Gloria Montanari

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia syndrome

The term diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) may be used to describe a clinico-pathological syndrome, as well as an incidental finding on histological examination, although there are obvious differences between these two scenarios. According to the World Health Organization, the definition of DIPNECH is purely histological. However, DIPNECH encompasses symptomatic patients with airway disease, as well as asymptomatic patients with neuroendocrine cell hyperplasia associated with multiple tumourlets/carcinoid tumours. DIPNECH is also considered a pre-neoplastic lesion in the spectrum of pulmonary neuroendocrine tumours, because it is commonly found in patients with peripheral carcinoid tumours. In this review, we summarise clinical, physiological, radiological and histological features of DIPNECH and critically discuss recently proposed diagnostic criteria. In addition, we propose that the term “DIPNECH syndrome” be used to indicate a sufficiently distinct patient subgroup characterised by respiratory symptoms, airflow obstruction, mosaic attenuation with air trapping on chest imaging and constrictive obliterative bronchiolitis, often with nodular proliferation of neuroendocrine cells with/without tumourlets/carcinoid tumours on histology. Surgical lung biopsy is the diagnostic gold standard. However, in the appropriate clinical and radiological setting, transbronchial lung biopsy may also allow a confident diagnosis of DIPNECH syndrome. DIPNECH embraces a range of conditions; we suggest the term DIPNECH syndrome to indicate a distinct patient subset http://ow.ly/YHwuK

Levels of circulating endothelial cells are low in idiopathic pulmonary fibrosis and are further reduced by anti-fibrotic treatments

BackgroundIt has been suggested that circulating fibrocytes and endothelial cells actively participate in the intense remodelling of the pulmonary vasculature in patients with idiopathic pulmonary fibrosis (IPF). Indeed, fibrotic areas exist that have fewer blood vessels, whereas adjacent non-fibrotic tissue is highly vascularized. The number of circulating endothelial cells (CEC) and endothelial progenitor cells (EPC) might reflect the balance between vascular injury and repair. Thus, fibrocytes as well as endothelial cells could potentially be used as biomarkers of disease progression and treatment outcome.MethodsPeripheral blood samples were collected from 67 patients with a multidisciplinary diagnosis of IPF and from 45 age-matched and sex-matched healthy volunteers. Buffy coat was isolated according to standard procedures and at least 20 million cells were stained with different monoclonal antibodies for the detection of CEC, EPC and circulating fibrocytes. For the detection of CEC and EPC, cells were stained with anti-CD45, anti-CD34, anti-CD133, anti-CD14, anti-CD309 and with the viability probe Far-Red LIVE/DEAD. For the detection of circulating fibrocytes, cells were first stained with LIVE/DEAD and the following monoclonal antibodies: anti-CD3, anti-CD19, anti-CD45, anti-CD34 and anti-CD14, then cells were fixed, permeabilized and stained with fluorochrome-conjugated anti-collagen I monoclonal antibodies.ResultsPatients with IPF displayed almost undetectable levels of circulating fibrocytes, low levels of CEC, and normal levels of EPC. Patients treated with nintedanib displayed higher levels of CEC, but lower levels of endothelial cells expressing CD309 (the type II receptor for vascular endothelial growth factor). Treatment with both nintedanib and pirfenidone reduced the percentage of CEC and circulating fibrocytes.ConclusionsLevels of CEC were reduced in patients with IPF as compared to healthy individuals. The anti-fibrotic treatments nintedanib and pirfenidone further reduced CEC levels. These findings might help explain the mechanism of action of these drugs and should be explored as predictive biomarkers in IPF.

Clinical usefulness of mepolizumab in severe eosinophilic asthma

Asthma is a chronic inflammatory disorder of the airways with variable clinical severity from very mild and occasional symptoms to recurrent critical exacerbations, at risk of fatal or near-fatal outcome, in a small percentage of patients. Within the different inflammatory cascades involved in asthma, eosinophils play a central role in the pathogenesis and largely influence disease severity. Interleukin-5 (IL-5) is the main cytokine controlling eosinophil activity and proliferation at the site of inflammation. Mepolizumab was the first biological humanized anti-IL-5 monoclonal antibody tested in randomized clinical trials on eosinophilic asthma and other eosinophilic diseases. On the basis of several positive clinical efficacy data, it has recently been approved by the US Food and Drug Administration for the treatment of severe eosinophilic asthma. Unfortunately, high costs are at present a critical issue. Future studies will probably help in the correct selection of a potential “responder phenotype”, allowing the prescription of this promising therapy to appropriate patients and best define cost-effectiveness issues.

Mindfulness-based stress reduction in patients with interstitial lung diseases: a pilot, single-centre observational study on safety and efficacy

Background Chronic, progressive respiratory symptoms are associated with great psychological and emotional impact in patients suffering from interstitial lung disease (ILD). This single-centre pilot study evaluated for the first time the safety, feasibility and efficacy of a Mindfulness Based Stress Reduction Program (MBSR) in a group of patients with ILD. Methods Prospective observational study set in a university hospital ILD outpatient clinic. Nineteen patients with different ILDs were recruited 2 months prior to the start of the 8-week MBSR program and followed up for 12 months. Primary outcomes were program safety and feasibility, while secondary outcomes were changes in moods and stress (assessed by Profile Of Mood State (POMS) and Perceived Stress Scale (PSS) questionnaires), symptoms (Shortness Of Breath (SOB) and Cough And Sputum Assessment (CASA-Q) questionnaires), lung function and exercise tolerance at 12 months. Results Two patients (10.5%) dropped out in the observational period before the start of the MBSR intervention because of non-respiratory causes. All 17 patients who entered the 8-week MBSR program managed to complete it with an adherence average of eight sessions of nine. No adverse events related to the mindfulness training were reported. Statistically significant improvements in the POMS total score and in several individual items of POMS and PSS were observed throughout the study. However, respiratory questionnaire scores, lung function and exercise tolerance did not show a significant difference over time. Conclusions An MBSR program appears to be safe and feasible in patients with ILD, and might affect perceived moods and stress producing a positive and lasting improvement in several stress-related negative domains. These findings pave the way to larger (possibly multicentre), randomised, controlled confirmatory trials.

Bronchial fibroepithelial polyp: a clinico-radiologic, bronchoscopic, histopathological and in-situ hybridisation study of 15 cases of a poorly recognised lesion.

Bronchial fibroepithelial polyp is an uncommon, poorly recognised lesion, lacking clear diagnostic criteria at histology, but possibly mimicking neoplastic growth on clinico‐radiologic and histopathological grounds. The aim of this study was to define the clinico‐pathological features, bronchoscopic appearance and treatment of bronchial fibroepithelial polyp.

Pharmacological Treatment of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common and most lethal diffuse fibrosing lung disease, with a mortality rate that exceeds that of many types of cancer. At present there is no effective standard treatment recommended by guideline documents. However, several high-quality clinical trials evaluating a number of novel therapies have recently been concluded. The results have mostly been disappointing, although some compounds have shown promising results. In particular, pirfenidone seems to be the most advanced agent for IPF treatment, having been approved in Europe, Japan, and India. In general, due to the complexity and the uncertainties intrinsic to IPF, it is essential that each therapeutic strategy be tailored to the individual patient after discussing the potential benefits and pitfalls. Randomized controlled trials still represent a valid choice for IPF patients, and their completion is critically important to achieving the ultimate goal of curing IPF.

The role of macrophages in interstitial lung diseases: Number 3 in the Series “Pathology for the clinician” Edited by Peter Dorfmüller and Alberto Cavazza

The finding of collections of macrophages/histiocytes in lung biopsy and bronchoalveolar lavage is relatively common in routine practice. This morphological feature in itself is pathological, but the exact clinical significance and underlying disease should be evaluated together with clinical data, functional respiratory and laboratory tests and imaging studies. Morphological characteristics of macrophages and their distribution along the different pulmonary structures should be examined carefully by pathologists. Indeed, haemosiderin-laden macrophages are associated with smoking-related diseases when pigment is fine and distribution is bronchiolocentric, while alveolar haemorrhage or pneumoconiosis are the main concerns when pigment is chunky or coarse and the macrophages show an intra-alveolar or perilymphatic location, respectively. In the same way, pulmonary accumulation of macrophages with foamy cytoplasm is generally associated with pathologies leading to broncho-bronchiolar obstruction (e.g. diffuse panbronchiolitis, hypersensitivity pneumonia or cryptogenic organising pneumonia) or alternatively to exogenous lipoid pneumonia, some drug toxicity (e.g. amiodarone exposure or toxicity) and metabolic disorders (e.g. type B Niemann–Pick disease). This pathology-based perspectives article is aimed at concisely describing the diagnostic possibilities when faced with collection of macrophages in lung biopsy and cytology. Morphology and localisation of macrophages in the lungs is helpful in the diagnosis of interstitial lung disease http://ow.ly/7bci30bBwmQ

Hemoptysis and Progressive Dyspnea in a 67-Year-Old Woman with History of Renal Transplantation

Hemoptysis and Progressive Dyspnea in a 67-Year-Old Woman with History of Renal Transplantation Filippo Lococo, Gloria Montanari, Maria Cecilia Mengoli, Filippo Ferrari, Paolo Spagnolo, and Giulio Rossi Unit of Thoracic Surgery, IRCCS-Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; Respiratory Disease Clinic, Pathologic Anatomy, and Laboratory of Microbiology, Azienda Ospedaliero-Universitaria Policlinico di Modena, Modena, Italy; and Medical University Clinic, Canton Hospital Baselland, and University of Basel, Liestal, Switzerland

Pulmonary Carcinosarcoma Arising in the Framework of an Idiopathic Pulmonary Fibrosis.

A 77-year-old man, former smoker, followed for idiopathic pulmonary fibrosis (IPF) presented with right side chest pain. Chest X-rays showed a right pulmonary mass of the lower lobe (absent the year before), and high-resolution computed tomography (HRCT) imaging confirmed the presence of a right lung mass (maximum diameter 65 9 32 mm) with relatively irregular margins in a diffuse infiltrative fibrotic interstitial disease (Fig. 1a, b) with radiological ‘‘UIP pattern’’ according to the official 2011 ATS/ERS/JRS/ALAT guidelines [1]. The lung mass showed intensive uptake of the radio-tracer at 18F-FDG PET/CT-scan (SUVmax = 25) with no other areas of uptake (Fig. 1c, d). A CT-scan-guided percutaneous biopsy revealed large areas of cartilage with cell atypia (Fig. 2a, b) and a spindleshaped neoplastic cell proliferation weakly expressing pancytokeratins (clone AE1/AE3) and p63 (Fig. 2c, d), but negative with TTF1. A tentative diagnosis of sarcomatoid carcinoma (SC) with heterologous chondrosarcomatous component (namely carcinosarcoma) was made. Despite the high comorbidity and the dismal long-term prognosis related to IPF, but considering the early-stage of the lung cancer (cT2N0M0) and the patient’s will, a multidisciplinary oncologic team recommended surgical removal and the patient underwent right lower lobectomy. The final pathological diagnosis of carcinosarcoma (stage pT2bN0) arising in the framework of IPF was made. A multiplex molecular analysis (Sequenom, MassARRAY Analyzer 4, Diatech Pharmacogenetics, Jesi, Italy) showed no gene alterations. The post-operative course was uneventful and the patient is still alive without relapse 3 months after surgery. Carcinosarcoma is an extremely uncommon variant of lung cancer belonging to the rubric of sarcomatoid carcinoma (according to the last 2015 WHO classification [2]). It usually runs an aggressive clinical course, with poorer prognosis, higher metastatic potential than other non-smallcell lung carcinomas (NSCLC) and very limited responsiveness to standard drugs [3]. On the other hand, IPF is the most severe idiopathic interstitial pneumonia, with typical HRCT features and histologic pattern of usual interstitial pneumonia (UIP). Despite that the epithelial-to-mesenchymal transition (EMT) has been supposed to be the key pathway strongly involved in both the pathogenesis of IPF and SC [3, 4], contrary to other conventional lung cancer histotypes (e.g., adenocarcinoma, squamous cell carcinoma, largecell and small-cell carcinoma) [5], carcinosarcoma has never been reported in association with IPF. Treating patients with both SC and IPF is a real challenge considering the dismal prognosis of both diseases and the high morbidity and mortality rate after pulmonary resection [5]. & Filippo Lococo filippo_lococo@yahoo.it