Clinicopathological and molecular features of metaplastic thymoma / 中华病理学杂志

Objective: To investigate the clinicopathological features, and molecular genetic alterations of metaplastic thymoma (MT). Methods: A total of ten MT cases, diagnosed from 2011 to 2021, were selected from the Department of Pathology of Jinling Hospital, Nanjing University Medical School, Nanjing, China for clinicopathological and immunohistochemical (IHC) examination and clinical follow-up. Fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and YAP1 C-terminus (YAP1-CT) IHC were performed to detect YAP1::MAML2 fusions. Results: There were four males and six females, ranging in age from 29 to 60 years (mean 50 years, median 54 years). Microscopically, all tumors showed a typical biphasic morphology consisting of epithelial components and gradually or abruptly transitioning spindle cell components. The two components were present in varying proportions in different cases. Immunophenotypically, the epithelial cells were diffusely positive for CKpan, CK5/6 and p63. The spindle cells were diffusely positive for vimentin and focally positive for EMA. TdT was negative in the background lymphocytes. Ki-67 proliferation index was less than 5%. YAP1 and MAML2 break-apart FISH analyses showed that all ten cases had narrow split signals with a distance of nearly 2 signal diameters and may be considered false-negative. Using YAP1::MAML2 fusion FISH assays, abnormal fusion signals were observed in all the ten cases. NGS demonstrated YAP1::MAML2 fusions in all eight cases with adequate nucleic acids; in two cases the fusions were detected by DNA sequencing and in eight cases by RNA sequencing. All ten cases of MT demonstrated loss of YAP1 C-terminal expression in epithelioid cells. Conclusions: MT is a rare and low-grade thymic tumor characterized by a biphasic pattern and YAP1::MAML2 fusions. Break-apart FISH assays may sometimes show false-negative results due to the proximity of YAP1 and MAML2, while YAP1 C-terminal IHC is a highly sensitive and specific marker for MT. Loss of YAP1 C-terminal expression can also be used to screen YAP1::MAML2 fusions for possible MT cases.

The Mycobacterium avium subsp. paratuberculosis fibronectin attachment protein, a toll-like receptor 4 agonist, enhances dendritic cell-based cancer vaccine potency

In this study, we showed the direct interaction between Mycobacterium avium subsp. paratuberculosis fibronectin attachment protein (FAP) and toll-like receptor4 (TLR4) via co-localization and binding by using confocal microscopy and co-immunoprecipitation assays. FAP triggered the expression of pro- and anti-inflammatory cytokines in a TLR4-dependent manner. In addition, FAP-induced cytokine expression in bone marrow-derived dendritic cells (BMDCs) was modulated in part by glycogen synthase kinase-3 (GSK-3). FAP-induced expression of CD80, CD86, major histocompatibility complex (MHC) class I, and MHC class II in TLR4+/+ BMDCs was not observed in TLR4-/- BMDCs. Furthermore, FAP induced DC-mediated CD8+ T cell proliferation and cytotoxic T lymphocyte (CTL) activity, and suppressed tumor growth with DC-based tumor vaccination in EG7 thymoma murine model. Taken together, these results indicate that the TLR4 agonist, FAP, a potential immunoadjuvant for DC-based cancer vaccination, improves the DC-based immune response via the TLR4 signaling pathway.

La citometría de flujo en el estudio de tumores mediastinales ricos en elementos linfoides / Flow cytometry for the study of mediastinal tumors with abundant lymphoid elements

El mediastino anterior es un sitio frecuente de localización de tumores ricos en elementos linfoides. La identificación correcta de cada entidad es de importancia en el tratamiento de los pacientes. En ocasiones puede plantearse el diagnóstico diferencial entre timoma y linfoma linfoblástico con fenotipo de precursor T (LLB-T). La Citometría de Flujo (CF) es una técnica complementaria útil para estos tumores de la cual se obtiene información cualitativa y cuantitativa. Revisamos 38 tumores mediastinales que tenían estudio de CF. Además comparamos los resultados de CF de timomas y tejido tímico normal con 42 casos de LLB-T de otras localizaciones anatómicas. De los 38 tumores mediastinales 6 eran lesiones benignas, 9 linfomas difusos de células grandes con fenotipo B (LDCG-B), 10 linfomas de Hodgkin (LH), 11 timomas y 2 LLB-T. En 24 casos la CF aportó información positiva, definiendo el inmunofenotipo de las células linfoides neoplásicas, o los linfocitos característicos que acompañan a los timomas. La CF en los 10 casos de LH y en 4 lesiones benignas permitió descartar otros tipos de linfoma (LDCG-B, LLB-T, etc.). Las marcaciones para CD3, CD4 y CD8 fueron las más útiles para el diagnóstico diferencial entre timomas y LLB-T. En conclusión, la CF es una técnica complementaria de utilidad que aporta información en lesiones mediastinales de manera rápida, requiriendo cantidades pequeñas de material, tanto para el diagnóstico inicial como para el monitoreo de estas enfermedades.

The anterior mediastinum is a common site of tumors with abundant lymphoid elements. Flow cytometry is a useful complementary technique to analyze this type of tumors, which provides qualitative and quantitative information. A differential diagnosis can be sometimes made between thymoma and precursor T-lymphoblastic lymphoma (T-LBL). Correct identification is of utmost importance for patient treatment. A total of 38 mediastinal tumors were analyzed, and samples were separated for flow cytometry. Flow cytometry data from thymomas and normal thymic tissue were compared with 42 cases of T-LBL from other anatomical locations. Among 38 mediastinal tumors, we found 6 benign lesions, 9 diffuse large B-cell lymphomas (DLBCL), 10 Hodgkin lymphomas (HL), 11 thymomas and 2 T-LL. Flow cytometry provided positive information in 24 cases, and defined lymphoid neoplastic cells immunophenotype or the typical lymphocytes accompanying thymomas. Flow cytometry helped differentiate 10 cases of HL and 4 benign lesions from other lymphomas (DLBCL, T-LBL, etc.). CD3, CD4 and CD8 expressions were most useful for the differential diagnosis of thymomas and T-LL. To conclude, flow cytometry is a valid complementary technique, which promptly provides information on mediastinal lesions, requiring small quantities of tissue for both early diagnosis and follow up of these diseases.