Commentary on pathologic diagnosis of asbestosis and critique of the 2010 Asbestosis Committee of the College of American Pathologists (CAP) and Pulmonary Pathology Society's (PPS) update on the diagnostic criteria for pathologic asbestosis.

We reviewed the 2010 Asbestosis Committee's update on the diagnostic criteria for pathologic asbestosis. We must respectfully disagree with many of the criteria set forth therein, especially for recognizing asbestosis at its earliest stages; with statements focusing on the number of asbestos bodies needed in order to make a pathologic diagnosis of asbestosis; and regarding the benefits and pitfalls of relying on fiber analysis for diagnostic purposes, especially where chrysotile asbestos is concerned, including the methodology used for fiber determination. This critique has become even more relevant with the 2014 Helsinki criteria publication, which adopted the 2010 CAP/PPS criteria. Based on our review of these newer criteria and our experience in this field, we find that the CAP-NIOSH 1982 criteria is still the most acceptable method for the pathologic diagnosis and grading of asbestosis, which can be described as pulmonary fibrosis caused by inhalation of asbestos fibers.

Fatal pulmonary hemorrhage after taking anticoagulation medication.

We describe a 64-year-old man with extensive diffuse acute lung hemorrhage, presumably as a result of anticoagulation therapy. We evaluated reports in the literature concerning acute exacerbation (acute lung injury of unknown cause) in UIP and other forms of fibrotic interstitial pneumonias. We also evaluated autopsy tissue in this case in order to determine the cause of death in this 64-year-old man, who was initially thought to have an asbestos-related disease. Based on the autopsy findings, this man died as a result of anticoagulation therapy; specifically, the use of Xarelto(®) (rivaroxaban).

Analysis of asbestos concentration in 20 cases of pseudomesotheliomatous lung cancer.

Mesothelioma is a rare neoplasm caused by asbestos exposure. The majority of mesotheliomas arise from the pleural lining of the thoracic cavity, but also involve the peritoneal and pericardial cavities. Another type of neoplasm referred to as pseudomesotheliomatous adenocarcinoma is rare. Most "pseudomesotheliomas" arise in the pleural tissue of the chest cavity and resemble pleural mesotheliomas, macroscopically and histologically. While most arise in the pleura, there are some that metastasize to the pleura from another site. We evaluated asbestos fiber concentrations in 20 cases of pseudomesotheliomatous lung cancer and found a significant number to contain an elevated concentration of asbestos in their lung tissue, which is similar with our study of 55 mesothelioma cases published in 1997. This would provide evidence that some pseudomesotheliomatous lung cancers are caused by asbestos.

Mesothelioma in an individual following exposure to crocidolite-containing gaskets as a teenager.

Mesothelioma is considered a signal tumor for asbestos exposure and typically occurs decades after first exposure to asbestos. Tissue analysis often indicates past exposure to mixed types of asbestos. This report describes the case of a 58-year-old man who developed mesothelioma after reported exposure to crocidolite from asbestos-containing gaskets beginning at age 16 during three summers during high school and for approximately four hours per day during the last semester of his senior year. He had no further known exposure to asbestos. Analytical transmission electron microscopy analysis of digested tissue samples revealed elevated levels of crocidolite asbestos fibers and the presence of crocidolite cored ferruginous bodies. This case is unique in that it establishes that relatively short and/or intense exposures to crocidolite asbestos traumatically released from a previously classified Category 1 nonfriable asbestos-containing material (NESHAP) was confirmed via tissue burden analysis years following the historically defined exposures.

Guidelines for pathologic diagnosis of malignant mesothelioma: a consensus statement from the International Mesothelioma Interest Group.

CONTEXT: Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: To develop practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: A pathology panel was convened at the International Mesothelioma Interest Group biennial meeting (October 2006). Pathologists with an interest in the field also contributed after the meeting. CONCLUSIONS: There was consensus opinion regarding (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the differential diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. The International Mesothelioma Interest Group recommends that markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist.

A technical comparison of evaluating asbestos concentration by phase-contrast microscopy (PCM), scanning electron microscopy (SEM), and analytical transmission electron microscopy (ATEM) as illustrated from data generated from a case report.

As reported in the literature, there are more than 30 different standard methods available for the analysis of asbestos in a variety of situations. The methods include those for determining asbestos concentration in air, water, bulk building materials, surface dust, soil, and lung tissue (Millette, 2006; Dodson, 2006). Knowledge of the various methodologies is essential in determining which methodology is appropriate for any given situation. To better understand the use of various techniques in evaluating asbestos, we use an example of an individual who was a machinist in an auto supply/parts business. His work activity during much of his professional career included grinding, arcing, and drilling brake components. Asbestos has been identified as an important component of friction products, particularly brakes, and exposure to asbestos brake dust is of concern, particularly in workers where grinding, arcing, sanding, and drilling of brake components are recognized as releasing appreciable dust. Various methods can be used to evaluate asbestos in tissue and air. The case reported herein was of an individual who died from a pleural mesothelioma. Paraffin-embedded lung tissue was examined by a laboratory using scanning electron microscopy (SEM) and was reported to contain elevated asbestos body concentrations and five fibers, of which two were asbestos (one chrysotile and one tremolite). Tissue from the same paraffin block was analyzed by the laboratory of one of us (RFD) using analytical transmission electron microscopy (ATEM). While one might think the number of asbestos bodies and fibers would be similar using SEM and ATEM, this was not the case. Slightly elevated numbers of ferruginous asbestos bodies were detected in the digestate by light microscopy. Large numbers of uncoated chrysotile fibers were found by ATEM, but not by SEM. The majority of the chrysotile structures were fibrils whose detection required resolution levels attainable only at higher magnification by ATEM. The findings in this case clearly indicate that analysis of lung tissue digestates by ATEM at a higher magnification (15,000x) identifies significant numbers of asbestos fibers that are not identified by SEM at 1000x. These results further indicate that if causation of an asbestos-induced disease such as mesothelioma is based on asbestos concentration of lung tissue, erroneous conclusions can be made by analyzing tissue only by SEM. Thus, the methodologies that are available to analyze asbestos in lung tissue are extensively discussed here with respect to the type of procedure that should be utilized in various situations.

Characteristics of asbestos concentration in lung as compared to asbestos concentration in various levels of lymph nodes that collect drainage from the lung.

Inhaled dust particulates are able to relocate to the extrapulmonary compartments, particularly the lymph nodes that drain the lung. There is little information about the concentration and type of asbestos in the lymphatics and lymph nodes. Quantitative analysis of asbestos lymph node burden conducted by light and analytical transmission electron microscopy has shown ferruginous bodies in lymph nodes that drain the lung and appreciable numbers of short asbestos fibers accumulate in lymph nodes in occupationally exposed individuals. The location of lymph nodes in the thoracic cavity was categorized according to the Naruke anatomical map. Tissue from eleven individuals with a history of asbestos exposure were selected for a comparative study of the asbestos content of lung with that found in the thoracic lymph nodes. The study used a digestion technique for tissue preparation and evaluated ferruginous body burden and concentration of asbestos fibers (> 0.5 microm in length). Comparison was made between sites and analysis was made as to the population of fibers detectable by light microscopy and defined as "Stanton fibers." The findings indicated the vast majority of all asbestos fiber types in all sites were shorter than 5 microm and would not have been counted in a light microscopy count scheme that included only those fibers > 5 microm. There were reproducible patterns of asbestos types of found in various lymph nodes, although there were variations in the amount of asbestos found in the sites sampled. In summary, asbestos fibers found in thoracic lymph nodes have predominately short fibers and, in this study group, consisted of a mixture of commercial and noncommercial amphiboles. When a long/thin fiber was found in the lung or lymph tissue, its detection required the use of analytical transmission electron microscopy for identification.

The dispersed neuroendocrine system, its bronchopulmonary elements, and neuroendocrine tumors presumed to be derived from them: myths, mistaken notions, and misunderstandings.

The increasing recognition of the dispersed neuroendocrine system and its importance in human physiology has impacted our understanding of physiology, pathophysiology, and histopathology. It has been the subject of a great deal of controversy and debate, giving rise to certain misunderstandings. This article attempts to put some of these issues in perspective, especially as they relate to the bronchopulmonary tree.

Approach to the diagnosis of neuroendocrine lung neoplasms: variabilities and pitfalls.

With the publication of the spectrum of neuroendocrine proliferations and neoplasms and the features and criteria for diagnosing neuroendocrine lung neoplasms, there is more agreement in making a specific pathologic diagnosis of a neuroendocrine lung neoplasm. However, problems exist, especially in diagnosing well-differentiated neuroendocrine carcinomas (atypical carcinoids), large-cell neuroendocrine carcinomas, and even some small-cell lung cancers. Some of this disagreement has to do with a pathologist's perception of sizes and shapes of cells. Nonneuroendocrine small-cell carcinomas exist and include small-cell squamous cell carcinoma, small cell adenocarcinoma, and basaloid carcinoma. Nonneuroendocrine lung cancers, especially large-cell undifferentiated carcinoma and poorly differentiated adenocarcinoma, not infrequently express neuroendocrine markers immunohistochemically.

Pleural mesothelioma in a woman whose documented past exposure to asbestos was from smoking asbestos-containing filtered cigarettes: the comparative value of analytical transmission electron microscopic analysis of lung and lymph-node tissue.

Asbestos has had many commercial applications, including its use as a major component in various types of filters. Between 1952 and 1956, crocidolite asbestos was used as a component of filters for cigarettes, reportedly greatly reducing tars and nicotine from mainstream smoke. This case report quantifies asbestos burden in lung and lymph node tissue in a 67-yr-old woman who succumbed to mesothelioma. Her only historically documented exposure to asbestos was from smoking crocidolite asbestos-containing filtered cigarettes between 1952 and 1956. Tissue digestion analysis by analytical transmission electron microscopy (ATEM) identified crocidolite fibers in lungs and thoracic lymph nodes. Combined ATEM data of lung and lymph node tissue clarified the patient's exposure to asbestos and particularly to crocidolite asbestos and thus to the presence of an entity recognized as the causal agent for mesothelioma.

Macroscopic, histologic, histochemical, immunohistochemical, and ultrastructural features of mesothelioma.

Mesotheliomas are uncommon neoplasms that arise from the cells forming the serosal membranes of the body cavities. Approximately 90-95% of mesotheliomas arise in the pleural cavity and 5-10% in the peritoneal cavity. Rare mesotheliomas arise in the pericardium and in the tunica vaginalis. Unlike many neoplasms, mesotheliomas grow in a diffuse distribution and tend to encase the organs in the various body cavities. A combination of histochemical, immunohistochemical, and ultrastructural features are often necessary to accurately diagnose mesotheliomas. These techniques are highlighted in this review article on mesothelioma.

Localized malignant mesothelioma.

Localized malignant mesotheliomas are uncommon sharply circumscribed tumors of the serosal membranes with the microscopic appearance of diffuse malignant mesothelioma but without any evidence of diffuse spread. Little is known about their behavior. We report 23 new cases. The mean age at presentation was 63 years, and the sex ratio was approximately 2:1 (male/female). Twenty-one tumors were pleural and 2 were peritoneal. Sixteen tumors reproduced microscopic patterns of diffuse epithelial mesotheliomas, 6 had mixed epithelial and sarcomatous patterns, and 1 was purely sarcomatous. After surgical excision of the tumor, 10 of 21 patients with follow-up data were alive without evidence of disease from 18 months to 11 years after diagnosis. Patients who died had developed local recurrences and metastases, but none had diffuse pleural spread. Localized malignant mesotheliomas should be separated from diffuse malignant mesotheliomas because of their localized presentation, quite different biologic behavior, and far better prognosis.

Quality control analysis of the potential for asbestos contamination during tissue processing in pathology laboratories.

CONTEXT: Various quality assurance procedures are applied in pathology and analytical microscopy laboratories to ensure accurate results. OBJECTIVE: To assess the potential of cross-contamination of tissue with asbestos fibers and asbestos bodies during the fixation and washing process. DESIGN: Lung tissue from 10 patients with potential asbestos-related disease was evaluated. Samples of fixative, water, and lung tissue from each case were evaluated by light and analytical transmission electron microscopy for asbestos bodies and uncoated asbestos fibers. RESULTS: The lung samples tested contained a range of asbestos bodies and uncoated asbestos fibers. One wash water sample contained one asbestos body. No asbestos bodies or uncoated asbestos fibers were found in any other water or fixative samples. CONCLUSIONS: The absence of uncoated asbestos fibers in wash water or fixative samples argues that the fixation process stabilizes asbestos fibers within tissue and the protocol used in this pathology laboratory protects against cross-contamination of tissue. The finding of one asbestos body in one water sample further supports the efficiency of the protective controls used in the testing methods, since this asbestos body was in the external solution that was being discarded before tissue sampling occurred.

The spectrum of Kit (CD117) immunoreactivity in lung and pleural tumors: a study of 96 cases using a single-source antibody with a review of the literature.

CONTEXT: The development of successful chemotherapeutic agents directed against the Kit receptor tyrosine kinase protein has generated intense interest in the Kit (CD117) immunoreactivity of various neoplasms. Immunoreactivity for Kit in small cell lung carcinoma (SCLC) has been well established. However, data on Kit immunostaining in other lung tumors is limited. Likewise, while solitary fibrous tumors of the gastrointestinal tract have been examined for Kit expression, the Kit staining characteristics of their counterpart in the pleura, namely, localized fibrous tumor, are not well known. OBJECTIVE: To characterize the Kit immunohistochemical profiles of major types of lung and pleural tumors. DESIGN: We stained 60 lung carcinomas, including 11 SCLCs, 4 large cell neuroendocrine carcinomas, 22 squamous cell carcinomas, 23 adenocarcinomas, 11 pulmonary carcinoid tumors, 19 pleural malignant mesotheliomas, and 6 localized pleural fibrous tumors with a commonly used polyclonal Kit antibody. RESULTS: Small cell lung carcinomas demonstrated Kit staining in 82% of cases, nearly all of which demonstrated moderate to intense immunoreactivity. Immunostaining was observed in 25% of large cell neuroendocrine carcinomas. Focal staining was observed in 9% of squamous cell carcinomas and 17% of adenocarcinomas. None of the pulmonary carcinoid tumors were immunoreactive. Moderately intense immunostaining was present in 50% of localized fibrous tumors. Malignant mesotheliomas were nonimmunoreactive for Kit in 95% of cases. CONCLUSION: Non-small cell lung carcinomas showed very limited expression of Kit. Lung tumors with neuroendocrine differentiation exhibited a wide spectrum of Kit immunoreactivity, ranging from rare in pulmonary carcinoid tumors to frequent in SCLC. The high frequency of Kit immunostaining in SCLC has important potential therapeutic implications. Demonstration of Kit positivity in some localized fibrous tumors in this study contrasts with absent immunoreactivity in solitary fibrous tumors of the gastrointestinal tract. The paucity of Kit staining in malignant mesothelioma suggests these tumors are unlikely to respond to currently available tyrosine kinase inhibitors.

Quantitative analysis of asbestos burden in a series of individuals with lung cancer and a history of exposure to asbestos.

Asbestos is recognized as a lung carcinogen. In the present study, tissue from 20 individuals who died from lung cancer and who had a history of exposure to asbestos was evaluated for the presence of asbestos bodies and uncoated asbestos fibers. A digestion procedure was used to isolate the particulates from the tissue. The samples were evaluated by light microcopy to quantify the numbers of ferruginous bodies in the tissue. The uncoated fibers (which included all fibers equal to or greater than 0.5 microm) were analyzed by analytical transmission electron microscopy. Seventeen of the 20 cases were positive for ferruginous bodies (which were morphologically consistent with asbestos bodies). Five of these were found to have concentrations within the range used in our laboratory for the general population (<20 ferruginous bodies/g wet tissue). Nineteen of the 20 cases were found to have asbestos fibers in the higher magnification scan (either 16 K or 20 K). Some of the asbestos fibers identified were specific for the types of exposures that were reported. Most individuals in this study were found to have mixed populations of asbestos fibers in the lung tissue. This suggests that when there are exposures to products containing commercial asbestos there are likely exposures to dust containing noncommercial asbestos. A contrast exists in the dust burden within the lung of these individuals as compared to samples from the general population in that occupational or "occupational-like" exposures such as in these cases are often reflected by the presence of longer fibers of asbestos in the tissue.

Pulmonary granulomatous vasculitis induced by insoluble particulates: a case report.

The authors report a case of a 39-year-old woman who sustained an injury to her left knee requiring arthroscopic surgical medial menisectomy and ganglionic block for reflex sympathetic dystrophy syndrome. Approximately 1 year after injury, the patient presented with an elevated white blood cell count and fever and was diagnosed to have a psoas muscle abscess, which was treated with antibiotics. She was also taking 4 different oral medications that contained microcrystalline cellulose as a filter. Approximately 1 month after being diagnosed with the psoas muscle abscess, the patient developed shortness of breath, marked weakness, diaphoresis, and intermittent emesis. She became hypotensive and tachyneic and expired. Postmortem examination showed granulomatous vasculitis with extensive occlusions of pulmonary arteries by birefringent crystalline material identified to be cellulose histochemically and by analytical electron microscopy evaluation. This case report describes the ultrastructural and chemical features of various medicinal tablet fillers and compares them to pure samples. This report also demonstrates the usefulness of analytical electron microscopy in accurately identifying birefringent material in lung tissue.

Quantitative analysis of asbestos burden in women with mesothelioma.

BACKGROUND: Lung tissue from 15 women who died from mesothelioma was evaluated for tissue burden of ferruginous bodies and uncoated asbestos fibers. The group contained individuals who had occupational exposure to asbestos and others had family members whose work history included vocations where contact with asbestos containing materials occurred. METHODS: Tissue samples from tumor free lung were digested and filtered and then investigated for ferruginous bodies by light microscopy and asbestos and non-asbestos fibers by analytical transmission electron microscopy (ATEM). Size and type of fibers were also analyzed. RESULTS: Asbestos bodies were found in 13 of the 15 samples and asbestos fibers were found in all cases. The most commonly found uncoated asbestos fiber in these individuals was amosite whereas tremolite was the second most commonly found form. The asbestos fiber burden in these females was often of mixed types. CONCLUSIONS: The asbestos body and fiber burden in these cases show variation in tissue burden. Some cases in this study had appreciable burden, which was attributed to secondhand exposure from occupationally exposed family members. Mesothelioma can occur also in individuals with comparatively low tissue burdens of asbestos.

Sclerosing hemangioma of the lung in a young woman with cutaneous melanoma: the role of electron microscopy in preventing an erroneous diagnosis of metastasis.

A young woman with a melanoma of the left forearm was found to have a right lung mass. This was initially interpreted as metastatic melanoma on the basis of clinical, radiographic, and light microscopic features, together with positive staining of tumor cells with antibody HMB-45. Electron microscopic examination performed for confirmation of the diagnosis revealed no evidence of melanocytic differentiation. Instead, there were features suggestive of the alternative diagnosis of sclerosing hemangioma (SH). This diagnosis was confirmed with additional immunocytochemical stains. To the authors' knowledge this is the first report of HMB-45 positivity in SH. This case illustrates a potentially disastrous diagnostic pitfall in interpreting lung tumors in patients with melanoma, and the vital role of electron microscopy in resolving conflicting and/or misleading immunocytochemical results.