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 over diagnosis of diffuse mesothelioma: An analysis of 311 cases with recommendations for the avoidance of pitfalls.

BACKGROUND: The diagnosis of mesothelioma may be challenging. We investigated a large database of cases in order to determine the frequency with which a diagnosis of mesothelioma was made incorrectly and the most frequent causes of error. DESIGN: A database including more than 4000 consultation cases of histologically confirmed mesothelioma was examined to identify cases in which mesothelioma was diagnosed by at least one pathologist when the available information pointed towards a different diagnosis. RESULTS: There were 311 cases misdiagnosed as mesothelioma. The most common category was metastatic carcinoma to the pleura or peritoneum (129 cases: 73 lung carcinomas, 15 renal cell carcinomas). The next most common category was primary lung cancer (111 cases: 55 sarcomatoid carcinoma, 56 pseudomesotheliomatous carcinoma). The third most common category was primary malignancies arising from or near the serosal membranes (33 cases). The fourth most common category was fibrous pleurisy (38 cases). The most common errors were failure to consider important radiographic information regarding the gross distribution of tumor, lack of awareness or consideration of another malignancy, overreliance on certain immunohistochemical results, and failure to perform certain diagnostic histochemical, immunohistochemical, or ultrastructural studies. CONCLUSIONS: There are a number of diagnostic pitfalls that can lead to the over diagnosis of mesothelioma. Careful attention to clinical and radiographic information as well as performance of appropriate ancillary tests can help to prevent such misdiagnoses. Detailed examples will be presented to assist in the avoidance of these pitfalls with emphasis on the most commonly observed errors.

Chronological trends in the causation of malignant mesothelioma: Fiber burden analysis of 619 cases over four decades.

Malignant mesothelioma is a relatively rare malignancy with a strong association with prior asbestos exposure. A percentage of cases is not related to asbestos, and fiber analysis of lung tissue is a useful methodology for identifying idiopathic or spontaneous cases. We have performed fiber analyses in more than 600 cases of mesothelioma over the past four decades and were interested in looking for trends in terms of fiber types and concentrations as well as percentages of cases not related to asbestos. Demographic information was also considered including patient age, gender, and tumor location (pleural vs. peritoneal). The histologic pattern of the tumor and the presence or absence of pleural plaques or asbestosis were noted. Fiber analysis was performed in 619 cases, using the sodium hypochlorite technique for digestion of lung tissue samples. Asbestos bodies were counted by light microscopy (LM) and coated and uncoated fibers by scanning electron microscopy (EM). The results were stratified over four decades. Trends that were observed included increasing patient age, increasing percentage of women, increasing percentage of peritoneal cases, and increasing percentage of epithelial histological type. There was a decreasing trend in the percentage of patients with concomitant asbestosis (p < 0.001). The percentage of cases with an elevated lung asbestos content decreased from 90.5% in the 1980s to 54.1% in the 2010s (p < 0.001). This trend also held when the analysis was limited to 490 cases of pleural mesothelioma in men (91.8% in the 1980s vs. 65.1% in the 2010s). There was a decrease in the median asbestos body count by LM from 1390 asbestos bodies per gram of wet lung in the 1980s to 38 AB/gm in the 2010s. Similar trends were observed for each of the asbestos fiber types as detected by EM. We conclude that there has been a progressive decrease in lung fiber content of mesothelioma patients during the past four decades, with an increasing percentage of cases not related to asbestos and an increase in median patient age.

An Immunogenic and Slow-Growing Cryptococcal Strain Induces a Chronic Granulomatous Infection in Murine Lungs.

Many successful pathogens cause latent infections, remaining dormant within the host for years but retaining the ability to reactivate to cause symptomatic disease. The human opportunistic fungal pathogen Cryptococcus neoformans establishes latent pulmonary infections in immunocompetent individuals upon inhalation from the environment. These latent infections are frequently characterized by granulomas, or foci of chronic inflammation, that contain dormant and persistent cryptococcal cells. Immunosuppression can cause these granulomas to break down and release fungal cells that proliferate, disseminate, and eventually cause lethal cryptococcosis. This course of fungal latency and reactivation is understudied due to limited models, as chronic pulmonary granulomas do not typically form in mouse cryptococcal infections. A loss-of-function mutation in the Cryptococcus-specific MAR1 gene was previously described to alter cell surface remodeling in response to host signals. Here, we demonstrate that the mar1Δ mutant strain persists long term in a murine inhalation model of cryptococcosis, inducing a chronic pulmonary granulomatous response. We find that murine infections with the mar1Δ mutant strain are characterized by reduced fungal burden, likely due to the low growth rate of the mar1Δ mutant strain at physiological temperature, and an altered host immune response, likely due to inability of the mar1Δ mutant strain to properly employ virulence factors. We propose that this combination of features in the mar1Δ mutant strain collectively promotes the induction of a more chronic inflammatory response and enables long-term fungal persistence within these granulomatous regions.

Comparison of Forceps, Cryoprobe, and Thoracoscopic Lung Biopsy for the Diagnosis of Interstitial Lung Disease - The CHILL Study.

RATIONALE: Transbronchial lung cryobiopsy (TBLC) has emerged as a less invasive method to obtain a tissue diagnosis in patients with interstitial lung disease (ILD). The diagnostic yield of TBLC compared to surgical lung biopsy (SLB) remains uncertain. OBJECTIVES: The aim of this study was to determine the diagnostic accuracy of forceps transbronchial lung biopsy (TBLB) and TBLC compared to SLB when making the final diagnosis based on multidisciplinary discussion (MDD). METHODS: Patients enrolled in the study underwent sequential TBLB and TBLC followed immediately by SLB. De-identified cases, with blinding of the biopsy method, were reviewed by a blinded pathologist and then discussed at a multidisciplinary conference. MAIN RESULTS: Between August 2013 and October 2017, we enrolled 16 patients. The raw agreement between TBLC and SLB for the MDD final diagnosis was 68.75% with a Cohen's kappa of 0.6 (95% CI 0.39, 0.81). Raw agreement and Cohen's kappa of TBLB versus TBLC and TBLB versus SLB for the MDD final diagnosis were much lower (50%, 0.21 [95% CI 0, 0.42] and 18.75%, 0.08 [95% CI -0.03, 0.19], respectively). TBLC was associated with mild bleeding (grade 1 bleeding requiring suction to clear) in 56.2% of patients. CONCLUSIONS: In patients with ILD who have an uncertain type based on clinical and radiographic data and require tissue sampling to obtain a specific diagnosis, TBLC showed moderate correlation with SLB when making the diagnosis with MDD guidance. TBLB showed poor concordance with both TBLC and SLB MDD diagnoses.

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.

Parenteral administration of oral medications in lung transplant recipients: An underrecognized problem.

Microcrystalline cellulose (MCC) is an insoluble material commonly used as a binder and filler in oral medications. Identification of pulmonary intravascular deposition of MCC in transbronchial biopsies from lung transplant (LT) recipients following parenteral injection of oral medications has only been reported once. A search of our surgical pathology electronic database was performed from January 1, 2000 to November 1, 2017 using the text "transplant transbronchial." The diagnosis field for all cases retrieved was then searched for the text "cellulose." These cases were queried for patient demographics and outcomes. Between January 1, 2000 and November 1, 2017, 1558 lung transplants were performed in 1476 individual patients at our institution; 12 were identified to have MCC in their lung tissue. Patients with MCC identified on biopsies were more likely to be transplanted for cystic fibrosis versus other indications and younger versus older. MCC identified in 2 of our cases was favored to be donor derived. Of the 12 patients, 6 (50%) are deceased. MCC within the pulmonary vasculature may be an indicator of increased complications, mortality, or shortened survival in LT recipients. Detecting intravascular MCC and distinguishing it from aspirated foreign material can be challenging. Awareness of the differential diagnosis for pulmonary foreign material is of paramount importance for the pathologist.

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.

Mechanisms of L-Serine-Mediated Neuroprotection Include Selective Activation of Lysosomal Cathepsins B and L.

L-serine is a naturally occurring dietary amino acid that has recently received renewed attention as a potential therapy for the treatment of amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), hereditary sensory autonomic neuropathy type I (HSAN1), and sleep induction and maintenance. We have previously reported L-serine functions as a competitive inhibitor of L-BMAA toxicity in cell cultures and have since progressed to examine the neuroprotective effects of L-serine independent of L-BMAA-induced neurotoxicity. For example, in a Phase I, FDA-approved human clinical trial of 20 ALS patients, our lab reported 30 g L-serine/day was safe, well-tolerated, and slowed the progression of the disease in a group of 5 patients. Despite increasing evidence for L-serine being useful in the clinic, little is known about the mechanism of action of the observed neuroprotection. We have previously reported, in SH-SY5Y cell cultures, that L-serine alone can dysregulate the unfolded protein response (UPR) and increase the translation of the chaperone protein disulfide isomerase (PDI), and these mechanisms may contribute to the clearance of mis- or unfolded proteins. Here, we further explore the pathways involved in protein clearance when L-serine is present in low and high concentrations in cell culture. We incubated SH-SY5Y cells in the presence and absence of L-serine and measured changes in the activity of proteolytic enzymes from the autophagic-lysosomal system, cathepsin B, cathepsin L, and arylsulfatase and specific activities of the proteasome, peptidylglutamyl-peptide hydrolyzing (PGPH) (also called caspase-like), chymotrypsin, and trypsin-like. Under our conditions, we report that L-serine selectively induced the activity of autophagic-lysosomal enzymes, cathepsins B and L, but not any of the proteasome-hydrolyzing activities. To enable comparison with previous work, we also incubated cells with L-BMAA and report no effect on the activity of the autophagic lysosomes or the proteasomes. We also developed an open-source script for the automation of linear regression calculations of kinetic data. Autophagy impairment or failure is characteristic of many neurodegenerative disease; thus, activation of autophagic-lysosomal proteolysis may contribute to the neuroprotective effect of L-serine, which has been reported in cell culture and human clinical trials.

Overview and Challenges of Bronchiolar Disorders.

Bronchiolar abnormalities are common and can occur in conditions that affect either the large airways or the more distal parenchyma. In this review, we focus on the diagnosis and management of primary bronchiolar disorders, or conditions in which bronchiolitis is the predominant pathologic process, including constrictive bronchiolitis, follicular bronchiolitis, acute bronchiolitis, respiratory bronchiolitis, and diffuse panbronchiolitis. Due to the nature of abnormalities in the small airway, clinical and physiological changes in bronchiolitis can be subtle, making diagnosis challenging. Primary bronchiolar disorders frequently present with progressive dyspnea and cough that can be out of proportion to imaging and physiologic studies. Pulmonary function tests may be normal, impaired in an obstructive, restrictive, or mixed pattern, or have an isolated decrease in diffusion capacity. High-resolution computed tomography scan is an important diagnostic tool that may demonstrate one or more of the following three patterns: 1) solid centrilobular nodules, often with linear branching opacities (i.e., "tree-in-bud" pattern); 2) ill-defined ground glass centrilobular nodules; and 3) mosaic attenuation on inspiratory images that is accentuated on expiratory images, consistent with geographic air trapping. Bronchiolitis is often missed on standard transbronchial lung biopsies, as the areas of small airway involvement can be patchy. Fortunately, many patients can be diagnosed with a combination of clinical suspicion, inspiratory and expiratory high-resolution computed tomography scans, and pulmonary function testing. Joint consultation of clinicians with both radiologists and pathologists (in cases where histopathology is pursued) is critical to appropriately assess the clinical-radiographic-pathologic context in each individual patient.

Novel intronic DICER1 variation associated with pleuropulmonary blastoma in two siblings.

Pleuropulmonary blastomas (PPB) are rare aggressive paediatric lung malignancies associated with DICER1 variants. We present two cases, a 2-year-old girl with upper respiratory tract symptoms as well as a 6-month-old girl sibling undergoing screening due to family history of malignancy. Imaging of the 2-year-old girl revealed a large mass filling the right hemithorax which was determined to be a type II PPB after pathological examination. Imaging of the 6-month-old sibling demonstrated a small cystic lesion in the posterior basal segment of the right lower lobe which was determined to be a type 1r PPB after pathological examination. The 2-year-old girl received adjuvant chemotherapy while the baby sister underwent resection alone and both are alive and well at 12 months and 7 months, respectively. Sequence analysis in both cases confirmed the same DICER1 variation, c.2437-2A>G (likely pathogenic), which has not been previously described in the literature.

Dendriform pulmonary ossification leading to bilateral lung transplant: a case report.

Metaplastic ossification within the lung is seen in a variety of diseases, usually as sequela of either a separate primary pulmonary parenchymal disease or an underlying cardiac disorder such as valvular disease. Primary intraalveolar ossification or ossification within the alveolar septa is a rare entity. Similarly, it is unusual to see overt, diffuse disease affecting the lung to the point of respiratory failure leading to lung transplant. We present a case of an adult male who underwent bilateral lung transplantation, with the native lung pathology showing diffuse, severe dendriform ossification of the bilateral upper and lower lung lobes. The gross and histologic findings along with the radiographic imaging are reviewed herein. Overall, primary ossification of the lung leading to lung transplant is a rare condition that pulmonologists caring for patients with interstitial lung disease should be aware of as a possible cause of the patient's symptoms and lung dysfunction.

Metastatic squamous cell carcinoma with pseudoangiosarcomatous features and aberrant expression of vascular markers.

Squamous cell carcinoma with pseudoangiosarcomatous features is a rare but well-recognized variant of squamous cell carcinoma. These tumors exhibit complex anastomosing channels lined by neoplastic cells, histologically mimicking a vasoformative mesenchymal tumor. Immunohistochemically, the published cases expressed epithelial markers and were consistently negative for vascular markers. Squamous cell carcinoma with pseudoangiosarcomatous features and aberrant expression of vascular markers has never been reported. Herein, we report two cases of metastatic poorly-differentiated squamous cell carcinoma with pseudoangiosarcomatous morphologic features which showed immunoreactivity for vascular markers (CD31, Fli-1, and ERG). One case (left thigh skin squamous cell carcinoma with abdominal wall metastasis) showed strong and diffuse positivity for vascular markers, and the final diagnosis was confirmed with electron microscopy. The second case (squamous cell carcinoma of unknown primary site with bone metastasis) showed patchy positivity for both squamous and vascular markers. This is the first report of squamous cell carcinoma with pseudoangiosarcomatous features and aberrant expression of vascular markers, which resembles angiosarcoma both morphologically and immunohistochemically, and may represent a potential diagnostic pitfall. It is of crucial importance for pathologists to be aware of metastatic squamous cell carcinoma with such unique features, so that misdiagnosis and inappropriate treatment will be avoided.

Large mesenteric lymphangioma in an adult patient: an unusual presentation of a rare disease.

Lymphangiomas are most commonly described as a small painless mass in the neck or a vesicular rash in an infant patient. Ninety per cent of cases are diagnosed before the age of 2. Treatment usually involves surgical resection. Intra-abdominal lymphangiomas and mesenteric lymphangiomas, as described in our case report, represent a rare pathology. The exact prevalence of this condition is unclear but it has been suggested in the literature that there have been as few as 820 cases since the 16th century. The clinical presentation is usually subacute and diagnosis made incidentally during a workup of chronic gastrointestinal symptoms. Acute abdominal symptoms, as in our case presentation, are unusual but may be explained by the mass effect of a large intra-abdominal lesion. Cross-sectional imaging is key in preoperative workup and operative planning. Complete surgical resection is recommended and curative in the majority of cases with a low risk of local recurrence.

Isoform-Specific Effects of Wild-Type Ras Genes on Carcinogen-Induced Lung Tumorigenesis in Mice.

The gene KRAS is commonly mutated in lung cancer to encode a constitutively active and oncogenic protein that is well established to initiate and maintain lung tumorigenesis. However, the remaining wild-type KRAS protein, or the other family members HRAS and NRAS, can still be activated in the presence of oncogenic KRAS. Moreover, loss of any one of these three genes has been shown to increase the sensitivity of mice to the carcinogen urethane, which induces Kras mutation-positive early lung lesions. To determine the contribution of progressively disrupting Hras and Nras genes on urethane lung tumorigenesis, mice with different combinations of wild-type and null alleles of Hras and Nras were exposed with urethane and tumor burden was assessed. As previously reported, loss of one allele of Hras increased the sensitivity of mice to this carcinogen, and this effect was further exacerbated by the loss of the second Hras allele. However, loss of one or both alleles of Nras failed to alter tumor burden, either in the absence or presence of Hras, after exposure to urethane. Additionally, no obvious difference between lung lesions in mice with wild-type versus null alleles was detected, suggesting that wild-type Ras proteins may exert a tumor suppressive effects at the time of initiation, although other interpretations are certainly possible. In summary, these data suggest that in some genetic backgrounds inactivation of different wild-type Ras genes can have different effects on urethane-induced lung tumorigenesis.

Immunostaining in lung cancer for the clinician. Commonly used markers for differentiating primary and metastatic pulmonary tumors.

Immunohistochemical stains have become invaluable for the diagnosis of pulmonary malignancies (both primary and metastatic), particularly given the small size of transbronchial and endobronchial biopsies and the increasing need to conserve tissue for molecular studies. There are many panels of immunostains currently available to help differentiate between common types of pulmonary malignancies. It is the purpose of this review to summarize some of the most commonly used immunostains for the distinction of primary pulmonary malignancies from one another in areas with histological overlap and for distinguishing primary pulmonary malignancies from other cancers with which they may be confused. These include differentiating between poorly differentiated adenocarcinoma and poorly differentiated squamous cell carcinoma, small cell/large cell neuroendocrine carcinoma and basaloid carcinoma, and primary and metastatic adenocarcinoma involving the lung. In addition, we address the distinction between mesothelioma and pulmonary adenocarcinoma. Pitfalls in the use of these markers are also addressed. Although not aiming to be comprehensive, this review aims to guide and influence common practice by furthering the clinician's knowledge on using immunohistochemical stains for characterization of pulmonary neoplasms. This summary of frequently used immunohistochemical stains can provide usefulness by allowing accurate characterization of pulmonary tumors, thereby allowing for conservation of tissue for additional molecular testing.

Estimating the prevalence of syringe-borne and sexually transmitted diseases among injection drug users in St Petersburg, Russia.

Injection drug users (IDUs) are the vanguard of the human immunodeficiency virus (HIV) epidemic in Russia. We sought a non-invasive method to estimate a point prevalence of HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis and risk behaviours in IDUs attending the syringe exchange programme (SEP) in St Petersburg, Russia. One hundred and one IDUs returning syringes to the St Petersburg SEP were invited to complete a questionnaire requesting demographic, knowledge, and behavioural information, and to provide their syringes for antibody testing. The median age of IDUs was 23 years. Syringe prevalences were: 10.9% for HIV, 78.2% for HCV, 15.8% for HBV, and 6.9% for syphilis. All respondents recognized drug-related risk factors for getting AIDS. Only two-thirds of subjects recognized condoms to prevent sexually transmitted infections and half knew that oil-based lubricants are not appropriate for condoms. The IDU population studied was young and requires additional interventions to encourage safer sexual behaviours.