Case Report: Middle lobe syndrome: a rare presentation in eosinophilic granulomatosis with polyangiitis.

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of disorders characterized by necrotizing inflammation of small- and medium-sized blood vessels and the presence of circulating ANCA. Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic ANCA-associated vasculitis, characterized by peripheral eosinophilia, neuropathy, palpable purpuras or petechiae, renal and cardiac involvement, sinusitis, asthma, and transient pulmonary infiltrates. Middle lobe syndrome (MLS) is defined as recurrent or chronic atelectasis of the right middle lobe of the lung, and it is a potential complication of asthma. Case presentation: Herein, we describe a case of MLS in a 51-year-old woman, never-smoker, affected by EGPA, presenting exclusively with leukocytosis and elevated concentrations of acute-phase proteins, without any respiratory symptom, cough, or hemoptysis. Chest computed tomography (CT) imaging documented complete atelectasis of the middle lobe, together with complete obstruction of lobar bronchial branch origin. Fiberoptic bronchoscopy (FOB) revealed complete stenosis of the middle lobar bronchus origin, thus confirming the diagnosis of MLS, along with distal left main bronchus stenosis. Bronchoalveolar lavage (BAL) did not detect any infection. Bronchial biopsies included plasma cells, neutrophil infiltrates, only isolated eosinophils, and no granulomas, providing the hypothesis of vasculitic acute involvement less likely. First-line agents directed towards optimizing pulmonary function (mucolytics, bronchodilators, and antibiotic course) were therefore employed. However, the patient did not respond to conservative treatment; hence, endoscopic management of airway obstruction was performed, with chest CT documenting resolution of middle lobe atelectasis. Conclusion: To the best of our knowledge, this is the first detailed description of MLS in EGPA completely resolved through FOB. Identification of MLS in EGPA appears essential as prognosis, longitudinal management, and treatment options may differ from other pulmonary involvement in AAV patients.

Extranodal localization of non-Hodgkin's lymphoma in systemic sclerosis: A diagnostic challenge and review of the literature.

Background: Systemic sclerosis is associated with an increased incidence of malignancies, in particular solid neoplasms. Hematological cancers have been also observed in autoimmune diseases, though rarely present with lung involvement. The latter may be misdiagnosed in systemic sclerosis patients, due to the frequent concomitant interstitial lung disease. Case description: Here, we present the case of a 63-year-old man affected by systemic sclerosis presenting with an atypical lung imaging and splenomegaly, who was diagnosed with splenic marginal zone lymphoma, thus raising the suspicion of lung secondarism. We discuss the diagnostic challenge of differential diagnosis in interstitial lung presentation and briefly review the available literature on this topic. Conclusion: Several reports have demonstrated an increased risk of malignancy in patients with systemic sclerosis. Still, the lack of concretely defined guidelines for systemic sclerosis, along with systemic sclerosis multifaceted organ involvement at presentation, may challenge diagnosis and management. Here, we remark the importance of clinical work-up and a multidisciplinary approach in systemic sclerosis, to early detect and treat concomitant hematological malignancies, especially during the first years of the disease.

The Role of the Multidisciplinary Evaluation of Interstitial Lung Diseases: Systematic Literature Review of the Current Evidence and Future Perspectives.

The opportunity of a multidisciplinary evaluation for the diagnosis of interstitial pneumonias highlighted a major change in the diagnostic approach to diffuse lung disease. The new American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society guidelines for the diagnosis of idiopathic pulmonary fibrosis have reinforced this assumption and have underlined that the exclusion of connective tissue disease related lung involvement is mandatory, with obvious clinical and therapeutic impact. The multidisciplinary team discussion consists in a moment of interaction among the radiologist, pathologist and pulmonologist, also including the rheumatologist when considered necessary, to improve diagnostic agreement and optimize the definition of those cases in which pulmonary involvement may represent the first or prominent manifestation of an autoimmune systemic disease. Moreover, the proposal of classification criteria for interstitial lung disease with autoimmune features (IPAF) represents an effort to define lung involvement in clinically undefined autoimmune conditions. The complexity of autoimmune diseases, and in particular the lack of classification criteria defined for pathologies such as anti-synthetase syndrome, makes the involvement of the rheumatologist essential for the correct interpretation of the autoimmune element and for the application of classification criteria, that could replace clinical pictures initially interpreted as IPAF in defined autoimmune disease, minimizing the risk of misdiagnosis. The aim of this review was to evaluate the available evidence about the efficiency and efficacy of different multidisciplinary team approaches, in order to standardize the professional figures and the core set procedures that should be necessary for a correct approach in diagnosing patients with interstitial lung disease.

Intravascular large B cell lymphoma presenting in the lung: the diagnostic value of transbronchial cryobiopsy.

BACKGROUND AND OBJECTIVE: intravascular large B-cell lymphoma is a distinct subtype of mature B-cell neoplasms, with uncommon primary presentation in the lungs. Diagnosis could be very difficult due to the lack of detectable tumor masses and it is usually made by surgical lung biopsy or autopsy examination. METHODS: two patients occurred primarily with interstitial lung disease and underwent a pulmonary biopsy using cryoprobes. RESULTS: the pathological analysis of the lung biopsies revealed in both cases a conclusive diagnosis of intravascular large B-cell lymphoma with primary lung involvement and patients have been safely diagnosed using transbronchial cryobiopsy for the first time in the literature. CONCLUSIONS: transbronchial cryobiopsy could be used as valid surrogate for surgical lung biopsy in lymphoprolipherative lung disorders (including intravascular lymphomas), as allows larger samples of tissue, greater  diagnostic yield, no crush artifacts and much less complications than surgical biopsy. 

Lung cryobiopsies: a paradigm shift in diagnostic bronchoscopy?

In 1963, the first bronchoscopic lung biopsy was performed. Less than 10 years later, the technique of transbronchial lung biopsy using a flexible bronchoscope was introduced into clinical practice, significantly reducing the rate of major complications and the rate of surgical lung biopsies in patients with diffuse parenchymal lung diseases. The diagnostic yield of transbronchial lung biopsy varies among various parenchymal lung diseases. In pulmonary sarcoidosis and lymphangitis carcinomatosa, a diagnosis can be obtained in up to 80% of patients. This method is considered inadequate, however, in identifying more complex histological patterns such as usual interstitial pneumonitis or nonspecific interstitial pneumonitis. Introduction of the 'jumbo forceps' and of a more 'surgically oriented' procedural setting (patients deeply sedated and intubated) allowed larger and more numerous lung specimens to be obtained without a significant increase of complications such as pneumothorax or bronchial bleeding. However, the possibility to obtain enough parenchymal tissue for a morphological diagnosis of complex patterns remained unmet. Recently, the use of cryoprobes has achieved a significant impact on this issue allowing to obtain large quantity of tissue. Recent studies document that with transbronchial cryobiopsies the diagnosis of usual interstitial pneumonitis can be made confidently by pathologists with a good inter-observer agreement. Pneumothorax is the main complication (reported in up to one fourth of cases in some series); bronchial bleeding is easily controlled using Fogarty balloon. Transbronchial cryobiopsy is a promising new technique that may become a valid alternative to surgical lung biopsy in the near feature.

Features and outcome of familial idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathicpulmonary fibrosis (IPF) has a sporadic occurrence in most instances,but can also occasionally occur in familial form. While clinicalfeatures of sporadic IPF are well defined, clinical presentation,complications, and outcome of familial IPF are still undefined. Thisretrospective study was undertaken to establish clinical parametersand survival time in a consecutive series of patients with familialIPF and to establish whether the phenomenon of anticipation could beobserved. METHODS: 30 patients had received a diagnosis of familial IPF at ourinstitution over the period from January 2005 and December 2011; in7 of them there was a parent-child relation.Clinical features and patient outcome were analyzed and contrasted toa well characterized cohort of 127 patients with non familial IPF. RESULTS: there was no significant difference in presenting symptoms and theoverall outcomes were quite similar in the two groups, but thefamilial group was much more enriched for females and we found astatistically significant lower age at onset in the youngergenerations (mean age 57,8 years versus 74,2 years, p 0,001). Acuteexacerbations, IPF progression and lung cancer were more frequent inthe familial IPF group as a cause of death (p < 0,005). CONCLUSION: familial IPF seems indistinguishable from sporadic IPF with respectto most clinical and physiologic findings; however the age of onsetwas slightly lower among the familial cases than in the sporadiccases of IPF and the phenomenon of anticipation could be observed.

Transbronchial lung cryobiopsy in the diagnosis of fibrotic interstitial lung diseases.

BACKGROUND: Histology is a key element for the multidisciplinary diagnosis of fibrotic diffuse parenchymal lung diseases (f-DPLD) when the clinical-radiological picture is nondiagnostic. Transbronchial lung cryobiopsy (TBLC) have been shown to be useful for obtaining large and well-preserved biopsies of lung parenchyma, but experience with TBLC in f-DPLD is limited. OBJECTIVES: To evaluate safety, feasibility and diagnostic yield of TBLC in f-DPLD. METHOD: Prospective study of 69 cases of TBLC using flexible cryoprobe in the clinical-radiological setting of f-DPLD with nondiagnostic high resolution computed tomography (HRCT) features. SAFETY: pneumothorax occurred in 19 patients (28%). One patient (1.4%) died of acute exacerbation. Feasibility: adequate cryobiopsies were obtained in 68 cases (99%). The median size of cryobiopsies was 43.11 mm(2) (range, 11.94-76.25). Diagnostic yield: among adequate TBLC the pathologists were confident ("high confidence") that histopathologic criteria sufficient to define a specific pattern in 52 patients (76%), including 36 of 47 with UIP (77%) and 9 nonspecific interstitial pneumonia (6 fibrosing and 3 cellular), 2 desquamative interstitial pneumonia/respiratory bronchiolitis-interstitial lung disease, 1 organizing pneumonia, 1 eosinophilic pneumonia, 1 diffuse alveolar damage, 1 hypersensitivity pneumonitis and 1 follicular bronchiolitis. In 11 diagnoses of UIP the pathologists were less confident ("low confidence"). Agreement between pathologists in the detection of UIP was very good with a Kappa coefficient of 0.83 (95% CI, 0.69-0.97). Using the current consensus guidelines for clinical-radiologic-pathologic correlation 32% (20/63) of cases were classified as Idiopathic Pulmonary Fibrosis (IPF), 30% (19/63) as possible IPF, 25% (16/63) as other f-DPLDs and 13% (8/63) were unclassifiable. CONCLUSIONS: TBLC in the diagnosis of f-DPLD appears safe and feasible. TBLC has a good diagnostic yield in the clinical-radiological setting of f-DPLD without diagnostic HRCT features of usual interstitial pneumonia. Future studies should consider TBLC as a potential alternative to SLBx in f-DPLD.

MMP-7 and fcDNA serum levels in early NSCLC and idiopathic interstitial pneumonia: preliminary study.

A non-invasive test to facilitate the diagnosis of non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF) is still not available and represents an important goal. Forty-eight patients with stage I NSCLC, 45 with IPF, 30 with other idiopathic interstitial pneumonias (IIPs) including idiopathic non-specific interstitial pneumonia (NSIP) and chronic hypersensitivity pneumonitis (HP), 35 with diffuse non-malignant disease and 30 healthy donors were enrolled onto the study. Free circulating (fc)DNA and MMP-7 levels were evaluated by Real Time PCR and ELISA, respectively. Median fcDNA levels were similar in NSCLC (127 ng/mL, range 23.6-345 ng/mL) and IPF (106 ng/mL, range 22-224 ng/mL) patients, and significantly lower in IIPs patients, in individuals with other diseases and in healthy donors (p < 0.05). Conversely, median MMP-7 values were significantly higher in IPF patients (9.10 ng/mL, range 3.88-19.72 ng/mL) than in those with NSCLC (6.31 ng/mL, range 3.38-16.36 ng/mL; p < 0.0001), NSIP (6.50 ng/mL, range 1.50-22.47 ng/mL; p = 0.007), other diseases (5.41 ng/mL, range 1.78-15.91, p < 0.0001) or healthy donors (4.35 ng/mL, range 2.45-7.23; p < 0.0001). Serum MMP-7 levels seem to be capable of distinguishing IPF patients from those with any other lung disease. fcDNA levels were similar in NSCLC and IPF patients, confirming its potential role as a biomarker, albeit non-specific, for the differential diagnosis of NSCLC.

Multiple marker detection in peripheral blood for NSCLC diagnosis.

BACKGROUND: Non-invasive early detection of lung cancer could reduce the number of patients diagnosed with advanced disease, which is associated with a poor prognosis. We analyzed the diagnostic accuracy of a panel of peripheral blood markers in detecting non small cell lung cancer (NSCLC). METHODS: 100 healthy donors and 100 patients with NSCLC were enrolled onto this study. Free circulating DNA, circulating mRNA expression of peptidylarginine deiminase type 4 (PAD4/PADI4), pro-platelet basic protein (PPBP) and haptoglobin were evaluated using a Real-Time PCR-based method. RESULTS: Free circulating DNA, PADI4, PPBP and haptoglobin levels were significantly higher in NSCLC patients than in healthy donors (p<0.0001, p<0.0001, p=0.0002 and p=0.0001, respectively). The fitted logistic regression model demonstrated a significant direct association between marker expression and lung cancer risk. The odds ratios of individual markers were 6.93 (95% CI 4.15-11.58; p<0.0001) for free DNA, 6.99 (95% CI 3.75-13.03; p<0.0001) for PADI4, 2.85 (95% CI 1.71-4.75; p<0.0001) for PPBP and 1.16 (95% CI 1.01-1.33; p=0.031) for haptoglobin. Free DNA in combination with PPBP and PADI4 gave an area under the ROC curve of 0.93, 95% CI=0.90-0.97, with sensitivity and specificity over 90%. CONCLUSIONS: Free circulating DNA analysis combined with PPBP and PADI4 expression determination appears to accurately discriminate between healthy donors and NSCLC patients. This non-invasive multimarker approach warrants further research to assess its potential role in the diagnostic or screening workup of subjects with suspected lung cancer.

Transbronchial biopsy is useful in predicting UIP pattern.

BACKGROUND: Usual interstitial pneumonia (UIP), is a necessary feature pathologically or radiologically for the diagnosis of idiopathic pulmonary fibrosis (IPF). The predictive value of transbronchial biopsy (TBB) in identifying UIP is currently unknown. The objective of this study is to assess the accuracy with which histopathologic criteria of usual interstitial pneumonia (UIP) can be identified in transbronchial biopsy (TBB) and to assess the usefulness of TBBx in predicting a the diagnosis of UIP pattern. We conducted a retrospective blinded and controlled analysis of TBB specimens from 40 established cases of UIP and 24 non-UIP interstitial lung diseases. RESULTS: Adequate TBB specimens were available in 34 UIP cases (85% of all UIP cases). TBB contained histopathologic criteria to suggest a UIP pattern (ie. at least one of three pathologic features of UIP present; patchy interstitial fibrosis, fibroblast foci, honeycomb changes) in 12 cases (30% of all UIP cases). Sensitivity, specificity, positive and negative predictive values for the two pathologists were 30% (12/40), 100% (24/24), 100% (12/12), 46% (24/52) and 30% (12/40), 92% (22/24), 86% (12/14), 55% (22/40) respectively. Kappa coefficient of agreement between pathologists was good (0.61, 95% CI 0.31-0.91). The likelihood of identifying UIP on TBB increased with the number and size of the TBB specimens. CONCLUSION: Although sensitivity is low our data suggest that even modest amount of patchy interstitial fibrosis, fibroblast foci, honeycomb changes detected on TBB can be highly predictive of a UIP pattern. Conversely, the absence of UIP histopathologic criteria on TBB does not rule out UIP.

Is medical thoracoscopy efficient in the management of multiloculated and organized thoracic empyema?.

BACKGROUND: Pleural empyema can be subdivided into 3 stages: exudative, multiloculated, and organizing. In the absence of clear septation, antibiotics plus simple drainage of pleural fluid is often sufficient treatment, whereas clear septation often requires more invasive treatment. OBJECTIVES: The aim of this study was to report our experience and analyze the safety and efficacy of medical thoracoscopy in patients with multiloculated and organizing empyema. METHODS: We performed a retrospective study reviewing the files of patients referred for empyema and treated by medical thoracoscopy at our department from July 2005 to February 2011. RESULTS: A total of 41 patients with empyema were treated by medical thoracoscopy; empyema was free flowing in 9 patients (22%), multiloculated in 24 patients (58.5%), and organized in 8 patients (19.5%). Medical thoracoscopy was considered successful without further intervention in 35 of 41 patients (85.4%): all of the 9 patients with free-flowing fluid, 22 of the 24 patients with multiloculated empyema (91.7%), and only 4 of the 8 patients with organizing effusion (50%). CONCLUSIONS: Our study confirms that multiloculated pleural empyema could safely and successfully be treated with medical thoracoscopy while organizing empyema can be resistant to drainage with medical thoracoscopy, requiring video-assisted thoracic surgery or open surgical decortications; among this population, the presence of separate 'pockets' not in apparent communication with each other often leads to a surgical approach.

Assessment of EGFR and K-ras mutations in fixed and fresh specimens from transesophageal ultrasound-guided fine needle aspiration in non-small cell lung cancer patients.

In non-small cell lung cancer (NSCLC) patients, somatic EGFR and K-ras mutations predict therapeutic effectiveness and resistance, respectively, to EGFR tyrosine kinase inhibitors (TKIs). Transesophageal ultrasound-guided fine needle aspiration (EUS-FNA) is a validated technique for diagnosis and staging of NSCLC. In the present study, we compared the feasibility and reliability of EGFR and K-ras gene mutation analysis in fixed and fresh mediastinal lymph nodes and extra-lymph nodal samples obtained by EUS-FNA in patients suspicious for NSCLC. Thirty-six patients were enrolled into the study. For each patient, DNA was extracted from both fresh samples and fixed cytological smears. Exons 18-21 of EGFR and exon 2 of K-ras were amplified by PCR and mutation status was determined by direct sequencing and pyrosequencing. All cases were eligible for analysis. NSCLC was diagnosed in 32 patients (25 adenocarcinomas and 7 squamous cell carcinomas) and 4 patients were free of malignancy. Of the 25 patients with adenocarcinoma, EGFR mutations were detected in 2 (8%) fresh tumor samples and in 3 (12%) fixed cytological smears. K-ras mutations were detected in 8 (32%) fresh samples, and in 9 (36%) fixed cytological smears. Fixed and stained cytological samples seem to be more reliable than fresh material for molecular analysis.

Increased levels of free circulating DNA in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is difficult to diagnose because of numerous interstitial lung diseases with similar symptoms. As serum DNA has proven useful for early lung cancer detection, we aimed to define the relevance of this marker in discriminating IPF from other fibrotic and nonfibrotic/nonmalignant lung diseases. DNA was quantified in 191 subjects: 64 healthy individuals, 58 patients with IPF, 17 patients with nonspecific pulmonary fibrosis (13 idiopathic nonspecific interstitial pneumonia, 4 chronic hypersensitivity pneumonitis), and 52 patients with other diffuse/nonmalignant lung diseases. The median value of free DNA in IPF patients was 61.1 ng/mL (range 7.1-405), which was significantly higher than that of healthy donors (median 6.8, range 2.2-184) (p<0.001) and that of patients with other diffuse/nonmalignant lung diseases (median 28.0, range 4.2-281) (p=0.004). The area under the ROC curve was 0.926 (95% CI 0.879-0.973) when IPF patients were compared with healthy donors, and 0.702 (95% CI 0.609-0.796) when a comparison was made with non-IPF pulmonary diseases. In conclusion, we observed significantly higher levels of free circulating DNA in patients with IPF than in those with other fibrotic or diffuse/nonmalignant lung diseases.