New Insights on Diagnostic Reproducibility of Biphasic Mesotheliomas: A Multi-Institutional Evaluation by the International Mesothelioma Panel From the MESOPATH Reference Center.

INTRODUCTION: The 2015 WHO classification of tumors categorized malignant mesothelioma into epithelioid, biphasic (BMM), and sarcomatoid (SMM) for prognostic relevance and treatment decisions. The survival of BMM is suspected to correlate with the amount of the sarcomatoid component. The criteria for a sarcomatoid component and the interobserver variability between pathologists for identifying this component are not well described. In ambiguous cases, a "transitional" (TMM) subtype has been proposed but was not accepted as a specific subtype in the 2015 WHO classification. The aims of this study were to evaluate the interobserver agreement in the diagnosis of BMM, to determine the nature and the significance of TMM subtype, and to relate the percentage of sarcomatoid component with survival. The value of staining for BRCA-1-associated protein (BAP1) and CDKN2A(p16) fluorescence in situ hybridization (FISH) were also assessed with respect to each of the tumoral components. METHODS: The study was conducted by the International Mesothelioma Panel supported by the French National Cancer Institute, the network of rare cancer (EURACAN) and in collaboration with the International Association for the Study of Lung Cancer (IASLC). The patient cases include a random group of 42 surgical biopsy samples diagnosed as BMM with evaluation of SMM component by the French Panel of MESOPATH experts was selected from the total series of 971 BMM cases collected from 1998 to 2016. Fourteen international pathologists with expertise in mesothelioma reviewed digitally scanned slides (hematoxylin and eosin - stained and pan-cytokeratin) without knowledge of prior diagnosis or outcome. Cases with at least 7 of 14 pathologists recognizing TMM features were selected as a TMM group. Demographic, clinical, histopathologic, treatment, and follow-up data were retrieved from the MESOBANK database. BAP1 (clone C-4) loss and CDKN2A(p16) homozygous deletion (HD) were assessed by immunohistochemistry (IHC) and FISH, respectively. Kappa statistics were applied for interobserver agreement and multivariate analysis with Cox regression adjusted for age and gender was performed for survival analysis. RESULTS: The 14 panelists recorded a total of 544 diagnoses. The interobserver correlation was moderate (weighted Kappa = 0.45). Of the cases originally classified as BMM by MESOPATH, the reviewers agreed in 71% of cases (385 of 544 opinions), with cases classified as pure epithelioid in 17% (93 of 544), and pure sarcomatoid in 12% (66 of 544 opinions). Diagnosis of BMM was made on morphology or IHC alone in 23% of the cases and with additional assessment of IHC in 77% (402 of 544). The median overall survival (OS) of the 42 BMM cases was 8 months. The OS for BMM was significantly different from SMM and epithelioid malignant mesothelioma (p < 0.0001). In BMM, a sarcomatoid component of less than 80% correlated with a better survival (p = 0.02). There was a significant difference in survival between BMM with TMM showing a median survival at 6 months compared to 12 months for those without TMM (p < 0.0001). BAP1 loss was observed in 50% (21 of 42) of the total cases and in both components in 26%. We also compared the TMM group to that of more aggressive patterns of epithelioid subtypes of mesothelioma (solid and pleomorphic of our large MESOPATH cohort). The curve of transitional type was persistently close to the OS curve of the sarcomatoid component. The group of sarcomatoid, transitional, and pleomorphic mesothelioma were very close to each other. We then considered the contribution of BAP1 immunostaining and loss of CDKN2A(p16) by FISH. BAP1 loss was observed in 50% (21 of 41) of the total cases and in both component in 27% of the cases (11 of 41). There was no significant difference in BAP1 loss between the TMM and non-TMM groups. HD CDKN2A(p16) was detected in 74% of the total cases with no significant difference between the TMM and non-TMM groups. In multivariate analysis, TMM morphology was an indicator of poor prognosis with a hazard ratio = 3.2; 95% confidence interval: 1.6 - 8.0; and p = 0.003 even when compared to the presence of HD CDKN2A(p16) on sarcomatoid component (hazard ratio = 4.5; 95% confidence interval: 1.2 - 16.3, p = 0.02). CONCLUSIONS: The interobserver concordance among the international mesothelioma and French mesothelioma panel suggests clinical utility for an updated definition of biphasic mesothelioma that allows better stratification of patients into risk groups for treatment decisions, systemic anticancer therapy, or selection for surgery or palliation. We also have shown the usefulness of FISH detection of CDKN2A(p16) HD compared to BAP1 loss on the spindle cell component for the separation in ambiguous cases between benign florid stromal reaction from true sarcomatoid component of biphasic mesothelioma. Taken together our results further validate the concept of transitional pattern as a poor prognostic indicator.

Diffuse alveolar damage after exposure to an oil fly ash.

Epidemiological investigation has established an association between exposure to particulate matter (PM) and both human mortality and diverse indices of human morbidity. However, attributing adverse health effects of specific individuals to PM exposure in these studies is not possible. Consequently, their clinical presentation remains ill-defined. We describe a 42-yr-old male with both respiratory damage, abnormal blood end points, and cardiac effects following an exposure to an emission source air pollution particle aerosolized during the cleaning of his domestic oil-burning stove. Early symptoms of shortness of breath and wheezing progressed over 2 wk to hypoxic respiratory failure necessitating mechanical ventilation. Blood indices were abnormal. Thoracoscopic biopsy demonstrated particle-laden macrophages and diffuse alveolar damage. Symptomatic and objective improvement rapidly followed initiation of corticosteroids. He developed typical anginal symptoms within 2 wk of discharge; however, coronary angiography did not identify any significant narrowing of the epicardial coronary arteries. This patient presents with the aggregate of potential injuries described by epidemiological methods to be associated with air pollution particle exposure.

Well-differentiated papillary mesothelioma.

Well-differentiated papillary mesothelioma is an unusual variant of epithelial mesothelioma considered to be of low malignant potential. The majority of previously reported cases developed in the peritoneum of young women without a history of asbestos exposure. The authors report 14 cases of well-differentiated papillary mesothelioma, seven of which originated in the pleura, six in the peritoneum, and one in the tunica vaginalis. Eleven of the patients were male and three were female, with an average age at presentation of 58 years (range 32-82 years). Six of the patients had a quantifiable history of asbestos exposure. Of the nine cases with complete follow-up, six had clinically indolent disease, one showed resolution after adjuvant chemotherapy, one pursued an aggressive course, and one died of other causes. These findings indicate that well-differentiated papillary mesothelioma is a rare variant of mesothelioma with a variable clinical prognosis that is etiologically related to asbestos exposure in some cases.

Environmental malignant mesothelioma in southern Anatolia: a study of fifty cases.

Malignant mesothelioma is a highly aggressive tumor of the serous membranes, which in humans results from exposure to asbestos and asbestiform fibers. Although occupational malignant mesothelioma is still the most common form of this lesion, naturally contaminated soil can play an important role in the development of environmental malignant mesothelioma in some parts of the world. Fifty cases of malignant mesothelioma (MM) from southern Turkey with no occupational history of asbestos exposure were reviewed regarding pathologic and clinical features. A case of hyaline fibrous plaque of the pleura was also included in this series. Histologically the cases were classified as epithelial (36 cases); sarcomatous (7 cases); and biphasic (7 cases). One of the sarcomatous cases was desmoplastic. Ultrastructural examination of the tumor tissue in three cases revealed long-surface microvilli in epithelial cells. Interstitial cells of the lung in one case showed electron-dense asbestos fibers in the cytoplasm. Mineralogical analyses of the lung tissue in three cases of MM and the case of pleural plaque showed high amounts of asbestos fibers most consistent with tremolite and actinolite. The clinical and pathologic features of our cases support that the environmental inhalation of asbestos is still a major health problem in some parts of Turkey.

Epithelioid hemangioendothelioma of the pleura: clinical and radiologic features.

OBJECTIVE: The purpose of our study was to describe the clinical and radiologic features of epithelioid hemangioendothelioma of the pleura. CONCLUSION: Pleural epithelioid hemangioendothelioma is an uncommon malignancy that typically affects older men, who present with chest pain and dyspnea. This lesion manifests on chest radiographs and CT scans with unilateral pleural fluid and nodular pleural thickening and appears similar to diffuse pleural carcinomatosis or mesothelioma.

Calcium oxalate and iron accumulation in sarcoidosis.

BACKGROUND: In many patients with sarcoidosis, the granulomas contain inclusion bodies within giant cells. Many giant cells contain crystalline oxalate that chemically coordinates iron on the surface of the crystal. If this iron is incompletely coordinated and capable of redox cycling, then oxalate might contribute to granuloma formation in the lung. METHODS: Using human tissues, isolated alveolar macrophages and respiratory epithelial cells, we measured the ability of calcium oxalate to sequester iron, stimulate cytokine release and cause granuloma formation. We then studied the effects of in vivo oxalate instillation on pulmonary granuloma formation over 3 to 6 months in rats. RESULTS: Calcium oxalate present in human sarcoid granulomas sequesters significant amounts of iron and ferritin. In alveolar macrophage cultures, oxalate accumulates iron and stimulates ferritin production and giant cell formation. In cultured respiratory epithelial cells, calcium oxalate increases the release of two interleukins (IL), IL-8 and IL-6, involved in granuloma formation by 8 to 10 fold within 24 hours. Intratracheal instillation of calcium oxalate crystals into the lungs of rats is associated with pulmonary iron and ferritin accumulation and organic carbonyl formation consistent with sustained oxidative stress. These exposures were accompanied by influx of alveolar macrophages, giant cell formation, and a granulomatous response in the lung. CONCLUSIONS: These results support an association between calcium oxalate deposition in the lung, iron mediated oxidative stress and formation of some of the granulomas of sarcoidosis.

Asbestos content of lung tissue and carcinoma of the lung: a clinicopathologic correlation and mineral fiber analysis of 234 cases.

The aim of this study was to investigate the asbestos content of lung tissue in a series of patients with lung cancer and some history of asbestos exposure. This information was then correlated with demographic information, occupational and smoking history, presence or absence of pathologic asbestosis or pleural plaques, and pathologic features of the cancer. The pulmonary concentration of asbestos fibers in 234 cases of primary carcinoma of the lung was determined by means of a tissue digestion technique. Asbestos body counts were performed in 229 cases and fiber analysis by scanning electron microscopy in 221 cases. Asbestos content was recorded as total asbestos fibers, commercial amphibole fibers, noncommercial amphibole fibers, and chrysotile fibers 5 microm or greater in length per gram of wet lung tissue. The study group included 70 patients with asbestosis (Group I), 44 patients with parietal pleural plaques but without asbestosis (Group II), and 120 patients with neither (Group III). The median asbestos body content of Group I was more than 35 times greater than Group II and more than 300 times greater than Group III. The total asbestos fiber count for Group I was nearly 20 times greater than Group II and more than 50 times greater than Group III. The difference was due almost entirely to commercial amphiboles. In a series of primary lung cancer cases with some history of asbestos exposure, a markedly elevated asbestos content was identified among those with pathologic asbestosis as compared with patients with pleural plaques alone or with neither plaques nor asbestosis.

Solitary pulmonary nodules: Part I. Morphologic evaluation for differentiation of benign and malignant lesions.

The solitary pulmonary nodule is a common radiologic abnormality that is often detected incidentally. Although most solitary pulmonary nodules have benign causes, many represent stage I lung cancers and must be distinguished from benign nodules in an expeditious and cost-effective manner. Evaluation of specific morphologic features of a solitary pulmonary nodule with conventional imaging techniques can help differentiate benign from malignant nodules and obviate further costly assessment. Small size and smooth, well-defined margins are suggestive of but not diagnostic for benignity. Lobulated contour as well as an irregular or spiculated margin with distortion of adjacent vessels are typically associated with malignancy. There is considerable overlap in the internal characteristics (eg, attenuation, cavitation, wall thickness) of benign and malignant nodules. The presence of intranodular fat is a reliable indicator of a hamartoma. The presence and pattern of calcification can also help differentiate benign from malignant nodules. Computed tomography (CT) (particularly thin-section CT) is 10-20 times more sensitive than standard radiography and allows objective, quantitative assessment of calcification. Initial evaluation often results in nonspecific findings, in which case nodules are classified as indeterminate and require further evaluation to exclude malignancy. Growth rate assessment, Bayesian analysis, contrast material-enhanced CT, positron emission tomography, and transthoracic needle aspiration biopsy can be useful in this regard.

The pathology of interstitial lung disease in nylon flock workers.

Flocking is a widely used industrial process in which short lengths of synthetic fibers are applied to backing fabric to produce plush material. In response to an apparent outbreak of interstitial lung disease in flock workers, the Centers for Disease Control hosted a clinical-pathological workshop to identify the defining characteristics of the disease and possible etiologic agents. Six pathologists reviewed 15 biopsies of 15 cases (out of a clinical caseload of 20 patients) and assessed the pattern, extent and degree of pulmonary inflammation, fibrosis, and other changes. A consensus clinical-pathologic diagnosis was reached for each patient and correlated with clinical and radiologic findings. Four of eight open lung biopsies and one of seven closed (transbronchial) lung biopsies demonstrated a characteristic pattern to which the descriptive terminology lymphocytic bronchiolitis and peribronchiolitis with lymphoid hyperplasia was applied. The other biopsies showed nonspecific inflammatory changes, airspace organization, and diffuse alveolar damage. One open lung biopsy demonstrated respiratory bronchiolitis with lymphoid hyperplasia. None of the lung biopsies showed more than mild interstitial fibrosis and no granulomas were identified. The consensus of the workshop was that lymphocytic bronchiolitis and peribronchiolitis with lymphoid hyperplasia was a characteristic and distinctive pattern of injury in the flock workers' lung biopsies. Although the etiology of this disease remains undefined at present, the injury pattern and environmental studies suggest a chronic immunologic response to inhaled material.

Allergic lung responses are increased in prostaglandin H synthase-deficient mice.

To investigate the function of prostaglandin H synthase-1 and synthase-2 (PGHS-1 and PGHS-2) in the normal lung and in allergic lung responses, we examined allergen-induced pulmonary inflammation and airway hyperresponsiveness in wild-type mice and in PGHS-1(-/-) and PGHS-2(-/-) mice. Among nonimmunized saline-exposed groups, we found no significant differences in lung function or histopathology, although PGE(2) was dramatically reduced in bronchoalveolar lavage (BAL) fluid from PGHS-1(-/-) mice, relative to wild-type or PGHS-2(-/-) mice. After ovalbumin sensitization and challenge, lung inflammatory indices (BAL cells, proteins, IgE, lung histopathology) were significantly greater in PGHS-1(-/-) mice compared with PGHS-2(-/-) mice, and both were far greater than in wild-type mice, as illustrated by the ratio of eosinophils in BAL fluid (8:5:1, respectively). Both allergic PGHS-1(-/-) and PGHS-2(-/-) mice exhibited decreased baseline respiratory system compliance, whereas only allergic PGHS-1(-/-) mice showed increased baseline resistance and responsiveness to methacholine. Ovalbumin exposure caused a modest increase in lung PGHS-2 protein and a corresponding increase in BAL fluid PGE(2) in wild-type mice. We conclude that (a) PGHS-1 is the predominant enzyme that biosynthesizes PGE(2) in the normal mouse lung; (b) PGHS-1 and PGHS-2 products limit allergic lung inflammation and IgE secretion and promote normal lung function; and (c) airway inflammation can be dissociated from the development of airway hyperresponsiveness in PGHS-2(-/-) mice.

Pulmonary cholesterol granulomas in patients with pulmonary artery hypertension: chest radiographic and CT findings.

OBJECTIVE: We describe the chest radiographic and CT findings of pulmonary cholesterol granulomas in patients with pulmonary artery hypertension. CONCLUSION: Histopathologic evidence of cholesterol granulomas was found in five (25%) of 20 patients with severe pulmonary hypertension. In three of these five patients, the granulomas manifested on chest radiographs and CT as small centrilobular nodules mimicking the appearance of sarcoidosis, bronchiolitis, hypersensitivity pneumonitis, or aspiration.

Ultrastructural features of diffuse malignant mesotheliomas.

The distinction of malignant mesothelioma from tumors metastatic to the serosal membranes can often be made based on the results of histochemical or immunohistochemical studies. However, in some cases, these techniques are inadequate to make a firm diagnosis. In these instances, electron microscopic studies with the observation of a constellation of characteristic ultrastructural findings may permit an unequivocal diagnosis of mesothelioma.

The diagnosis of desmoplastic malignant mesothelioma and its distinction from fibrous pleurisy: a histologic and immunohistochemical analysis of 31 cases including p53 immunostaining.

We studied 31 patients with fibrotic pleural lesions and classified them as desmoplastic malignant mesothelioma (DMM) or fibrous pleurisy (FP) using predetermined histologic criteria, including a paucicellular fibrotic pleural lesion with a storiform pattern or the "patternless pattern " of Stout, plus 1 or more of the following: invasion of chest wall or lung, bland necrosis, frankly sarcomatoid areas, and distant metastases. Staining for p53 was performed in 22 cases. Follow-up was obtained on all cases and compared with the histologic diagnoses. For 24 cases, the consensus diagnosis was DMM; 19 of these displayed frankly sarcomatoid areas, 16 showed invasion, and 8, bland necrosis. Of the 24, 23 patients died of disease and 1 was alive with disease. The remaining 7 cases were classified as FP, and all were alive without disease. The concordance among 3 pathologists using the criteria was excellent. Staining for p53 was more common in DMM than in FP, but the difference was not statistically significant. The concordance in interpreting the p53 stains by the same 3 pathologists was moderate. The distinction between DMM and FP in a predominantly fibrotic pleural lesion can be made in most cases with adequate sampling and the use of specific criteria.

Pleural macrophage recruitment and activation in asbestos-induced pleural injury.

The pathogenesis of asbestos-induced pleural fibrosis is poorly understood. Moreover, there has been a long-standing controversy regarding the relative potential of different commercial types of asbestos to cause pleural disease. We postulated that inhaled asbestos fibers translocate to the pleural space where they stimulate the recruitment and activation of pleural macrophages. To test this hypothesis, and to determine whether there are differences between inhaled amphibole and serpentine asbestos, Fischer 344 rats were exposed by intermittent inhalation (6 hr/day for 5 days/week over 2 weeks) to either National Institute of Environmental Health Sciences (NIEHS) crocidolite (average concentration 7.55 mg/m3) or NIEHS chrysotile fibers (average concentration 8.51 mg/m3). Comparisons were made with sham-exposed rats. The rats were sacrificed at 1 and 6 weeks after the cessation of exposure. More pleural macrophages were recovered at 1 and 6 weeks after crocidolite and chrysotile exposure than after sham exposure. Small numbers of crocidolite fibers (approximately 1 per 4000 cells) were detected in the pleural cell pellet of one crocidolite-exposed rat by scanning electron microscopy. Pleural macrophage supernatants were assayed for production of nitric oxide (NO) (by the Griess reaction) and tumor necrosis factor alpha (TNF-alpha) (by an enzyme-linked immunosorbent assay method). Significantly greater amounts of NO as well as TNF-alpha were generated by pleural macrophages at 1 and 6 weeks after either crocidolite or chrysotile inhalation than after sham exposure. Conceivably, translocation of asbestos fibers to the pleural space may provide a stimulus for persistent pleural space inflammation, cytokine production, and the generation of toxic oxygen and nitrogen radicals. Enhanced cytokine secretion within the pleural space may in turn upregulate adhesion molecule expression and the synthesis of extracellular matrix constituents by pleural mesothelial cells. Thus, our findings may have significance for the development of asbestos-induced pleural injury.

Silica-induced pleural disease: an unusual case mimicking malignant mesothelioma.

A 57-year-old man with a history of exposure to silica for 32 years presented with pleural thickening of the lower lobe of the left lung and a chronic right-sided pleural effusion without any radiographic evidence of parenchymal nodules in either lung. Light microscopic examination of a left visceral pleural biopsy specimen revealed markedly thickened pleura with fibrosis and macrophages containing birefringent silica and silicates. Occasional rounded intrapleural silicotic nodules were present. The underlying lung tissue did not show fibrosis or silicotic nodules. An energy-dispersive x-ray analysis confirmed the presence of silica. In the absence of lung involvement, this case represents a very unusual pathologic reaction caused by silica and silicates and adds to the clinical differential diagnosis of chronic pleuritis and malignant mesothelioma.

Iron accumulation in lung allografts after transplantation.

Lung transplantation has become a therapeutic option for end-stage pulmonary diseases, but after transplantation, infections and obliterative bronchiolitis (OB) are major causes of long-term morbidity and mortality. OB is a fibroproliferative disease, of poorly understood etiology, characterized by an irreversible decline in allograft function. Because diseases with tissue iron overload are characterized by fibrosis and end-organ failure, we studied the iron concentrations in BAL fluid and lung tissue in 10 lung allograft patients. BAL fluid revealed significantly elevated iron concentrations in allograft patients compared with five normal volunteers (135+/-16.54 micromol/L vs 33.65+/-7.48 micromol/L, respectively). Prussian blue staining of biopsy specimens of lung allograft tissue revealed an accumulation of iron primarily in alveolar macrophages. Immunohistochemical stains for ferritin revealed accumulation of the protein in macrophages, interstitium, vascular walls, and bronchiolar epithelium. Iron studies of the blood (serum ferritin and iron concentrations) revealed no evidence for systemic iron overload. In conclusion, patients with pulmonary allografts appear to have elevated concentrations of iron in lung tissue. This iron overload may place the allografts at increased risk of metal-mediated injury and fibrosis.

Prevalence of pulmonary atypical alveolar cell hyperplasia in an autopsy population: a study of 100 cases.

A precursor lesion of pulmonary adenocarcinoma has not been clearly defined. Previous studies suggested that atypical alveolar cell hyperplasia (AACH) might represent such a precursor lesion. Most previous studies showed an association between AACH and adenocarcinoma in surgical resection specimens. In this study, we searched for the prevalence of AACH and nonatypical alveolar cell hyperplasia (ACH) in a general autopsy population. Cases in which there was clinical or anatomic evidence of pulmonary neoplasia were excluded from the study. In the 100 consecutive autopsies examined, we found four cases of ACH and two cases of AACH. The two AACH lesions showed cytologic atypia and stained positively for p53 and c-erb-2. These findings suggest a possible role for AACH as a precursor lesion of adenocarcinoma of the lung.

Effect of erionite on the pleural mesothelium of the Fischer 344 rat.

OBJECTIVE: This study sought to assess the fibrogenic and carcinogenic potential of erionite (a fibrous zeolite) on the pleural mesothelium of the Fischer 344 rat (n = 24). DESIGN: The study was designed to examine rat pleural mesothelial changes by three independent observers at timed intervals, ranging from 1 to 480 days postinoculation using erionite from the Pine Valley, Nevada (USA) area. The mean length and width of the erionite fibers were 2.29 and 0.48 microns, respectively. Only microscopic observations made by majority (2/3) or unanimity (3/3) were accepted for final diagnosis. RESULTS: Pleural and lung tissue were available for examination in 21 of the 24 rats. Fibrosis, chronic inflammation, and foreign body reaction occurred in 6 of 21 rats. Mesothelial hyperplasia and dysplasia occurred in 9 and 3 of the 21 rats, respectively. A single mesothelioma was identified at 434 days in a rat that had gross nodular pleural lesions. CONCLUSIONS: The findings reported herein confirm the strong fibrogenic potential of erionite but are at variance with previous studies reporting much higher yields of mesothelioma. The reasons for the low yield of mesothelioma in this study are not known, but may be related to the study design, the strict criteria used for histopathologic diagnosis, and/or possible differences in erionite physicochemical properties, associated with its geographic distribution, most previous animal studies having used erionite from the Rome, Oregon (USA) area.

In vivo accumulation of iron on crocidolite is associated with decrements in oxidant generation by the fiber.

In vivo exposures to fibrous silicates are characterized by the formation of asbestos bodies. These structures consist of the original fiber with a coating of inexact composition, but it will include iron and protein. We tested the hypothesis that this iron, accumulated on asbestos bodies, participates in electron transport and oxidant generation. Thirty-day-old, male guinea pigs were intratracheally instilled with 1.0 mg crocidolite. Six months later, the animals were anesthetized, euthanized, and the fibers were isolated from the lungs. Energy-dispersive x-ray analysis and x-ray photoelectron spectroscopy confirmed an accumulation of metal onto the fiber after in vivo exposure. Stains for iron demonstrated a heterogeneous distribution of the metal on the silicate, while the uptake of a commercially available polyclonal antibody to ferritin localized to beaded enlargements along the coated fibers. Chelatable [Fe3+] associated with the fiber increased after in vivo exposure. However, oxidant generation by asbestos bodies was decreased relative to uncoated fibers despite the elevation in the concentration of metal associated with the crocidolite. We conclude that iron is accumulated onto fibers in the lungs of guinea pigs. Some portion of this accumulation of iron is in the form of ferritin, and this metal is not chemically reactive in oxidant production. Asbestos bodies may represent a successful attempt by the host to sequester the metal adsorbed to the surface of a fiber and diminish the oxidative challenge introduced by a fibrous silicate. Subsequently, the generation of free radicals by the fibrous silicate is diminished.