Fabíola Del Carlo Bernardi

Endosonography vs Conventional Bronchoscopy for the Diagnosis of Sarcoidosis: The GRANULOMA Randomized Clinical Trial

IMPORTANCE Tissue verification of noncaseating granulomas is recommended for the diagnosis of sarcoidosis. Bronchoscopy with transbronchial lung biopsies, the current diagnostic standard, has moderate sensitivity in assessing granulomas. Endosonography with intrathoracic nodal aspiration appears to be a promising diagnostic technique. OBJECTIVE To evaluate the diagnostic yield of bronchoscopy vs endosonography in the diagnosis of stage I/II sarcoidosis. DESIGN, SETTING, AND PATIENTS Randomized clinical multicenter trial (14 centers in 6 countries) between March 2009 and November 2011 of 304 consecutive patients with suspected pulmonary sarcoidosis (stage I/II) in whom tissue confirmation of noncaseating granulomas was indicated. INTERVENTIONS Either bronchoscopy with transbronchial and endobronchial lung biopsies or endosonography (esophageal or endobronchial ultrasonography) with aspiration of intrathoracic lymph nodes. All patients also underwent bronchoalveolar lavage. MAIN OUTCOMES AND MEASURES The primary outcome was the diagnostic yield for detecting noncaseating granulomas in patients with a final diagnosis of sarcoidosis. The diagnosis was based on final clinical judgment by the treating physician, according to all available information (including findings from initial bronchoscopy or endosonography). Secondary outcomes were the complication rate in both groups and sensitivity and specificity of bronchoalveolar lavage in the diagnosis of sarcoidosis. RESULTS A total of 149 patients were randomized to bronchoscopy and 155 to endosonography. Significantly more granulomas were detected at endosonography vs bronchoscopy (114 vs 72 patients; 74% vs 48%; P < .001). Diagnostic yield to detect granulomas for endosonography was 80% (95% CI, 73%-86%); for bronchoscopy, 53% (95% CI, 45%-61%) (P < .001). Two serious adverse events occurred in the bronchoscopy group and 1 in the endosonography group; all patients recovered completely. Sensitivity of the bronchoalveolar lavage for sarcoidosis based on CD4/CD8 ratio was 54% (95% CI, 46%-62%) for flow cytometry and 24% (95% CI, 16%-34%) for cytospin analysis. CONCLUSION AND RELEVANCE Among patients with suspected stage I/II pulmonary sarcoidosis undergoing tissue confirmation, the use of endosonographic nodal aspiration compared with bronchoscopic biopsy resulted in greater diagnostic yield. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00872612.

Detection of SS18-SSX fusion transcripts in formalin-fixed paraffin-embedded neoplasms: analysis of conventional RT-PCR, qRT-PCR and dual color FISH as diagnostic tools for synovial sarcoma

Synovial Sarcoma consistently harbors t(X;18) resulting in SS18-SSX1, SS18-SSX2 and rarely SS18-SSX4 fusion transcripts. Of 328 cases included in our study, synovial sarcoma was either the primary diagnosis or was very high in the differential diagnosis in 134 cases: of these, amplifiable cDNA was obtained from 131. SS18-SSX fusion products were found in 126 (96%) cases (74 SS18-SSX1, 52 SS18-SSX2), using quantitative and 120 by conventional reverse transcriptase–polymerase chain reaction (RT-PCR). One hundred and one cases in a tissue microarray, analyzed by fluorescence in situ hybridization (FISH), revealed that 87 (86%) showed SS18 rearrangement: four RT-PCR positive cases, reported as negative for FISH, showed loss of one spectrum green signal, and 15 cases had multiple copies of the SS18 gene: both findings are potentially problematic when interpreting results. One of three cases, not analyzed by RT-PCR reaction owing to poor quality RNA, was positive by FISH. SS18-SSX1 was present in 56 monophasic and 18 biphasic synovial sarcoma: SS18-SSX2 was detected in 41 monophasic and 11 biphasic synovial sarcoma. Poorly differentiated areas were identified in 44 cases (31%). There was no statistically significant association between biphasic, monophasic and fusion type. Five cases were negative for SS18 rearrangement by all methods, three of which were pleural-sited neoplasms. Following clinical input, a diagnosis of mesothelioma was favored in one case, a sarcoma, not otherwise specified in another and a solitary fibrous tumor in the third case. The possibility of a malignant peripheral nerve sheath tumor could not be excluded in the other two cases. We concluded that the employment of a combination of molecular approaches is a powerful aid to diagnosing synovial sarcoma giving at least 96% sensitivity and 100% specificity but results must be interpreted in the light of other modalities such as clinical findings and immunohistochemical data.

Immune receptors and adhesion molecules in human pulmonary leptospirosis

Pulmonary involvement in leptospirosis has been increasingly reported in the last 20 years, being related to the severity and mortality of the disease. The pathogenesis of pulmonary hemorrhage in leptospirosis is not understood. Lung endothelial cells have been proposed as targets in the pathogenesis of lung involvement in leptospirosis through the activation of Toll-like receptor 2 or the complement system, which stimulates the release of cytokines that lead to the activation of adhesion molecules. The aim of this study was to investigate the involvement of immune pathways and of the intercellular and vascular cell adhesion molecules (intercellular adhesion molecule and vascular cell adhesion molecule, respectively) in the lungs of patients with pulmonary involvement of leptospirosis. We studied the lungs of 18 patients who died of leptospirosis and compared them with 2 groups of controls: normal and noninfectious hemorrhagic lungs. Using immunohistochemistry and image analysis, we quantified the expression of the C3a anaphylatoxin receptor, intercellular adhesion molecule, vascular cell adhesion molecule, and Toll-like receptor 2 in small pulmonary vessels and in the alveolar septa. There was an increased expression of intercellular adhesion molecule (P < .03) and C3a anaphylatoxin receptor (P < .008) in alveolar septa in the leptospirosis group compared with the normal and hemorrhagic controls. In the vessels of the leptospirosis group, there was an increased expression of intercellular adhesion molecule (P = .004), vascular cell adhesion molecule (P = .030), and Toll-like receptor 2 (P = .042) compared with the normal group. Vascular cell adhesion molecule expression in vessels was higher in the leptospirosis group compared with the hemorrhagic group (P = .015). Our results indicate that immune receptors and adhesion molecules participate in the phenomena leading to pulmonary hemorrhage in leptospirosis.

Histological examination has a major impact on macroscopic necropsy diagnoses

Background: Necropsy is the gold standard for clinicopathological discrepancy studies and epidemiological surveys. Inadequate sampling or lack of tissue may hamper the final interpretation and quality of the necropsy. Aim: To compare the histological and gross necropsy diagnoses of different organs. Methods: A retrospective comparison of the provisional reports (gross findings only) and the final reports (after histological examination) of the necropsies performed at the department of pathology of the Hospital das Clínicas, Sao Paulo University, Brazil, a large tertiary care complex, in 2001. The total number of diagnoses listed for the lungs, heart, liver, pancreas, kidneys, and spleen were calculated. Findings were categorised into concordant/refined diagnosis, discordant/additional diagnosis, histology needed, and inconclusive. Results: Three hundred and seventy one postmortem reports were analysed. There were 214 men and 157 women, with a mean age of 50.3 years, ranging from 1 to 92. The lung received the highest number (954) and the pancreas the lowest number (390) of diagnoses. The highest frequencies of discrepancies between the gross and microscopic findings were found in the lung and the liver: 38.7% and 35.1%, respectively. The brain had the lowest frequency of discrepancies. In a small number of cases, the final diagnosis could only be achieved through microscopic analysis, with the highest frequency being found in the kidneys (8.5%). Conclusions: Histological analysis has a major impact on previously performed gross diagnosis at necropsy, especially in the lungs, liver, and kidneys. Adequate sampling and histological analysis are important for necropsy quality.

Immunopathological aspects of schistosomiasis-associated pulmonary arterial hypertension

OBJECTIVES Pulmonary hypertension is a lethal complication of chronic hepatosplenic schistosomiasis. Little is known of the underlying (immuno-)histopathological characteristics of lung vasculopathy. METHODS We characterized vasculopathy and inflammation in lung tissue of 10 patients with Schistosomiasis-associated PH (SCH-PH) in comparison to 22 idiopathic pulmonary arterial hypertension (IPAH) patients and 10 normal controls. SCH-PH cases were younger than controls. RESULTS Plexiform lesions and/or angiomatoid lesions were found in 10/10 SCH-PH, and 19/22 IPAH patients (χ² p = 0.22). Lung granulomas with Schistosoma eggs were found in 2/10 of SCH-PH cases. PAH cases had increased peri-arterial density of CD3+ T cells, chymase+ and tryptase+ mast cells when compared to controls (p ≤ 0.047). SCH-PH showed increased density of CD4+ cells when compared to controls (p = 0.025), paralleled by an increased density of dendritic CD83+ cells when compared to both controls and IPAH patients (p ≤ 0.022). CONCLUSION Both SCH-PH and IPAH feature plexogenic arteriopathy and increased periarterial T cell and mast cell density. SCH-PH and IPAH differ only with respect to the density of dendritic CD83+ cells. These findings imply ongoing antigenic stimulation in SCH-PH, yet a pattern of pulmonary vasculopathy similar to IPAH, suggestive of a final common pathway in their pathogenesis of PAH.

Traqueobronquite aguda causada por Aspergillus: relato de caso e achados de imagem

Acute tracheobronchitis is a rare manifestation of invasive aspergillosis, generally occurring in severely immunocompromised patients. The authors report the case of a patient presenting with this condition after bone-marrow transplantation, with emphasis on tomographic findings.Acute tracheobronchitis is a rare manifestation of invasive aspergillosis, generally occurring in severely immunocompromised patients. The authors report the case of a patient presenting with this condition after bone-marrow transplantation, with emphasis on tomographic findings.

Pulmonary arterial involvement leading to alveolar hemorrhage in lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a rare disorder of unknown cause that affects women of reproductive age. The disorder is characterized by the proliferation of atypical smooth muscle cells (LAM cells) around airways, blood vessels, and lymphatics with cystic destruction of the lung.1-3 LAM may occur sporadically or may be associated with tuberous sclerosis complex (TSC).1 Clinically, patients may develop progressive dyspnea, cough, wheezing, spontaneous pneumothorax, chylothorax, and hemoptysis.3 The diagnosis is confirmed by the identification of diffuse thin-walled lung cysts via thoracic high resolution computed tomography (HRCT) that are associated with a positive tissue biopsy or by the presence of chylothorax, angiomyolipoma, or TSC.1,2 Acute respiratory failure that is secondary to diffuse alveolar hemorrhage is an extremely rare manifestation in LAM patients, with only two previous cases described. The mechanism responsible for the comorbid presentation of acute respiratory failure and diffuse alveolar hemorrhage, however, is unknown. Nonetheless, it is speculated to be secondary to the obstruction of pulmonary venules by LAM cell proliferation, thereby promoting pulmonary venous hypertension.4,5 In the present work, we describe a patient with a diffuse alveolar hemorrhage that led to acute respiratory failure and death. A diagnosis of LAM and pulmonary arterial disruption caused by LAM cells was confirmed during the autopsy.

Tissue maturation during the growth of juvenile nasopharyngeal angiofibroma.

Juvenile nasopharyngeal angiofibroma involves a specific age group and changes from vascular tissue to fibrous tissue. The goal of this study was to investigate the correlation among tumor extension, the histologic characteristics of the tumor, and the patients age. We performed a prospective study of 43 male patients with untreated juvenile nasopharyngeal angiofibroma (average age, 15.42 years). We correlated the patients age with the extension of the tumor (analyzing the computed tomographic scan) and the immunohistologic characteristics of the tumor (morphological and morphometric analysis of the central portion of the tumor, the sphenopalatine foramen region). We observed that the larger the tumor, the smaller the number of vessels and cells, but the larger the fibrous component and the higher the grade of maturation of the tissue. The patients age was not correlated with tumor extension or the histologic characteristics of the tumor. However, the grade of maturation of the tissue in the region of the sphenopalatine foramen was higher in larger tumors.

Differential elemental distribution of retained particles along the respiratory tract

Context: Prolonged exposure to ambient particles is associated with premature mortality due to cardio-respiratory diseases and lung cancer. The size and composition of these particles determine their toxicity, which is aggravated by their long-term retention in the lungs. Objective: To compare the elemental profile of particles retained along the bronchial tree and lymph nodes by combining laser capture microdissection (LCM) and elemental composition analysis through energy dispersive x-ray (EDX) and scanning electron microscopy (SEM). Material and methods: Twenty-four right lung middle lobes from autopsied cases were obtained from two cities with different pollution backgrounds. Lung samples were collected from three distinct sites within the lung at the time of autopsy: peribronchial tissue, peripheral parenchyma and hilar lymph nodes. Areas of potentially increased particle deposition were microdissected using LCM and analyzed for elemental composition through EDX “allied” with SEM. Results: Elemental analyses of the particles retained along the bronchial tree showed two groups of distribution: peribronchiolar or lymph node deposition. The elemental profile of peribronchial areas were significantly different between the two cities and were better discriminators of past air pollution exposure. Conclusion: Our data suggest that particle uptake varies along the bronchial tree and human lung tissue retains particles indicative of regional air pollution background.

Uma rara causa de dispnéia com apresentação singular na tomografia computadorizada de tórax: síndrome de ativação macrofágica

Macrophage activation syndrome is a rare and potentially life-threatening disease. It occurs due to immune dysregulation manifested as excessive macrophage proliferation, typically causing hepatosplenomegaly, pancytopenia and hepatic dysfunction. Here, we report an unusual case of macrophage activation syndrome presenting as dyspnea, as well as (reported here for the first time) high resolution computed tomography findings of an excavated nodule, diffuse ground glass opacities and consolidations (mimicking severe pneumonia or alveolar hemorrhage). The patient was successfully treated with human immunoglobulin. We recommend that macrophage activation syndrome be considered in the differential diagnosis of respiratory failure. Rapid diagnosis and treatment are essential to achieving favorable outcomes in patients with this syndrome.