The diagnosis of asbestosis in the 21st century: a clinicopathological correlation of 102 cases.

Asbestosis, defined as diffuse pulmonary fibrosis caused by inhalation of asbestos fibers, occurs after heavy exposures to asbestos dust over several decades. Because workplace exposures have been significantly curtailed since the banning of asbestos in insulation products, we were interested in examining the clinicopathological characteristics of cases diagnosed in the 21st century. The consultation files of one of the authors (VLR) were reviewed for cases of asbestosis diagnosed since 1/1/2001. 102 cases were identified, with a median age of 75 years (range: 45-89). There were 100 men and 2 women. The women were from Turkey and Brazil (none from the United States). Malignancies were present in 78 cases, including 38 lung cancers, 29 pleural mesotheliomas, and 8 peritoneal mesotheliomas. The grade of asbestosis was available in 88 cases (median severity of 2; scale: 1-4). Pleural plaque was present in 94% of cases. The most common exposure categories were insulators (39), shipyard workers (16), asbestos manufacturing (9), boiler workers (8) and pipefitter/welders (6). The median duration of exposure was 33 years (range: 2-49 years). Lung fiber burden analysis was performed in 34 cases, with amosite being the predominant fiber type. Results were compared with similar information for 475 cases diagnosed prior to 1/1/2001.

The cell of origin and subtype of K-Ras-induced lung tumors are modified by Notch and Sox2.

Cell type-specific conditional activation of oncogenic K-Ras is a powerful tool for investigating the cell of origin of adenocarcinomas in the mouse lung. Our previous studies showed that K-Ras activation with a CC10(Scgb1a1)-CreER driver leads to adenocarcinoma in a subset of alveolar type II cells and hyperplasia in the bronchioalveolar duct region. However, no tumors develop in the bronchioles, although recombination occurs throughout this region. To explore underlying mechanisms, we simultaneously modulated either Notch signaling or Sox2 levels in the CC10+ cells along with activation of K-Ras. Inhibition of Notch strongly inhibits adenocarcinoma formation but promotes squamous hyperplasia in the alveoli. In contrast, activation of Notch leads to widespread Sox2+, Sox9+, and CC10+ papillary adenocarcinomas throughout the bronchioles. Chromatin immunoprecipitation demonstrates Sox2 binding to NOTCH1 and NOTCH2 regulatory regions. In transgenic mouse models, overexpression of Sox2 leads to a significant reduction of Notch1 and Notch2 transcripts, while a 50% reduction in Sox2 leads to widespread papillary adenocarcinoma in the bronchioles. Taken together, our data demonstrate that the cell of origin of K-Ras-induced tumors in the lung depends on levels of Sox2 expression affecting Notch signaling. In addition, the subtype of tumors arising from type II cells is determined in part by Notch activation or suppression.

Talc and mesothelioma: mineral fiber analysis of 65 cases with clinicopathological correlation.

Malignant mesothelioma is strongly associated with prior asbestos exposure. Recently there has been interest in the role of talc exposure in the pathogenesis of mesothelioma. We have analyzed lung tissue samples from a large series of malignant mesothelioma patients. Asbestos bodies were counted by light microscopy and mineral fiber concentrations for fibers 5 µm or greater in length were determined by scanning electron microscopy equipped with an energy dispersive spectrometer. The values were compared with 20 previously published controls. Among 609 patients with mesothelioma, talc fibers were detected in 375 (62%) and exceeded our control values in 65 (11%). Elevated talc levels were found in 48/524 men (9.2%) and 17/85 women (20%). Parietal pleural plaques were identified in 30/51 informative cases (59%) and asbestosis in 5/62 informative cases (8%). Commercial amphiboles (amosite and/or crocidolite) were elevated in 52/65 (80%) and noncommercial amphiboles (tremolite, actinolite or anthophyllite) in 41/65 (63%). Both were elevated in 34/65 (52%). Asbestos body counts by light microscopy were elevated in 53/64 informative cases (83%). A history of working in industries associated with asbestos exposure and increased mesothelioma risk was identified in 36/48 cases in men, and a history of exposure as household contacts of an occupationally exposed individual was identified in 12/17 cases in women. We conclude that among patients with mesothelioma, the vast majority have talc levels indistinguishable from background. Of the remaining 11% with elevated talc levels, the vast majority (80%) have elevated levels of commercial amphibole fibers.

Dusting off the numbers of in situ particle analysis: a 35-year experience.

A variety of fibrotic lung diseases are caused by the inhalation of organic dusts. Many of these disorders have distinctive histopathology and can be readily diagnosed by routine histopathologic examination. However, in some instances, there is overlap in morphology between diseases caused by dust inhalation (mineral pneumoconiosis) and other lung diseases. In such cases, analytical scanning electron microscopy (SEM) can provide valuable information to assist the pathologist in making the correct diagnosis. We report herein our findings in 96 cases in which in situ particle analysis (ISPA) was performed with the SEM. This included 56 cases of pneumoconiosis as well as 40 cases of other types of interstitial lung disease. The most common diagnosis for which ISPA was performed in individuals with pneumoconiosis was mixed dust pneumoconiosis (14 cases). The most common diagnoses for which ISPA was performed in individuals with other diseases were sarcoidosis (13 cases) and hypersensitivity pneumonitis (10 cases). In addition to a detailed description of our methodology, we also report other circumstances in which ISPA assists in the diagnosis of pulmonary disease.

A hard (metal) case: Value of analytical scanning electron microscopy.

Exposure to hard metal (tungsten carbide) dust is a rare cause of interstitial lung disease. Although most cases have a distinctive morphology known as giant cell interstitial pneumonitis, other patterns have been described as well. In such cases, the true nature of the interstitial process may be difficult to recognize. We present a case with unusual morphological features in which analytical scanning electron microscopy (SEM) was used to detect the presence of tungsten as well as other metallic particles. A combination of careful exposure history and examination by analytical SEM is useful for arriving at the correct diagnosis in such difficult cases.

Carcinoma of the lung in the absence of asbestosis: The value of lung fiber burden analysis.

Asbestos is universally recognized as a carcinogen for the lower respiratory tract. However, asbestos is a contributory factor in a small fraction of lung cancers, the vast majority of which are related to cigarette smoking. The challenge for the pathologist is to determine when a lung cancer may be attributed to past asbestos exposure. The finding of asbestosis either clinically or pathologically is a useful marker for such a determination. However, in the absence of asbestosis, it has been suggested that a fiber burden as determined by analytical electron microscopy within the range of asbestosis is sufficient for determination of a causal contribution. We report here an example of a case of lung cancer in which fiber burden studies showed an asbestos concentration within the range of asbestosis as determined by scanning electron microscopy (SEM).

Endogenous pneumoconiosis: Analytical scanning electron microscopic analysis of a case.

Pneumoconiosis is often considered a disease of the lung initiated by exposure to dust or other airborne particles, resulting in injury to the lungs. The term "endogenous pneumoconiosis" has been used in the literature to describe the deposition of compounds on the elastic fibers of the lung, usually in the setting of cardiac failure. In the case we present here, the patient aspirated a foreign body resulting in damage to the lung tissue and subsequent deposition of endogenous compounds on the elastic fibers of the pulmonary parenchyma and vasculature. We determined the composition of this mineral and mapped the distribution of elements using a combination of backscattered electron microscopy and energy dispersive spectrometry.

Malignant mesothelioma not related to asbestos exposure: Analytical scanning electron microscopic analysis of 83 cases and comparison with 442 asbestos-related cases.

Epidemiological studies indicate that 80-90% of mesotheliomas are asbestos related. This suggests that 10-20% are not. Lung fiber burden analysis provides objective information about past exposures to asbestos. We have performed lung fiber burden analysis on a large cohort of mesothelioma cases and compared the findings with a reference population. Herein we report our findings along with demographic and exposure data.

Pulmonary Actinomycosis in a 65-Year-Old Female with Poor Oral Dentition.

Pulmonary actinomycosis is an uncommon clinical entity that can be challenging to diagnose due to its non-specific symptomatology. Misdiagnosis and delayed treatment may result in invasive procedures and extended antimicrobial treatment courses. We report a case involving a 65-year-old female with poor oral dentition admitted for acute respiratory failure subsequently found to have a left-sided pleural effusion and perihepatic abscess formation. Cytopathology examination and microbiology studies confirmed the diagnosis of pulmonary actinomycosis.

Diagnostic Approach to Pulmonary B-Cell Lymphomas in Small Biopsies, with Practical Recommendations to Avoid Misinterpretation.

Pulmonary lymphomas are rare. With the current less invasive approaches used to obtain material for diagnosis, the diagnosis of pulmonary lymphoma is now frequently established in a small biopsy rather than in a resection. Therefore, the diagnosis has become more challenging and requires correlation with the clinico-radiologic presentation and with ancillary studies (immunohistochemistry, flow cytometry, cytogenetics, and/or molecular analysis). Due to the rarity of pulmonary lymphomas, clinical suspicion of a lymphomatous process is low at initial presentation, and material may be only submitted for histopathology. For this reason, herein, we provide recommendations to arrive at the correct diagnosis of the most common lung B-cell lymphomas (marginal zone lymphoma of mucosa-associated lymphoid tissue, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, lymphomatoid granulomatosis) in the setting of small biopsies, utilizing only immunohistochemistry. The differential diagnosis varies according to the lymphoma subtype and includes reactive conditions, solid tumors, and other hematolymphoid malignancies. Although morphology and immunohistochemistry may be sufficient to establish a diagnosis, in some cases, the best recommendation is to obtain additional tissue via a VATS biopsy/wedge resection with material submitted for flow cytometry, cytogenetics, and/or molecular studies to be able to properly classify a pulmonary lymphoid process.

Mineralogy of asbestos.

The term asbestos collectively refers to a group of naturally occurring fibrous minerals which have been exploited in numerous commercial and industrial settings and applications dating to antiquity. Its myriad uses as a "miracle mineral" owe to its remarkable properties of extreme resistance to thermal and chemical breakdown, tensile strength, and fibrous habit which allows it to be spun and woven into textiles. Abundant in nature, it has been mined considerably, and in all continents save Antarctica. The nomenclature concerning asbestos and its related species is complex, owing to the interest held therein by scientific disciplines such as geology, mineralogy and medicine, as well as legal and regulatory authorities. As fibrous silicates, asbestos minerals are broadly classified into the serpentine (chrysotile) and amphibole (crocidolite, amosite, tremolite, anthophyllite, actinolite) groups, both of which may also contain allied but nonfibrous forms of similar or even identical chemical composition, nonpathogenic to humans. Recently, fibrous amphiboles, not historically classified or regulated as asbestos (winchite, richterite), have been implicated in the causation of serious disease due to their profusion as natural contaminants of vermiculite, a commercially useful and nonfibrous silicate mineral. Although generally grouped, classified, and regulated collectively as asbestos, the serpentine and amphibole groups have different geologic occurrences and, more importantly, significant differences in crystalline structures and chemical compositions. These in turn impart differences in fiber structure and dimension, as well as biopersistence, leading to marked differences in relative potency for causing disease in humans for the group of minerals known as asbestos.

Sarcomatoid mesothelioma: a clinical-pathologic correlation of 326 cases.

Sarcomatoid mesothelioma is the least common, but most aggressive of the three major histological types of mesotheliomas. This study comprises 326 cases of sarcomatoid mesotheliomas among 2000 consecutive malignant mesothelioma cases received in consultation (16%). Patients included 312 men (96%) and 14 women (4%), with a median age of 70 years (range 41-94 years). Most tumors were pleural (319; 98%), and 7 were peritoneal (2%). Some desmoplastic features were identified in 110 cases (34%), and 70 (21%) were classified as desmoplastic. Rare subtypes included two cases with a lymphohistiocytoid pattern (<1%) and eight heterologous mesotheliomas (2%). Labeling for cytokeratins (CKs) was observed in 261/280 cases (93%), and for calretinin and vimentin in 31 and 91%, respectively. Pleural plaques were present in 79% of cases for which information was available, and asbestosis was diagnosed in 34/127 cases (27%). Median survival was 3.5 months. Fiber analysis was performed in 61 cases. The median asbestos body count was 1640/g wet lung tissue (by light microscopy). Amosite fibers were the most commonly identified fibers using energy-dispersive X-ray analysis and were significantly higher in the sarcomatoid cases, as were uncoated fibers using scanning electron microscopy. This study represents the largest series of sarcomatoid and desmoplastic malignant mesotheliomas to date and confirms the diagnostic usefulness of CK immunohistochemistry. The relationship with asbestos exposure--particularly amosite--and an association with pleural plaques and less often asbestosis is confirmed.

Comparison of transbronchial lung biopsy yield between standard forceps and electrocautery hot forceps in swine.

BACKGROUND: Transbronchial lung biopsy (TBLB) is a commonly performed bronchoscopic procedure. Previous studies have suggested that larger biopsy forceps may improve diagnostic yield; however, the risk of bleeding associated with larger samples may be increased. The hot forceps are large forceps that are connected to an electrocautery system to minimize bleeding at the time of biopsy. OBJECTIVES: We evaluated the hot forceps for improvement in biopsy size and the number of sampled alveoli. METHODS: TBLBs were performed in 2 swine using one type of the forceps, followed by the other forceps 24 h later. Electrocautery was applied from closure of the forceps to retrieval of the sample. A blinded pathologist measured the size of each sample in its longest dimension and calculated the total alveolar content within the largest cross-section from each biopsy. RESULTS: A total of 74 biopsies were collected using each forceps type. Alveolar tissue was present in 25/74 and 26/74 of the biopsies using the hot and conventional forceps, respectively. There was no difference in the size of biopsies collected (2.10 +/- 1.10 vs. 1.83 +/- 0.94 mm; p = 0.164) or in the amount of alveoli per sample (343.2 +/- 402.4 vs. 439.5 +/- 463.5 alveoli; p = 0.433) for hot and conventional forceps, respectively. There was no artifact related to the use of electrocautery, and bleeding was minimal using either forceps system. CONCLUSIONS: The use of the electrocautery hot forceps for TBLB did not result in improvement of the size of biopsies or the amount of collected alveolar tissue in healthy pigs.

Malignant Diffuse Mesothelioma in Women: A Study of 354 Cases.

We reviewed 354 cases of malignant diffuse mesothelioma (MM) in women from a database of 2858 histologically confirmed MM cases. There was a pleural predominance with 78% pleural MM and 22% peritoneal MM. The pleural tumors consisted of 72% epithelioid, 19% biphasic, and 9% sarcomatoid variant. The peritoneal tumors consisted of 82% epithelioid, 13% biphasic, and 5% sarcomatoid. The immunohistochemical profile was typical of what is well-accepted and previously described for MM. When examining tumor subtype and location, there was a trend toward epithelioid subtype and peritoneal location; however, this did not reach statistical significance. Age at the time of diagnosis ranged from 19 to 93 years with a mean of 60 years. The median age at time of diagnosis for pleural MM was 65 years and for peritoneal MM was 52 years. A further look at age and histologic subtype showed no statistically significant difference in age between MM subtypes. Survival was greatest for epithelioid variant, and this was magnified in the peritoneum. A majority of our cases were exposed to asbestos through a household contact. Asbestosis and parietal pleural plaque were present in 5% and 50% of cases with data, respectively. Fiber analysis data was available in 67 cases; 38 cases had elevated asbestos fiber burden, and tremolite was the most common asbestos fiber type detected. Commercial and noncommercial amphibole asbestos fibers were elevated in nearly equal numbers of cases.

The synthetic triterpenoids CDDO-methyl ester and CDDO-ethyl amide prevent lung cancer induced by vinyl carbamate in A/J mice.

We report the first use of new synthetic triterpenoids to prevent lung cancer in experimental animals. Female A/J mice were treated with the mutagenic carcinogen vinyl carbamate, which induces adenocarcinoma of the lung in all animals within 16 weeks. If mice were fed either the methyl ester or the ethyl amide derivative of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO-ME and CDDO-EA, respectively), beginning 1 week after dosing with carcinogen, the number, size, and severity of lung carcinomas were markedly reduced. The mechanisms of action of CDDO-ME and CDDO-EA that are germane to these in vivo findings are the following results shown here in cell culture: (a) suppression of the ability of IFN-gamma to induce de novo formation of nitric oxide synthase in a macrophage-like cell line RAW264.7, (b) induction of heme oxygenase-1 in these RAW cells, and (c) suppression of phosphorylation of the transcription factor signal transducers and activators of transcription 3 as well as induction of apoptosis in human lung cancer cell lines.

The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis.

Female A/J mice injected with the carcinogen vinyl carbamate develop atypical adenomatous hyperplasias in lungs 4 weeks after injection with the carcinogen. The number and severity of tumors then increase over time, making these mice a useful model for evaluating potential chemopreventive agents. The rexinoid LG100268 (LG268), a selective ligand for the retinoid X receptor, and the methyl amide of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) both significantly reduced the number, size, and severity of the histopathology of lung tumors in female A/J mice when fed in diet for 14 to 20 weeks. The total tumor burden was 85% to 87% lower in mice fed LG268 and CDDO-MA than in controls, and the percentage of high-grade tumors decreased from 59% in the controls to 25% or 30% with CDDO-MA and LG268. Erlotinib, which is used to treat lung cancer patients and is an inhibitor of the epidermal growth factor receptor, was less effective in this model. Immunohistochemical staining of geminin, a marker of cell cycle progression, was higher in lung sections from control mice than in mice treated with LG268. Because rexinoids and triterpenoids signal through different biological pathways, they should be tested in combination for the prevention of lung cancer.

Mesothelioma of the tunica vaginalis testis.

Malignant mesothelioma (MM) arising from the serosal membranes of the tunica vaginalis testis (TVT) is rare. Most examples in the published medical literature are individual case reports. This study presents the clinicopathological findings of mesothelioma of the TVT in one of the largest series to date. Individuals with mesothelioma of the TVT were identified from a database of more than 4000 mesothelioma cases, and their clinicopathological features were recorded. Eighteen men with MM and 2 with well-differentiated papillary mesothelioma of the TVT were identified, which represented 0.6% of males with mesothelioma in study population. The median age at diagnosis was 72 years (range, 32-85 years). A neoplasm was not suspected preoperatively in 12 of the 17 (71%) men whose clinical presentation was known, 7 of whom presented with hydrocele and 5 with inguinal hernia. The other 5 had a clinically recognized mass. Seven of the men underwent herniorrhaphy; 7, radical orchiectomy; 3, hydrocelectomy; and 3, paratesticular mass biopsy or excision as the initial diagnostic procedure. Twelve of the MM cases were epithelioid and 6 were biphasic. Among the 6 men with MM who had ≥6 months of follow-up, 1 was alive with no evidence of disease at 6 months, and 5 were known to have died of disease 8-74 months (median = 31.5 months) following diagnosis. Three men with MM had received either chemotherapy or radiation therapy. Of the 2 men initially diagnosed with well-differentiated papillary mesothelioma, 1 was alive without evidence of disease 5 years after diagnosis, while the other had findings more compatible with MM with peritoneal involvement 2 years following initial diagnosis. In 15 of the 18 cases of MM (83%), there was documented occupational or paraoccupational exposure to asbestos, the average duration of which was 33 years (range, 2-46 years). Information regarding the presence or absence of pleural plaques was available in 5 of the MM cases, and pleural plaques had been found in 4. Lung tissue was not available for fiber analysis in any of the cases. One additional case originally diagnosed at another institution as MM of the TVT was reclassified as adenocarcinoma following performance of additional immunohistochemical testing. TVT is a rare site of MM, the diagnosis of which is often unsuspected preoperatively. Like its counterparts at other serosal sites, MM of the TVT is an aggressive tumor with a poor prognosis that evidence would suggest is etiologically associated with asbestos in at least some cases.

Pulmonary histopathology in an experimental model of chronic aspiration is independent of acidity.

Gastroesophageal reflux has become a major health concern in industrialized countries, with drugs aimed at blocking acid production being more frequently prescribed than any other drug. Damage to lung tissue as a result of chronic aspiration of gastric fluid is a primary health risk associated with gastro-esophageal reflux, with such aspiration being suspected in the induction or exacerbation of asthma and other lung diseases. In this study, a rodent model of chronic aspiration was used to characterize the pulmonary histopathology produced by repetitive aspiration events and to investigate the pathologic roles of individual gastric fluid components such as acid and particulate food matter. Rats exposed to chronic aspiration of whole gastric fluid developed a pathology distinct from that of acute lung injury, characterized by granulomatous interstitial pneumonitis with prominent formation of multinucleated giant cells. This pattern of injury could be reproduced with chronic aspiration of particulate food matter and with chronic aspiration of pH-neutralized gastric fluid, but not with chronic aspiration of hydrochloric acid. Thus, since acid-neutralizing therapy is currently the mainstay of treatment for patients with reflux-associated respiratory symptoms, these results strongly suggest that alternative therapeutic approaches aimed at preventing chronic-aspiration induced lung injury may be warranted.

PET of hypoxia and perfusion with 62Cu-ATSM and 62Cu-PTSM using a 62Zn/62Cu generator.

OBJECTIVE: Copper-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) and copper-pyruvaldehyde-bis(N4-methylthiosemicarbazone) (Cu-PTSM) are being studied as potential markers of hypoxia and perfusion, respectively. The use of short-lived radionuclides (e.g., 62Cu) has advantages for clinical PET, including a lower radiation dose than long-lived radionuclides and serial imaging capability. A 62Zn/62Cu microgenerator and rapid synthesis kits now provide a practical means of producing 62Cu-PTSM and 62Cu-ATSM on-site. Tumors can be characterized with 62Cu-PTSM, 62Cu-ATSM, and 18F-FDG PET scans during one session. We present the initial clinical data in two patients with lung neoplasms. CONCLUSION: Hypoxia and perfusion are important parameters in tumor physiology and can have major implications in diagnosis, prognosis, treatment planning, and response to therapy. We have shown the feasibility of performing 62Cu-ATSM and 62Cu-PTSM PET together with FDG PET/CT during a single imaging session to provide information on both perfusion and hypoxia and tumor anatomy and metabolism.