Document dYeRLbb00dgoaVGZoZdpLRKK0

Pathology of Human Asbestosis: A Critical Review t Victor L. Roggti, M.D. Deportment of Pathology. Du am Veterans Administration and Duke University Medical Centers. Durham. North Carolina p Although health hazards related to exposure lo asbestos dust have been recognized since ancient times, it was not until after the widespread usage of asbestos during the Industrial Revolution that asbestos-related pulmo nary disease was identified and defined in modem terms.1 Dr. H. Mon tague Murray is generally credited with the first description of asbestos-re lated pulmonary disease, which was reported to a British parliamentary committee in 1906.2 The patient was a 33-year-old man who had worked for 14 years in the carding room of an asbestos textile plant In 1914, the German pathologist T. Fahr described the characteristic appearance of pul monary interstitial fibrosis in a 35-yrihr-old asbestos worker. Fahr called at tention to crystals in the lung tissue and attributed the pulmonary fibrosis to asbestos exposure, *' Dr. W.E. Cooke provided the first detailed de scription of asbestosis in the general medical literature in 1924 and subse quently coined She lerm asbestosis.4 Since then, numerous cases of asbes tosis have been published in the medical literature in workers exposed (o asbestos dust through mining and milling, manufacture of asbestos prod ucts, or utilization of asbestos-containing products.1 Asbestosis has subsequently been defined by a number of investigators in slightly different ways,5' 7 but none of these definitions has gained wide acceptance or been uniformly applied by pathologists. The most compre hensive description of asbestosis and perhaps most widely cited definition are found in the 1982 report*1 of the Pneumoconiosis Committee of the College of American Pathologists and the National Institute for Occupa tional Safety and Health. This group defined the minimum features that, permit the morphologic diagnosis of asbestosis as the "demonstration of discrete foci of fibrosis in the walls of respiratory bronchioles associated with accumulations of asbestos bodies." In addition, a scheme for the pathologic grading of asbestosis was proposed, and the inlraobserver and interobserver variability lor pathologists using this scheme was assessed. Although previous protocols for the histologic grading ol asbestosis had been published,11 they have not been 'applied systematically in largescale studies.8 Atfi> P.Nh.'f V M mi l*m'f t !' Vivtr lU.ik tni t*4) w h* 31 HWBUI0010438 ncenc Ma otic Tend E llis S. Benson, M.D. Professor and Head, Department of Laboratory Medicine and Pathology. University of Minnesota Medical School. Minneapolis, Minnesota 03 3 &o ? 3 n 5D* 8 &3 'Ccr SO33*r CO y X. S or'c Ksr o3-' O3 ! pi * p) ?3 crS ^a mg. QO3 Bl m *OCr o p s>: o3 3. 3' Q3 O. Q3 a fl) 3, 3* tff6t 3 Q 5' r t ~uu* A c A 0. I^ & CD a *o 5 3* oI* H?* . s? 2 b3 OO HWBUI0010439 Though corr-iprehensivt; in its scorn;, Ihe aforementioned description ol asbestosis leaves a number of questions unanswered. How many asbes tos bodies rnusl be observer! before the diagnosis of asbestosis can be made? 1 bis point is not directly addressed, although the description o! "as bestos bodies" presumably means at least two. Other investigators have suggested tbal urn; asbestos body is sultioienl when found in the presence ol (lifluse interstitial fibrosis," whereas others have staled that "clusters of three" asbestos bodies are needed.12 Also left unspecified are the number ol lissue sections lhal should be searched (or asbestos bodies, the magnifi cation to be used in the search, or whether hematoxylin and eosin (H&E) or iron-stained sections should be examined. In addition, the preferred staining method {H&E or Masson's trichrome) for assessing fibrosis is not identified. It is the purpose of this study lo.describe in detail the pathologic features of asbestosis, to address the questions outlined above, and to ex amine the rote of quantification of tissue asbestos burden in our under standing of human asbestosis. Asbestos and Asbestos Bodies Asbestos, from the Greek word meaning "unquenchable," refers to a group of fibrous silicates with the qualities of thermal and chemical resis tance. flexibility, and high tensile strength. As a result of these qualities, asbestos is an extremely useful material for many industrial applications, and thus it has been incorporated into more than 3,000 commercial pro ducts.1'' The two major types of asbestos are serpentine and amphibole forms (Table l). Chrysotile is the sole fibrous member of (he serpentine family of minerals, and it accounts for some 90% to 95% of asbestos used commercially. The fibers tend to be curly rather than straight, a feature that derives from mismatching of the sheet silicate and brucile layers in the crystal structure.M Chrysotile has a very unusual structure, which consists TABLE 1. Types of Asbestos ______ Serpentine Chrysotile Commercial amptiibotes Amosile Crociriolite Noncommercial amptiibotes Aclinolite Anlhophyllile Tremolilc )**/)/*r/v / f fnin A i nlu tit /{rrm*n> ` A 1 of a magnesium silicate forming a sheet that is rolled up like a scroti. Con sequently, each individual fibril has a centra! capillary that can be readily visualized at high magnification in a transmission electron microscope. Chrysotile fibers are composed of numerous individual fibrils, and the fi bers have a tendency to split longitudinally into smaller fibrillar bundles or individual fibrils. The amphibole group includes commercially valuable forms, crocidoiile and amosile, and the noncommercial forms, tremolite, anlhophyllile, and actinolite.IS The latter are primarily important as con taminants of other minerals, such as talc or chrysotile asbestos. All of Ihe amphibole fibers lend to be straight and do not break apart into individual fibrils as readily as does chrysotile. The amphiboles are distinguished from one another based on differences in chemical composition. 14~16 Asbestos bodies are the histologic hallmark of prior exposure to asbes tos. They were first described as "pigmented crystals" In the lung by Marchand in 1906,17 and early observers apparently confused these golden brown, segmented structures with fungi.'1 Cooke1 and Gloyne18 were among the first to recognize that these curious bodies had asbestos fibers al their core. They were initially termed asbestosis bodies, which was subsequently changed to asbestos bodies when it was discovered that they occurred In the lungs of some workers who did not have asbestosis.1 Ex perimental animal studies showed that a number of fibrous dusts (fibrous aluminum silicate, silicon carbide whiskers, cosmetic talc, and fibrous glass), when administered by intratracheal instillation into the lungs of hamsters, resulted in the formation of structures indistinguishable from as bestos bodies. These findings led Gross et al.19 to propose Ihe noneommilal term "ferruginous body" when the precise nature of Ihe fibrous core was unknown. Churg and Wamock20-2 then employed energy dispersive spectrometry and electron diffraction to show that ferruginous bodies iso lated from human lungs and having a thin, translucent fibrous core were virtually always true asbestos bodies. The structure and development of the asbestos body has been described in detail by Suzuki and Churg22 and more recently by Churg and Warnock,2-1 and Morgan and Holmes.24 Asbestos bodies form when an asbes tos fiber is inhaled and deposited in (he distal regions of the lung paren chyma. Here the alveolar macrophages attempt to phagocytose the fiber (but fail because of its size) arid in Ihe process cover the fiber with a layer of ferroprotein material. The iron component gives the structure its charac teristic golden brown appearance and also gives a strong reaction with the Prussian blue slain. The peculiar segmentation is thought to be due to frag mentation of the smooth, sheath-like coating, and it is thought that further "weathering" and dissolution of the coating eventually occurs.2'9,26 This sequence of events has been supported by scanning electron microscopic observations of asbestos bodies isolated from human tissues.27 Hence for mation of asbestos bodies is a dynamic process, with libers becoming coated, Ihe coating material undergoing segmentation and dissolution, and Hie fiber eventually becoming uncoateri and thus available to initiate ihe process all over again. Asbestos bodies are gonoi.itlv 2 to A jini in diamc- HWBUI0010440 V I. tiiKpili Asbeslos Consumption Asbestos Body Composition 90 15 V. Chi yfiolil* / 96 V. '\ Commercial AwpNibeles Amositi nnd CrocldolMe \5&IO' %J Cf OCidoiile Chf ysotflo Non-**' Commercial AmoMbples Percent of Totat Composition of Asbestos Consumption Asbestos Body Cores FIG 1. The industrial consumption ol asbeslos by fiber type compared with the composi tion ol the cores ol asbestos bodies by liber type. (From Roggli VL, Brody AR: Im aging techniques for application to lung toxicology, in Gardner DE. Crapo JD, Massaro DJ (eds): Toxicology of the Lung, New York, Raven Press, 1988, pp 117- M5. Used by permission.) i I I ler, 21 allhough by scanning electron microscopy I have observed bodies that were only about 0.5 p.m in diameter. Their length ranges from 10 to over 250 p.m23 and averages about 35 p.m.2fl Fiber length is an important variable in determining the formation of asbestos bodies: Morgan and Holmes29 have shown that fibers less than 20 p.m in length rarely become coated, whereas virtually all fibers 80 p.m or greater in length are coated. The vast majority ol asbestos bodies isolated from human lungs have an amphibole asbestos core: commercial amphiboles, amosile or crocidolite, form the cores of most bodies isolated from the lungs of asbestos work ers'6 and of men in the general population,30 whereas noncommercial am phiboles, tremolite or anlhophyllite, account for most of the bodies isolated from women in the general population.30 This finding is possibly related to i contamination of commercial talcum powder with tremolite and anlhophyl lite. The predominance of amphibole asbestos body cores is somewhat cu rious, considering that the bulk of asbestos used commercially is chrysoble asbestos {Fig 1). The reason for this anomaly apparently lies in the ready FIG 2. Comparison of the ,ip|x>arance of typical asbestos bodies with various types of pseudoasbestos bodies on Nudepore filter preparations ot lung tissue digests. A, typical asbestos bodies isolated from the lung of an insulator with asbestosis and pleural mesothelioma. Thin translucent cores are visible In several bodies forrouiheads). Magnified 680 x. B, pseudoasbestos bodies of Ihe sheet silicate type, iso lated from the lungs ot nn insulator with asbestosis and small cell carcinoma of the lung, have broad yellow cores (arrows)- True asbestos bodies are also present (upper center and lower frff). Magnified 62(lx. C, pseudonsbeslos body isolated Irom the Uinyvuf a coal worker lias a black cnilxm core that is coaled with seg Pflifmbmiv tif i fumnn Ashr, A (.'rifirot ! .'> mented ferroproteln material. Magnified 8(X)x. D, pseudoasbestos body with a dark, slightly curved core composed ol chromium, isolated from the lungs of a metal polisher. Magnified 670 x. (Part C from Roggli VL. Maslin JP. Shelburne JD. e! al: Inorganic particulates in human lung: Relationship to the inflammatory re sponse. in Lynn WS fed): Inflammatory Cells and Lung Disease. Boca Raton, Fla. CRC Press 1983. pp 29-62. Used by permission. Pari D (torn Roggli VL: Analyt ical scanning electron miscroscopy in Ihe investigation ot unusual exposures, in llnrntg AD, Chambers WF (rds)' Microheam Analysis -- 1986. San Francisco. San Francisco Press, l9K(i. pp 686- 688. Used bv tx'tmission. 1 HWBUI0010441 Irngnirnlalinn >! ( lirvsotile inln slm'li-r. fibrils and tin* lari Mia! asbi'S los bur lies lend in (nun only on Mums Ilwit are 20 |im of greater In IlMMjlIl. As noli'tl earlier, libfons iltisls oilier limn asbestos ran become coaled' with iron, or lenuyiniml. so lliol one mosl he cautious in identifying asbes tos luxlies by liqhi microscopy, Fortunately. mosl ol Ibe nonasbestos ler* mrjinous bodies, or [iseudoasbestos bodies, can be distinguished Irom true asbestos bodies at the light microscopic level/" The typical appearances ol !rue asbestos bodies and the more common types ol pseudoasbestos bod ies are illustrated in Figure 2. Bodies with broad yellow cores and promi nent knobbed ferroprotein coaling on the ends or sides usually have sheet silicate (e.g., laic) cores.21-A number of metal oxides can assume on oc casion a fibrous form -- e.g.. aluminum oxide, chromium oxide,'12 iron ox ide,l:l and titanium oxide--and these form lerruglnous bodies with dark brown to black cores. In addition, coal dust and wood-stove dust may con tain librous fragments ol coal or burnt wood, and these too can form fer ruginous bodies with black cores.34 Finally, Ihe fibrous zeolite known as ebonite can form ferruginous bodies that at Ihe light microscopic level are indistinguishable from asbestos bodies/'3 Zeolile bodies have not yet been reported in lung Tissues Irom individuals in North America. Pathologic Features Gross Morphology Asbeslosis is characterized by linear interstitial fibrosis that tends to be more severe in the lower lobes." These findings are in contrast to silicosis, which is characterized by nodular fibrosis that is more severe in the upper lobes.'1'1 Lungs with asbeslosis have a reduced volume (Fig 3), which cor relates with restrictive findings on pulmonary function tests. The weight of the lungs is increased, Ihe consistency is firm, and close inspection of the cut surface demonstrates gray streaks ol librous tissue (Fig 4). In advanced cases, honeycomb changes may be observed (Fig 5) and are mosl promi nent subpteurally and In Ihe lower lobes." Progressive massive fibrosis has been rarely described in asbeslosis, and it is usually Ihe result of exposure to a mixture of dusts. In exceptional cases, fibrosis in asbeslosis is more severe in Ihe upper lobes/'3 The tracheobronchial tree and hilar lymph nodes do not show any characteristic changes in asbeslosis." Although the gross features previously described may be observed in a number of chronic interstitial lung diseases, a useful feature in asbestosis is Ihe frequently associated pleural Involvement." Diffuse pleural thickening is often present, and adhesions are variable. More characteristic of asbeslos exposure is Ihe line liny ol parietal pleura! plaques, which are localized ar eas of ivory colored pleural thickening with either a smooth or knobby, "candle-wax dripping" surface (Fig 6). These are usually located over the domes of the diaphragm or on Ihe posterolateral chesl wall, running along FIG 3. A, posteroanterior chest roentgenogram Irom an insulator with asbestosis. showi small lung volumes and bilateral reticulonodular infiltrates most prominent in 1 lung bases. B, CT scan from the sdme Individual, showing prominent intersti markings with honeycomb changes and peripheral accentuation. (Courtesy of I Colleen Bergin, Department of Radiology, Duke University Medical Center.) the direction of Ihe ribs/17-;w The plaques are frequently calcified. Th may develop after brief or low level exposures to asbeslos and are oft found in the absence ol parenchymal fibrosis/'7, w These pleural abnt malilies thus differ Irom the parenchymal disease in terms of epidemiolor clinical features, and prognosis,''' and the term "asbestosis" should not HWBUI0010442 I l A'r i I FIG 6. A. Gross appearance of hemidinphrogm wilh parietal pleural plaque shows irregu lar. 10 cm plaque wilh hoth smooth and nodular areas, the latter tesembing can dle-wax drippings. B. photomicrograph ol typical plaque shows bundles of acellu lar, hyatinized collagen arranged in a "basket-weave" pattern. A focus of chronic inflammation is present at the interface of plaque and adjacent pleura. H&E, mag nified 68 x. (Pari A from Wain SL. Roggli VL. Foster WL: Parietal pleural plaques, asbestos bodies, and neoplasia; A clinical, pathologic, and roenlgenographic study of 2b consecutive cases Chest 1984; 86:707-713. Used by permission.) dislally lo involve the terminal bronchioles and alveolar duels in the librotic process. Ultimately, there is radial extension lo alveolar sepia surrounding these slruclures (Pig 8). The fibrosis is usually most severe in the subpleural regions and in alveoli in closes! proximity to the bronchioles. Scarring and distortion of bronchioles occasionally results in the lining of adjacentalveoli by cuboidal bronrhiolnr epithelium, a process sometimes referred to FIG 7. Coronal section of lung from an insulator and cigarette-smoker showing moderate asbestosis ancl severe centrilobular emphysema, j Note the visceral pleural thickening enveloping the lung and extending into the interlobar] fissure. as pulmonary adenomatosis. Secondary lobular septa may be of marked Increased thickness due to collagen deposition, and there is ollen difiu: fibrotic thickening of the visceral pleura. In the most advanced cases, late zones of lung consist of alveoli with librotic walls, and there may be hoi eycomb change. The latter is characterized by irregular, cystlike structure 1 to 15 mm in diameter, which are lined by cuboidal to low columnar e: Ithelium and have fibrotic walls. Pools of mucus often accumulate in the: spaces, A background of chronic inflammatory cells, consisting ol lymph < vies and plasma cells, Is often scattered within the librotic inlersliHum. A beslos bodies may be found lying free within alveolar spaces or embedd> within the fibrotic pulmonary interstilium (see Fig 8). The detection ol < bestos bodies in histologic seclions can often be enhanced by iron star (e.g., Prussian bfue}, particularly when there are few bodies present. Fi thermore, connective tissue stains (e g., Masson's trichrome) may facility the assessment ol the extent of pulmonary interstitial fibrosis. The fibre process tends to be patchy, so that many sections may need lo searched lo find the diagnostic features.K Other histologic abnormalities are seen less commonly in patients ul HWBUI0010443 FIG 4. Coronal section o! ihe Sower portion of the long ol an insulator with asbeslosis. There is pale gray, linear Interstitial fibrosis especially prominent in the lower lobe. Note the visceral pleural thickening laterally and adhesion ol the diaphragm lo the undersurface of the lung. applied lo Ihe pleural lesions,*-1,9 Others have argued lhat when one con siders lhal both pleural and parenchymal fibrosis derive from exposure to asbestos. Ihe need lor any distinction disappears.'10 One has only to con sider Ihe fact lhal asbestos exposure can produce asbeslosis and malignant mesothelioma to see the fallacy in this argument. Asbestos workers are more often than not cigarette smokers, and the pa thologist must take care lo distinguish abnormalities related to smoking from those related to asbestos. For example, severe emphysema of the centrilobular type may be present and can overshadow the fibrosis of as bestoses (Fig 7). Emphysema must be distinguished from honeycomb changes, and in this regard, distribution is a useful guide; emphysema tends to be most severe in the upper lobes, whereas honeycomb changes are most severe in the lower lobes. The cystic spaces of honeycombing are rather uniform, averaging about 0.5 cm in diameter and having visibly thickened, librotic walls. The spaces ol emphysema are variable in size, ranging from just visible up to several centimeters across and do not have "walls." Strands (representing remnants ol blood vessels) are often seen traversing emphysematous spaces, and grossly visible fibrosis is not an ex pected associated finding in centrilobular emphysema.41 As is the case for most other pathologic changes in the lungs, the lesions of asbeslosis can be best assessed by careful inspection ol slices prepared from lungs that have been fixed under pressure by prolonged inlrnbronchinl instillation of fixa tive solulion.* 41 Coronal section of the left lung of an Insulator with asbeslosis and c; squamous cell carcinoma of Ihe right, lower lobe. Note Ihe honeycomb char the medial portion of the lower lobe. Hlstopathofogy There Is a range of microscopic changes in asbeslosis depending up< severity of (he process. These have been extensively illustrated in a monograph* and only the main features need be summarized her* two microscopic features that are the sine qua non for (he histologic nosis ol asbestosis are pulmonary interstitial fibrosis and asbestos be Experimental animal studies42 and studies of autopsy lung tissue fre bestos workers* suggest lhal the earliest changes of asbeslosis invo creased collagen deposition in the infersfitium surrounding resp bronchioles, allhough this idea has been challenged by some inv tors.4,1 With more exiunsive disease, there is extension both proxima HWBUI0010444 *\N- FIG 8. A, low-power photomicrograph o! a bronchiole from an insulator with asbestosis. There Is peribronchiolar fibrosis with distortion ol the bronchiole. The fibrosis extended to involve adjacent alveoli. H&E, magnified 52x. B, higher magnification of area In box A shows asbestos bodies embedded within librotic peribronchiolar connectfve tissue (arrowheads). H&E, magnified 250 x. C, elsewhere, clusters of typical asbestos bodies are present embedded within fibrotic Interstitium. H&E, magnified 325x. >*(V* / /ft 1III.1M .{, * ,!f|, ,,j }u; asbeslosis (Tablt* 21 AllliiHicjli inrriMsi'd numt'fis ol .ilvi-ol.u m.n inph.iq are often seen within alveolar spaces in ashestosis. in Mime t the alv oli are packed with sheets ol macrophages in a pattern similar to tlesqu mafive interstitial pneumonitis (Fig 9). Occasionally, foreign body type < ant cells may be seen within the alveoli or, less commonly, within the brotic interstitium I lyperplastic alveolar type II cells often line the fibros* alveolar sepia in asheslosis, and in some cases (roughly 7% ol all cas with histologically documented asbestosis in the author's series), these ty 11 cells contain irregular, waxy appearing. deeply eosinophilic material If 10). This cytoplasmic hyalin has the same bnctorial and ultrastmctu characteristics as the alcoholic hyalin observed in hepatocytes.44 Howev> this abnormality is not specific to asbestos and probably represents a pec liar, nonspecific reaction to injury.4* These uncommon histologic abm malities are in the author's experience observed in the more advanc stages of asbestosis. Rarely observed in patients with asbestosis are the so-called pulmoni blue bodies. These basophilic, laminated concretions are present in alvc lar spaces and consist primarily of calcium carbonate.46 They are not vi: afized with polarizing microscopy in H&E-stained tissue sections, but brightly birelringent in filter preparations of tissue digests (Fig 11) or in i stained histologic sections. Their mechanism of formation is unknov although asbestos can cause abnormal accumulations of calcium salts the lung parenchyma in experimental animal models of asbestosis.'17 P monary blue bodies are not specific for asbestosis and may also be TABLE 2. Histologic Findings In 100 Cases of Asbestosis Histologic Feature Always present Asbestos bodies Peribronchiolar fibrosis Ollen present Alveolar septal fibrosis Occasionally present , *f Honeycomb changes Foreign body giant cells Pulmonary adenomatosis Cytoplasmic hyalin Desquamative interstitial pneumonitislike areas Rarely present Osseous, metaplasia (dendriform pulmonary ossification) Pulmonary blue bodies Percent too TOO 82 15 15 10 7 6 2 l HWBUI0010445 FIG 9. Low power photomicrograph of lung of patient with asbestosis showing alveoli packed with sheets of alveolar macrophages (asterisks). This pattern resembles that seen in desquamative interstitial pneumonitis. I-IA E. magnified 68 x. served in patients with asbestos exposure who do not meet histologic cri teria for the diagnosis of asbeslosis. An additional unusual process that is rarely observed in patients with advanced asbeslosis is dendriform pulmo nary ossification.'*" This is characterized by branching spicules of bone (often with bone marrow) in association with pulmonary scarring, appar ently resulting from metaplasia of interstitial fibroblasts to osteoblasts. An- '* * , f-?$ ''"T 'i*\ -'C, t ti*x 8/ "s Li: V* r* --< . > . A -W " r)"' FIG !0. Photomicrograph ol lung of palienl wilh asbeslosis showing hyperplastic alveolar type II pneumocyles, many containing cytoplasmic hyalin (arrowheads). This ma terial has the same tinctorial characteristics as (he hyalin found within hepotocytes in patients wilh alcoholic hepatitis. HftF., magnilied 6R0x. FIG 11. A, these Intraalveolar pulmonary blue bodies have a somewhat laminated app ance farrows) and consist primarily of calcium carbonates. H&E. magnilied tiC B, Nudepore filter preparation ol lung tissue digested In sodium hypochlorite, fl same case illustrated In A. When examined by polarizing microscopy, the 'j bodies" are brightly blrefringenl and the laminations clearly visible (onowhea Magnified 325*. {Courtesy of Dr. Fred Askin, Department of Pathology, Unive* of North Carolina, Chapel Hitt, NC.) other peculiar association with asbestosis Is Aspergillus pneumonia. Hi! dal and-Hecksher reported four cases of this unusual combination,'*9 the author has personally observed five additional cases50 (and und tfshed observations). No other opportunistic fungal infections associa with asbeslosis have to my knowledge been described. The mechani may involve the suppression of cell-mediated immunity by asbestos,51! though the reason for the specific predisposition for Aspergillus specie not known. Il is not (he purpose ol this review to discuss asbestos-related maligr cles, and the interested reader Is referred elsewhere for detailed discus of this subject."'52 However, the pathologist should be aware of 9 nonneoplastic pulmonary parenchymal processes that can mimic neopll both clinically and radiographically, since he or she may be called upon examine such cases by frozen section. The author has observed sevl cases of organizing pneumonia in patients with asbestos exposure who P derwent thoracotomy for suspected malignancy. Organizing pneumonil a well-known mimicker ol carcinoma of Ihe lung.'"* Whether this proJ has on increased incidence in patients wilh asbestosis or whether these HWBUI0010446 I'. * i !.,> -..its nri' meirlv observed mine closely [hi jxilrnli.il m.iliijtinncv is Un known In addition. ;i prrnlinr pimv; known ns rounded atelectasis (also known ns folded lung syndrome) ran occur adjacent !> lliirkened. buckled pleura. and lliis lesion can radiographically resemble a peripheral coin lc sion I Pig 12), lls radirxjraphic features arc described elsewhere/'1 On hislologic examination, [he lung parenchyma may be atelectatic or normal, although flic overlying visceral pleura is invariably Ihickened. The palholo- FIG 12. A, lateral chest roi'nlijcnograin shows n peripheral mass posteriorly (arrowheads). B, CT scan from the same individual shows dislorted bronchovascular bundles coursing into the mass which abuts llie pleura. This radiographic appearance is characteristic of rounded atelectasis, (Courtesy of Or, Colleen IJergin, Department of Radiology. Dukr University Medirat Center,) / '.tfftr >l> J| >f I Ill'IM' I -.1. .|ff ttf Kl'l'ti'tl gist should look tpi ... tiodie'. ,uid jienbion, hi'.Ln t.l.i. m It..* jacent llini). MUl r tin*- | >M x O'.1. IS bi-i|uniillv .r.si.i Mill I uilti I >1 It r.iifi- li beslos '" Differential Diagnosis Asbestosis must be distinguished from pulmonary injury secondary to ii lalion of other toxic substances and also from other forms of pulmoi interstitial fibrosis Peribronchiolar fibrosis may be associated with ini lion of other mineral dusts, such as silica, iron oxides, or aluminum oxidi and with exposure to cigarette smoke, although the percentage of s airways with abnormalities due to these exposures is generally less (hat observed with asbestos exposure."'1' `w Diffuse interstitial fibrosis also be seen with exposure to a variety of inorganic particulates.34 T (he finding of peribronchiolar or diffuse alveolar septa! fibrosis alone is sufficient for a diagnosis of asbestosis, and the identification of asbc bodies in histologic sections is necessary to relate the fibrosis to asbe This is also true for idiopathic pulmonary fibrosis of the usual or des mative type, which has many features that overlap with asbestosis. Ind since idiopathic pulmonary fibrosis Is a diagnosis of exclusion, asbeslo: one of the conditions that should be ruled out to make that diagnosis, presence of asbestos bodies and visceral pleural fibrosis are helpful lures in this regard, as is the identification of parietal pleural plaques. Individuals who are occupationally exposed to asbestos are often posed to other dusts as well. For example, shipyard workers may rec substantial exposures to silica, talc, or welding fumes as well as asbe Crystalline silica constitutes one component of the lining of steam bolle ships and is sometimes still used in sandblasting. Individuals engage boiler-scaling or sandblasting or working in the vicinity ol these operal often have silicotic nodules in the hilar lymph nodes and occasional the lung parenchyma, especially In the upper lobes.3" Shipyard welder ten are exposed to asbestos, so that care should be taken to disting welder's pneumoconiosis from asbestosis. Welders are exposed to n oxides (especially iron oxide), and sheet silicates. Iron oxides appear a terstidal deposits of dark brown to black spherical particles, often wi golden brown rim.3" There is very little collagen deposition in respon; these particles. Pseudoasbestos bodies with black or broad yellow c may be identified in histologic sections. Among 12 cases of welder's pi moconlosis in shipyard workers from the author's consultation files, four cases satisfied histologic criteria for the diagnosis of asbestosis,s peribronchiolar fibrosis and true asbestos bodies. Quantitation of Tissue Asbestos Burden A number of studies have demonstrated that when digeslion-concentra techniques art: employed to analyze adequate amounts of lung tis HWBUI0010447 ................. -.Ml1" l> >i Hi. I III II,, '. ! \`i||iu1iy .til . t* l i lr it- " >!-!(!.]} I iii'ii!((', Ihr mrir tlcmoi!'>!ri!ion nl Ihr ]sn-.cm-f nl nsh('ilos in listin' digc'sls is of no parlinilnt value. and qunnlilnlive studies arc required lo understand Ihe relaliondtip belwc'cn tissue' liber burdens nnd various disease prexesses. A variety of techniques have been de scribed for Ihe isolation and quantification ol tissue asbestos content.'''' ('7 and it is beyond the scope of this review to consider these here. Rather, the intent is to review the information that has been obtained regarding the asbestos content o( lung tissue in palients with asbestosis. Relatively few studies have been published examining the asbestos con tent of lung tissue In series of patienls with asbestosis. '71 The data from these studies and the author's own series are compared in Table 3. Wilh the exception oi the unusually high median count for asbestos bodies in the study by Ashcroft and Hcppleslon, and the high mean count (or un coated libers by electron microscopy in (he study by Wagner el a!., the val ues are roughly similar among the reported series. This is rather remark able considering the wide range of values obtained when different labora- TABLE 3. Asbestos Content of Lung Tissue In Reported Series of Patients with Asbestosis* Source Whltwell el al/"TM No. of Cases 23 Methodt PCLM Asbestos Bodles/gm Dried Lung Ashcroft and Heppleslon"' Wernock cl al.7" 22 PCLM 22 TEM1 Wagner et al.71 100 PCLM 122 (0.49-192) 0.123 (0.001- 7.38) 170 TEM Roggli (present study) 76 SEMt 0.3785 (0.006-16) Uncosted FIbers/gm Dried Lung 8 11.0-70) 32 (1.3-493) 5.68 (1.6-121) 1.5 (0.001-31.6) 372 (<1.0-10.000) (0.18-125) Values reported are Ihe median counts for millions (Kf'\ of asbestos bodies or uncoated fibers per gram of dried lung tissue, with ranges Indicated in parentheses, except for the study of Wagner et pi ,71 where only tire mean value could be obtained from Ihe dala pre sented. tPCLM - phase contrast light microscopy- TCM - transmission electron microscopy: SEM scanning electron microscopy. tin these two shulies. asbestos bodies were counter! by conventional light microscopy. UVahies multiplied try a l.rclnr of 10 (approximate ralio nl wel to dry lung weight! for pur poses ol comparison hun"- r.V-rlililu' l in- --mu' n 111 >Ii * -n ul 11 iir.n lrimi| I In' > lill.-h-ni let lum [lies employed in t'.rclt nl the studies teleried tn in Iable .`I I nr example. Adi ,-inll and T lt'ppls'str ill"' UM'd phase cniilin'-l liqhl mii'uiM npv Il'CI.M) ;il .1 magnification of 400x and ColMiled all visible lihyis. enumetnfiii<| r ri.rlcil and uocoated fibers separately. Whilwelt ct al.,'!< used PCl.M and counted all fibers greater than or equal lo 6 p in length, counting coated and uncoa(ed fibers together. Wamock et al.70 used transmission electron micros copy (TEM) and counted all libers that exceeded 0.25 (cm in length and had an aspect ratio (length to width) of 3 or greater. Wagner et al, used the PCLM method of Ashcroft and Heppleston69 as well as TEM. The present author's results were obtained by scanning electron microscopy (SEM) at a magnification of l,000x counting all visible fibers with a length greater than or equal to 5 p.m.,<; The study by Wamock et al.70 and the study by Roggli also counted asbestos bodies by conventional light mi- FIG 13. Histogram of asbestos body counts In 76 patients with asbestosis. 16 patients with idiopathic pulmonary fibrosis, and 64 nonexposed "controls." Horizontal bars Indi cate median values. Note logarithmic scale. HWBUI0010448 r< n *1 tn 11 >v ini < m . i!< t V l > iiii< x.ifi'tl III m*i*. ! ;i i m >i ji \ ih m ! t u jM If* mi: in rals with noim.il limji''. aini no known nt Mipniirmeil ,v,!h'*.fuh t*>v|vn sui . approximately 0 034 * If)1' fibcrs/gm. The asbestos body content ol I he hint) in 7f> patients will i hisHilot[irnllu confirmed asbestosis is shown in Figure 13 and is compared wills Iho re- soils from lb patients wtlli idiopathic pulmonary fibrosis (IPF) and with 01 nonexposed controls. The results are expressed on a logarithmic scale as asbestos bodies per gram of wet lung tissue (which can he approximately converted to bodies per gram of dry lung' tissue by mulliplying by a factor of 10). The median count for (lie patients with asbeslosis is 37,800 as bestos bodies per gram of wet lung tissue (AB/gm), whereas the median values for the patients with IPF Is 16 AB/gm and for the controls is 0.4 AB/gm. There is substantial overlap between the IPF and "control" groups, although a few IPF patients with low-level asbestos exposure have slightly elevated values. It should be noted that for 95% of the cases of asbeslosis. the asbestos body content is I ;700 AB/gm or greater. This finding is useful because, a! this tissue asbestos body concentration, if has been shown that several asbestos bodies should be observed on most 2 x 2 cm histologic sections when the sections are stained (or iron and system atically examined.28 Thus the finding of asbestos bodies in histologic sec tions is a reasonable histopathologic discriminator between asbeslosis and IPF. A few studies have investigated the relationship between tissue asbestos burden and the fibrotic response in humans, and these are summarized in Table 4. The study by Whitwetl et al.68 shows a progressive increase in median total coated and uncoated fiber count from patients with mild (1 + ) to severe (3 +) fibrosis. Ashcroft and Hepplestonfw showed similar progres sion in severity of fibrosis with increasing uncoated fiber count from no fi brosis to moderate (2 + ) fibrosis, but no further increase in fiber count from moderate to severe disease. The latter authors concluded that additional factors other than tissue fiber burden must be involved in the progression from moderate to severe disease.59 Wamock et a1.7<1 graded the severity of fibrosis on a scale of 0 to 3 + based on visual inspection of the cut surface of inflation fixed specimens, with '/z+ defined as microscopic fibrosis only (Table 4). Their data show no apparent correlation between the severity of fibrosis and total fiber content for ail fibers 0.25 p.m or greater In length as assessed by.TEM. Wagner et al.71 graded the severity of fibrosis micro scopically on a scale of 0 to 4, which for the sake of convenience has been tabulated as 0 to 3 in Table 4 with (heir grade 1 fibrosis listed under VH-. Their data show a progressive increase in optically visible and electron microscopically enumerated fibers with increasing severity of asbeslosis. The relationship between histologic asbeslosis score using the method recently proposed by the Pneumoconiosis Committee of the College of American Pathologists" and the tissue content of uncoaled fibers 5 pm or A sbestos!* vs. Tissue Asbestos C ontent as Total Fibers/gm D ried Lung- 1.. ' 1 Asbestos!* Grade "I ______ __ ___ it * 5 i >.I - Tf PVj * ip E: IT1usJ "sJsI i V XXXXX & s 3 aS3 C4 o imMi'*h--*'*h--*'*h'h"<'h**" K E S3 X X X X X S > 3 ez s-i o sip o 5 Il I !r& --! Sf i XXx P^i^ s ^ * O 6 O o00 -o u jS si S1s o otb o - --* XXxX 13a5**i fag-gl eI " a cvi^8 o e1*- = C o "Pie B 3^33 HWBUI0010449 gnviii'f in It'tisjllt ns .wssi'tl by Sl.M is shown in litum1 14. Tln'sc il.il.i arc based on [In' .'!(> mil opsin I rases of asbestosis ftom the1 author's ron sultalinn fifes for whiili (issue wns available (or analysis of asbestos con lent. There .is a statistically skjnificnn! (/'. .Ill ) relationship between histo logic score and tmeoated fiber content. although there is a wide range of scatter of (he data points. The degree of correction would likely improve with more extensive histologic and mineralogic sampling ol the lungs and expression of (he data as total lung burden rather than fiber concentra tion. " furthermore, the intercept for the regression line is approximately 100,000 fibers per gram ol wet lung (or one million fibers per gram ol dry lung), which coincides with the lower limit of the range of values shown in Table 3. In addition, it can be seen from Figure 14 that very lew patients with alveolar septal fibrosis (grade 4 or higher) have uncoated fiber counts less than 100,000 per gram, although some patients with fibrosis confined Correlation between uncoalcd liber count by scanning electron microscopy and histologic assessment ol the severity ot asbestosis for 36 autopsled cases, using grading scheme ol College ot American Pathologists and National Institute for Oc cupational Safety and Health.H The correlation coefficient (r) for the linear regres sion line is 0.46 (P ''0.011. SEM - scanning electron microscopy. / I,, |l|t- W.lll n! Mll.lll ailW.iy. (*{).) h - ,1 U| 1<ll.lVf '..tliliWill I'.'linv llil-. li'Vi'l I his ntiM'iv.ilii in r. in .tpirrnirnl with tin- tinilm r- i'V < lniii( if n l nlivrlv k'W tissue aslieslrI', httulen III t liry.riMe ttniirr. mill hhur.r. mu fined l<> the walls of small airways I here is also a slalislu allv siijmln .ml association between histologic score and total (coaled plus uncoalcd) libei content as assessed by SF.M, but not between histologic score and asbes tos body content as measured by light microscopy (Table 5). Finally, in (his study, there was no significant association between histologic score and pa tient .age, duration of occupational exposure, or pack years of smoking (sec Table 5) Wamock et at.70 have reported finding large numbers of commercial amphiboles, noncommercial amphiboles, and chrysolite fibers in patients with asbestosis. These authors used analytical TEM and examined all de tectable fibers 0.25 p-m or greater in length. For comparison, the data from more than 1,200 libers isolated from 76 patients with asbestosis and iden tified using analytic SEM are shown in Table 6. These data show that for libers greater than 5|xm in length, the vast majority (92%) are commercial amphiboles (mostly amosite with some crocldolite). Less than 2% are non commercial amphiboles and less than 1% chrysotile. Of interest is the observation that lor fibers in the stated size range, nonasbestos mineral fibers'*1 are more common than chrysotile and noncommercial amphiboles combined. Diagnostic Criteria The histologic diagnosis of asbestosis is Important because it provides inde pendent assessment of the presence or absence of pulmonary intersitifial TABLE S. Correlation of Histologic Grade of Asbestosis With Tissue Asbestos Content and Other Parameters* Uncoated fibers/gm (>5p.m)SEM Total fibers/gm (coated and uncoaledf, SEM Asbestos bodies/gm, LM Smoking history, pk-yr Age Duration of exposure, yr Correlation Coefficient (r) 046 0.44 026 0.22 0.12 0.06 P <0.01 <0.01 NS NS NS NS `St-.M = scanning electron microscopy. LM = llghl microscopy, pk-yr r packs smoked daily * no. years smoked. HWBUI0010450 1LE 6. ..'.rgy Dispersive X-ftny Analysis Data on 1.215 libers From 76 Patients With Asbestosis Coaled Uncoated Total (%) Commercial Amphlboles 197 622 1,119(92) Noncommercial Amplilbolcs_____ Chrysotlle 4 19 23 (1.9) 0 8 8 (0.6) Other* 13 52 65(5.5) "Includes laic, stliea, rutile, kaolinllc. miscellaneous silicates, fiberglass. Iron-rich fi bers. and aluminum-rich fibers. fibrosis resulting from Inhalation of asbestos-containing dust. Based on the foregoing analysis, reasonable criteria for the histologic diagnosis of asbesfosls can be established. Asbestosis may be defined as the presence of peribronchiolar fibrosis arid asbeslos bodies in histologic sections, with or without alveolar septal fibrosis. Since other experimental exposures can produce some peribronchiolar fibrosis,43,55 it is recommended that in the absence of atveolar septal fibrosis, a histologic diagnosis of asbestosis should be made only when the majority of the bronchioles show increased amounts of fibrous tissue. Occasionally the assessment of fibrosis can be difficult in uninflaled tissue that is collapsed, congested, or consolidated by pneumonia, and the pathologist should be careful not to overinterpret such material as showing alveolar septal fibrosis.74 In cases where the assess ment of presence and extent of fibrosis is not straightforward on H&Estained sections, it Is recommended that Masson's trichrome stains be ob tained to assist In this evaluation. Similarly, the pathologist should be care ful not (o interpret ferruginous bodies with black or broad yellow cores as asbestos bodies, and only structures with the typical morphology that has been described'2012I-3tf-31 should be interpreted as asbestos bodies. In cases where asbestosis is suspected and asbeslos bodies are not readily Identified on H&E-siained sections, it is recommended that Iron-stained sections be prepared and examined systematically using a mechanical stage and it magnification of 200 x.28 With this approach, an average value of five or more asbestos bodies per cm2 of tissue section area exam ined would be expected in 95% of our cases of asbestosis, and two or more asbestos bodies per cm2 in all of our cases. Of course, asbestos bod ies are not necessarily distributed evenly in histologic sections.28 Therefore, more than one section should be examined in cases where asbestos bodies are sparse. Fibrosis was confined to the peribronchiolar region in 18% of the cases In our series (see Table 2), and some invosligalors have challenged the in clusion of such cases in the definition of asbestosis on the grounds that ex- l: hi oris 1 ' Willi iri|.inl In I In lusl ainnm.-nl. tin- '.mu' p. l> ,> i |(|l< i-.< interstitial (i.e., alvool.ir r-i'pt.il) libmsfc as Im |ii'iiliinni liml.n mv m ,-i (her case, the finding of asbestos bodies in bislologir MVlitms gnsillv in creases one's confidence that the fibrosis observed is related to nriieslos exposure.11 If one further restricts the definition to cases where Ihe major ity of bronchioles are involved, the chances of overdiagnosing such lesions as being asbeslos related is further reduced. With regard to the second ar gument, it Is true that progression from peribronchiolar to alveolar septal fibrosis has not been demonstrated experimentally, although the peribron chiolar area appears to be an early site of abnormality in experimental an imal studies.42 It should be noted that peribronchiolar fibrosis Is a form of Interstitial fibrosis, since the pulmonary tnterstitium Includes not only the interstitium of the alveolar septa, but the subpleural connective tissue, sec ondary lobular septa, and connective tissue enveloping bronchovascular and bronchioloyascular bundles as well AH of these sites may show in creased fibrous tissue deposition in individuals exposed to asbeslos, and it is this writer's opinion that the preponderance of the evidence does justify Inclusion of peribronchiolar fibrosis In the definition of asbestosis. Other Investigators have challenged the requirement of finding asbestos bodies In tissue sections before a histologic diagnosis of asbestosis is ren dered. The Justification for that opinion has been firstly the observation that chrysotile forms asbestos bodies less readily than do the amphibotes and many workers are exposed primarily to chrysotile,75 and secondly that some Individuals coat fibers to form bodies much less efficiently than oth ers.76, 77 With: regard to the first argument Holden and ChurgTM have shown that asbestos bodies are readily found In histologic sections of chrysotile miners with asbestosis, and that these asbestos bodies do in fact have chrysotile asbestos cores. With regard to the second argument there have been a few cases reported of patients with pulmonary fibrosis where the asbestos body content of the tissue was low (less than 100 per gram of wet lung tissue) but the uncoaled fiber content of the tissue by TEM was considered high.76,77 Such cases are apparently rare, as no similar cases were observed In our series of 76 patients with asbestosis. Furthermore, Ihe 16 patients In our series with Idiopathic pulmonary fibrosis who had relatively low asbestos body counts {see Fig 13) also had low uncoated fi ber counts,16 and it Is unlikely that any of these cases were misclassified. The classification of the uncommon cases with Interstitial fibrosis, absence of asbestos bodies in histologic sections, and elevated tissue asbestos fiber burden remains problematic, but the existence of cases of pulmonary fi brosis due to asbestos fiber inhatation that do not fulfill histologic criteria for the diagnosis of asbestosis seems plausible. In consideration of the lack of a uniform method for the analysis of tis sue mineral fiber content and the variable results obtained from different laboratories analyzing the same sample, it is not presently possible io rec ommend a specific tissue asbeslos fiber content to be used as a criterion HWBUI0010451 11 * 1 * *' i M 1 ' <' " J< t I'l ,|*1!2h3 4-5.i6t 7I 8r9.10 *(1*2 t| li'll M I MVt I 1 M ' |I*` . I.) I. > in | ,t, j| MTins iiiililti'lv Htill a [Kilirtil wilh clinically siq nifirnill pulitidiwitv fibro:;!S who Slits lewcr lit,in SO1' fillers ft jini or gri'.iliT in k'tit jlli jv>r gram of dry Itroy (issue (10'` liburs/gin we I kmjj (issue) is' sutffriin] from asbeslosis. Whereas (lie tibrogenicily of asbestos fibers ,r> |tm or greater in lenylh is well established,(he fibrogenkily of fibers less than 5 jun in lengib remains unproved.*0 Therefore, no tissue level of filters in the latter size range should a! the present time be pro posed ns a criterion lot the diagnosis of asbeslosis. Adknowfedgmen t The author gratefully acknowledges Susan Embry, James E. Unthicum. and Kenneth Holt for assistance with the illustrations, and Diane Evans for preparation of the manuscript. References 1. Castletnan Bl: Asbestos: Medical and Legal Aspects. New York, Harcourt, Brace, Jovanovich, 1984. 2. Lee DHK, Selikoff U: Historical background to the asbestos problem. Environ Res 1979; 18:300-314. 3. Craighead JE: Eyes tor the epidemiologist: The pathologist's role In shaping our understanding of the asbestos-associated diseases. Am J Clin Pathol 1988; 89:281-287. 4. Cooke WF.: Pulmonary asbeslosis. Br Med J 1927; 2:1024-1025. 5. 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Environ Res 1987; 44:29- 44. 78. Holden J. Churg A: Asbestos bodies and the diagnosis of asbestosis ir chrysotile workers. Enuiron Res 1986; 39:232--236. 79. Wright GW. Kuschner M: The influence of varying lengths of glass and asbes HWBUI0010453 .. ....... ,- ttt i|iniHM in VV.ilhm Wl I htfaifiul I (tilt <!rs IV. Oxlotil, SVrqntmm Press. I`#77. pp 'IWi~474. 80. Davis JMG. Beckett ST, Bolton, HI), fit al: Mass and number of fibres In (he pathogenesis of asbestos-related lung disease In rats. Br J Cancer 1978. 37:673 - 688. 81. Crapo JD, Barry BE. Brody AR, O'Neil JJ: Morphological, morphometric, and X-ray microanalyticai studies on lung tissue of rats exposed to chrysolite asbes tos in Inhalation chambers, in Wagner JC fed): Biological Effects of Mineral Fibres. Lyon, France, IARO Scientific Publicalions. 1980, pp 273-283, no. 30. vol 1. 82. Lee KP, Bartas CE. Griffith FD, el al: Comparative pulmonary responses to inhaled Inorganic fibers with asbeslos and fiberglass. Environ Res 1981; 24:167-191. 83. Gross P: Is short-fibered asbestos dust a biological hazard? Arch Environ Health 1974; 29:115-117. Forensic Toxicology Drugs-of-Abuse Testin Jim Standefer, PhJ Director of Toxicology, Department of Pathology, University of New Me> School of Medicine, Albuquerque, New Me> The estimated annual cos! of employee productivity lost due to alcol and drug abuse In the United States Is estimated to be $100 billion.1 T lower productivity seems to coincide with an increase In drug use Indlcal by reports from emergency room visits from 1980 to 1985 (Fig 1). C< cem over Increasing drug use and Its costs has prompted a flurry of activ related (o drugs*of-abuse screening and as a consequence, forensic uri drug testing Is one of the fastest growing areas within forensic toxicology has been estimated that one-fourth of the largest firms in the United Sta f havelristlhited programs for drugs-of-abuse screening and that four oul 100'employees are subject to mandatory drug testing.2 The federal DRUG USE: DAWN REPORTS 1980-1985 400 350 300 t- 250 | 200 DRUG . HflROKI __ ___ cocwr __________ maruuah ___ . ___ AMPICTAI ..................POP Ui o- 150 100 50 -L, OISM 1961 1982 <983 1984 inflli YEAR FIG 1. Drug use based on Drug Abuse Warning Network emergency room reports. (( from Frank RS: Drugs of abuse: Data collection systems of DEA and recent he J Anal Toxicol 1987; 11:237-241. Ads ParW 2 Cl -<K. 1<MW C IW, m Bool, Mnfcal PuMtihm. Inc sw .TXflWMB OAi rm $m m HWBUI0010454