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1.
Cell Mol Biol (Noisy-le-grand) ; 70(5): 155-160, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38814221

RESUMO

In order to explore a new mode for the diagnosis of angioimmunoblastic T-cell lymphoma (AITL), 31 cases of AITL and 28 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) were used as the study subjects. Identifying T follicular helper (TFH) cells with CD4, CD10, Bcl-6, and PD-1, identifying proliferative B cells with CD20 and EZH2, identifying proliferative follicular dendritic cells (FDCs) with CD21 and CD23, and analyzing the value of TFH/B/FDC proliferation and immunolocalization in the diagnosis of AITL. (1) Outside the inherent lymphoid follicles, simultaneous proliferation of TFH/B/FDC (a new diagnostic mode) were observed in AITL [83.87%; 26/31], with their immunolocalizations in the same site [83.87%; 26/31], while this phenomenon was not observed in 28 cases of PTCL-NOS (P<0.05). (2) The sensitivity and specificity of using this new mode to diagnose AITL were both high (83.87%, 100%), which was superior to CD2 (100%, 0%), CD3 (100%, 0%), CD4 (100%, 32.14%), CD5 (100%, 25%), CD10 (61.9%, 100%), Bcl-6 (42.86%, 100%), PD-1 (83.87%, 96.43%), and its Youden Index (0.84) was the highest. The areas under the curve (AUC) of CD10, Bcl-6, PD-1, and new mode to diagnosis AITL were 0.81, 0.71, 0.90, and 0.92, respectively, while the new mode had the highest AUC. The simultaneous proliferation of TFH/B/FDC cells outside the inherent lymphoid follicles can be used to assist in the diagnosis of AITL, and the simultaneous spatiotemporal proliferation of TFH/B/FDC cells is a specific immunomorphology of AITL.


Assuntos
Proteínas Proto-Oncogênicas c-bcl-6 , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Neprilisina/metabolismo , Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/patologia , Células Dendríticas Foliculares/patologia , Células Dendríticas Foliculares/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Adulto , Linfoma de Células T/diagnóstico , Linfoma de Células T/patologia , Linfoma de Células T/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proliferação de Células , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células T Auxiliares Foliculares/imunologia , Células T Auxiliares Foliculares/metabolismo , Receptores de Complemento 3d/metabolismo , Receptores de Complemento 3d/análise , Antígenos CD20/metabolismo , Antígenos CD20/análise , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/patologia , Antígenos CD4/metabolismo , Sensibilidade e Especificidade , Idoso de 80 Anos ou mais , Imuno-Histoquímica/métodos , Curva ROC
3.
Indian J Pathol Microbiol ; 67(2): 452-455, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38391301

RESUMO

ABSTRACT: Angioimmunoblastic T-cell lymphoma (AITL), a subtype of peripheral T-cell lymphoma (PTCL), is associated with unique clinical, morphological, and immunohistochemical features. The peripheral circulation might show presence of an occasional reactive plasma cell but significant plasmacytosis masquerading as plasma cell leukemia is rare. We report a case of AITL in a 42-year-old male, who presented with two-month history of generalized lymphadenopathy. On investigations, he had hypergammaglobulinemia and plasmacytosis in the peripheral blood and bone marrow masquerading as plasma cell leukemia. Immunohistochemistry and serum protein electrophoresis revealed polyclonal nature of plasma cells. Diagnosis of AITL was made on cervical lymph node biopsy. This case highlights the diagnostic challenge faced due to heterogeneity in the clinical presentation and pathological findings and to alert the clinician so that timely accurate diagnosis can be made to initiate the treatment.


Assuntos
Medula Óssea , Imuno-Histoquímica , Linfonodos , Linfoma de Células T Periférico , Plasmócitos , Humanos , Masculino , Adulto , Medula Óssea/patologia , Plasmócitos/patologia , Linfonodos/patologia , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/patologia , Diagnóstico Diferencial , Biópsia , Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/patologia , Hipergamaglobulinemia/diagnóstico , Linfadenopatia/patologia , Linfadenopatia/diagnóstico , Leucemia Plasmocitária/diagnóstico , Leucemia Plasmocitária/patologia
4.
Zhonghua Bing Li Xue Za Zhi ; 53(1): 29-33, 2024 Jan 08.
Artigo em Chinês | MEDLINE | ID: mdl-38178743

RESUMO

Objective: To investigate the characteristics of gene mutations in angioimmunoblastic T-cell lymphoma (AITL). Methods: Seventy-five AITL cases diagnosed at the Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China from June 2021 to June 2023 were included. Their formalin-fixed and paraffin-embedded or fresh tissues were subject to targeted next generation sequencing (NGS). The sequencing data was collected, and the distribution and type of gene mutations were analyzed. Results: 492 potential driver mutations were identified in 74 out of the 84 genes. Targeted sequencing data for the 75 AITL patients showed that the genes with mutation frequencies of ≥10% were TET2 (89.3%), RHOA (57.3%), IDH2 (37.3%), DNMT3A (36.0%), KMT2C (21.3%), PLCG1 (12.0%), and KDM6B (10.7%). There were significant co-occurrence relationships between TET2 and RHOA, TET2 and IDH2, and RHOA and IDH2 gene mutations (P<0.05), respectively, while TET2 and KDM6B gene mutations were mutually exclusive (P<0.05). Conclusions: The study reveals the mutational characteristics of AITL patients using NGS technology, which would provide insights for molecular diagnosis and targeted therapy of AITL.


Assuntos
Linfadenopatia Imunoblástica , Linfoma de Células T , Humanos , Linfoma de Células T/genética , Linfoma de Células T/patologia , China , Linfadenopatia Imunoblástica/diagnóstico , Mutação , Taxa de Mutação , Histona Desmetilases com o Domínio Jumonji/genética
6.
Chinese Journal of Pathology ; (12): 29-33, 2024.
Artigo em Chinês | WPRIM (Pacífico Ocidental) | ID: wpr-1012420

RESUMO

Objective: To investigate the characteristics of gene mutations in angioimmunoblastic T-cell lymphoma (AITL). Methods: Seventy-five AITL cases diagnosed at the Department of Pathology, Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China from June 2021 to June 2023 were included. Their formalin-fixed and paraffin-embedded or fresh tissues were subject to targeted next generation sequencing (NGS). The sequencing data was collected, and the distribution and type of gene mutations were analyzed. Results: 492 potential driver mutations were identified in 74 out of the 84 genes. Targeted sequencing data for the 75 AITL patients showed that the genes with mutation frequencies of ≥10% were TET2 (89.3%), RHOA (57.3%), IDH2 (37.3%), DNMT3A (36.0%), KMT2C (21.3%), PLCG1 (12.0%), and KDM6B (10.7%). There were significant co-occurrence relationships between TET2 and RHOA, TET2 and IDH2, and RHOA and IDH2 gene mutations (P<0.05), respectively, while TET2 and KDM6B gene mutations were mutually exclusive (P<0.05). Conclusions: The study reveals the mutational characteristics of AITL patients using NGS technology, which would provide insights for molecular diagnosis and targeted therapy of AITL.


Assuntos
Humanos , Linfoma de Células T/patologia , China , Linfadenopatia Imunoblástica/diagnóstico , Mutação , Taxa de Mutação , Histona Desmetilases com o Domínio Jumonji/genética
7.
Altern Ther Health Med ; 29(8): 733-737, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37708543

RESUMO

Objective: This study aimed to investigate the clinical features of angioimmunoblastic T-cell lymphoma (AITL) mimicking systemic lupus erythematosus (SLE) and raise awareness about AITL among rheumatologists in order to prevent misdiagnosis and missed diagnosis. The study reports on a case of AITL mimicking SLE and provides a literature review. Methods: Using key words as search terms, relevant articles published in PubMed before 2022-05 were searched, and their clinical characteristics were collected and analyzed. Results: The literature review retrieved six case reports, including four cases initially diagnosed with SLE and then with AITL. The other two case diagnoses were SLE and AITL, respectively. The two diseases are pathogenically associated and share some common features. The clinical manifestations of AITL are complex. The disease is closely associated with abnormal immune functions and is highly heterogeneous. Conclusion: Patients with AITL generally have a poor prognosis. Rarely do reported cases show AITL mimicking SLE. AITL should be considered during clinical practice to prevent missed diagnoses or misdiagnoses.


Assuntos
Linfadenopatia Imunoblástica , Lúpus Eritematoso Sistêmico , Linfoma de Células T , Humanos , Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/complicações , Linfadenopatia Imunoblástica/patologia , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/complicações , Linfoma de Células T/diagnóstico , Linfoma de Células T/complicações , Linfoma de Células T/patologia
8.
Br J Haematol ; 203(5): 807-819, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37646306

RESUMO

Molecular and clinical stratification of patients with angioimmunoblastic T-cell lymphoma (AITL) is unsatisfactory, which hinders the development of personalized therapies. This study aimed to identify molecular biomarkers for AITL based on peripheral cell-free DNA (cfDNA) that could be used to predict prognosis and guide treatment non-invasively. A customized panel containing 46 genes was used to study pretreatment cfDNA and paired tumour tissues in 64 Chinese AITL patients from three clinical centres, and gene mutations in cfDNA and tumour tissue were assessed for concordance (34 paired samples). Then, the association of gene mutations and prognosis was analysed, and a functional enrichment analysis was performed. The sequencing results showed good consistency between cfDNA samples and paired tissue samples. KDM5A, STAT1, FANCM, ERBB4, PIK3R5 and NSD1 were identified as novel recurrent mutations. Mutations in FANCM or combinations of RHOA, KDM5A and FAT1 were associated with poor prognosis. Additionally, functional analysis revealed that RHOAG17 might serve as a predictive biomarker of PD-1 blockade respondence. Our findings confirmed the role of cfDNA as a liquid biopsy in AITL, and revealed novel molecular determinants that can stratify patients and guide treatment options.


Assuntos
Ácidos Nucleicos Livres , Linfadenopatia Imunoblástica , Linfoma de Células T Periférico , Linfoma de Células T , Humanos , Linfoma de Células T/genética , Prognóstico , Impressões Digitais de DNA , Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/genética , Linfadenopatia Imunoblástica/patologia , Mutação , Linfoma de Células T Periférico/genética , Proteína 2 de Ligação ao Retinoblastoma/genética , DNA Helicases/genética
9.
J Med Case Rep ; 17(1): 347, 2023 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-37537623

RESUMO

BACKGROUND: Angioimmunoblastic T-cell lymphoma is an uncommon subtype of peripheral T-cell lymphoma in children with fewer than 20 cases reported in literature. CASE PRESENTATION: A 3-year-old Omani boy was diagnosed with ataxia-talengectasia presenting with fever and generalized lymphadenopathy. His biopsy revealed atypical lymphocytic infiltrate consistent with the diagnosis of angioimmunoblastic T-cell lymphoma. Within 3 weeks from the initial presentation and without any neoadjuvant therapy, he showed complete recovery of symptoms with absence of fever and regression of all previously affected lymph nodes. He has remained in remission ever since. CONCLUSION: This is the first report of spontaneous improvement of angioimmunoblastic T-cell lymphoma in a patient with ataxia-telangiectasia who was 3 years old at presentation. Owing to the paucity of similar cases, this report adds valuable diagnostic, therapeutic, and monitoring data.


Assuntos
Ataxia Telangiectasia , Linfadenopatia Imunoblástica , Linfoma de Células T Periférico , Masculino , Humanos , Criança , Pré-Escolar , Ataxia Telangiectasia/complicações , Ataxia Telangiectasia/patologia , Remissão Espontânea , Linfadenopatia Imunoblástica/complicações , Linfadenopatia Imunoblástica/tratamento farmacológico , Linfadenopatia Imunoblástica/diagnóstico , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/patologia , Linfonodos/patologia
10.
Leuk Lymphoma ; 64(11): 1782-1791, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37477443

RESUMO

In our Asian multicenter retrospective study, we investigated the clinical prognostic factors affecting the outcomes of AITL patients and identified a novel prognostic index relevant in the Asian context. In our 174-patient cohort, the median PFS and OS was 1.8 years and 5.6 years respectively. Age > 60, bone marrow involvement, total white cell count >12 × 109/L and raised serum lactate dehydrogenase were associated with poorer PFS and OS in multivariate analyses. This allowed for a prognostic index (AITL-PI) differentiating patients into low (0-1 factors, n = 64), moderate (2 factors, n = 59) and high-risk (3-4 factors, n = 49) subgroups with 5-year OS of 84.0%, 44.0% and 28.0% respectively (p < 0.0001). POD24 proved to be strongly prognostic (5-year OS 24% vs 89%, p < 0.0001). Exploratory gene expression studies were performed and disparate immune cell profiles and cell signaling signatures were seen in the low risk group as compared to the intermediate and high risk groups.


Assuntos
Linfadenopatia Imunoblástica , Linfoma de Células T , Humanos , Prognóstico , Linfoma de Células T/patologia , Estudos Retrospectivos , Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/patologia , Fatores de Risco
13.
Am J Clin Pathol ; 159(4): 379-394, 2023 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-36880300

RESUMO

OBJECTIVES: To explore the approach to the diagnosis of malignant serous effusion (SE) caused by angioimmunoblastic T-cell lymphoma (AITL). METHODS: The clinical, cytomorphologic, immunophenotypic, and molecular features of 6 patients were summarized. RESULTS: Clinically, SE caused by AITL was predominant in middle-aged and older male patients with multiple SEs and lymphadenopathy. Cytomorphology showed small to medium-sized, irregular lymphocytes with clear cytoplasm and mixed with various inflammatory cells and apoptosis. Hodgkin/Reed-Sternberg-like cells were detected in 2 of 6 cases. Furthermore, 2 patterns of cytomorphology were described for the first time. Flow cytometry revealed abnormal T-cell populations with loss of surface CD3 (3/4 cases) and CD7 (3/4 cases). In addition, B-cell populations lacking surface immunoglobulin (Ig) were identified in 2 of 4 cases. Immunocytochemical staining revealed expression of at least 2 T follicular helper markers. Epstein-Barr virus-encoded RNA (EBER)-positive cells were demonstrated in 4 of 5 cases. Clonal T-cell receptor γ chain rearrangement was detected in 6 cases, and 3 of them had concomitant clonal immunoglobulin gene rearrangement. Moreover, 2 cases revealed discrepant findings regarding IgH/Igκ rearrangements in cytohistologic correlation. CONCLUSIONS: This study broadens the morphologic spectrum of malignant SE caused by AITL and provides diagnostic criteria in routine practice.


Assuntos
Infecções por Vírus Epstein-Barr , Linfadenopatia Imunoblástica , Linfoma de Células T Periférico , Pessoa de Meia-Idade , Humanos , Masculino , Idoso , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/patologia , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4 , Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/patologia , Linfócitos T/patologia
14.
J Clin Pathol ; 76(5): 320-326, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-34697030

RESUMO

AIMS: Angioimmunoblastic T cell lymphoma (AITL) is often misdiagnosed in cytology. Hence, the present study was conducted to identify the distinctive cytomorphological features of AITL in lymph node fine-needle aspirates (LN-FNA). METHODS: This was a 4-year retrospective case-control study. Cases included LN-FNAs from patients with histopathologically confirmed AITL. The controls included LN-FNAs from patients with histopathologically confirmed reactive lymphoid hyperplasia (RLH; n=25). Eleven cytomorphological features were assessed in all the aspirates; the strength of association was determined by OR, Cramer's V and multiple correspondence analysis (MCA). RESULTS: Of a total of 22 cases of AITL reported on histopathology, 19 adequate aspirates from 14 patients (63.6%) were available for review. On univariate analysis, 5 of 11 cytomorphological variables were found to be significant for AITL; however, on MCA, 3 of these parameters, viz absence of tingible body macrophages (OR=0.014; V=0.74), presence of atypical lymphoid cells (OR=10.8; V=0.41) and singly scattered epithelioid cells (OR=19.3; V=0.31), were found to be the strongest predictors of AITL. CONCLUSIONS: The absence of tingible body macrophages, presence of atypical lymphoid cells and singly scattered epithelioid cells in polymorphic LN-FNAs are significant cytomorphological predictors of AITL in comparison with RLH. Knowledge of these diagnostic predictors, supplemented by clinicoradiological correlation and appropriate ancillary studies, can help diagnose AITL on aspiration cytology.


Assuntos
Linfadenopatia Imunoblástica , Linfoma de Células T , Humanos , Estudos de Casos e Controles , Estudos Retrospectivos , Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/patologia , Biópsia por Agulha Fina , Linfoma de Células T/diagnóstico , Linfoma de Células T/patologia
15.
Intern Med ; 62(4): 595-600, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-35732446

RESUMO

Angioimmunoblastic T-cell lymphoma (AITL) is an intractable type of T-cell lymphoma. We and others have identified that the p.Gly17Val RHOA mutation is specifically identified in AITL. We herein report a patient whose condition deteriorated, resulting from massive pericardial effusion one month after undergoing autologous transplantation for AITL. He was diagnosed with cardiac tamponade caused by AITL recurrence in the presence of the p.Gly17Val RHOA mutation as well as T-lineage cells with an aberrant immune-phenotype in the pericardial effusion. This case suggests that a precision medicine approach by detecting the presence of a p.Gly17Val RHOA mutation is useful for the management of AITL.


Assuntos
Tamponamento Cardíaco , Linfadenopatia Imunoblástica , Linfoma de Células T , Derrame Pericárdico , Masculino , Humanos , Linfadenopatia Imunoblástica/complicações , Linfadenopatia Imunoblástica/genética , Linfadenopatia Imunoblástica/diagnóstico , Mutação/genética , Linfoma de Células T/complicações , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Proteína rhoA de Ligação ao GTP/genética
16.
Pathobiology ; 90(3): 187-198, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36423589

RESUMO

INTRODUCTION: Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive T-cell lymphoma commonly associated with B-cell dysregulation. Correlations involving B-cell dysregulation and clinicopathological features remain unclear. METHODS: We prospectively collected blood samples from 11 AITL patients and 17 healthy controls. The percentages of B-cell subpopulations and lymphocytes with IL-21 production were assessed using flow cytometry. Peripheral blood lymphocyte morphology was evaluated microscopically. RESULTS: Six of 11 (54.5%) patients presented with polyclonal hypergammaglobulinemia. Three of 11 (27.3%) tumor biopsies showed monoclonal immunoglobulin gene rearrangement. The patients exhibited significantly lower levels of naive (p < 0.001) and class-switched (p < 0.001) B cells than controls. The percentages of IgD-CD27- B cells (p = 0.007) and antibody-secreting cells (ASCs) (p = 0.001) were increased. Blood smears revealed atypical lymphocytes and immature plasma cells with morphological diversity. In comparison to normal controls, IL-21 production significantly increased in CD4+ (p < 0.001) and CD8+ (p = 0.020) T cells. B-cell clonality, RHOA G17V mutation, and the presence of sheets of clear cells and immature/mature plasma cells in lymph nodes were significantly associated with percentages of class-switched B cells and ASCs. The patients with circulating EBV DNA had a lower percentage of naive B cells (p = 0.009). CONCLUSIONS: Our results demonstrated a wide spectrum of peripheral B-cell morphologies and immunophenotypes of peripheral B cells in AITL. These findings correspond to dysregulated B-cell immunity and heterogeneous clinicopathological features.


Assuntos
Linfadenopatia Imunoblástica , Linfoma de Células T Periférico , Linfoma de Células T , Humanos , Citometria de Fluxo , Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/genética , Linfadenopatia Imunoblástica/patologia , Linfoma de Células T Periférico/patologia , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Linfoma de Células T/patologia , Linfócitos B/patologia
19.
Dermatol Online J ; 28(4)2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-36259861

RESUMO

Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common types of peripheral T-cell lymphoma. Laboratory examination exhibits immunological abnormalities, such as polyclonal hypergammaglobulinemia and hemolytic anemia. Skin lesions are also observed in approximately half of AITL cases. However, the relationship of skin involvement with the clinical course and prognosis is unknown. Herein, we report the case of a patient with AITL with elevated serum immunoglobulin A (IgA) level, which was a predictive element of poor prognosis, and infiltration of IgA-positive plasma cells into the skin lesions. Based on this case, we believe that skin manifestations could be used to identify the characteristics of immune disorders and prognosis of AITL.


Assuntos
Linfadenopatia Imunoblástica , Linfoma de Células T , Dermatopatias , Humanos , Plasmócitos/patologia , Linfadenopatia Imunoblástica/complicações , Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/patologia , Prognóstico , Linfoma de Células T/diagnóstico , Imunoglobulina A
20.
Curr Oncol ; 29(10): 7637-7644, 2022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36290880

RESUMO

Angioimmunoblastic T-cell lymphoma is one of the peripheral T-cell lymphomas. Reactive plasma cells can occasionally be observed in AITL patients' peripheral blood and bone marrow. Plasmacytic pleural effusion as the presentation of AITL has not been reported before. The mechanisms of plasmacytic pleural effusion are not fully understood. Here we present an 82-year-old male with exuberant plasma cells in his pleural effusion in addition to his peripheral blood and bone marrow aspiration. By presenting this case, we would like to expand the spectrum of disease presentations in AITL and discuss the significance of flow cytometry in the differential diagnosis of pleural effusion. To our knowledge, this is the first case report in the literature, which will be crucial to assist the hematopathologist in accurate diagnosis and treatment.


Assuntos
Linfadenopatia Imunoblástica , Linfoma de Células T Periférico , Derrame Pleural , Masculino , Humanos , Idoso de 80 Anos ou mais , Plasmócitos/patologia , Linfadenopatia Imunoblástica/complicações , Linfadenopatia Imunoblástica/diagnóstico , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/patologia , Derrame Pleural/diagnóstico , Derrame Pleural/etiologia , Derrame Pleural/patologia , Diagnóstico Diferencial
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