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 prevascular (anterior) mediastinal lymphomas: when thoracic pathology meets hematopathology.

Lymphomas are among the most common malignant tumors occurring in the anterior/prevascular mediastinum. Their diagnoses can be challenging in small biopsies, the current most common method of sampling of an anterior mediastinal mass. Because the initial clinical and/or imaging impression may not be that of lymphoma, these specimens may first be evaluated by cytopathologists, surgical pathologists, and thoracic pathologists rather than hematopathologists. Therefore, it is crucial for this group of pathologists to have a practical diagnostic approach to these neoplasms, know their common diagnostic pitfalls, and their main differential diagnoses. This is important because the diagnosis of lymphoma carries significant therapeutic implications (chemotherapy and/or radiotherapy and not surgical resection). Similarly, securing and properly triaging a sample at the time of tissue collection will translate into direct patient benefit since a subset of lymphomas (T-lymphoblastic lymphoma) may present exclusively as an anterior mediastinal mass and the tissue obtained from this site may be the only one available to evaluate prognostic markers and potential targetable molecular alterations. Once a proper initial diagnostic work-up has been performed, a case can be transferred to a hematopathologist for assistance with a refined diagnosis. In this review, we focus on the practical diagnostic approach to the most common prevascular/anterior mediastinal lymphomas with an emphasis on the findings in small biopsies and provide best practice tips for case triage.

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.

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer.

OBJECTIVES: Pembrolizumab is a programmed death receptor-1 masking antibody approved for metastatic non-small cell lung cancer. This Phase 2 study (NCT02818920) of neoadjuvant pembrolizumab in non-small cell lung cancer had a primary end point of safety and secondary end points of efficacy and correlative science. METHODS: Patients with untreated clinical stage IB to IIIA non-small cell lung cancer were enrolled. Two cycles of pembrolizumab (200 mg) were administered before surgery. Standard adjuvant chemotherapy and radiation were encouraged but not required. Four cycles of adjuvant pembrolizumab were provided. RESULTS: Of 35 patients enrolled, 30 received neoadjuvant pembrolizumab and 25 underwent lung resection. Only 1 patient had a delay before surgery attributed to pembrolizumab; this was due to thyroiditis. All patients underwent anatomic resection and mediastinal lymph node dissection; the majority (18/25%, 72%) of patients underwent lobectomy. Of the 25 patients, 23 had an initial minimally invasive approach (92%); 5 of these were converted to thoracotomy (21.7%). R0 resection was achieved in 22 patients (88%), and major pathologic response was observed in 7 of 25 patients (28%). The most common postoperative adverse event was atrial fibrillation, affecting 6 of 25 patients (24%). Median chest tube duration and length of stay were 3 and 4 days, respectively. One patient required readmission to the hospital within 30 days. There was no mortality within 90 days of surgery. CONCLUSIONS: In this study, pembrolizumab was safe and well tolerated in the neoadjuvant setting, and its use was not associated with excess surgical morbidity or mortality. Minimally invasive approaches are feasible in this patient population, but may be more challenging than in cases without neoadjuvant immunotherapy. Pathologic response was higher than typically observed with standard neoadjuvant chemotherapy.

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.

Multi-Institutional Prospective Validation of Prognostic mRNA Signatures in Early Stage Squamous Lung Cancer (Alliance).

INTRODUCTION: Surgical resection is curative for some patients with early lung squamous cell carcinoma. Staging and clinical factors do not adequately predict recurrence risk. We sought to validate the discriminative performance of proposed prognostic gene expression signatures at a level of rigor sufficient to support clinical use. METHODS: The two-stage validation used independent core laboratories, objective quality control standards, locked test parameters, and large multi-institutional specimen and data sets. The first stage validation confirmed a signature's ability to stratify patient survival. The second-stage validation determined which signature(s) optimally improved risk discrimination when added to baseline clinical predictors. Participants were prospectively enrolled in institutional (cohort I) or cooperative group (cohort II) biospecimen and data collection protocols. All cases underwent a central review of clinical, pathologic, and biospecimen parameters using objective criteria to determine final inclusion (cohort I: n = 249; cohort II: n = 234). Primary selection required that a signature significantly predict a 3-year survival after surgical resection in cohort I. Signatures meeting this criterion were further tested in cohort II, comparing risk prediction using baseline risk factors alone versus in combination with the signature. RESULTS: Male sex, advanced age, and higher stage were associated with shorter survival in cohort I and established a baseline clinical model. Of the three signatures validated in cohort I, one signature was validated in cohort II and statistically significantly enhanced the prognosis relative to the baseline model (C-index difference 0.122; p < 0.05). CONCLUSIONS: These results represent the first rigorous validation of a test appropriate to direct adjuvant treatment or clinical trials for patients with lung squamous cell carcinoma.

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.