Clinically Occult Diffuse Pleural Mesothelioma in Patients Presenting With Spontaneous Pneumothorax.

OBJECTIVES: To report histologic features of unsuspected diffuse pleural mesothelioma (DPM) in surgical specimens for pneumothorax and demonstrate how ancillary markers support a diagnosis of malignancy in this context. We explored whether pneumothorax may be a clinical manifestation of mesothelioma in situ (MIS). METHODS: A single-institution database search identified patients who underwent surgical resection for spontaneous pneumothorax (n = 229) and/or were diagnosed with DPM (n = 88) from 2000 to 2020. RESULTS: Spontaneous pneumothorax without clinical, radiologic, or intraoperative suspicion of mesothelioma was the initial presentation in 2 (2.3%) of 88 patients diagnosed with DPM. This represented 0.9% (2/229) of all patients undergoing surgical management of pneumothorax but accounted for a larger proportion of older patients (12.5% older than 70 years). Immunohistochemistry for BAP-1 and/or MTAP confirmed the diagnosis of DPM in 2 cases. Mesothelioma in situ was identified retrospectively by immunohistochemistry in 1 case of spontaneous pneumothorax from a 77-year-old man who developed invasive DPM 25 months later. No additional cases of MIS were identified in 19 surgical lung resections for spontaneous pneumothorax. CONCLUSIONS: Histologic examination of bleb resections with ancillary testing for cases with ambiguous features is essential for detection of early DPM. It is uncertain whether spontaneous pneumothorax may represent a clinical manifestation of MIS.

Interstitial lung disease pathology in systemic sclerosis.

Interstitial lung disease is a relatively frequent manifestation of systemic sclerosis with approximately one-third of patients developing clinical restrictive lung disease. Fibrotic nonspecific interstitial pneumonia is the most common cause of diffuse parenchymal lung disease in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), followed by usual interstitial pneumonia (UIP). Radiographic pleuroparenchymal fibroelastosis-like changes may accompany other forms of interstitial lung disease, most commonly UIP. In an appropriate clinical setting with supportive high-resolution computed tomography findings, lung biopsy is not needed to confirm the presence of interstitial lung disease and surgical lung biopsies are often reserved for atypical presentations. In this review, we discuss the histological findings that define the most common patterns of SSc-ILD and outline other findings sometimes encountered in lung biopsies obtained from systemic sclerosis patients, including pulmonary vascular changes, aspiration, chronic pleuritis, and diffuse alveolar damage.

Lung and gut microbiota are altered by hyperoxia and contribute to oxygen-induced lung injury in mice.

Inhaled oxygen, although commonly administered to patients with respiratory disease, causes severe lung injury in animals and is associated with poor clinical outcomes in humans. The relationship between hyperoxia, lung and gut microbiota, and lung injury is unknown. Here, we show that hyperoxia conferred a selective relative growth advantage on oxygen-tolerant respiratory microbial species (e.g., Staphylococcus aureus) as demonstrated by an observational study of critically ill patients receiving mechanical ventilation and experiments using neonatal and adult mouse models. During exposure of mice to hyperoxia, both lung and gut bacterial communities were altered, and these communities contributed to oxygen-induced lung injury. Disruption of lung and gut microbiota preceded lung injury, and variation in microbial communities correlated with variation in lung inflammation. Germ-free mice were protected from oxygen-induced lung injury, and systemic antibiotic treatment selectively modulated the severity of oxygen-induced lung injury in conventionally housed animals. These results suggest that inhaled oxygen may alter lung and gut microbial communities and that these communities could contribute to lung injury.

Diagnosis of Lung Carcinoma on Small Biopsy.

Given the growing desire in clinical practice to detect lung carcinoma early, small biopsies are becoming more common and vital to the diagnostic process. Accurately diagnosing lung carcinoma on small biopsies is challenging but can significantly affect patient management. The challenge is due in part to the overlapping features between benign, reactive, and malignant processes and the lack of discriminating biomarkers. Specimen preservation for ancillary tests is also increasingly important to provide targeted precision medicine. We focuses on the morphologic features and diagnostic pitfalls of the most common lung carcinoma seen in small biopsies and the appropriate specimen handling practice.

Hypersensitivity Pneumonitis: Radiologic Phenotypes Are Associated With Distinct Survival Time and Pulmonary Function Trajectory.

BACKGROUND: Hypersensitivity pneumonitis (HP) is an interstitial lung disease with a better prognosis, on average, than idiopathic pulmonary fibrosis (IPF). We compare survival time and pulmonary function trajectory in patients with HP and IPF by radiologic phenotype. METHODS: HP (n = 117) was diagnosed if surgical/transbronchial lung biopsy, BAL, and exposure history results suggested this diagnosis. IPF (n = 152) was clinically and histopathologically diagnosed. All participants had a baseline high-resolution CT (HRCT) scan and FVC % predicted. Three thoracic radiologists documented radiologic features. Survival time is from HRCT scan to death or lung transplant. Cox proportional hazards models identify variables associated with survival time. Linear mixed models compare post-HRCT scan FVC % predicted trajectories. RESULTS: Subjects were grouped by clinical diagnosis and three mutually exclusive radiologic phenotypes: honeycomb present, non-honeycomb fibrosis (traction bronchiectasis and reticulation) present, and nonfibrotic. Nonfibrotic HP had the longest event-free median survival (> 14.73 years) and improving FVC % predicted (1.92%; 95% CI, 0.49-3.35; P = .009). HP with non-honeycomb fibrosis had longer survival than IPF (> 7.95 vs 5.20 years), and both groups experienced a significant decline in FVC % predicted. Subjects with HP and IPF with honeycombing had poor survival (2.76 and 2.81 years, respectively) and significant decline in FVC % predicted. CONCLUSIONS: Three prognostically distinct, radiologically defined phenotypes are identified among patients with HP. The importance of pursuing a specific diagnosis (eg, HP vs IPF) among patients with non-honeycomb fibrosis is highlighted. When radiologic honeycombing is present, invasive diagnostic testing directed at determining the diagnosis may be of limited value given a uniformly poor prognosis.

A Review of Smoking-Related Interstitial Fibrosis, Respiratory Bronchiolitis, and Desquamative Interstitial Pneumonia: Overlapping Histology and Confusing Terminology.

Smoking-related lung diseases traverse a spectrum of clinicopathologic entities, with cases often comprising a complex mixture of findings. The complexity of the diagnostic process extends beyond the histologic findings to the nomenclature, which is murky from a seemingly unending expansion of terms being applied to a handful of pathologic changes. Here, we focus our review on smoking-related interstitial fibrosis, respiratory bronchiolitis, and desquamative interstitial pneumonia, 3 entities that perhaps show the most histologic overlap and suffer from competing terminology.

Development and validation of a radiological diagnosis model for hypersensitivity pneumonitis.

High-resolution computed tomography (HRCT) may be useful for diagnosing hypersensitivity pneumonitis. Here, we develop and validate a radiological diagnosis model and model-based points score.Patients with interstitial lung disease seen at the University of Michigan Health System (derivation cohort) or enrolling in the Lung Tissue Research Consortium (validation cohort) were included. A thin-section, inspiratory HRCT scan was required. Thoracic radiologists documented radiological features.The derivation cohort comprised 356 subjects (33.9% hypersensitivity pneumonitis) and the validation cohort comprised 424 subjects (15.5% hypersensitivity pneumonitis). An age-, sex- and smoking status-adjusted logistic regression model identified extent of mosaic attenuation or air trapping greater than that of reticulation ("MA-AT>Reticulation"; OR 6.20, 95% CI 3.53-10.90; p<0.0001) and diffuse axial disease distribution (OR 2.33, 95% CI 1.31-4.16; p=0.004) as hypersensitivity pneumonitis predictors (area under the receiver operating characteristic curve 0.814). A model-based score >2 (1 point for axial distribution, 2 points for "MA-AT>Reticulation") has specificity 90% and positive predictive value (PPV) 74% in the derivation cohort and specificity 96% and PPV 44% in the validation cohort. Similar model performance is seen with population restriction to those reporting no exposure (score >2: specificity 91%).When radiological mosaic attenuation or air trapping are more extensive than reticulation and disease has diffuse axial distribution, hypersensitivity pneumonitis specificity is high and false diagnosis risk low (<10%), but PPV is diminished in a low-prevalence setting.

Morphoproteomics Identifies SIRT1 and EZH2 Pathways as Commonalities in B-cell Acute Lymphoblastic Leukemia: Pathogenetic Implications and Opportunities for Therapeutic Intervention.

B-cell acute lymphoblastic leukemia (ALL) represents a malignant process in which bone marrow-derived lymphoblasts retain their undifferentiated state. Genetic testing has revealed either no identifiable cytogenetic and genomic abnormalities in such patients or a wide range of aberrations that may or may not contribute to the block in differentiation and the associated proliferation of the malignant lymphoblasts in cases of B-cell ALL. In this study, we applied morphoproteomics to a representative spectrum of cases of newly diagnosed B-cell ALL in order to identify pathways that are known to be associated with the maintenance of the undifferentiated state while promoting proliferation. Our results showed nuclear expression in a majority of the lymphoblasts from bone marrow clot preparations of each of the study cases for both silent mating type information regulation 2 homolog 1 (SIRT1), an NAD+ histone deacetylase and enhancer of Zeste homolog 2 (EZH2), a histone methyltransferase. These represent pathogenetic pathways capable of blocking differentiation and promoting proliferation of the B-cell ALL lymphoblasts. Data mining of the National Library of Medicine's MEDLINE Database and Ingenuity Pathway analysis revealed agents of relatively low toxicity-melatonin, metformin, curcumin and sulforaphane-that are capable of inhibiting directly or pharmacogenomically one or both of the SIRT1 and EZH2 pathways and should, in a combinatorial fashion, remove the block in differentiation and decrease the proliferation of the B-cell ALL lymphoblasts.

Diagnostic Pathology of Lung Cancer.

In the past 5 years, there has arguably been a shift in the pathologic diagnosis of lung cancer, especially adenocarcinoma, moving toward a more patient-centered approach to reporting that works to incorporate information that may be clinically meaningful to prognosis and impactful to clinical management strategy. As the demand for specialty team care surges, the need for effective communication between specialties continues to increase, particularly to ensure that we are all speaking the same language with regard to diagnostic certainty and the implementation of new terminology. This review of lung cancer pathology is not all-inclusive; but rather, in addition to providing salient histologic and immunohistochemical features of selected topics in adenocarcinoma, squamous cell carcinoma, neuroendocrine tumors, and large cell carcinoma, it also attempts to highlight problems in cancer diagnosis from the pathologist's perspective, including addressing variations in interobserver agreement and limitations to the diagnostic process with regard to immunohistochemistry. In the end, many times, problematic cases might reach resolution not through the narrow-sighted ocular of pathology, but rather through employment of a multidisciplinary approach.