Outcomes after lung transplantation for patients with occupational lung diseases.

Occupational lung diseases (OLD) including silicosis, asbestosis, and pneumoconiosis progress to end stage lung disease requiring lung transplantation (LT). Prognosis and treatment of OLDs are poorly understood and a paucity of data exists regarding LT outcomes. Additionally, transplant operative complexity for patients with OLD is high. A single center retrospective review of all single and bilateral LT recipients between May 2005 and Oct 2016 was performed. Patients were grouped by OLD, and nearest neighbor matching was performed at a ratio of 1:3 cases to controls. Thirty cases were matched to 88 controls. Seventeen patients (57%) with OLD required intraoperative support with either extra-corporeal membrane oxygenation (ECMO) or cardiopulmonary bypass (P = 0.02), and 5 (17%) required delayed chest closure (P = 0.05) which was more frequent than matched controls. In addition, operative time was significantly longer in patients with OLD (P = 0.03). Despite these factors, there were no significant differences in immediate post-operative outcomes including mechanical ventilator support, post-operative ECMO, and tracheostomy. Chronic lung allograft dysfunction and long-term survival were also similar between cases and controls. OLDs should not preclude LT. The operation should be performed at experienced centers.

Characteristics of lung cancer among patients with idiopathic pulmonary fibrosis and interstitial lung disease - analysis of institutional and population data.

BACKGROUND: Lung Cancer is occasionally observed in patients with Idiopathic Pulmonary Fibrosis (IPF). We sought to describe the epidemiologic and clinical characteristics of lung cancer for patients with IPF and other interstitial lung disease (ILD) using institutional and statewide data registries. METHODS: We conducted a retrospective analysis of IPF and non-IPF ILD patients from the ILD center registry, to compare with lung cancer registries at the University of Pittsburgh as well as with population data of lung cancer obtained from Pennsylvania Department of Health between 2000 and 2015. RESULTS: Among 1108 IPF patients, 31 patients were identified with IPF and lung cancer. The age-adjusted standard incidence ratio of lung cancer was 3.34 (with IPF) and 2.3 (with non-IPF ILD) (between-group Hazard ratio = 1.4, p = 0.3). Lung cancer worsened the mortality of IPF (p <  0.001). Lung cancer with IPF had higher mortality compared to lung cancer in non-IPF ILD (Hazard ratio = 6.2, p = 0.001). Lung cancer among IPF was characterized by a predilection for lower lobes (63% vs. 26% in non-IPF lung cancer, p <  0.001) and by squamous cell histology (41% vs. 29%, p = 0.07). Increased incidence of lung cancer was observed among single lung transplant (SLT) recipients for IPF (13 out of 97, 13.4%), with increased mortality compared to SLT for IPF without lung cancer (p = 0.028) during observational period. CONCLUSIONS: Lung cancer is approximately 3.34 times more frequently diagnosed in IPF patients compared to general population, and associated with worse prognosis compared with IPF without lung cancer, with squamous cell carcinoma and lower lobe predilection. The causality between non-smoking IPF patients and lung cancer is to be determined.

Myositis-associated usual interstitial pneumonia has a better survival than idiopathic pulmonary fibrosis.

Objective: To compare the survival outcomes between myositis-associated usual interstitial pneumonia (MA-UIP) and idiopathic pulmonary fibrosis (IPF-UIP). Methods: Adult MA-UIP and IPF-UIP patients were identified using CTD and IPF registries. The MA-UIP cohort included myositis or anti-synthetase syndrome patients with interstitial lung disease while manifesting UIP on high-resolution CT chest and/or a lung biopsy revealing UIP histology. IPF subjects met American Thoracic Society criteria and similarly had UIP histopathology. Kaplan-Meier survival curves compared cumulative and pulmonary event-free survival (event = transplant or death) between (i) all MA-UIP and IPF-UIP subjects, (ii) MA-UIP with biopsy proven UIP (n = 25) vs IPF-UIP subjects matched for age, gender and baseline forced vital capacity (±10%). Cox proportional hazards ratios compared the survival controlling for co-variates. Results: Eighty-one IPF-UIP and 43 MA-UIP subjects were identified. The median cumulative and event-free survival time in IPF vs MA-UIP was 5.25/1.8 years vs 16.2/10.8 years, respectively. Cumulative and event-free survival was significantly worse in IPF-UIP vs MA-UIP [hazards ratio of IPF-UIP was 2.9 (95% CI: 1.5, 5.6) and 5.0 (95% CI: 2.8, 8.7) (P < 0.001), respectively]. IPF-UIP event-free survival (but not cumulative) remained significantly worse than MA-UIP with a hazards ratio of 6.4 (95% CI: 3.0, 13.8) after controlling for age at interstitial lung disease diagnosis, gender, ethnicity and baseline forced vital capacity%. Respiratory failure was the most common cause of death in both groups. A sub-analysis of 25 biopsy-proven MA-UIP subjects showed similar results. Conclusion: MA-UIP patients demonstrated a significant survival advantage over a matched IPF cohort, suggesting that despite similar histological and radiographic findings at presentation, the prognosis of MA-UIP is superior to that of IPF-UIP.

Enhancing Autophagy with Drugs or Lung-directed Gene Therapy Reverses the Pathological Effects of Respiratory Epithelial Cell Proteinopathy.

Recent studies have shown that autophagy mitigates the pathological effects of proteinopathies in the liver, heart, and skeletal muscle but this has not been investigated for proteinopathies that affect the lung. This may be due at least in part to the lack of an animal model robust enough for spontaneous pathological effects from proteinopathies even though several rare proteinopathies, surfactant protein A and C deficiencies, cause severe pulmonary fibrosis. In this report we show that the PiZ mouse, transgenic for the common misfolded variant α1-antitrypsin Z, is a model of respiratory epithelial cell proteinopathy with spontaneous pulmonary fibrosis. Intracellular accumulation of misfolded α1-antitrypsin Z in respiratory epithelial cells of the PiZ model resulted in activation of autophagy, leukocyte infiltration, and spontaneous pulmonary fibrosis severe enough to elicit functional restrictive deficits. Treatment with autophagy enhancer drugs or lung-directed gene transfer of TFEB, a master transcriptional activator of the autophagolysosomal system, reversed these proteotoxic consequences. We conclude that this mouse is an excellent model of respiratory epithelial proteinopathy with spontaneous pulmonary fibrosis and that autophagy is an important endogenous proteostasis mechanism and an attractive target for therapy.

Relationship between fibroblastic foci profusion and high resolution CT morphology in fibrotic lung disease.

BACKGROUND: Fibroblastic foci profusion on histopathology and severity of traction bronchiectasis on highresolution computed tomography (HRCT) have been shown to be predictors of mortality in patients with idiopathic pulmonary fibrosis (IPF). The aim of this study was to investigate the relationship between fibroblastic foci (FF) profusion and HRCT patterns in patients with a histopathologic diagnosis of usual interstitial pneumonia (UIP), fibrotic non-specific interstitial pneumonia (NSIP) and chronic hypersensitivity pneumonitis (CHP). METHODS: The HRCT scans of 162 patients with a histopathologic diagnosis of UIP or fibrotic NSIP (n = 162) were scored on extent of groundglass opacification, reticulation, honeycombing, emphysema and severity of traction bronchiectasis. For each patient, a fibroblastic foci profusion score based on histopathologic appearances was assigned. Relationships between extent of fibroblastic foci and individual HRCT patterns were investigated using univariate correlation analysis and multivariate linear regression. RESULTS: Increasing extent of reticulation (P < 0.0001) and increasing severity of traction bronchiectasis (P < 0.0001) were independently associated with increasing FF score within the entire cohort. Within individual multidisciplinary team diagnosis subgroups, the only significant independent association with FF score was severity of traction bronchiectasis in patients with idiopathic pulmonary fibrosis (IPF)/UIP (n = 66, r(2) = 0.19, P < 0.0001) and patients with chronic hypersensitivity pneumonitis (CHP) (n = 49, r(2) = 0.45, P < 0.0001). Furthermore, FF score had the strongest association with severity of traction bronchiectasis in patients with IPF (r(2) = 0.34, P < 0.0001) and CHP (r(2) = 0.35, P < 0.0001). There was no correlation between FF score and severity of traction bronchiectasis in patients with fibrotic NSIP. Global disease extent had the strongest association with severity of traction bronchiectasis in patients with fibrotic NSIP (r(2) = 0.58, P < 0.0001). CONCLUSION: In patients with fibrotic lung disease, profusion of fibroblastic foci is strikingly related to the severity of traction bronchiectasis, particularly in IPF and CHP. This may explain the growing evidence that traction bronchiectasis is a predictor of mortality in several fibrotic lung diseases.

Asthmatic granulomatosis: a novel disease with asthmatic and granulomatous features.

RATIONALE: Severe asthma represents 5-10% of all asthma, yet remains problematic and poorly understood. Although it is increasingly recognized as consisting of numerous heterogenous phenotypes, their immunopathology, particularly in the distal airways and interstitium, remains poorly described. OBJECTIVES: To identify the pathobiology of atypical difficult asthma. METHODS: We report 10 from a total of 19 patients (17 women and 2 men) meeting asthma and severe asthma definitions, requiring daily systemic corticosteroid (CS) use, with inconsistent abnormalities on chest computed tomography scans, who underwent video-assisted thoracoscopic biopsies for further diagnosis and management. MEASUREMENTS AND MAIN RESULTS: The pathology of 10 of the 19 cases revealed small airway changes consistent with asthma (eosinophilia, goblet cell hyperplasia), but with the unexpected finding of interstitial nonnecrotizing granulomas. These patients had no evidence for hypersensitivity pneumonitis, but 70% of cases had a personal or family history of autoimmune-like disease. The 10 cases were treated with azathioprine, mycophenolic acid, methotrexate, or infliximab. Nine of 10 showed decreased CS requirements and improved or maintained FEV(1) despite lower CS doses. Of the remaining nine patients, six manifested asthmatic small airway disease, alone or in combination with alveolar septal mononuclear cells, but no granulomas, whereas three manifested other pathologic findings (aspiration, pneumonia, or thromboemboli). CONCLUSIONS: These data suggest that a subset of severe "asthma" manifests a granulomatous pathology, which we term "asthmatic granulomatosis." Although identification of this disease currently requires a thorascopic biopsy, alternative approaches to therapy lead to improvement in outcomes.

Matrix metalloproteinase-19 is a key regulator of lung fibrosis in mice and humans.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by epithelial phenotypic changes and fibroblast activation. Based on the temporal heterogeneity of IPF, we hypothesized that hyperplastic alveolar epithelial cells regulate the fibrotic response. OBJECTIVES: To identify novel mediators of fibrosis comparing the transcriptional signature of hyperplastic epithelial cells and conserved epithelial cells in the same lung. METHODS: Laser capture microscope and microarrays analysis were used to identify differentially expressed genes in IPF lungs. Bleomycin-induced lung fibrosis was evaluated in Mmp19-deficient and wild-type (WT) mice. The role of matrix metalloproteinase (MMP)-19 was additionally studied by transfecting the human MMP19 in alveolar epithelial cells. MEASUREMENTS AND MAIN RESULTS: Laser capture microscope followed by microarray analysis revealed a novel mediator, MMP-19, in hyperplastic epithelial cells adjacent to fibrotic regions. Mmp19(-/-) mice showed a significantly increased lung fibrotic response to bleomycin compared with WT mice. A549 epithelial cells transfected with human MMP19 stimulated wound healing and cell migration, whereas silencing MMP19 had the opposite effect. Gene expression microarray of transfected A549 cells showed that PTGS2 (prostaglandin-endoperoxide synthase 2) was one of the highly induced genes. PTGS2 was overexpressed in IPF lungs and colocalized with MMP-19 in hyperplastic epithelial cells. In WT mice, PTGS2 was significantly increased in bronchoalveolar lavage and lung tissues after bleomycin-induced fibrosis, but not in Mmp19(-/-) mice. Inhibition of Mmp-19 by siRNA resulted in inhibition of Ptgs2 at mRNA and protein levels. CONCLUSIONS: Up-regulation of MMP19 induced by lung injury may play a protective role in the development of fibrosis through the induction of PTGS2.

Role of molecular studies in the diagnosis of lung adenocarcinoma.

Molecular alterations in adenocarcinoma of the lung have resulted in new therapeutic options for treatment of high-stage disease. Such changes are usually mutually exclusive and can be documented in small specimen samples. Most analyses are DNA-based, utilizing sequencing or fluorescence in situ hybridization to observe amplifications or translocations. Particular success in theranostics has focused on epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase gene (ALK), and BRAF gene changes, each allowing personalized therapies. Interestingly, these molecular changes have correlated with distinct, although not unique, demographics, histopathologies, and response to pharmacological agents.

Increased levels of tumor-infiltrating lymphocytes are associated with improved recurrence-free survival in stage 1A non-small-cell lung cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) have been found to increase survival in many forms of cancer, including, endometrial, bile ductal, colonic, esophageal, and urothelial cancers, as well as melanoma and follicular lymphoma. The relevance of TILs in the prognosis of non-small-cell lung cancer (NSCLC), however, still remains controversial. We compared the outcomes of stage 1A NSCLC with and without tumor infiltrating lymphocytes to evaluate the effects of TILs on recurrence and survival patterns. MATERIALS AND METHODS: From 2000 to 2009, 273 anatomic segmentectomies and lobectomies were performed on stage 1A NSCLC. Patients were stratified into TIL- and TIL+ cohorts based on pathologic evaluation. Further investigation was conducted on the effects of TILs in patients with and without angiolymphatic invasion. Variables analyzed include overall survival, recurrence-free survival, and type of recurrence. RESULTS: Overall 5-y survival was not affected by TIL status (65% versus 60%, P = 0.469). Five-year recurrence-free survival (RFS) was significantly increased in the TIL+ group versus the TIL- group (87% versus 73%, P = 0.011), most significantly in women (P = 0.016). The presence of angiolymphatic invasion (ALI) was associated with decreased 5-y RFS versus patients without ALI (61% versus 85%, P < 0.001). Interestingly, in the ALI negative group, TIL+ patients experienced a significantly increased 5-y recurrence-free survival versus TIL- patients (93% versus 80%, P = 0.036). CONCLUSIONS: High levels of intratumoral TILs are associated with improved recurrence-free survival in stage 1A NSCLC patients as well as a reduced likelihood of systemic recurrence. When angiolymphatic invasion is not present, the beneficial effects of TILs become even more profound.

Inhibition and role of let-7d in idiopathic pulmonary fibrosis.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually lethal fibrotic lung disease characterized by profound changes in epithelial cell phenotype and fibroblast proliferation. OBJECTIVES: To determine changes in expression and role of microRNAs in IPF. METHODS: RNA from 10 control and 10 IPF tissues was hybridized on Agilent microRNA microarrays and results were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization. SMAD3 binding to the let-7d promoter was confirmed by chromatin immunoprecipitation, electrophoretic mobility shift assay, luciferase assays, and reduced expression of let-7d in response to transforming growth factor-beta. HMGA2, a let-7d target, was localized by immunohistochemistry. In mice, let-7d was inhibited by intratracheal administration of a let-7d antagomir and its effects were determined by immunohistochemistry, immunofluorescence, quantitative real-time polymerase chain reaction, and morphometry. MEASUREMENTS AND MAIN RESULTS: Eighteen microRNAs including let-7d were significantly decreased in IPF. Transforming growth factor-beta down-regulated let-7d expression, and SMAD3 binding to the let-7d promoter was demonstrated. Inhibition of let-7d caused increases in mesenchymal markers N-cadherin-2, vimentin, and alpha-smooth muscle actin (ACTA2) as well as HMGA2 in multiple epithelial cell lines. let-7d was significantly reduced in IPF lungs and the number of epithelial cells expressing let-7d correlated with pulmonary functions. HMGA2 was increased in alveolar epithelial cells of IPF lungs. let-7d inhibition in vivo caused alveolar septal thickening and increases in collagen, ACTA2, and S100A4 expression in SFTPC (pulmonary-associated surfactant protein C) expressing alveolar epithelial cells. CONCLUSIONS: Our results indicate a role for microRNAs in IPF. The down-regulation of let-7d in IPF and the profibrotic effects of this down-regulation in vitro and in vivo suggest a key regulatory role for this microRNA in preventing lung fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT 00258544).

Clinicopathological predictors of EGFR/KRAS mutational status in primary lung adenocarcinomas.

Screening for EGFR and KRAS mutations in patients with lung adenocarcinomas can be used to predict the patient's response to EGFR tyrosine kinase inhibitors, but there is a lack of guidelines for testing in clinical practice. We analyzed the morphological and clinicopathological characteristics, including tumor stage, size, presence of scar, inflammatory response, angiolymphatic and pleural invasion, of 345 surgically treated primary lung adenocarcinomas with respect to their EGFR and KRAS mutational profile and EGFR FISH. EGFR and KRAS mutations were found in 33 (10%) and 78 (23%) of lung adenocarcinomas, respectively, whereas 226 (67%) cases were negative for both mutations. There was a large overlap in the analyzed clinicopathological characteristics among the three study groups. Statistically significant predictors for the presence of EGFR mutations included history of never smoking (OR 5.939; 95% Wald confidence limit 1.662-21.223, P=0.0149), mild lymphocytic host response (OR 4.724; 95% Wald confidence limit 1.33-1.776; P=0.0163), female gender (OR 2.571; 95% Wald confidence limit 1.015-6.511, P=0.0463) and absence of solid growth pattern. Statistically significant predictors for the presence of KRAS mutations included older age (OR 1.034; 95% Wald confidence limit 1.007-1.062, P=0.0132), history of smoking (OR 0.617, 95% Wald confidence limit 0.357-1.066, P=0.0412) and mucinous differentiation. EGFR FISH positivity as defined by the Colorado criteria was a significant predictor of EGFR mutations, with high polysomy as the strongest predictive criteria. Despite statistically significant differences among the study groups and because of the large overlap in the analyzed clinicopathological criteria, none of these could be implemented as the selection criteria for molecular testing in clinical practice. The cost-effectiveness of lung carcinoma mutational testing would be improved by initial determination of KRAS mutational status as negative predictor of the patient's response to EGFR tyrosine kinase inhibitors, followed by EGFR mutational analysis, if necessary.

The pulmonary histopathologic manifestations of the anti-Jo-1 tRNA synthetase syndrome.

Of the idiopathic inflammatory myopathies, the anti-aminoacyl tRNA synthetase syndrome has the greatest association with interstitial lung disease (ILD). We reviewed 13 open surgical lung biopsies, four autopsies, and three native lungs resected at transplantation, for pulmonary ILD associated with the presence of anti-histidyl tRNA synthetase (anti-Jo-1) autoantibodies. Fifty percent (N=10) of patients presented with an acute decompensation of pulmonary function manifested as diffuse alveolar damage, although in five patients (25%) this marked diminution in function was superimposed on an underlying chronic interstitial pneumonia (usual interstitial pneumonia (three); nonspecific interstitial pneumonia(two)). Seven (35%) patients had usual interstitial pneumonia and two (10%) had nonspecific interstitial pneumonia exclusively, whereas one patient presented with an organizing pneumonia (5%). This study is the first to highlight the high biopsy incidence of diffuse alveolar damage in this patient population both de novo and superimposed on underlying chronic ILD, and also shows that usual interstitial pneumonia remains a significant pattern of interstitial injury in this autoimmune group. On the basis of coexisting patterns of lung injury, this study also suggests that nonspecific interstitial pneumonia in connective tissue disorders may progress over time to a usual interstitial pneumonia pattern of fibrosis, an observation that could be better assessed with future inclusion of autopsy and transplanted native lungs in study groups.

Gene expression profiles of acute exacerbations of idiopathic pulmonary fibrosis.

RATIONALE: The molecular mechanisms underlying acute exacerbations of idiopathic pulmonary fibrosis (IPF) are poorly understood. We studied the global gene expression signature of acute exacerbations of IPF. OBJECTIVES: To understand the gene expression patterns of acute exacerbations of IPF. METHODS: RNA was extracted from 23 stable IPF lungs, 8 IPF lungs with acute exacerbation (IPF-AEx), and 15 control lungs and used for hybridization on Agilent gene expression microarrays. Functional analysis of genes was performed with Spotfire and Genomica. Gene validations for MMP1, MMP7, AGER, DEFA1-3, COL1A2, and CCNA2 were performed by real-time quantitative reverse transcription-polymerase chain reaction. Immunohistochemistry and in situ terminal deoxynucleotidyltransferase dUTP nick end-labeling assays were performed on the same tissues used for the microarray. ELISA for alpha-defensins was performed on plasma from control subjects, patients with stable IPF, and patients with IPF-AEx. MEASUREMENTS AND MAIN RESULTS: Gene expression patterns in IPF-AEx and IPF samples were similar for the genes that distinguish IPF from control lungs. Five hundred and seventy-nine genes were differentially expressed (false discovery rate < 5%) between stable IPF and IPF-AEx. Functional analysis of these genes did not indicate any evidence of an infectious or overwhelming inflammatory etiology. CCNA2 and alpha-defensins were among the most up-regulated genes. CCNA2 and alpha-defensin protein levels were also higher and localized to the epithelium of IPF-AEx, where widespread apoptosis was also detected. alpha-Defensin protein levels were increased in the peripheral blood of patients with IPF-AEx. CONCLUSIONS: Our results indicate that IPF-AEx is characterized by enhanced epithelial injury and proliferation, as reflected by increases in CCNA2 and alpha-defensins and apoptosis of epithelium. The concomitant increase in alpha-defensins in the peripheral blood and lungs may suggest their use as biomarkers for this disorder.

A randomized trial of inhaled cyclosporine in lung-transplant recipients.

BACKGROUND: Conventional regimens of immunosuppressive drugs often do not prevent chronic rejection after lung transplantation. Topical delivery of cyclosporine in addition to conventional systemic immunosuppression might help prevent acute and chronic rejection events. METHODS: We conducted a single-center, randomized, double-blind, placebo-controlled trial of inhaled cyclosporine initiated within six weeks after transplantation and given in addition to systemic immunosuppression. A total of 58 patients were randomly assigned to inhale either 300 mg of aerosol cyclosporine (28 patients) or aerosol placebo (30 patients) three days a week for the first two years after transplantation. The primary end point was the rate of histologic acute rejection. RESULTS: The rates of acute rejection of grade 2 or higher were similar in the cyclosporine and placebo groups: 0.44 episode (95 percent confidence interval, 0.31 to 0.62) vs. 0.46 episode (95 percent confidence interval, 0.33 to 0.64) per patient per year, respectively (P=0.87 by Poisson regression). Survival was improved with aerosolized cyclosporine, with 3 deaths among patients receiving cyclosporine and 14 deaths among patients receiving placebo (relative risk of death, 0.20; 95 percent confidence interval, 0.06 to 0.70; P=0.01). Chronic rejection-free survival also improved with cyclosporine, as determined by spirometric analysis (10 events in the cyclosporine group and 20 events in the placebo group; relative risk of chronic rejection, 0.38; 95 percent confidence interval, 0.18 to 0.82; P=0.01) and histologic analysis (6 vs. 19 events, respectively; relative risk, 0.27; 95 percent confidence interval, 0.11 to 0.67; P=0.005). The risks of nephrotoxic effects and opportunistic infection were similar for patients in the cyclosporine group and the placebo group. CONCLUSIONS: Inhaled cyclosporine did not improve the rate of acute rejection, but it did improve survival and extend periods of chronic rejection-free survival. (ClinicalTrials.gov number, NCT00268515.).

The surgical pathology of pulmonary infarcts: diagnostic confusion with granulomatous disease, vasculitis, and neoplasia.

Twenty-three cases of surgically resected pulmonary infarcts sent in consultation were reviewed to evaluate their morphology and to assess reasons for consultation. The morphology of these infarcts demonstrated that only a minority had the classical triangular shape at low magnification (26%) whereas the majority were either spherical (17%) or had a geographic pattern of necrosis (35%). The margin of the infarcted tissue often had a pseudogranulomatous appearance due to palisaded histiocytes, foam cells, or perpendicularly oriented proliferations of fibroblasts and myofibroblasts (74%) and occasional cholesterol- and hemosiderin-laden giant cells. Basophilic granular karyorrhectic necrosis was seen focally (52%) as was vascular inflammation (56%) raising the differential diagnosis of Wegener's granulomatosis or infectious granulomas. These nonclassical features combined with a low incidence of clinical hemoptysis, chest pain and pleurisy, and a primary radiographic diagnosis of 'nodule r/o malignancy' highlight the need to consider thromboembolic pulmonary infarcts in the differential diagnosis of necrotic lung nodules with a histiocytic and fibroproliferative rim.

Chronic follicular pleuritis: a B cell-rich form of nonspecific pleuritis/fibrosis.

The parietal pleura is often biopsied in patients with idiopathic pleural effusion, and in up to 40% of cases, a diagnosis of nonspecific pleuritis/fibrosis (NSP) is rendered. The histology of this reaction has not been well described including a pattern of B cell lymphoid hyperplasia described as "chronic follicular pleuritis (CFP)". Thirty-two cases of NSP were studied, of which 13 (41%) corresponded to CFP with the remainder displaying a fibrinous and organizing pleuritis with varying degrees of collagenization. CFP had similar etiologies as NSP with long term follow-up, including cardiac disease, pericarditis, asbestos exposure, and occult malignancy. The importance of recognizing a previously undescribed B cell/plasma cell pleural inflammatory response in reactive pleural disease is discussed.

Pulmonary pathologic alterations associated with biopsy inserted hydrogel plugs.

The prevention of pneumothorax after percutaneous lung biopsy is a major patient safety concern. The insertion of hydrogel plugs into biopsy sites to mitigate this complication is a new intervention. The histology of the plug has not been previously reported, and in this study the histologic reaction is reported in 13 cases. The hydrogel plug forms a spherical basophilic matrix pool with an adjacent foreign body giant cell reaction and patchy eosinophilia. No extension to the pleural surface is present. The potential diagnostic errors related to the presence of the plug are discussed.

Gross cystic disease fluid protein-(GCDFP-15): expression in primary lung adenocarcinoma.

A total of 211 cases of primary lung adenocarcinoma were tested for expression of gross cystic disease fluid protein-15 (GCDFP-15) and only 11 cases (5.2%) were positive. The cases occurred with an equal sex distribution in older individuals whose carcinomas were frequently identified on screening radiographs. The adenocarcinomas were peripheral lesions and had an average size of 2.9 cm (range, 1.1 to 7.0). Histologically, they were usually mixed acinar and papillary adenocarcinomas with abundant extracellular mucin production, with the neoplastic cells having a polygonal shape, round to oval nuclei, diffuse powdery chromatin, and abundant eosinophilic granular cytoplasm. Clear cells and apocrinelike cells with prominent central nucleoli were common. GCDFP-15 was expressed in conjunction with thyroid transcription factor-1 in 81% of cases and synaptophysin was seen in 65%. Estrogen and progesterone receptors were not expressed. EGFR gene amplification and mutations of exons 19 and 21 were rare. KRAS mutations and HER2 gene amplification were not seen. This report details the first 11 cases of pulmonary adenocarcinoma to express GCDFP-15 and their distinctive morphology with frequent mucin production and coexpression of thyroid transcription factor-1 and synaptophysin.

Anti-human leukocyte antigen antibodies, vascular C4d deposition and increased soluble c4d in broncho-alveolar lavage of lung allografts.

BACKGROUND: The hallmark of humoral rejection is the presence of subendothelial C4d in the allograft. A simultaneous determination of vascular C4d with soluble C4d in broncho-alveolar lavage fluid (BAL) and circulating anti-human leukocyte antigen (HLA) antibodies (HLA-Ab) has not been reported in lung transplantation. METHODS: Forty-two consecutive lung-transplant patients were included in this cross-sectional study. The presence and specificity of HLA-Ab was determined at the same frequency with transbronchial biopsies. Soluble C4d levels were measured by enzyme-linked immunosorbent assay in all 42 patients. In a subgroup of 32 patients with available timely matched paraffin-embedded tissue sections, the vascular C4d deposition was also assessed. RESULTS: The presence of HLA-Ab in 16 patients was associated with biopsy-proven acute rejection (10/16 vs. 3/16, P<0.01) and increased immunosuppression (13/16 vs. 4/16, P<0.005). Pulmonary function was also decreased in patients with HLA-Ab (mean forced expiratory volume in 1 second=49%) when compared with the control group (mean forced expiratory volume in 1 second=66%, P<0.05). Nine patients exhibited specific vascular C4d deposition and in eight of nine (89%) cases HLA-Ab were detected, versus 8 of 23 (35%) in C4d-negative patients (P<0.05). Soluble C4d in BAL was highly (>0.5 microg/mL) elevated in patients with HLA-Ab and vascular C4d and was moderately (0.2 microg/mL) increased in patients with antibodies but C4d-negative. In contrast, only a slight elevation of soluble C4d (<0.1 microg/mL) was detected in patients without HLA-specific antibodies. CONCLUSIONS: The association of HLA-specific antibodies with vascular C4d deposition and soluble C4d in BAL, in addition to the reduced pulmonary function, might constitute a diagnostic triad for antibody-mediated rejection in lung transplant patients.

Renal cell carcinoma from a transplanted allograft: two case reports and a review of the literature.

We report 2 cases of renal cell carcinoma (RCC) in which the tumor arose from a transplanted allograft. The first case is a 52-year-old man with a failed cadaveric renal transplantation found to have metastatic RCC. The tumor was proven to be from the allograft, as fluorescence in situ hybridization analysis of biopsy material showed a female karyotype, consistent with his female donor. The second patient is a 45-year-old man who had undergone cadaveric renal transplantation in 1985 for chronic glomerulonephritis and, after 22 years, presented with renal failure. Biopsy and subsequent allograft nephrectomy revealed innumerable microscopic foci of RCC. There are only a few reported cases of RCC arising in kidney allografts and even fewer with reports of metastatic disease from the allograft. Treatments in patients with disease confined to the kidney have included partial nephrectomy and total nephrectomy. A literature search did not find any reports of treatment of metastatic RCC that arose from a renal allograft.