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With the approval of antifibrotic medications to treat patients with idiopathic pulmonary fibrosis and progressive pulmonary fibrosis, radiologists have an integral role in diagnosing these entities and guiding treatment decisions. CT features of early pulmonary fibrosis include irregular thickening of interlobular septa, pleura, and intralobular linear structures, with subsequent progression to reticular abnormality, traction bronchiectasis or bronchiolectasis, and honeycombing. CT patterns of fibrotic lung disease can often be reliably classified on the basis of the CT features and distribution of the condition. Accurate identification of usual interstitial pneumonia (UIP) or probable UIP patterns by radiologists can obviate the need for a tissue sample-based diagnosis. Other entities that can appear as a UIP pattern must be excluded in multidisciplinary discussion before a diagnosis of idiopathic pulmonary fibrosis is made. Although the imaging findings of nonspecific interstitial pneumonia and fibrotic hypersensitivity pneumonitis can overlap with those of a radiologic UIP pattern, these entities can often be distinguished by paying careful attention to the radiologic signs. Diagnostic challenges may include misdiagnosis of fibrotic lung disease due to pitfalls such as airspace enlargement with fibrosis, paraseptal emphysema, recurrent aspiration, and postinfectious fibrosis. The radiologist also plays an important role in identifying complications of pulmonary fibrosis-pulmonary hypertension, acute exacerbation, infection, and lung cancer in particular. In cases in which there is uncertainty regarding the clinical and radiologic diagnoses, surgical biopsy is recommended, and a multidisciplinary discussion among clinicians, radiologists, and pathologists can be used to address diagnosis and management strategies. This review is intended to help radiologists diagnose and manage pulmonary fibrosis more accurately, ultimately aiding in the clinical management of affected patients. ©RSNA, 2024 Supplemental material is available for this article.
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Tomografia Computadorizada por Raios X , Humanos , Tomografia Computadorizada por Raios X/métodos , Fibrose Pulmonar/diagnóstico por imagem , Diagnóstico Diferencial , Fibrose Pulmonar Idiopática/diagnóstico por imagemRESUMO
Silencing of interleukin-32 (IL-32) in a differentiated human promonocytic cell line impairs killing of Mycobacterium tuberculosis (MTB) but the role of IL-32 in vivo against MTB remains unknown. To study the effects of IL-32 in vivo, a transgenic mouse was generated in which the human IL-32γ gene is expressed using the surfactant protein C promoter (SPC-IL-32γTg). Wild-type and SPC-IL-32γTg mice were infected with a low-dose aerosol of a hypervirulent strain of MTB (W-Beijing HN878). At 30 and 60 d after infection, the transgenic mice had 66% and 85% fewer MTB in the lungs and 49% and 68% fewer MTB in the spleens, respectively; the transgenic mice also exhibited greater survival. Increased numbers of host-protective innate and adaptive immune cells were present in SPC-IL-32γTg mice, including tumor necrosis factor-alpha (TNFα) positive lung macrophages and dendritic cells, and IFN-gamma (IFNγ) and TNFα positive CD4(+) and CD8(+) T cells in the lungs and mediastinal lymph nodes. Alveolar macrophages from transgenic mice infected with MTB ex vivo had reduced bacterial burden and increased colocalization of green fluorescent protein-labeled MTB with lysosomes. Furthermore, mouse macrophages made to express IL-32γ but not the splice variant IL-32ß were better able to limit MTB growth than macrophages capable of producing both. The lungs of patients with tuberculosis showed increased IL-32 expression, particularly in macrophages of granulomas and airway epithelial cells but also B cells and T cells. We conclude that IL-32γ enhances host immunity to MTB.
Assuntos
Interleucinas/metabolismo , Mycobacterium tuberculosis/patogenicidade , Tuberculose/imunologia , Tuberculose/prevenção & controle , Imunidade Adaptativa/imunologia , Animais , Antígenos Ly/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas , Humanos , Imunidade Inata/imunologia , Interferon gama , Pulmão/imunologia , Pulmão/microbiologia , Pulmão/patologia , Linfonodos/imunologia , Linfonodos/patologia , Macrófagos Alveolares/imunologia , Camundongos Transgênicos , Mutação/genética , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo , Proteína C Associada a Surfactante Pulmonar/metabolismo , Sítios de Splice de RNA/genética , Linfócitos T Reguladores/imunologia , Transfecção , Transgenes , Tuberculose/microbiologia , Fator de Necrose Tumoral alfa/metabolismo , Virulência/imunologiaRESUMO
Granulomatous-lymphocytic interstitial lung disease (GLILD) is a lymphoproliferative and granulomatous pulmonary manifestation of primary immune deficiency diseases, notably common variable immunodeficiency (CVID), and is an important contributor of excess morbidity. As with all forms of ILD, the significance of utilizing a multidisciplinary team discussion to enhance diagnostic and treatment confidence of GLILD cannot be overstated. In this review, key clinical, radiological, and pathological features are integrated into a diagnostic algorithm to facilitate a consensus diagnosis. As the evidence for diagnosing and managing patients with GLILD is limited, the viewpoints discussed here are not meant to resolve current controversies. Instead, this review aims to provide a practical framework for diagnosing and evaluating suspected cases and emphasizes the importance of a multidisciplinary approach when caring for GLILD patients.
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Cases of disseminated nontuberculous mycobacterial (NTM) infection are difficult to treat. We encountered an elderly man with disseminated Mycobacterium chelonae infection. The clinical evaluation and treatment of patients with this type of systemic infection pose unique challenges. Disseminated NTM infection with bone involvement often requires surgical intervention in addition to antimicrobial therapy.
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Caveolae are cell plasma membrane microdomains implicated in organizing and concentrating many signaling molecules. In the lung, caveolae are in endothelium, smooth muscle, fibroblasts, and pneumocytes. Caveolin is the main structural protein of caveolae. Caveolin 1 is down-regulated in transformed cells and may be a tumor suppressor protein. Caveolin 2 is coexpressed and hetero-oligomerizes with caveolin 1. Because the cells of the plexiform lesions in severe pulmonary hypertension (PH) are phenotypically altered, we wondered whether these cells lack caveolin. We now demonstrate by immunolocalization that while caveolin is expressed in lung endothelial, smooth-muscle, and alveolar septal cells, its expression is absent or decreased in plexiform lesions and in some muscularized precapillary arterioles. In contrast, Western blot analysis of total lung extracts from patients with severe PH shows no significant reduction in caveolin. Similar to the human lung tissue, a rat model of severe PH demonstrates absent-to-decreased caveolin expression in the complex vascular lesions. Additionally, it appears that caveolin and heme oxygenase 1 (HO-1) [a heat shock protein] are co-expressed since HO-1 expression parallels caveolin expression in vascular lesions. We propose that loss of caveolin expression in the cells of the complex vascular lesions in severe PH reflects the proliferating and apoptosis-resistant nature of these cells.
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Caveolina 1/metabolismo , Caveolina 2/metabolismo , Heme Oxigenase (Desciclizante)/metabolismo , Hipertensão Pulmonar/metabolismo , Adulto , Idoso , Animais , Arteríolas/metabolismo , Western Blotting , Endotélio/metabolismo , Feminino , Hemangioma/metabolismo , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Ratos , Ratos Sprague-DawleyRESUMO
Prostacyclin (PGI2) causes vasodilation and inhibition of platelet aggregation in vivo. PGI2 is also postulated to affect pulmonary vascular remodeling, at least partly through anti-proliferative effect via PGI2 receptor (PGIR). However, the mechanism(s) of action by which (PGI2) exerts its therapeutic effect is still not clear despite clear clinical benefit seen in severe pulmonary hypertension (PH) patients. We performed a histopathologic and morphometric study on the explanted lung tissues from PGI2-treated patients prior to lung transplantation (n = 9), in an attempt to elucidate morphologic changes associated with PGI2 treatment. Explanted lungs from PH patients without PGI2 treatment were examined as the control (n = 11). We also studied the possible differences in PGIR expression between the treated and untreated groups by immunohistochemical method. Seven out of 9 treated patients showed moderate to severe bronchial and perivascular inflammation, as opposed to only 1 such case in the control group. Five out of 9 treated cases showed moderate to severe alveolar edema with or without evidence of old hemorrhage, in contrast to only 1 case showing moderate alveolar edema in control patients. Morphometry did not reveal any significant difference between the two groups either in the % thickness of intima, media, or adventitia or in the density of plexiform lesions. Immunostain also failed to demonstrate any notable difference in PGIR expression. In conclusion, PGI2-treated cases revealed more pronounced pulmonary alveolar edema and inflammation, but no morphological evidence of altered vascular remodeling or PGIR expression after PGI2 therapy.
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Anti-Hipertensivos/uso terapêutico , Epoprostenol/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Transplante de Pulmão , Pulmão/patologia , Adulto , Feminino , Humanos , Inflamação , Pulmão/citologia , Masculino , Pessoa de Meia-Idade , Artéria Pulmonar/metabolismo , Artéria Pulmonar/patologia , Edema Pulmonar , Receptores de Epoprostenol/metabolismo , Estudos RetrospectivosRESUMO
CONTEXT: - The histopathologic criteria for idiopathic pulmonary fibrosis were revised in the American Thoracic Society/European Respiratory Society/Japan Respiratory Society/Latin American Thoracic Association guidelines in 2011. However, the evidence of diagnosis based on the guidelines needs further investigation. OBJECTIVE: - To examine whether the revised histopathologic criteria for idiopathic pulmonary fibrosis improved interobserver agreement among pathologists and the predicted prognosis in patients with interstitial pneumonia. DESIGN: - Twenty, consecutive, surgical lung-biopsy specimens from cases of interstitial pneumonia were examined for histologic patterns by 11 pathologists without knowledge of clinical and radiologic data. Diagnosis was based on American Thoracic Society/European Respiratory Society guidelines of 2002 and 2011. Pathologists were grouped by cluster analysis, and interobserver agreement and association to the patient prognosis were compared with the diagnoses for each cluster. RESULTS: - The generalized κ coefficient of diagnosis for all pathologists was 0.23. If the diagnoses were divided into 2 groups: usual interstitial pneumonia (UIP)/probable UIP (the UIP group) or possible/not UIP (the non-UIP group), according to the 2011 guidelines, the κ improved to 0.37. The pathologists were subdivided into 2 clusters in which 1 showed an association between UIP group diagnosis and patient prognosis (P < .05). CONCLUSIONS: - Agreement about pathologic diagnosis of interstitial pneumonia is low; however, results after division into UIP and non-UIP groups provided favorable agreement. The cluster analysis revealed 1 of the 2 clusters providing high interobserver agreement and prediction of patient prognosis.
Assuntos
Fibrose Pulmonar Idiopática/diagnóstico , Doenças Pulmonares Intersticiais/diagnóstico , Pulmão/patologia , Adulto , Idoso , Biópsia , Análise por Conglomerados , Terapia Combinada , Europa (Continente) , Feminino , Seguimentos , Humanos , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/fisiopatologia , Fibrose Pulmonar Idiopática/terapia , Japão , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/fisiopatologia , Doenças Pulmonares Intersticiais/terapia , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Guias de Prática Clínica como Assunto , Prognóstico , Sociedades Médicas , Análise de Sobrevida , Cirurgia Torácica Vídeoassistida , Resultado do Tratamento , Estados UnidosRESUMO
RATIONALE: Granulomatous-lymphocytic interstitial lung disease (GLILD) has emerged as a major cause of morbidity in patients with common variable immunodeficiency (CVID). While GLILD is among the most serious noninfectious pulmonary complications of CVID, risk factors for this condition have not been reported. OBJECTIVES: To identify clinical, physiologic, and serologic risk factors for GLILD in adults with CVID. METHODS: Of 345 consecutive adult patients with CVID, we identified 34 in the National Jewish Health research database who had a radiographic-pathologic diagnosis of GLILD evaluated between 2002 and 2014. Each case was age and sex matched to 52 CVID control subjects. We used logistic regression to determine independent predictors of GLILD. A mixed effects model was used to estimate the longitudinal change in percent predicted FVC. MEASUREMENTS AND MAIN RESULTS: The mean time from CVID diagnosis to GLILD detection was 7.8 years. Compared with matched control subjects, cases were more likely to have a history of autoimmune cytopenia, hypersplenism, polyarthritis, lower marginal zone and switched memory B cells, and restrictive lung function. Multivariate analysis revealed that hypersplenism (odds ratio [OR], 24; 95% confidence interval [CI], 4.5-179.1), polyarthritis (OR, 19; 95% CI, 2.3-206.8), and percent predicted FVC (OR, 0.93; 95% CI, 0.87-0.98) were independently associated with the development of GLILD. The rate of change of percent predicted FVC (slope, P = 0.48) did not vary significantly in patients with GLILD over a mean follow-up of 7 years after diagnosis. CONCLUSIONS: Hypersplenism and polyarthritis are strong risk factors for GLILD in patients with CVID. Percent predicted FVC remained stable over time in patients with GLILD.
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Imunodeficiência de Variável Comum/complicações , Granuloma/patologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Adulto , Artrite/complicações , Estudos de Casos e Controles , Bases de Dados Factuais , Feminino , Humanos , Hiperesplenismo/complicações , Leucopenia/complicações , Modelos Logísticos , Pulmão/patologia , Doenças Pulmonares Intersticiais/etiologia , Doenças Pulmonares Intersticiais/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Radiografia , Fatores de Risco , Estados UnidosRESUMO
BACKGROUND: Current understanding of the clinical course of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is poor and based predominantly on small case series. In our clinical experience, we have found that the diagnosis of DIPNECH is frequently delayed because respiratory symptoms are ascribed to other lung conditions. The objectives of this study were to collect and analyze longitudinal clinical data on pulmonary physiology, chest high-resolution CT (HRCT) imaging, and therapies to better delineate the course of disease. METHODS: We established a cohort of patients (N = 30) with DIPNECH seen at our institution. We used descriptive statistics to summarize cohort characteristics and longitudinal analytic techniques to model FEV1 % predicted (FEV1%) over time. RESULTS: All subjects were women who presented with long-standing cough and dyspnea. The majority had an FEV1% < 50% at the time of diagnosis. Forty percent were given a diagnosis of asthma as the cause for physiologic obstruction. The mean FEV1% for the entire cohort showed no statistically significant decline over time, but 26% of the subjects experienced a 10% decline in FEV1 within 2 years. Among the pathology samples available for review, 28% (five of 18) had typical carcinoids and 44% had associated constrictive bronchiolitis. We propose clinical diagnostic criteria for DIPNECH that incorporate demographic, pulmonary physiology, HRCT imaging, and transbronchial and surgical lung biopsy data. CONCLUSIONS: DIPNECH is a female-predominant lung disease manifested by dyspnea and cough, physiologic obstruction, and nodules on HRCT imaging. Additional research is needed to understand the natural history of this disease and validate the proposed diagnostic criteria.
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Pneumopatias/patologia , Pulmão/citologia , Células Neuroendócrinas/patologia , Bronquiolite/patologia , Proliferação de Células , Feminino , Volume Expiratório Forçado , Humanos , Hiperplasia/patologia , Pulmão/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Nódulos Pulmonares Múltiplos/complicações , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
CONTEXT: Gastrin-releasing peptide receptors (GRPRs) activate mitogen-activated protein kinase signaling pathway primarily through epidermal growth factor receptor activation and are under investigation as a molecular target because they are overexpressed in several solid tumors. OBJECTIVE: To determine GRPR expression in both non-small cell lung carcinoma and small cell lung carcinoma, comparing results with clinical stages and demographic data. DESIGN: We analyzed the immunohistochemical expression of GRPR in 200 non-small cell lung carcinoma and 38 small cell lung carcinoma archival cases from 2004 to 2008. RESULTS: Non-small cell lung carcinoma cases tended to be higher GRPR expressers at a rate of 62.5% (weak, moderate, and strong expression in 41.5%, 13.5%, and 7.5%, respectively), compared with 52.62% in small cell lung carcinoma cases (weak, moderate, and strong expression in 34.21%, 15.78%, and 2.63%, respectively; P = .30). In non-small cell lung carcinoma there was a trend for higher percentages of strong expression in adenocarcinoma cases (10%; P = .67), and in patients with advanced stages (III and IV; 9.43% and 6.9%; P = .01). CONCLUSIONS: To the best of our knowledge, this is the first study to demonstrate GRPR tissue expression in a large population of patients with lung cancer. Although GRPR expression was similar in small cell and non-small cell carcinoma, the expression was more pronounced in an advanced-stage lung cancer, particularly in adenocarcinoma cases, and may represent a potential target for the development of new treatment approaches in this population.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Pequenas/metabolismo , Neoplasias Pulmonares/metabolismo , Receptores da Bombesina/biossíntese , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Pequenas/mortalidade , Carcinoma de Células Pequenas/patologia , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Receptores da Bombesina/análise , Estudos RetrospectivosRESUMO
BACKGROUND: Fibrosis or inflammation of the bronchioles is a well-known manifestation of connective tissue disease (CTD). However, the natural history of CTD-related bronchiolitis is largely unknown. METHODS: We analyzed consecutive patients evaluated at National Jewish Health (Denver, CO) from 1998 to 2008 with CTD and surgical lung biopsy-confirmed bronchiolitis. Linear mixed effects models were used to estimate the longitudinal postbronchodilator FEV1 %predicted (%pred) course and differences between subjects with or without constrictive bronchiolitis (CB). RESULTS: Of 28 subjects with a mean age of 53 ± 9 years, fourteen (50%) had CB. The most common CTD diagnosis was rheumatoid arthritis (n = 14; 50%). There were no significant differences in demographics, smoking status, underlying CTD diagnoses, 6-min walk distance, dyspnea score or drug therapy between subjects with CB and those with cellular bronchiolitis. Three subjects with CB (11%) and four with cellular bronchiolitis (14%) died. Compared with subjects with CB, those with cellular bronchiolitis had higher mean FEV1 %pred at all times. There were no significant differences in FEV1 %pred slope within- or between-groups (CB vs. cellular bronchiolitis) preceding surgical lung biopsy or afterward. CONCLUSION: Subjects with CTD-related CB had lower FEV1 %pred values than those with CTD-related cellular bronchiolitis at all time points, but FEV1 %pred remained stable over time in both groups regardless of therapy received.
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Bronquiolite Obliterante/fisiopatologia , Doenças do Tecido Conjuntivo/complicações , Volume Expiratório Forçado/fisiologia , Adulto , Biópsia , Bronquiolite Obliterante/etiologia , Bronquiolite Obliterante/mortalidade , Bronquiolite Obliterante/patologia , Feminino , Seguimentos , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória/métodos , Estudos Retrospectivos , Fatores Sexuais , Estados Unidos/epidemiologia , Capacidade Vital/fisiologiaRESUMO
OBJECTIVE: We sought to characterize a novel cohort of patients with lung disease, anti-cyclic citrullinated peptide (CCP) antibody positivity, without rheumatoid arthritis (RA) or other connective tissue disease (CTD). METHODS: The study sample included 74 subjects with respiratory symptoms, evaluated January 2008-January 2010 and found to have a positive anti-CCP antibody but no evidence for RA or other CTD. Each underwent serologic testing, pulmonary physiology testing, and thoracic high-resolution computed tomography (HRCT) scan as part of routine clinical evaluation. RESULTS: The majority of subjects were women, and most were former cigarette smokers. Four distinct radiographic phenotypes were identified: isolated airways disease (54%), isolated interstitial lung disease (ILD) (14%), mixed airways disease and ILD (26%), and combined pulmonary fibrosis with emphysema (7%). This cohort had a predominance of airways disease, either in isolation or along with a usual interstitial pneumonia-pattern of ILD. Among subjects with high-titer anti-CCP positivity (n=33), three developed the articular manifestations of RA during a median follow-up of 449 days. CONCLUSION: We have described a unique cohort of patients with anti-CCP antibody positivity and lung disease in the absence of existing RA or other CTD. The lung phenotypic characteristics of this cohort resemble those of established RA and a few of these patients have developed articular RA within a short period of follow-up. The implications of a positive anti-CCP antibody among patients with lung disease but not RA are not yet known, but we believe requires further investigation.
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Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Broncopatias/imunologia , Doenças Pulmonares Intersticiais/imunologia , Peptídeos Cíclicos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Broncopatias/patologia , Broncopatias/fisiopatologia , Doenças do Tecido Conjuntivo/imunologia , Feminino , Humanos , Doenças Pulmonares Intersticiais/patologia , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Testes de Função Respiratória , Estudos Retrospectivos , Tomografia Computadorizada por Raios X/métodos , Adulto JovemAssuntos
Infecções por HIV/complicações , Doenças Pulmonares Intersticiais/complicações , Pneumonia por Pneumocystis/complicações , Fibrose , Humanos , Doenças Pulmonares Intersticiais/microbiologia , Masculino , Pessoa de Meia-Idade , Pneumocystis carinii , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Micropapillary lung adenocarcinoma (MPA) has been reported as an aggressive variant of adenocarcinoma, frequently manifesting at high stage with a poor prognosis. We analyzed the clinical and molecular profile of 15 primary MPAs for K-ras, EGFR, and BRAF mutations and performed fluorescence in situ hybridization for EGFR amplification. In our study, 11 (73%) of 15 MPAs harbored mutually exclusive mutations: 5 (33%) K-ras, 3 (20%) EGFR, and 3 (20%) BRAF. Mutations in all 3 genes occurred in patients with a smoking history and tumors with mucinous differentiation and secondary lepidic, acinar, and solid growth, suggesting that in a Western population, cytomorphologic correlation with genetic mutations is more unpredictable than in Japanese cohorts. We conclude that K-ras, EGFR, and BRAF mutations are disproportionately seen in adenocarcinomas of lung with a dominant micropapillary growth pattern compared with conventional adenocarcinoma in our institutional experience.
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Adenocarcinoma Papilar/genética , Genes erbB-1/genética , Genes ras/genética , Neoplasias Pulmonares/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adenocarcinoma Papilar/metabolismo , Adenocarcinoma Papilar/patologia , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , DNA de Neoplasias/análise , Feminino , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Mucinas/metabolismo , PrognósticoRESUMO
The translocation t(11;19)(q21;p13) results in the gene fusion of mucoepidermoid carcinoma translocated 1-mammalian mastermind like 2 genes that is the major chromosomal abnormality observed in mucoepidermoid carcinomas of salivary glands but has not been studied in bronchopulmonary mucoepidermoid carcinoma. To investigate the importance of the mammalian mastermind like 2 gene rearrangement and mucoepidermoid carcinoma translocated 1-mammalian mastermind like 2 fusion gene in bronchopulmonary mucoepidermoid carcinoma tumorigenesis and its differential diagnosis with primary pulmonary non-small-cell carcinomas, we evaluated the presence of the mammalian mastermind like 2 gene rearrangement and the mucoepidermoid carcinoma translocated 1-mammalian mastermind like 2 fusion in formalin-fixed, paraffin-embedded tissue sections from 17 adult bronchopulmonary mucoepidermoid carcinoma, 16 adenosquamous carcinomas, 24 squamous cell carcinomas, and 41 primary adenocarcinomas by fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction. We detected mammalian mastermind like 2 gene rearrangement by fluorescence in situ hybridization analysis in 13 (77%) of 17 bronchopulmonary mucoepidermoid carcinoma cases (10 of 10 being low grade and 3 of 7 being high grade). Reverse transcriptase polymerase chain reaction analysis confirmed positive fluorescence in situ hybridization results in 6 (43%) of 14 mucoepidermoid carcinoma cases. None of the squamous, adenosquamous, or adenocarcinoma cases revealed the mammalian mastermind like 2 gene rearrangement by fluorescence in situ hybridization, and the mucoepidermoid carcinoma translocated 1-mammalian mastermind like 2 fusion product by reverse transcriptase polymerase chain reaction was not identified specifically in our adenosquamous carcinoma cases. In conclusion, our study demonstrates that mammalian mastermind like 2 gene rearrangement and mucoepidermoid carcinoma translocated 1-mammalian mastermind like 2 fusion product can be detected by fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction analysis performed on low- and high-grade primary bronchopulmonary mucoepidermoid carcinoma and can be used to help discriminate low- and high-grade mucoepidermoid carcinoma from adenocarcinoma, adenosquamous carcinoma, and squamous cell carcinoma mimics in histologically challenging cases.
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Neoplasias Brônquicas/genética , Carcinoma Mucoepidermoide/genética , Proteínas de Ligação a DNA/genética , Neoplasias Pulmonares/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Fatores de Transcrição/genética , Adenossarcoma/genética , Adenossarcoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Brônquicas/patologia , Carcinoma Adenoescamoso/genética , Carcinoma Adenoescamoso/patologia , Carcinoma Mucoepidermoide/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Feminino , Fusão Gênica , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transativadores , Translocação GenéticaRESUMO
CONTEXT: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in diverse human cancers and plays a critical role in tumor cell survival, proliferation, migration, invasion, angiogenesis, and inhibition of apoptosis. The phosphorylated active form of STAT3 (pSTAT3) mediates its effects via nuclear transcriptional activity. However, it was recently observed that the nonphosphorylated, cytoplasmic, inactive form of STAT3 is involved in cell motility and consequently tumor invasion. It appears that, although STAT3 is not absolutely required for tumor formation, tumors that develop in the presence of STAT3 become dependent on its expression for their survival, making it a potential therapeutic target. OBJECTIVE: To investigate the possible utility of STAT3 as a future therapeutic target in non-small cell lung carcinoma (NSCLC) and malignant mesothelioma (MM). DESIGN: Immunohistochemical expression of MIB-1, STAT3, and pSTAT3 was assessed in 303 NSCLC and 44 MM archival cases. RESULTS: A more conspicuous expression of inactive STAT3 (91.44% in NSCLC and 79.5% in MM cases) was present compared with the nuclear activated form pSTAT3 (60.53% in NSCLC and 61.4% in MM cases). MIB-1 did not correlate with the expression of STAT3 or pSTAT3. CONCLUSIONS: The strong expression of cytoplasmic inactive STAT3 in NSCLC and MM cases implies a major role for STAT3 in tumor motility, invasion, and metastasis via a nontranscriptional pathway. We conclude that STAT3 and pSTAT3 are up-regulated in a high percentage of NSCLCs and MMs, regardless of tumor type, age, sex, smoking status, stage and grade of tumor, or survival, providing a basis for therapeutic intervention.