of steel-girdered build ings to prevent fire damage. This application now is prohibited in the United States because of its unre stricted pollution of the ambient air. Asbestos-containing products are used extensively to insulate electrical and heat-generating equipment and in the plumbing and shipbuilding industries. These products contain asbestos in amounts that range from 10% to almost 100%. Because the material is relatively uncontained and is manipulated during processing and use, breakdown products create a severe hazard. Thus, contamination of the environment often is subtle and the overall importance of the problem with regard to health is difficult to assess. Almost two million persons are employed in automotive sales, service, and repair, of whom some 900,000 are believed to be exposed frequently to asbestos from automobile brakes and clutch repair. Additional thousands are exposed elsewhere in the trans portation industries. Asbestos is used in yarns and fab rics for protective clothing, safety curtains, and fire blankets. Asbestosreinforced plastics are used in second ary industries too numerous to men tion. Contemporary standards adopted by the US Occupational Safety and Health Administration are based on the demonstration of fibers 5 fim or longer in ambient air using fight microscopy. At present, no more than an average of 2 fibers per cubic centi meter of air during an eight-hour work period is permissible in the occu pational setting. Criteria based on concentrations of "long" fibers are a practical but relatively crude means for assessing environmental pollution, because the "short" (ie, <5 nm) asbestos fibers are not counted. Although long fibers are thought to play a major role in the pathogenesis of asbestosis and mesothelioma, the importance of short fibers in carcino genesis and fibrogenesis in the lungs is uncertain. Nonoccupational exposure to asbes tos is particularly insidious. It occurs in persons who reside near asbestos mines and mills, construction and Arch Pathol Lab Med--Vol 106, Oct 8. 1982 Asbestos-Associated Disease--Craighead et at 545 ASARCO ALV 0006637 building demolition sites, and asbes tos dumps. Members of the household of asbestos workers may be exposed to contaminated work clothes. Avocational exposure occurs in those under taking do-it-yourself home repairs and auto body work. Obviously, it is difficult to document the severity of these types of exposure. MINERALOGY OF ASBESTOS The term asbestos refers to a family of naturally occurring, flexible, fibrous hydrous silicate minerals that are relatively indestructible and heatresistant, and have a high lengthto-breadth ratio (aspect ratio). Al though fibrous minerals are ubiqui tous in the earth's crust, only a few types have commercial importance: (1) chrysotile, derived from serpentine rock, and (2) crocidolite, amosite, and anthophyllite, which are classified as amphiboles (Fig 1). Fibers of both the serpentine and amphibole types consist of subunit fibrils. Individual serpentine fibers are made up of fibrils that have a layered, silicate structure, formed into scroll-like or concentric cylindric tubes. Presumably because of the high surface concentrations of magnesium hydroxide, these fibers exhibit a strong positive surface charge. The basic subunit of the amphibole is a silicon dioxide tetrahedron arranged in parallel chains and linked laterally by various cations. Amphiboles, in contrast to the serpentines, possess a slightly negative charge. Naturally occurring fibers of both types vary considerably in length, as well as in overall diameter. Fragmentation into shorter fibers and subunit fibrils occurs both with industrial processing and in tissue after inhalation (Figs 2 and 3). Belts of serpentine rock are located in nearly every mountain chain in the world. Chrysotile is found cryptically in rocks and soils of several types, and in potable water in many parts of the United States. It is mined in Califor nia and Vermont. About 8% of the earth's crust con sists of amphibole rock minerals. Because of the complexity of the structure and chemistry of the amphi boles, a wide variety of geologic strata Fig 1.--Mmeralogic classification and chemical composition of common commercial types of asbestos (from New England Journal of Medicine, 1932.306.1446-1455). and soils contain fibrous and nonfibrous minerals somewhat akin to commercial amphiboles. The mineral ogy and nomenclature of these sub stances is complex. Amphiboles often are found with commercial deposits of chrysotile; eg, Canadian chrysotile, which is used widely in the United States today, contains variable amounts of tremolite. The different types of asbestos seem to vary with regard to their importance in the causation of dis ease. Crocidolite is generally consid ered to be the most "dangerous" asbestos because of its strong associa tion with mesothelioma. It now is banned from importation into the United Kingdom, but it is still used to a limited extent in the United States. Amosite is used less widely in this country today. More than 95% of the asbestos used in the United States is chrysotile, which comes from either domestic or Canadian sources. How ever, it often is impossible to deter mine the type of asbestos a patient has been exposed to, because the vari ous types of asbestos commonly are used interchangeably and as mix tures. ASBESTOS FIBERS IN TISSUE Two forms of asbestos fibers char acteristically are found in the lungs. One, the uncoated, "bare" fiber, is identical to the inhaled particle unless altered by physical and chemical events in the tissue. Because of their narrow diameter, even relatively long fibers (> 5 pm) of inhalable size are detected only with difficulty by light microscopy; shorter fibers (which often are present in large numbers) are demonstrable only by electron microscopy. Polarized light microsco py is of limited use in detecting asbes tos in lung tissue because these rela tively thin fibers are only weakly birefringent. Similarly, the fibers cannot be identified positively in tissue by phase optics microscopy. The second form of fiber, the asbes tos body, is the hallmark of asbestos exposure (Color Fig 1). It consists of a fiber of variable length that is coated with proteins and iron compounds. The core of the fiber is transpar ent, colorless, and usually straight and unbranched; however, curved, branched bodies sometimes are seen. Their appearance has been described 546 Arch Pathol Lab Med--Vol 106. Oct 8. 1982 Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006638 Fig 2.--Scanning electron micrographs of Canadian chrysotite (top, X7.500; bottom, X 18.000). Note curled features as wen as variable lengths and diameters of fibers. Top, Fibrillary makeup of individual fibers is evident. In tissue, fibers often break down into individual fibrils and thus may not bo evident by light microscopy. AM specimens in Figs 2 and 3 were prepared under auspices of Union Internationale Contre Cancer and consist of commercial products. Properties of minerals extracted from individual geologic deposits of asbestos differ, which may affect pathogenicity. ASARCO ALV 0006639 Fig 3.--Scanning electron micrographs of South African crocidoJite (top, X7.500: bottom, X 18,000). Note rodlike features of rigid fibers of crocidolrte and their variable lengths and diameters. Fibular substructure of fibers is apparent. See Fig 2. *8 Arch Pathol Lab Med--Vol 106, Oct 8, 1982 Asbestos-Associated Disease--Craiobead at at ASARCO ALV 0006640 4 "t '^5.h 4/- X ^tier&ei'?fcz %%bjbT ''j'r*,&X*f.-v*f -***<? ~\ a^*V*x' IlNst.. -'V '^*'*f '%V;*^'r. g'k*. >4d&?T ** ? . v%~> %tv r. ,v, %V~ X1 .. V; V< "-4 *% .' 'f4 ~K*>. ASl ._,*. Cg|j^ * SrVfr V Xf. % f).v \* Tfe Vx . <Sx ->1 #}* -* * JW*' > > - f -* ^ & /\ ?V-:" x " v v `<%y,\h /\ -v -X ,, -*"'"* '--i -K ^ X/': -., . '^%'tflXX-!' ' T V* "';* <,r^. ` 'X V.v.. * - : ,;i , ->* * . ~tW' 3&. . ' * * `^'^'^ ivrrv **' '&''11r'rr* Color Fig 1.--Typical asbestos bodies in lung exhibiting grade 3 asbestosis. Note characteristic hollow cores ol many fibers. y Phagocytic muitmucleate cells are unusually prominent in this tissue (hematoxylin-eosin). Arch Pathol Lab Med--Vol 106. Oct 8. 1982 'I i Asbestos-Associated O.sease-Craighead at al 549 ASARCO ALV 0006641 Pig 4.--Configurations of Prussian biue- stained asbestos bodies in lung with asbesto4* sia. Bodies were identified in photomicro graphs of lung and cut out to prepare mon tage Asbestos bodies consist of an asbestos fiber core and surface deposits of protein- and iron-containing compounds. j.jw.vyvv?.v it.yxtg-y> Wi'.Vyl^Sv --^. y*.' *'--;'v`.;`^*_ ^ ^ -' ^V;"*' ' /.* . '.'> **/* as "dumbbell," "drumstick," "beadednecklace," and "sausage," among oth er descriptors (Fig 4). Typical asbes tos bodies are from 10 to more than 300 /rm long, although the usual length is about 30 to 50 pm. However, much smaller bodies of various shapes often are seen free in the tissue or in the cytoplasm of macrophages. The width is less than 3 pm, whereas the core can vary from 0.1 to 1.0 pm. A histologic stain for iron often is help ful in demonstrating asbestos bodies in tissue and should be used when the bodies are not readily demonstrated in lesions believed to be due to asbes tos exposure. The ratio of uncoated fibers to asbestos bodies in the lungs is high, often ranging from 5:1 to 10,000:1." The term ferruginous body has been suggested as a general descriptor for a fiber in tissue with an iron-protein coat.1* Ferruginous bodies derived from a variety of inorganic and organ ic fibers have been identified in human lungs. Structures formed around carbon particles have black cores by light microscopy, and bodies formed on other silicates, eg, talc and mica, often have yellow cores. As most ferruginous bodies with colorless, transparent cores in human lungs consist only of asbestos, we prefer to use the more specific term asbestos body When birefringent material is present in the lungs in large amounts, exposure to common silicates like mica, talc, and kaolinite is likely. In workers exposed to talc, the inhaled dust usually contains asbestos be cause small amounts of the fibrous Pifl 5.--Energy-dispersive x-ray spectrometry (microprobe) spectra of the tour commercially important types of asbestos. Individual ele mental components of liber are displayed at various loci along horizontal axis of cathode ray image: height of peak indicates relative amount of each element present. Upper left shows chrysotile: upper right, crocidolite: low er left, anthophyllite: and lower right, amo* site. SO Arch Pathol Lab Med--Vot 106. Oct 8, 1932 Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006642 :g 6.--Electron microscopic diffraction pat* erns of chrysotile (top) and crocidoiite (bot* om). Chrysotile pattern is distinctive. Crocidote pattern is not specific, but is consistent vrth amphibole mineral. It is possible to identi* y mineral type using x*ray spectrometry and ilectron diffraction. mineral customarily are present in commercial deposits of talc. Evidence cf exposure to silica dust, eg, quartz, often is found in conjunction with asbestosis. Pulmonary disease conse quent to a mixture of dusts, including asbestos, is an important consider ation in some occupational groups, and this should be reflected in the diagnosis by the pathologist. The mineralogic identification of either a specific fiber or a nonfibrous mineral in tissues is a difficult and time-consuming task that requires specialized equipment and highly trained personnel. Usually, it is neces sary either to digest tissues in alkali or to incinerate them before analy sis. Light microscopic and ultrastructural methods have been developed for the identification and quantifica tion of fibers and asbestos bodies in tissue (appendix 1). These techniques may be useful for documenting expo sure in persons with no history of exposure, and for identifying the spe cific mineral or minerals involved. However, it is difficult to relate the fiber content of tissue to the extent and severity of parenchymal disease of the lung. The physical characteristics of par ticles in tissue vary, and in part reflect changes that occur after inha lation. For example, chrysotile fibers fragment into subunits and are leached of certain mineral constitu ents with the passage of time.11 Ultrastructural examination of individual fibers by either scanning or transmis sion electron microscopy is not a use ful technique for the identification of fibers because the individual fiber types have few specific structural fea tures. Energy-dispersive x-ray spec trometry (electron probe) and electron diffraction transmission mi croscopy permit the chemical and crystallographic analysis of a fiber in tissue (Figs 5 and 6). Because of the specialized nature of these time-con suming techniques, they are of limited diagnostic usefulness. ASBESTOS-ASSOCIATED PLEURAL AND PULMONARY DISEASE Long-term exposure to asbestos may result in disease that is restricted to either the pleura or the pulmonary parenchyma, although lesions of vary ing severity commonly are present in both anatomic locations. Pleural Plaque* Plaques of the parietal and dia phragmatic pleura often are found in persons exposed to asbestos.1* In recent years, these lesions have been considered one of the pathologic and radiologic hallmarks of exposure. Plaques may prove to be the only evidence. The interval between the time of initial exposure and the devel opment of plaques is not clearly defined, but ten to 20 years usually elapse before they become evident clinically (Fig 7). As might be ex pected, the prevalence in groups of workers exposed to asbestos increases with age. In some series of cases, more than 50% of the study group exhibited radiologic evidence of plaques 30 to 40 years after exposure1''11 (Fig 8). All commercial types of asbestos induce plaques. In one study, the prev alence differed 13-fold between work ers in two regions mining the same vein of chrysotile in Quebec. Plaques are also found in members of the families of asbestos workers and in persons who reside in communities near asbestos mines and mills. They have been reported in persons exposed to mica, industrial talc (which con tains asbestos fibers), fibrous diatomaceous earth, fibrous zeolite, and other silicates. Plaques commonly occur among members of the general population in certain areas of Finland,11 various places in central Europe, and in a few localities in Turkey.2 Because evidence of occupa tional exposure in these areas is usu ally lacking, it has been suggested that the lesions are due to the inhala tion of fiber and minerals that are found in soils and geologic outcrops. The plaques on the parietal pleura typically are located on the postero lateral aspect of the lower part of the thorax and on the dome of the thorac ic surface of the diaphragm (Figs 9 and 10). Customarily, they are not found adjacent to the apices of the lung or in the costophrenic angles. Plaques also are situated at scattered sites on the peritoneal surfaces of the abdominal cavity, but these are rela tively rare lesions. Thin plaques usually are smooth and grayish white, whereas the thick er lesions are ivory-white and either have a smooth surface or are coarsely nodular. The size and shape vary" whereas plaques on the surface of the diaphragm typically are round and disklike, those located over the inter costal spaces are elongate and have an irregular configuration (Figs 11 through 13). Plaques customarily do not form on the visceral pleura, although this surface often is either diffusely or focally thickened by fibrous tissue. This latter lesion ranges in severity from a simple loss of translucency to a shell of white, fibrous tissue that encases the whole lung. When honeycombing of the lung parenchyma exists, the surface may Arch Pathol Lab Med--Vol 106. Oct 8, 1982 Asbestos-Associated Disease--Craighead et al 551 ASARCO ALV 0006643 60 50 40 30 U 8. UXJ - 20 10 Aabesto* Ettuaion Pulmonary Fibroais Pleural Plaques Pleural Calcification 1 3-9 10-19 20-29 30-39 40-49 Years Since First Exposure Fig 7.--Clinical occurrence of various asbes tos-associated lesions among industrial work ers Chronically exposed to airborne mineral fibers. Data are based on physical examina tions and roentgenograms obtained systemat ically during 50-year period (from Epler and Ga easier'*). B{SBWaiMR -I.J1 ..l--1.-! ?, ' . ~' ' -SW Jf*T. pig 8.---Chest roentgenogram of 68-year-old construction contractor who was hospitalised for treatment ot recurrent transitional cell car cinoma of bladder. There were no unusual respiratory complaints. Calcified plaques on parietal pleural surface ol rib cage, pericardi um, and diaphragm were incidental finding. -.y*fc*-T"rry~>j:: .Sg**"i V ** , *7. X 552 Arch Pathol Lab Med--Vd 106, Oct 8, 1982 Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006644 Skihltuiey Fig 9.--Parietal pleural surfaces ol thoracic cages of two Finnish men at autopsy. Lungs and mediastinal structures have been removed. Lett, Note nodularity of plaques. Right. Note smooth, confluent, sheetlike plaques. Diaphragmatic surface exhibits large, circumscribed, disiuike plaques. There was no history of occupational exposure to asbestos. Arch Pathol Ub Med--Vol 106. Oct 8, 1982 Asbestos-Associated Disease-Cra.ghead et at 553 ASARCO ALV 0006645 Fig 10.--Computed tomograms of pleural plaques (arrows). Left. Calcified paravertebral and peripheral plaques. Right, Calcified mediastinal, paravertebral plaques (from Preger"). Fig 11.--Parietal pleural surface and parietal pericardium (PP) of diaphragm of American man with history of occupational exposure to asbestos. Disklike configuration and nodularity are typical of these lesions. 554 Arch Pathol Lab Med--Vol 106, Oct 8. 1982 'i ! Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006646  1 Fig 13.--Nodular plaques on pleural surface of membranous diaphragm of Finnish man with no known occupational exposure to asbestos. rch Pathol Lab Med--Vol 106. Oct 8, 1982 Asbestos-Associated Disease--Craighead et al 5S5 ASARCO ALV 0006647 Fig 14.--Microscopic features of typical pleural plaque. Note "basket-weave" arrangement of collagen bundles and relative aceltulanty of tissue. These lesions usually are not vascularized. 556 Arch Pathol Lab Med--Vol 106, Oct 8. 1982 Asbestos-Associated Disease--Craighead el al ASARCO ALV 0006648 have & coarse nodularity that resem bles a cirrhotic liver. Adhesions between the visceral and parietal pleura are common, particularly at the lung bases. The degree of pleural thickening does not reflect the severi ty of the pulmonary parenchymal dis ease and it can occur in the absence of fibrosis. Pleural pigmentation is not a feature of asbestosis and its presence suggests exposure to other types of dust Microscopically, pleural plaques consist of dense strands of hyalinized, relatively acellular, nonvascular col lagen lined by a surface of mesothelial cells. The collagen fibers lie parallel to the surface and show a reticulated raesh appearance, the so-called bas ket-weave pattern (Fig 14). The colla gen fibers in nodular plaques have a whorled arrangement. Occasional plaques exhibit elastic fibers and scat tered, thin-walled blood vessels. Inflammatory cells are not present, but may be found nearby. Calcifica tion is a common but variable feature that has proved useful in radiologic epidemiology. Occasionally, fibers of asbestos can be found in plaques by electron microscopy after either digestion or incineration of the tis sue. Asbestos!* Asbestosis is pulmonary fibrosis consequent to the accumulation of air borne asbestos in the lungs. It does not refer to the lesions of the pleura already described. The severity of the disease varies. It depends in large part on the type and duration of exposure, the concentration of dust in the ambi ent air, and the fiber "burden" of the lung. Factors unique to the host (eg, immunologic responsiveness, concom itant disease processes, exposure to other types of dust, and cigarette use) also are believed to be important, although their relative significance in the evolution of the disease is uncer tain. Asbestosis is a chronic and often progressive disease. Although decades usually elapse before its signs and symptoms become clinically evident, shorter latency periods have been noted in asbestos workers who experi enced exceptionally heavy exposure. Gross Features.--The pathologic fea- tures of the advanced stages of pulmo nary asbestosis have been recorded in the classic descriptions of the disease. As expected from physiologic studies and the chest films, the lungs are small and firm. The cut surface is striking because of its dark-brown color. Gray streaks of fibrous tissues outline interlobar and lobular septa and focally interdigitate the lung tis sue. The visceral pleura is thickened by dense collagenous tissue (Fig 15). The occurrence of adhesions varies. The parenchymal fibrosis, which is linear and reticular, is most promi nent in the lower lobes. The bronchi are normal unless the patient has been a heavy smoker or other diseases exist. The tracheobronchial lymph nodes do not have characteristic changes. Commonly, they are en larged and brown-black, but are nei ther firm nor fibrotic. In advanced cases, the parenchyma exhibits honeycombing that is most prominent subpleurally and in the lower lobes (Color Fig 2). In contrast with emphysema, the airspaces of the honeycomb lung result from tissue fibrosis, with retraction of the residu al structures (Fig 16). These revised cavities have diameters that range from 1 to 15 mm, and have visibly thickened walls. No evidence indicates that exposure to asbestos contributes to the development of emphysema. Although progressive, massive fibro sis (as in coal workers' pneumoconio sis" and silicosis") has been described in persons with asbestosis, it is rare and usually consequent to exposure to a mixture of dusts. The evaluation of fibrosis of the parenchyma on gross examination of the lungs requires a careful inspection of slices of tissue that have been inflated by the intratracheal instilla tion of fixative solution. Because the lesions of advanced asbestosis usually are most prominent in the lower lobes and sulipleural tissue, a detailed description of the gross changes is mandatory. In addition, photographic documentation is recommended. The pathologist should attempt to deter mine the relative proportion of a whole lung section that exhibits fibro sis. Although these features are typical of the overt case of asbestosis, the lungs of others with less severe expo sure exhibit only moderate degrees of parenchymal fibrosis that are not clearly evident on gross examination. In the evaluation of these specimens, the histologic assessment of the lungs using the diagnostic criteria to be summarized may be pivotal in estab lishing a diagnosis. Microscopic Features.--The severity of the histologic changes in the lungs in asbestosis varies, presumably in large part because of differences in the intensity and duration of expo sure. At one extreme, the features of typical asbestosis are obvious after a brief examination of a tissue section; at the other, the lesions are subtle, for they may be identified only at scat tered sites in representative histologic sections of the pulmonary tissue. It should be remembered that the lower lobes and subpleural regions of the lung are involved most severely by the disease. Pathologists must critically evaluate the lesions of pulmonary fibrosis using the criteria to be cited before implicating asbestos. A history of exposure is supportive but not definitive evidence. Conversely, it3 absence does not exclude the diagnosis because so many cryptic forms of exposure exist. Correlative evaluation of experi mental and human materials has pro vided insight into the morphogenesis of the disease at an early stage of evolution. Inasmuch as the patholo gist often is obliged to establish a diagnosis in cases with undocumented exposure and mild disease, this sec tion will emphasize the lesions we believe occur early in the pathogenetic sequence of events. Accordingly, an attempt has been made to develop a construct based on our concept of the disease from its initial stages to the more severe, overt form. Little is known about the develop ment of the early lesion of asbestosis in man. Thus, the evolution of the process must be inferred from a study of animals exposed to asbestos in inhalation chambers."-" Asbestos seems to be deposited first in the respiratory bronchiole and the alveo lar duct. Some observers believe an acute polymorphonuclear leukocyte Arch Pathol Lab Med--Vol 106. Oct 8. 1982 Asbestos-Associated Disease--Craighead et at 557 'I 1 ASARCO ALV 0006649  Fig 15.--Examples of fibrosis of visceral pleura (top) and interlobar septum (bottom) in lungs of two English dockworkers with long histories of exposure to asbestos. There is pulmonary asbestosis, grade 28. Note adhesions (arrow and arrowhead) to parietal pleura. In contrast with plaques, which typically are found on parietal pleura, these lesions often are vascularized and consist of irregular bundles of nonhyalinized fibrous tissue. Involvement of interlobar septum (bottom) is typical of asbestosis (hematoxylin-eosin). 558 Arch Pathol Lab Med--Vol 106, Oct 8, 1982 Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006650 esponse is provoked as an early and ransient reaction to dust deposiion-"' 10 (J. Abramowitz, MD, personal ommunication, June 8, 1981). Alhough this might bccur, the macro'hage usually is the prominent cell in he distal airways at the time of 'athologic examination. In the respiratory bronchioles, the esion associated with asbestos depoition consists of a thickened wall ittributable to the accumulation of eticulin and collagen. Either cuboilalization of the epithelial cells or olh squamous cell and goblet cell netaplasia can be observed in the nucosa. In typical early asbestosis, mly an occasional pulmonary subunit s affected (Figs 17 and 18). Thus, listologic sections obtained from rep resentative sites throughout the lungs oust be examined. The criteria that permit the pathol ogist to establish the diagnosis of asbestosis have evolved during a review of many cases of the disease. Presently, the minimal features that permit the diagnosis are the demon stration of discrete foci offibrosis in the walls of respiratory bronchioles associated with accumulations of asbestos bodies. These morphologic findings, although adequate to estab lish the diagnosis of asbestosis in an early evolutionary stage, have not been shown to result in functional and radiologic alterations. The demonstra tion of asbestos bodies in the absence of Jibrosis is insufficient evidence to justify the diagnosis ofasbestosis. Con versely, a definitive diagnosis of asbestosis cannot be made in cases that show characteristic fibrosis in the absence of asbestos bodies, even in a patient with a history of exposure. Because asbestos bodies are unevenly distributed in tissue, an adequate number of samples should be exam ined thoroughly. In the lesions, asbestos bodies are located either in the walls of the bron chioles or in the airspaces, where they are often closely associated with mac rophages. When only a single asbestos body is found in a histologic section, it is necessary to demonstrate addition al bodies (either in deeper sections of the same block or in other samples of tissue) to establish the diagnosis of asbestosis. Initially, first-order respiratory- bronchioles are affected by the fibrotic process; in more advanced stages, the second- and third-order branches and alveolar ducts are involved. Con comitantly, the terminal bronchioles Arch Pathol Lab Med--Vot 106. Oct 8. 1982 1I Asbestos-Associated Disease--Craighead at at . 559 ASARCO ALV 0006651 ASARCO ALV 0006652 ^olor Fig 2.--Thin sections (=300 mm) of freeze-dried left fung of 51-year-old man with grade 4C asbestosis. Note diffuse sbrosis with honeycombing that is particularly prominent in basat portions of lower lobe, and in subpleural parenchyma, toneycombing is typical of end-stage diffuse pulmonary fibrosis of many different causes, but prominence of tesions subjacent to pleura and in lower lobes of this case is typical of asbestosis. irch Pathol Lab Med--Vol 106, Oct 8, 1982 Asbestos-Associated Disease-Craigbead et at 561 ASARCO ALV 0006653 Fig 17.--Lung tissue from 65-year-old woman who had been employed in textile winding operation tor 37 years. Top, Grade 1 lesion. Fibrosis is limited to walls of respiratory bron chioles (hematoxylin-eosin (HE]). Bottom. Enlargement of boxed area in upper illustra tion shows two asbestos bodies (arrows) (HE). 562 Arch Pathol Lab Med--Vol 106, Oct 8. 1982 Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006654-  Fig 18.--Lung tissue from 64-year-old man who had been employed as spinner in textile mill for 34 years. Top, Grade 2 lesion. Fibrosis is primarily located around respiratory bronchioles, but there is extension into adjacent alveolar septae (hematoxylin-eosin [HE]). Bottom. Enlargement of boxed area in upper illustration shows several asbestos bodies (arrows). There are fragmented bodies and anthracotic pigment in the fibrotic tissue and pulmonary macrophages (HE). .- . ASARCO ALV 0006655 I 54 Arch Pathol Lab Med--Vol 106. Oct 8. 1982 Asbestos-Associated Disease--Craighead et al 1I ASARCO ALV 0006656 ch Pathol Lab Med--Vol 106, Oct 8. 1982 Asbestos-Associated Disease--Craighead et al 565 lI ASARCO ALV 0006657  Fig 21.--Lung parenchyma of case of grade 2 asbestosis revealing extension of fibroiic process to involve adjacent respiratory units. Note fibrosis in walls of both respiratory bronchioles and alveolar ducts (hematoxylin-eosin). Tissue in lower illustration was stained to demonstrate elastic fibers. 66 Arch Pathol Lab Med--Vol 106. Oct 8, 1982 Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006658 .-\y fc f i.*i i I i I' ch Pathol Lab Med--Vol 106, Oct 8, 1982 Asbestos-Associated Disease--Craighead et al 567 ASARCO ALV 0006659 Fig 23.--Upper left and right. Grades 2 to 3 lesions. Fibrosis is centered around respiratory bronchioles and involves acescent respiratory units (hematoxylin-eosin [HE]). Lower left and lower right. Asbestos bodies (arrows) in boxed areas of upper left and upper right illustrations, respectively (HE). 568 Arch Pathol Lab Med Vol 106, Oct 8. 1982 Asbe3tos-Associated Disease--Craighead et al ASARCO ALV 0006660 ASARCO ALV 0006661 I Fig 24.--Lung tissue of 48-year-old man who worked 28 years in manufacture of chrysotile-coated textiles!'Lesionis grade 3, but elsewhere grade 4 lesions were found (hematoxylln-eosin). . " "v exhibit changes. Often the septa adja cent to the respiratory bronchioles are affected so that the fibrosis appearsto radiate out from the immediate vicinity of the affected subunit. This process involves variable numbers of acini (Figs 19 through 21). With further progression*'of the process, increasing amounts of adja cent lung tissue are affected, seeming ly in a centrifugal fashion (Figs 22 through 24). In later stages, the parenchyma is diffusely involved, although the overall structural conti nuity of the lung is preserved (Fig 24). As the scarring process progresses, the parenchyma is obliterated by fibrous tissues, and fibrous-walled cysts form, particularly in the subpleural and paraseptal regions of the lower lobes (Fig 25). At this stage in the evolution of the disease, peribron chial and perivascular fibrosis also is seen. Asbestos bodies often are observed in and around the lymphatic vessels adjacent to these structures. Asbestos bodies usually are obvious in the advanced stages of the disease (Fig 26). However, this is not invari ably the case, because fibers are cleared from the lungs and undergodissolution and fragmentation with time. Thus, paradoxically, in some cases it may be difficult to demon strate asbestos bodies. In our experi ence, this is a rare occurrence. In the absence of asbestos bodies, there is no satisfactory means to establish the diagnosis in histologic material. Although the demonstration of asbes tos fibers by the electron microscopic study of tissue digestates (appendix 1) provides evidence of exposure, ultrastructural technique cannot be used to establish definitively the etiologic role of asbestos in disease. Multinucleate giant cells are a vari able feature of the lesion; in some cases they are prominent; whereas in others they rarely are seen (Figs 4 and 27). Infiltrates of lymphocytes and plasma cells are found in scattered sites in the lungs of some patients. The importance of this inflammatory process is uncertain, although it could be related to the immunologic reac tions that have been described in some patients with asbestosis. Interstitial cellular infiltrates usually are not prominent in asbestosis. The finding of macrophage accumu lations in air spaces is of no diagnostic usefulness because this feature is commonly associated with the smok ing of cigarettes and other forms of pulmonary injury. However, in occa sional cases of asbestosis, prominent numbers of macrophages in the air spaces and the histologic picture sug gest the pattern of desquamative interstitial pneumonitis (Fig 28). Cytoplasmic hyaline bodies have 570 Arch Pathol Lab Med--Vol 106. Oct 8, 1982 Asbestos-Associated Disease--Craighead et al 'l ASARCO ALV 0006662 ien described in the reactive euboiil cells that line the air spaces of the ngs in asbestosis.51 Although this Hular lesion often is seen in asbesto3, it is not specific because similar langes occasionally are found in iopathic fibrosis and other types of ilmonary disease55 (Fig 29). No systematic studies of the traleobronchial tree and the pulmonary isculature have been reported in )cumented cases of asbestosis. There :ems to be no specific lesion attribut)le to asbestos in the airways prori al to the terminal bronchioles. Scle>tic pulmonary vascular changes are rident in advanced cases of the disise. Although this may be secondary i the parenchymal lesion and the dated hypoxemia, there is insuffient information available to estabsh the pathogenesis of the lesion. Asbestos workers often are exposed i respirable mineral dusts of a nonfirous type. The pathologist should be lert to the possibility of exposure to a fixture of dusts, even in lungs that chibit large numbers of asbestos odies. Modern analytic techniques ow make it possible to document the resence of such minerals as silica, ale, feldspar, and other aluminum ilicates in lung tissue (Figs 30 and 1). Assay Techniques.--The demonstra- ion of asbestos bodies in lung tissue nth typical fibrotic' lesions is equired to establish the diagnosis athologically. In our experience, hese structures are not distributed niformly in the tissue, even in dvanced forms of the disease. Thus, aultiple histologic sections must be tudied. As previously noted, most of he asbestos fibers in the lung tissue .re not coated and are usually relaively small (ie, <5 pm long). Jncoated short fibers of chrysotile annot be visualized by bright-field, ihase, or polarization light microscoiy, and do not stain by the Prussian due technique. Amphibole fibers are nore easily identified in tissue by ight microscopic techniques. Methods have been developed for he semiquantitative assessment of isbestos bodies and fibers in digesates and incinerated samples of lung issue. These are research techniques, subject to considerable variation in lungs can be evaluated adequately if inexperienced hands, and their value - tissue blocks are obtained from the for the pathologist who is occasionally apices of each lobe and, in addition, responsible for the autopsy of a sub the diaphragmatic portions of the ject with asbestosis is doubtful (ap lower lobes. Samples also should be pendix 1). prepared to include (1) the visceral Despite variations introduced by pleura and subpleural tissue, (2) deep the techniques in use, the burden of parenchyma, and (3) portions of pulmonary fibers in members of the major bronchi, with adjacent paren general population is many times less chyma from each lobe. Examination than in asbestos workers. The data for of the lungs in this manner is neces persons with modest exposure often sary because the lesions of asbestosis are less definitive. The demonstration are distributed irregularly and tend to and measurement of asbestos fibers in be most severe beneath the pleura and lung tissue by these approaches are in the lower lobes. The blocks should not a substitute for careful histologic be appropriately labeled so that the study and the demonstration of asbes distribution of lesions can be assessed tos bodies in association with the typ subsequently. Obviously, additional ical lesions of the disease. blocks of tissue can be selected to evaluate other grossly evident lesions METHODS FOR PATHOLOGIC STUDY Postmortem Studies at the discretion of the pathologist. The processing of tissue requires no special techniques. When asbestos A complete examination of the bodies are common in lung tissue, respiratory tract, including the larynx they can be detected readily using 5- and thoracic cavity, is critical to the to 6-pm-thick sections stained with thorough evaluation of the suspected hematoxylin-eosin. The standard iron case of asbestosis. When pleural stain helps identify these structures. lesions, eg, adhesions and plaques, are Without this stain, one may overlook widespread or a mesothelioma is many asbestos bodies, even when present, the thoracic contents should using high magnification to screen the be removed en bloc. Often this is a tissue. difficult and time-consuming task, . The use of thick sections (eg, =30 but it will yield detailed information ' Tim) has been recommended by several with regard to the severity and distri workers to help demonstrate asbestos bution of the disease. bodies. Although this technique Because pleural plaques often' are. increases the mass of lung tissue found in the absence-of significant examined, it introduces artifacts and pulmonary disease and a documented complicates the detailed evaluation of history of exposure to asbestos, exam the lung tissue. Thick-section exami ination of the parietal pleura is a nation is an ancillary technique that mandatory routine procedure in good can be used when asbestos bodies are autopsy practice. Plaques often are not identified in tissue sections of overlooked and their importance as an standard thickness. indicator of exposure to asbestos is not universally appreciated. Unless Lung Biopsy other considerations dictate, one lung The radiologic demonstration of should be inflated through the major diffuse fibrotic pleural and parenchy airway with buffered formalin; ideal mal disease in a person with docu ly, the perfusion pressure should be mented occupational exposure to regulated to 25 cm H20. Apparatuses asbestos customarily is considered have been fabricated for permanent ample to establish the diagnosis of installation in the morgue, or for rap asbestosis. Lung biopsy rarely is justi id assembly for temporary use. After fixation for at least 24 hours at a sustained pressure, the lungs should be sliced for gross assessment and blocks of tissue prepared for micro fied in such patients unless the evi dence suggests other complicating, treatable conditions. Accordingly, bi opsy of the lung should be carried out when the nature of the pulmonary scopic study. We believe that the lesion is obscure. Vch Palho) Lab Med--Vo! 106. Ocl 8. 1982 Asbestos-Associated Disease--Craighead et at 571 'I ' ASARCO ALV 0006663 572 Arch Pathol Lab Med--Vol 106, Oct 8. 1982 if*' - Asbestos-Associated Disease--Craighead et al 'l ASARCO ALV 0006664 ASARCO ALV 0006665 Pig 26.--Grade 3 asbestosis. Occasionally only "heads" of asbestos bodies are evident in histologic material. They are seen as golden spheres (arrowneads) that approximate pulmonary macrophages in size (hematoxyiin-eosin). 574 Arch Pathol Lab Med--Vol 1C6. Oct 8. 1982 Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006666 \.s noted, the lesions of asbestosis en have a spotty distribution when ! disease is of either mild or moder- severity. Adequate sampling of lung parenchyma is critical and n lung biopsy is strongly recomnded. Transthoracic needle aspiraa and transbronchial biopsy usualdo not yield sufficient tissue to 'mit a diagnosis in these cases, nples of tissue collected by these hniques cannot be used to exclude diagnosis of asbestosis. V biopsy' procedure that yields ated, well-fixed tissue has been cribed." Areas of relatively nor1-appearing and fibrotic lung tis- are identified and sampled to .mine tissue at various stages in evolution of the disease. Severely otic tissue may show honeycomband is of limited use for pathologic erpretation because this lesion is . specific. The tips of the lingula 1 middle lobe are to be avoided ause they often are scarred noncifically. A wedge biopsy specimen mid be preserved in an inflated te at the time of surgery. The lung maintained in distention by the sthesiologist while a wedge is isoed with two sets of clamps. The geon cuts between the clamps and wedge of tissue is given to the hologist, who fixes it with the mps in place to prevent collapse. A hnique for either vascular or bronal perfusion of biopsy specimens i been described." Often, it is useful en the specimen is collapsed. Sputum and Lavage Examination Lsbestos bodies usually are. demonable in sputum specimens from sons chronically exposed to the neral dust and can be present when mges in the chest roentgenogram : not evident.15-" The bodies are ind in the mucin and in close assotion with clusters of alveolar macihages (Fig 32). The presence of >estos bodies in the sputum cannot used as a diagnostic criterion of jestosis. On the other hand, most lestos workers with restrictive pulnary function and radiologic ions yield sputum with asbestos lies. Asbestos bodies in sputum ongly suggest past exposure to asbestos and reflect the presence of a significant asbestos burden in the lungs. Systematic studies of persons exposed to asbestos using the tech nique of bronchopulmonary lavage have not yet been reported. This approach undoubtedly would provide large numbers of pulmonary macro phages for examination, and thus might prove to be a sensitive indicator of exposure. CLINICAL FEATURES OF ASBESTOSIS Asbestosis is clinically indistin guishable from other forms of diffuse pulmonary fibrosis. The clinical pic ture ranges from dyspnea associated with exertion to respiratory failure accompanied by cardiac decompensa tion. In addition to exertional dysp nea, symptoms of early disease in clude a nonproductive cough, fatig ability, and a vague feeling of being "unwell." Obviously, these features are not specific because cardiovascu lar and neuromuscular disorders produce similar symptom complexes. As the fibrotic process progresses, shortness of breath becomes apparent at lesser levels of physical activity and ultimately occurs at rest. Cough may be troublesome and difficult to con trol, although sputum production is unusual in the absence of coexisting chronic bronchitis. There are no specific symptoms and signs of early asbestosis, but endinspiratory crackles (rales) occasion ally are prominent at the lung bases. Crackles are found in a variety of conditions associated with relative underinflation of lung because they result from the rapid opening of peripheral lung units. They are not unique, nor are they more prevalent in asbestosis than in other conditions in which similar pathologic factors exist Thus, the clinician should be cautious in attributing specificity to these sounds or even considering them a sensitive means for detecting early asbestosis. As the disease progresses, lung volume reduction leads to a pat tern of rapid, shallow breathing. Hy poxemia develops when significant ventilation-perfusion discrepancies develop and gas exchange fails. Occa sionally it is clinically manifested as cyanosis, initially on exercise, and in the later stages at rest As with other forms of advanced respiratory dis eases, clubbing of the digits can be present, but it is neither specific nor common in asbestosis. Effusions of serous fluid occasional ly occur in persons with pleural and parenchymal disease due to asbestos. The prevalence seems to be dosage related. Usually, the fluid accumula tions are relatively small and often they are asymptomatic (Fig 7). PHYSIOLOGIC FEATURES OF ASBESTOSIS (PULMONARY FUNCTION) In considering the physiologic con sequences of exposure to asbestos dust, one must distinguish between alterations encountered early in the course of the respiratory disease (such as might be found in a working popu lation) and the impaired lung function associated with well-established, ad vanced asbestosis (which is accompa nied by the characteristic clinical and roentgenographic findings). In the former case, spirometrically deter mined lung volumes and expiratory flow rates are affected adversely in a dose-related manner, at least in the experience of some investigators. This effect can precede roentgenographic evidence of the disease. Similarly, total lung capacity and exercise venti lation become abnormal in relation to the level of exposure to dust. Thus, vital capacity and forced expiratory volumes and flows reflect cumulative exposure. In some cases, diffusing capacities are a sensitive measure of parenchymal disease. That maximum expiratory flow limitation occurs in the early stages of asbestosis is not surprising in view of the pathologic demonstration of bronchiolar lesions in the initial stages of the disease. However, it should not be assumed that clinically significant functional impairment necessarily accompanies early morphologic lesions. Determina tions of pulmonary diffusing capacity can be used to separate persons with well-established asbestosis from those who do not have roentgenographically detectable alterations. Although the diffusing capacity is abnormal in advanced disease, it is not a particularly sensitive means for h Pathol Lab Med--Vol 106. Oct 8. 1982 Asbestos-Associated Disease--Craiflhead et al 575 lI ASARCO ALV 0006667 Fig 27.--Grade 3 asbestosis exhibiting prom inent numbers of muttinucleate cells, many of which contain asbestos fibers and bodies (arrows). Evidence of phagocytosed fibers is variable feature. Muttinucleate cells are partic ularly prominent in case material from Finland, where anthophyllite exposure occurs (hematoxylin-eosin). *76 Arch Pathol Lab Med--Vol 106, Oct 8, 1982 Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006668 ASARCO ALV 0006669 ASARCO ALV 0006670 Fig 28.--Pronvnont accumulations of macrophages in air spaces of lungs of patient exhibiting grade 3 fibrosis. This nonspecific cellular response occasionally resembles tissue reaction observed In desquamative interstitial pneumonitis. Arrows indicate subtle asbestos bodies. ASARCO ALV 0006671 \ i 580 Arch Pathol Lab Med--Vol 106. Oct 8. 1982 Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006672 if' Fig 29.--Network of flocculent hyaline material in alveolar epithelial cell in lung of patient with asbestosis (upper left). This enlarged cell has large nucleus with prominent nucleolus (hematoxylin-eosin, original magnification X 1,250). Upper right and lower left. Electron micrographs demonstrate dense core of inclusion. Lower right, Meshwork of fibrils comprise it (uranyl acetate-lead citrate) (from Kuhn and Kuo5'). Arch Pathol Lab Med--Voi 106, Oct 8. 1982 Asbestos-Associated Disease--Craighead et al 581 ASARCO ALV 0006673 Fig 30.--Lung tissue of patient with advanced asbestosis and evidence of exposure to dusts other than asbestos. Analysis of similar dust maculae in this lung showed crystalline aluminum silicates and anthracolic pigment (hematoxyfin-eosin). Fig 31.--Confluent nodular lesion consistent with silicosis superimposed on lesions of asbestosis. Note deposits of anthracotic pigment and prominent accumulations of mononuclear cells in and around silicotic nodules (hematoxylin-eosin). ASARCO ALV 0006674  Ro 32__ Papanicolaou-stained' sputum smears showing asbestos bodies associated with pulmonary ^cfophaS^w indicates uncoated portion ot asbestos fiber from worker in amosite asbestos pipe insulation plant (from McUrty et al and from Rogl. et at ). Arch Pathol Lab Med--Vol 106. Oct 8. 1982 Asbestos-Associated Disease--Craighead et at 583 ASARCO ALV 0006675 products industry." The appearance of the small, irregular opacities that are believed to indicate pulmonary fibrosis was related to cumulative exposure to dust. Progression of pleu ral thickening and plaques, however, was influenced by the duration of exposure and the elapsed time from initial exposure, but not to cumulative dosage. Fig 33.--Roentgenogram of 68-year-old man who worked for 35 years as insulator. He had no history of cigarette use. His overall health was considered good until about two years before death, when exertional dyspnea was noted. About five months before death, he was forced to retire because of severe respiratory distress. Radiologic examination disclosed evidence of. asbestosis and right pleural effusion. Note linear streaks and small irregular opacities in lungs, and "shaggy" heart border. At autopsy, there was grade 3 asbestosis (from Pathology Annual, 1980:2:77-104). demonstrating a dose relationship in a working population. However, in one study, abnormal diffusing capacity correlated with the severity of the histologic lesion demonstrated in the lung biopsy specimen." ROENTGENOGRAPHIC FEATURES OF ASBESTOSIS The earliest roentgenographic evi dence of pulmonary fibrosis due to asbestos inhalation appears in the lower lung zones. Typically, small, lin ear, and irregular opacities are lo cated symmetrically at the lung bases. The densities usually have a "fine" character, but at times are somewhat coarse. The middle and upper lung zones become involved as the fibrotic process progresses. Subsequently, the densities increase in number and size. Eventually, these opacities may oblit erate the definition of normal adja cent structures, resulting in the so- called shaggy heart and an indistinct diaphragm (Fig 33). Massive conglom erate and coalescent densities are uncommon, but the changes of the honeycomb lung are evident in late stages of the disease. Diffusely dis tributed small, rounded opacities gen erally are not expected as the result of exposure to "pure" asbestos, but are encountered when there also has been exposure to silica dust. Although roentgenographic features of asbesto sis are nonspecific and can be seen in any form of diffuse pulmonary fibro sis, the presence of diaphragmatic plaques and pleural thickening associ ated with fibrosis in the lower lobes strongly suggests the diagnosis. Often, but not invariably, asbestosis is a progressive disease, either with or without continued exposure. Using paired serial chest roentgenograms, evidence of progression was evaluated in workers in the asbestos-building MESOTHELIOMA Malignant mesotheliomas of the pleura and -peritoneum either are exceptionally rare or never occur in persons not exposed to asbestos. It is now apparent that asbestos plays an important role in the pathogenesis of these tumors. Although the relative risk is difficult to determine (as the prevalence in the general population is negligible), mesothelioma accounts for about 10% of all deaths in some occupational groups. In a recent study of insulation workers, 112 peritoneal and 63 pleural mesotheliomas were identified among 2,271 deaths, a prev alence of 8%." By comparison, there were 486 deaths (21%) from lung can cer in the same group. Mesothelioma typically develops many years after the initial exposure; in most series, no increase in frequency is observed before 25 to 30 years have passed, and cases with a latency of more than 40 years have been reported.*0 The protracted interval between exposure and the development of the tumor is important with regard to our expectations for the future occurrence of mesotheliomas. Because a substan tial number of shipyard and industri al workers were exposed to asbestos during World War II, an increasing incidence can be expected during the remaining decades of this century. A rigidly defined relationship to dosage has not been established for mesothelioma, although most cases are found among members of occupa tional groups that experienced heavy exposure. The neoplasm also occurs in persons with relatively limited expo sure. The tumor is found in persons with asbestosis and pleural plaques, but many cases were associated with neither. Malignant mesothelioma in its fully developed form is a diffuse tumor that 584 Arch Pathol Lab Med--Vol 106, Oct 8, 1982 Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006676 ASARCO ALV 0006677  Fig 35.--Histologic features of mesotheliomas. Upper left. Typical epithelial mesothelioma of tubulcpapiltary type (hematoxylin-eosin [HE], X50). Upper right. Tumor shown at upper left illustrating spaces lined by cuboidal cells, and formation of papillary structures within spaces (HE. X500). Lower left. Typical sarcomatous mesothelioma (HE. X50). Lower right. Tumor pattern shown at lower left illustrating spindled cells forming storiform pattern. This pattern of growth is common in sarcomatous mesotheliomas (HE, X500). 586 Arch Pathol Lab Med--Vol 106, Oct 8. 1982 Asbestos-Associated Disease--Craighead et af ASARCO ALV 0006678 Fig 36.--Roentgenograms of 76-year-old fur nace worker with long history of cigarette use. He was hospitalized terminally and died with out treatment. Radiologic studies demon strated immobile right diaphragm and pleural effusion (top). Circumscribed cavitary lesion was found by tomography. Postmortem exam ination showed pulmonary asbest03is (grade t). noncaicified plaques in pleura, and wellditferenb'ated cavitary squamous cell carcino ma. Right pleural cavity contained 300 mL of fluid (bottom). Arch Pathot Lab Med--Vol 106, Oct 8, 1982 Asbestos-Associated Disease--Craighead et at 587 ASARCO ALV 0006679 tends to surround one and sometimes tive, diastase-resistant mucin within both lungs and mediastinal structures cytoplasmic droplets, whereas epithe (Fig 34). In the abdomen, it encases lial cells in mesotheliomas may con the bowel, often leading to obstruc tain glycogen that is removed by pre tion. Less commonly, pleural mesothe treatment with diastase. The epitheli lioma is a discrete mass that invades al ceils of the mesothelioma often lung. In early cases, it may be difficult contain droplets of hyaluronic acid to distinguish the tumor grossly from that do not react with the Schiff pleural plaques (eg, at the time of reagent. This acid polysaccharide exploratory thoracotomy). For this stains with either colloidal iron or reason, the pathologist is advised to Alcian blue; it can be removed by obtain multiple samples of the lesion digestion with testicular hyaluroni- when biopsy is performed for the pur dase. The demonstration of hyaluron poses of diagnosis. Although plaques ic acid by electrophoresis of tumor are found in persons with mesothelio tissue also may be valuable.41 ma, no evidence suggests that meso Electron microscopy probably is of theliomas are derived from plaques. little help in establishing the diagno Asbestos bodies are customarily not sis, because the ultrastructural fea found in the tumor tissue. tures of mesothelioma are similar to Mesothelioma may penetrate the those of many carcinomas and sarco diaphragm and invade viscera. Metas- mas. Specifically, the epithelial types tases once were considered to be an show the features of secretory cells, indicator that a tumor was not a including the formation of lumina, mesothelioma. However, metastases, whereas the sarcomatous forms are particularly within lung and local similar ultrastructurally to fibrosar lymph nodes, are not rare. A charac comas and malignant fibrous histio teristic feature of mesothelioma is the cytomas. tendency to grow along needle tracts In recent immunocytochemical and through surgical incisions. studies, material resembling carci- The microscopic patterns of meso noembryonic antigen was demon thelioma are numerous and not clear strated consistently in both bronchial ly defined, particularly in the case of adenocarcinomas and bronchioloal the sarcomatous tumors (Fig 35). veolar carcinomas, but not in meso Mesotheliomas are grouped generally theliomas.43 On the other hand, inter into epithelial, sarcomatous, and mediate fibers made up of keratin mixed types. Detailed descriptions of usually were found in the cells of the gross and microscopic features of mesotheliomas.43 These new histo- malignant mesotheliomas are beyond chemical approaches may prove help the scope of this monograph and are ful to the pathologist. published elsewhere.* Assistance in the diagnosis of mesothelioma is pro CARCINOMA OF THE LUNG vided by panels of pathologists in both The association of lung cancer with the United States and Canada (appen exposure to asbestos has been estab dix 2). lished conclusively by epidemiologic The most crucial step in the diagno studies conducted in a number of dif sis of malignant mesothelioma is to ferent population groups. Asbestos- distinguish these tumors from prima associated lung cancer usually has a ry bronchogenic adenocarcinomas, latency period in excess of 20 years, and from metastatic carcinoma and but generally occurs at an earlier age sarcoma The autopsy finding of a than does lung cancer in nonexposed typical gross appearance and the persons43 (Fig 36). All histologic types absence of another primary neoplasm are represented, although in some are useful, but care should be taken to series adenocarcinomas predomi rule out the occasional adenocarcino nate.44 The latter neoplasms tend to be ma of lung that spreads over the located in areas of fibrosis and thus pleura Staining for mucins often is are more common in the lower helpful in differentiating an adeno lobes43-44 (Fig 37). carcinoma from a mesothelioma The The relationship of the number of carcinomas often contain PAS-posi asbestos bodies and uncoated fibers in the lungs with the pathogenesis of the neoplasm has not been resolved. The greater the cumulative exposure to asbestos, the higher the risk of lung cancer developing.47-19 All types of as bestos seem to be carcinogenic; how ever, the relative carcinogenicity of each type of asbestos is not defined and remains a matter of controversy. Asbestos workers who smoke have an incidence of lung cancer higher than that of nonexposed smokers and of those who work with asbestos but do not smoke.30 In one study of insula tion workers,' nonsmokers had an approximately fivefold increase in the risk of lung cancer compared with a nonsmoking population.31 This in crease in prevalence of neoplasms in nonsmoking asbestos workers has not been found in most studies. On the other hand, the risk of lung cancer was increased greater than 50-fold in asbestos workers who smoked, com pared with nonsmokers who lacked exposure to asbestos.30-31 These obser vations cannot be accounted for on the basis of an additive effect of two independently acting carcinogens, which suggests that asbestos and cig arette smoke act synergistically.33 PATHOGENETIC IMPORTANCE OF DIFFERENT TYPES OF ASBESTOS Asbestos is not one, but a number of different, commercially available, fi brous minerals that have different physical and chemical properties. Fiber length and diameter, as well as the fiber aspect ratio (ie, ratio of length to diameter) are critical with regard to transport of particles in the respiratory tract. The diameter of the fiber is a major determinant of the depth of penetration into the lung.33 All types of asbestos can produce pulmonary fibrosis, and no evidence suggests that the morphologic fea tures of the lesions differ. This state ment must be qualified, however, because much of the case material available for study represents severe, far-advanced disease in which subtle differences in the pathogenicity of the dust and the morphologic aspects of the lesion would be difficult to dis cern. In addition, documentation of exposure to only one type of mineral 588 Arch Pathol Lab Med--Vol 106. Oct 8. 1982 Asbestos-Associated Disease--Craighead at al ASARCO ALV 0006680 Fig 37.--Top, Che3t roentgenogram of 44year-old man whose chest film had been normal three years earlier. Solitary right lowerlobe lesion is seen, with slight increase in linear, reticular marking in both lower lung fields. No pleural changes are evident. Patient had been exposed to asbestos for t7 years while working as boiler tender in Navy. He had smoked two to three packs of cigarettes per day for 30 years. Ventilation perfusion scan was normal, except for evidence of chronic obstructive pulmonary disease. Patient under went right lower lobectomy. Bottom, Right lower-lobe lesion proved to be adenocarcino ma. presumable arising in scar.' Asbestotic lesions of varying severity were located else where in specimen (see Figs 21 and 28). This finding emphasizes importance of thorough evaluation of pulmonary tissue in persons exposed to asbestos (hematoxylin-eosin). & _i*. * v Arch Pathol Lab Med--Vot 106, Oct 8. 1982 Asbestos-Associated Disease--Craighead et al 589 ASARCO ALV 0006681 Fig 38.--Recommended sites (or preparation of tissue sections in left lung. Right lung is sampled in similar manner, although specimens are also prepared from middle lobe. can rarely be established with cer tainty. From a practical point of view, it must be emphasized that many commercial asbestos products contain mixtures of more than one type of fiber. Because exposure may occur over a worker's lifetime, and because industrial processes change and are often poorly documented, it is rare when only one type of fiber is involved in the disease. The physical characteristics of the fiber seem to be of paramount impor tance in mesothelioma. When either naturally occurring or man-made fibers are introduced experimentally into the pleural cavity of rats, those fibers longer than 8 #rm and of a diameter less than 1.5 pm produce mesotheliomas with a high degree of efficiency.1 Because the chemical com position and origin of the material does not seem to be critically impor tant, the aspect ratio of the asbestos particles must be a factor that deter mines the pathobiologic properties of a mineral species. A possible confir mation of this notion has come from recent reports of mesothelioma that developed in persons who lived in areas of Turkey where the soil and building materials contain large amounts of a zeolite fiber, erionite.22 These fibers are similar in size and shape to many types of amphibole asbestos, but they are dissimilar structurally and chemically. The importance of different types of asbestos in the pathogenesis of meso thelioma in man has been explored in numerous epidemiologic studies. Anthophyllite failed to produce the tumor, even though pleural plaques occur commonly in populations ex posed to this mineral." The apparent benignity of anthophyllite is believed to reflect the relatively broad diame ter. of its fiber. Mesotheliomas, were strongly associated with crocidolite. However, the physical characteristics of this mineral type (and, thus, the prevalence of mesothelioma) differ from one mine to another. Crocidolite from the Transvaal region of South Africa is considerably less likely to induce the tumor than are the fibers extracted in the Northwest Cape region.' The importance of chrysotiie in the etiology of mesothelioma is less clear, and the question remains a sub ject of controversy. HOST FACTORS IN ASBESTOSIS Although persons may differ in their susceptibility to the pathologic effects of asbestos* the possibility is not well documented. A genetic pre disposition to asbestosis has been sug gested. In two studies, HLA-B27 was demonstrated more commonly in per sons with asbestosis than in members of the general population."-54 Subse quent investigations failed to confirm this observation.57 Additional detailed studies using carefully selected groups of patients and controls will be required before- possible association between a specific histocompatibility antigen and disease can be estab lished. Immunologic aberrations have been documented in blood sera of workers exposed to asbestos, especially those with roentgenographic evidence of disease. Considerable clinical evidence suggest that disturbances of immunoregulation may be operative in asbes tosis. For example, impaired expres sion of cell-mediated immunity has been demonstrated5*^0 Persons with asbestosis also exhibit altered humor al immune responsiveness, as exem plified by the occurrence of nonorgan-specific autoantibodies (rheu matoid and antinuclear factors) in relatively low concentrations in the blood serum.41-42 Increased concentra tions of serum secretory immunoglob ulin are frequently noted. The patho genetic and clinical significance of these immunologic alterations have not been defined. Because similar aberrations are observed in other forms of interstitial lung disease, the finding lacks diagnostic significance. 590 Arch Pathol Lab Med--Vol 106, Oct 8, 1982 Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006682 Appendix 1: Methods for the Assessment of Lung Fiber Concentrations Techniques have been developed to neasure the relative numbers of incoated and coated asbestos bodies n lung tissue. Most of the studies thus :ar reported have been performed on lutopsy specimens, although biopsy material also can be used. Although these techniques seem simple, labora tories differ in the number of fibers demonstrated in tissues from persons with seemingly comparable degrees of exposure. Experience and critical con trol of variables are required to obtain meaningful data. Unfortunately, as of this writing only a few laboratories in North America accept specimens of tissue for routine quantitative study. (Interested parties should write to the authors for further information.) The size (particularly length) and the relative number of coated and uncoated particles in the lung influ ence the sensitivity of the method. Because some asbestos fibers either break down into smaller subunits in tissue over time or are inhaled as small particles, the burden of dust in the lung may not be reflected accu rately in light microscopic counts of fibers longer than 5 jim. In addition, the various types and sizes of fibers are probably cleared from the lung at different rates. These considerations provide some basis for the observation that particle counts by light microsco py do not correlate directly with the severity of the pulmonary parenchy mal disease. Both formalin-fixed and fresh lung tissue can be used in the techniques to be described. Contamination of the fixative and glassware with asbestos theoretically is a problem because many municipal water supplies con tain fibers in concentrations of 1 to 5 X 10VL. This may prove to be an important consideration in some labo ratories. Examination of histologic sections from patients with asbestosis has demonstrated the uneven distribution of asbestos bodies in the lungs. This finding has been confirmed by quanti tative studies.17-47 In addition to seem ingly random variation within a given area of parenchyma, short fibers tend to concentrate under the pleura. An uneven distribution of fibers seems to be greater in scarred lungs. .These factors should be borne in mind when. selecting tissue for analysis; for exam--' pie, variations in fiber distributionmay make the use of small biopsy specimens unreliable. Most published studies used one of the following two techniques. In one, fixed lung tissue is dissolved in sodi um hypochlorite (Chlorox). The resulting slurry is washed to remove organic debris and the material col lected on a membrane filter. The filter then is mounted on a slide and exam ined in a light microscope to demon strate fibers and asbestos bodies.*444 Alternatively, pieces of the filter can be placed on electron microscope grids and the fibers transferred to the grid by dissolving the filter in an appropri ate solvent. This method has the advantages of (1) gentle chemical digestion, (2) maximal concentration of the sample (a feature of great importance in persons whose exposure has been minimal), and (3) the preser vation of a permanent sample for light and electron microscopy. These preparations are excellent for count ing asbestos bodies by light microsco py and uncoated fibers by electron microscopy, but are not suitable for counting uncoated fibers by light microscopy. Ashcroft and Heppleston described an alternate method.47 Tissue is dis solved in concentrated potassium hydroxide solution and an appropriate volume of the digestate is placed in a standard counting chamber to be examined by phase-contrast micros copy. Generally, this method neither produces as much concentration of the sample as the technique just de scribed, nor is the counting chamber sample permanent. However, it does permit counting of long (>5 ^m) uncoated fibers by light microscopy. Determination of the number of asbestos bodies in lung tissue digestates provides a quick, although some what crude, estimate of the pulmo nary burden of fibers. When many bodies are found by this method, the result usually can be considered indic ative of substantial exposure to asbes tos (although the actual values found in patients with occupational expo sure vary from laboratory to laborato ry). When small numbers of bodies are identified, occupational exposure is less certain. As discussed in the section entitled "Asbestos Fibers in Tissue," refined analytical studies are required to document the types of minerals present in tissue. The num bers and types of asbestos fibers and bodies found in patients with various asbestos-related diseases are detailed in several reports.41-** Arch Pathol Lab Med--Vol 106. Oct 8, 1982 Asbe3tos-Associated Disease--Craighead et at 591 ASARCO ALV 0006683 Appendix 2: Mesothelioma Panels Panels of experienced pathologists were established by the Union Inter nationale Contre Cancer (UICC) Working Group on Asbestos and Can cer in 1964 to provide a referral mech anism for the diagnosis of this rela tively rare tumor. The function of these panels was recently evaluated.TM In 1972, the US panel reviewed 168 cases. Of the lesions, 70% were con sidered either probable or definite mesotheliomas and 16% were thought to be possible mesotheliomas. In the remainder, the diagnosis of mesothe lioma was rejected. Members of the panel customarily concurred; in only 10% of the cases was there substan tial disagreement. The present US panel organized under the auspices of the UICC is chaired by Charles Carrington, ML (Department of Pathology, Stanford University, Stanford, CA 94305). The Canadian panel is chaired by W. T. E. McCaughey, MD (Clinical Studies Unit Bldg, 60 Ruskin Ave, Ottawa. Ontario, Canada K1Y 4M9). Appendix 3: Pathologic Grading of Asbestosis The classification and grading of morphologic lesions has potential use in epidemiologic investigations and correlative studies of various aspects of disease. A useful system should be functional and acceptable to the pathologist who is expected to apply it consistently and in a reproducible fashion. In addition, the interobserver variability must be sufficiently low to permit the application of the system to studies that involve large numbers of cases and, thus, different patholo gists. In 1965, the Working Group on Asbestos and Cancer of the UICC rec ommended a classification schema for asbestosis that was based on both the assessment of the severity of fibrosis and the extent of the changes in the lung as a whole.71 Shortly thereafter, Hinson et al77 proposed a grading pro tocol based on gross and microscopic criteria that could be applied to pul monary fibrosis in general, and to asbestosis specifically. To the best of our knowledge, this grading system has not been applied systematically in large-scale studies. Grading protocols for the radiologic assessment of the pneumoconioses are at an advanced stage of development Groups of radiologists working large ly under the auspices of the UICC and the International Labor Organization (ILO) proposed protocols that were generally accepted and have been applied in numerous epidemiologic studies. Moreover, it has been possible to train many radiologists in many parts of the world in the application of the system. The UICC and ILO grading systems were developed with silicosis and coal workers' pneumoco niosis in mind, and were not as appli cable to asbestosis as might be desired. Because of this problem, the standard UICC and ILO systems were amalgamated into the UICC-ILO 1971 system (updated in 1980), which now is used universally for all pneumoco nioses, including asbestosis. To date, no attempt has been made to correlate the radiologic severity of disease with studies of pathologic material. A universally acceptable grading system for pathologic evaluation of fibrotic lungs would have relevance to the clinical and radiologic investiga tion of asbestosis. In addition, it could provide a common language for com munication among pathologists and with other groups in the health fields. The histologic grading system pro posed here is a further modification and extension of the protocol of Hin son et al,7! although it is based exclu sively on microscopic criteria. It pre supposes systematic study of the lung tissue at the time of autopsy and requires the representative sampling of the lungs described earlier (see "Methods for Pathologic Study) (Fig 38). Although perfusion fixation would be highly desirable, the schema is applicable to lung tissue obtained under less-than-ideal conditions of fixation (ie, without perfusion). It also can be used in the evaluation of lung biopsy material, accepting the limita tions of the sample. Under this cir cumstance, evaluation of the patho logic material might appropriately be carried out in conjunction with radiologic studies to assess the distribution of disease. GRADING OF ASBESTOSIS The grading system is intended only for the semiquantitative estimation of the degree of asbestosis, and not as an aid to diagnosis. Therefore, the diag nosis of asbestosis should be estab lished before grading is attempted. Because fibrosis of the peribronchio lar and interstitial tissues is the key lesion in asbestosis, this grading sys tem is based solely on the evaluation 592 Arch Pathol Lab Med--Voi tOS. Oct 8. 1982 Asbestos-Associated Disease--Craighead et ai ASARCO ALV 0006684 some alveoli may be obliterated com pletely. Grade 4: Fibrosis appears as in grade 3, but with formation of new spaces of a size larger than alveoli, ranging up to as much as 1 cm; this lesion has been termed honeycombing. Spaces may or may not be lined by epithelium. Description of a hypothetical case. 4UL indicates right upper lobe; RML, right middle lobe; RIL. right lower lobe; LUL. left upper lobe; and LLL, ower lobe. Second slide missing. 3rade is total score divided by the number of lobes examined. Table 2.--Asbestosis Grading Schema Score Magnitude of increase Score Magnitude at increase Grades Prom Products 12 3 4 2X I.5X I.3X Straight Grades 1+ 2+ 3+ 4+ 2X 1.5X 1.3X 6 1.5X 541.25X 8. 9 1.5X 6+ 1.2X 12 t.3X 7+ MX 'Quantitative comparison of incremental intervals between histologic grades, determined either as a duct (severity X extent) or as an evaluation of sequential changes in disease seventy. fibrosis. Numbers of asbestos dies, macrophages, and inflammary cells within the tissues and anges in the epithelium are not nsidered. Each histologic slide is evaluated om two perspectives. Initially, the verity of the lesion either in or grounding the bronchioles is as;ssed and the numeric score reirded. Then, the proportion of the ronchioles in the section that have ny degree of involvement is evaluatd (not just the proportion involved to he most severe degree). This grade, hich represents extent of disease, is ecorded as a letter score. To establish an overall grade for a issue section, the distribution letter core is converted to a number and nultiplied by the lesion score. To haracterize the disease of a patient, he products of the scores of all the slides are added and the sum divided oy the number of slides examined. This average indicates the degree of disease. Table 1 gives data from a hypothetic case to demonstrate the suggested format for recording data. ASBESTOS1S GRADING SCHEMA Severity Lesions associated with individual respiratory bronchioles are evaluated. The grade is based on the most severe lesion in the slide, not a visual average of the changes found in the various individual respiratory units, as fol lows. Grade 0: No fibrosis is associated with bronchioles. Grade 1: Fibrosis involves wall of at least one respiratory bronchiole with or without extension into the septa of the immediately adjacent layer of alveoli; no fibrosis is present in more distant alveoli. Grade 2: Fibrosis appears as in grade 1, plus involvement of alveolar ducts or two or more layers of adja cent alveoli; there still must be a zone of nonfibrotic alveolar septa between adjacent bronchioles. Grade 3: Fibrosis appears as in grade 2, but with coalescence of fibrotic change such that all alveoli between at least two adjacent bron chioles have thickened, fibrotic septa; Extent The proportion of the respiratory bronchioles involved by the disease process is assessed. The grades per tain to the relative numbers of bron chioles in the slide involved by any degree of- fibrosis--not just the num bers involved to the maximum .degree as recorded under severity--as fol lows. Grade A (1) Only occasional bron chioles are involved--most show no lesion. Grade B (2): More than occasional involvement is seen, but less than half of all bronchioles are involved. Grade C (3): More than half of all bronchioles are involved. Multiplication of the scores for severity and extent requires explana tion because it might be argued that a product score is inappropriate. For example, a product score of 4 obtained on a tissue with grade 4 severity with an extent score of A has implications with regard to disease that differ from a tissue with grade 2 severity and grade B extent. Although theoret ically the validity of this argument cannot be refuted, in the evaluation of our case material the severity and extent of the lesions were not found to vary independently, but seemed to be interdependent. Thus, severe lesions are usually found when disease is widespread in the tissue. The second concept, which argues for the multiplication of the severity and extent scores, relates to the range of possible scores that result (Table 2). Thus, the products of grades (1 x 1, 1X2, 2X3, etc) produce a series of eight possible scores (1, 2, 3, 4, 6, 8, 9, and 12). As shown in Table 2, the magnitude of increment between products remains relatively constant throughout the range. This is not the case when a numeric grading system (1+ through 74-) is used (Table 2). Arch Pathol Lab Med--Vol IOS. Oct 8. 1982 Asbestos-Associated Disease--Craighead et al 593 ASARCO ALV 0006685 Appendix 4: Preliminary Evaluation of Grading Schema We evaluated the proposed grading system using pathologic material in the files of the Armed Forces Insti tute of Pathology, Washington, DC. In this study, we were interested only in determining the applicability of the system to a series of cases of asbestosis of varying degrees of severity and assessing preliminarily both the in terobserver and intraobserver varia tions in scoring. Two tissue sections from each of 20 representative cases were chosen by John Rust, MD, of the Pulmonary Disease Section, Armed Forces Institute of Pathology. Nine pathologists (ourselves and Dr Rust) :hen reviewed the material micro scopically. All 40 slides were exam.ned once by each participant, and 20 slides were evaluated twice, once in :he morning and again in the afterloon. The results of an analysis of ntraobserver variability in the evalultion of the 20 histologic sections are pven in Table 3. As can be seen, jbservers scored slides differently on. ;he two occasions, but the average ilgebraic' difference between the noming and afternoon readings for she group as a whole wa3 --0.3. Disrejarding temporal considerations, the /ariability was 0.47, which is 4% of he total possible range of 0 to 12. iVhen the mean of all differences in .he scoring of individual slides is evallated, the average difference was only 1.3 (ie, 10.8% of the total possible range). This latter analysis magnified differences maximally. We concluded that the degree of intraobserver vari ability was acceptable. The average scores of the nine pathologists on all 40 slides for morn ing and afternoon readings are given in Table 4. As might be expected, differences between observers were found, but the SD of the mean score (6.5) for all readings was 0.8. This SD is 12% of the mean value, or 7% of the total range. The coefficient of correlation be tween the scores of every possible pair of pathologists on individual slides was evaluated. The average of all coef ficients was .69 (P < .0001). Parametric statistical methods were used in these evaluations. It could be argued that this approach is inappropriate as the "scores" are not a true measure of disease. According ly, a nonparametric analysis was also carried out." In this evaluation, the data on the cases were arranged in order of increasing severity as deter mined by each pathologist, and the agreement in ranking by the observ ers was analyzed. When the coeffi cient of concordance was determined, the overall concordance among the pathologists as a group was +.71 (.P = .001). Additional analyses were per formed to address objections to a grading system based on the multipli cation of the extent and severity scores. The measures of severity and extent were evaluated individually by determining the agreement between all possible pairs of pathologists. With both measures, it was found that the scores of the pairs of observations were identical for more than half of the slides reviewed. In nine of ten slides, the maximum discrepancy was only one grade. The preliminary evaluation was carried out by pathologists who have a special interest in pulmonary disease. The members of the group had worked together to evaluate pathologic mate rial from almost 200 cases of asbestosis. It would be unrealistic to suggest that they are unbiased subjects for a test of the proposed grading system. Nonetheless, it is evident that agree ment among members of the group with regard to evaluating both severi ty and extent of the lesions was excel lent. At this juncture, further evalua tions of the grading system by pathol ogists with different backgrounds seems appropriate. In addition, studies should be undertaken to deter mine whether the pathologic and radiologic grades correlate. Table 3.--Evaluation of Asbestosis Grading Schema* Pathologist 1 2 3 4 5 6 7 8 9 Average Mean Algebraic Difference 0.5 -0.7 -0.3 0.1 -0.6 -0.1 -0.3 -0.7 -0.7 -0.3t Mean Random Difference 0.5 0.7 0.3 0.1 0.6 0.1 03 0.7 0.7 0.47* Mean Absolute Difference 1.6 1.0 1.6 1.1 1.8 1.3 1.0 1.3 1.3 1.3 *lntraobserver variation in the evaluation of disease grade for 20 histologic ections examined by nine pathologists in the morning and afternoon of the same ay. tAfterooon grades were slightly lower than the morning grades. {Score is 4% of total range (0 to 12). Score is 10.8% of total range (O to 12). Table 4.--Asbestosis Grading Test* Pathologist 1 2 3 4 5 6 7 8 9 Average Slide A (AU) 7.4 7.1 8.0 6.6 6.8 5.4 5.6 6.8 6.1 6.6 Slide A (PU) 7.8 6.4 7.7 6.7 5.9 S.4 5.3 6.1 5.5 6.3 Slide B (AM) 7.9 7.1 7.0 7.5 7.0 5.6 4.4 6.3 5.7 6.5 Average 7.7 6.9 7.6 6.9 6.5 5.5 5.1 6.4 5.6 6.5 0.8f * Mean of the grades determined on 20 histologic sections by nine pathologists in the morning and afternoon of the same day. fTbe SD is 12% of the mean. 94 Arch Pathol Lab Med--Vol 106, Oct 8, 1982 Asbestos-Associated Disease--Craighead et al ASARCO ALV 0006686 Daring its deliberations the Committee condied many scientists and pathologist* in this ,untry and abroad* including the following. . . like Attfield, MS, Appalachian Laboratory for ccupationaJ Respiratory Disease, NIOSH. Mormiown, WVa rufessor Jean Bignon, Laboratoire de Recher\es sur lea Affections Respiratoires et L'envinnement, Cretcil, France harles Carrington, MD, College of Medicine, tanford University, Palo Alto, Calif rian Corrin, MD, Bromptom Hospital, London ohn M. Dement, PhD, Appalachian Laboratory >r Occupational Respiratory Diseases, NIOSH, lorgantown tiward A. Gaensler, MD, School of Medicine, oston University . Donald Greenberg, MD, College of Medicine, aylor University, Houston lusseli A. Harley, Jr, MD, School of Medicine, `niversity of South Carolina, Charleston aul Kotin, MD, Manville Corp, Denver larvin Kuschner, MD, College of Medicine, State 'niversity of New York at Stony Brook ames A. Merchant, MD, Appalachian Laboratoy for Occupational Respiratory Diseases, .'IOSH, Morgantown .. 0. Meurman, MD, University Hospital, Turku, 'inland loger Seal, MD, Llandough Hospital, Penarth, Glamorgan, United Kingdom rving J. Selikoff, MD, Environmental Science Laboratory, Mt Sinai School of Medicine, New York.- Professor P. Sebastian, Direction des Affaires Sanitaires et Sociales, Paris Geoffrey Taylor, MD, Wausau Medical Center, Wausau, Wise J. H. Tucker, Appalachian Laboratory for Occu pational Respiratory Disease, NIOSH, Morgan town Frank Whitwell, MD, Broadgreen Hospital, Liv erpool, England Ralph Yodaiken, MD, NIOSH, Rockville, Md J. C. Wagner, MD, of the Medical Research Council, Pneumoconiosis Unit, Llandough Hospi tal, Penarth, Glamorgan, graciously provided case material for the study of the committee, including the material shown in Figs 15 and 31, and spent many hours discussing his views on the pathologic aspects of the disease with the chair man. We wish to acknowledge the interest and help of Peter C. Elmes, MD, director of the unit, and the members of his staff. Liselotte Hochholzer, MD. director of the pul monary disease section, Armed Forces Institute of Pathology, and her associate John Rust, MD, made available selected material from the collec tion of the institute for the purpose of evaluating our grading system. COL Elgin Cowart, director of the institute, provided support and encourage ment. Jean R. Lemieux, MD, Directeur des Services Medicaux, and Louis-Gilles Cloutier, MD, of the Commission de la Sante et de la Securite du Travail du Quebec, made available for study representative histologic sections of asbestosis from the province of Quebec. Much of this case material had been previously examined and clas sified by the late Roland Guy, MD, consultant pathologist to the commission for several decades. We sincerely acknowledge the privilege granted us to review this valued material. Yrjo Collan, MD, professor of pathology and director of pathology at the University of Kuo pio, Finland, graciously provided pathologic material from Finland for study, including the material shown in Fig 27. Jack Abramowitz, MD, of the Institute of Occupational Health, Johannesburg, South Afri ca, made available to the committee material from his country* for study. The collection of pulmonary diagnostic materi al assembled by the late Averrill A. Liebow, MD, was used in this study. The Department of Pathology, University of California (San Diego), gave us access to the collection. The illustrations shown in Figs 2 and 3 were supplied by Craig Woodworth, University of Ver mont, Burlington. The illustrations shown in Fig 9 were supplied by L. O. Meurman, MD, University Hospital, Ttirku, Finland. The material shown in Figs 18, 22 and 24 was supplied by Russell A. Harley, MD, University of South Carolina, Charleston. The material shown in Fig 19 was supplied by D. Groth, MD, NIOSH, Cincinnati. The material shown in the color figure on the inside back cover was supplied by-Serge Masse, MD, University of Sherbrooke, Quebec. 1. Zenker FA: Iron lung: Sclerosis pulmonum. Jtsch Arch Klin Med 1867;2:116-120. 2. Cooke WE: Fibrosis of the lungs due to the nhalation of asbestos dust Br Med J 1924;147- 50. 3. Lynch JM, Smith WA: Pulmonary asbesto- :is: Carcinoma of the lung in asbesto-silicosis. Im J Cancer 1935;24:56-64. - ... 4. Klemperer P, Rabin CB: Primary neoplasms f the pleura. Arch Pathol Lab Med 1931;11:385-. H2. 5. Weiss A: Pleurakrebs bei Lungenasbestose, n vivo morphologisch Gesichert MedizinUche .953;3:93-100. 6. Leichner F: Primary mesothelial-cell tumor if the peritoneum in asbestosis. Arch Geicerbe- x:thol Gewerbehyg 1954;13:382-390. 7. Wagner JC, Sleggs CA, Marchand P: Diffuse )ieural mesothelioma and asbestos exposure in Northwestern Cape Province. Br J Ind Med 1960,17:260-270. 8. 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