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AIM: The spread of lung adenocarcinoma cells into the bronchi and bronchioles is not well documented. We termed this histological finding "endobronchial spreading of adenocarcinoma" (EBSA) and investigated its prevalence and clinical significance. METHODS AND RESULTS: We reviewed 320 resected specimens from patients diagnosed with invasive adenocarcinoma, and EBSA was observed in 144 patients (45%). EBSA was significantly associated with advanced pathological stage, higher histological grade, larger tumour invasion, lymphovascular infiltration, and spread through air spaces. Patients with EBSA had significantly shorter relapse-free survival (RFS) and cancer-specific survival (CSS) in univariate analysis (P < 0.001). In a subgroup analysis of patient with small-sized (invasion size ≤30 mm) adenocarcinoma in the localized stage, EBSA was an independent inferior prognostic indicator in multivariate analysis. In a subgroup analysis of patients with small-sized Grade 1 nonmucinous adenocarcinoma (n = 61), EBSA was observed in 11 patients, and the presence of EBSA was associated with significantly shorter RFS and CSS (P = 0.026 and P = 0.001, respectively). CONCLUSION: Our results demonstrated that EBSA is a significant risk factor for disease recurrence and cancer-related deaths. EBSA can be regarded as a distinctive pattern of invasion and its recognition can be beneficial in the diagnosis of lung adenocarcinoma.
Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Humanos , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão/patologia , Neoplasias Pulmonares/patologia , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos RetrospectivosRESUMO
Regulatory T cells (Tregs) play an important role in creating an immunosuppressive microenvironment in cancer tissues. However, the mechanisms by which Tregs are activated and suppress cancer immunity remain unclear. To elucidate these mechanisms, we performed a T cell receptor (TCR) repertoire analysis of Tregs and conventional T cells in peripheral blood, draining lymph nodes (DLNs), and cancer tissues of patients with head and neck squamous cell cancer (HNSCC). We found that the TCR repertoire was skewed in cancer tissue and metastatic DLNs (M-DLNs) compared with non-metastatic DLNs, and TCR repertoire similarities in Tregs and CD8+ T cells between M-DLNs and cancer tissue were high compared with those at other sites. These results suggest that Tregs and CD8+ T cells are activated in M-DLNs and cancer tissues by cancer antigens, such as neoantigens, and shared antigens and Tregs suppress CD8+ T cell function in a cancer antigen-specific manner in M-DLNs and cancer tissue. Moreover, M-DLNs might be a source of Tregs and CD8+ T cells recruited into the cancer tissue. Therefore, targeting Tregs in M-DLNs in an antigen-specific manner is expected to be a novel immunotherapeutic strategy for HNSCCs.
Assuntos
Linfócitos T CD8-Positivos , Neoplasias de Cabeça e Pescoço , Linfonodos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Linfócitos T Reguladores , Linfócitos T Reguladores/imunologia , Humanos , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Linfonodos/patologia , Linfonodos/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Masculino , Microambiente Tumoral/imunologia , Metástase Linfática/patologia , Metástase Linfática/imunologia , Feminino , Pessoa de Meia-Idade , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Idoso , Receptores de Antígenos de Linfócitos T/imunologiaRESUMO
The identification of CD30 expression by immunohistochemistry is essential for the treatment of lymphomas using an antibody-drug conjugate targeting CD30. However, no standardized protocol for CD30 staining has been available. In this study, we compared three common automated immunostaining platforms {Bond III (B III), Dako Omnis (DO) and Ventana BenchMark ULTRA (VBMU)}. A primary antibody for CD30, the Ber-H2 clone, was diluted 50- to 400-fold for B III and DO, and ready-to-use antibody was used for VBMU. An enhancement step using a linker was introduced in all protocols. First, several candidate dilutions were selected for each platform by staining six cases. These candidate conditions were then confirmed with 60 cases of various types of peripheral T-cell lymphomas (PTCLs). The concordance rates of CD30 expression among platforms differed depending on cutoff values and antibody dilutions, except for anaplastic large cell lymphoma. The concordance rates among three platforms in the evaluation of "positive" or "negative" were 100% and 97% when the cutoff values were 1% and 10% respectively, if using 400-diluted antibody in B III and 100-diluted antibody in DO. This study demonstrated the feasibility of equalizing CD30 staining of PTCLs among different platforms by adjusting protocols.
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Branchioma is a rare benign neoplasm occurring in the lower neck. Occurrence of malignant neoplasms arising in branchioma is extremely rare. Here, we report a case of adenocarcinoma arising in branchioma. A 62-year-old man had a right supraclavicular mass measuring 7.5 cm in diameter. The tumor contained an adenocarcinoma component encapsulated in a benign branchioma component. The adenocarcinoma component consisted of high- and low-grade components, with the former accounting for 80% of the adenocarcinoma. The high-grade component was immunohistochemically characterized by diffuse strong p53 expression, while the low-grade component and branchioma component were negative for p53. Targeted sequencing analysis for the branchioma and adenocarcinoma components revealed that the adenocarcinoma component harbored pathogenic mutations in KRAS and TP53. No definitive oncogenic drivers were detected in the branchioma component. Based on these immunohistochemical and molecular findings, we suggest that the KRAS mutation contributed to the pathogenesis of the adenocarcinoma, and the TP53 mutation played a key role in the transition from low-grade to high-grade adenocarcinoma.
Assuntos
Adenocarcinoma , Branquioma , Masculino , Humanos , Pessoa de Meia-Idade , Branquioma/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Proteína Supressora de Tumor p53/genética , Adenocarcinoma/patologia , MutaçãoRESUMO
Clinical and genomic features of prostate cancer (PCa) vary considerably between Asian and Western populations. PTEN loss is the most frequent abnormality in intraductal carcinoma of the prostate (IDC-P) in Western populations. However, its prevalence and significance in Asian populations have not yet been well studied. In the present study, we evaluated PTEN expression in IDC-P in a Japanese population and its association with ERG expression. This study included 45 and 59 patients with PCa with and without IDC-P, respectively, who underwent radical prostatectomy. PTEN loss was observed in 10 patients with PCa with IDC-P (22%) and nine patients with PCa without IDC-P (17%). ERG expression was relatively frequent in patients with PCa with PTEN loss, although a significant difference was not observed. The co-occurrence of PTEN loss and ERG expression was observed in four patients with PCa with IDC-P and one without IDC-P. PTEN loss and ERG expression did not affect progression-free survival, regardless of the presence of IDC-P. The frequency of PTEN loss in IDC-P is lower in Asian patients than in Western patients. Our results indicate that mechanisms underlying IDC-P in Asian populations are different from those of Western populations.
Assuntos
Carcinoma Intraductal não Infiltrante , Neoplasias da Próstata , Masculino , Humanos , Próstata/patologia , Carcinoma Intraductal não Infiltrante/patologia , Incidência , População do Leste Asiático , Neoplasias da Próstata/patologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismoRESUMO
Patients with advanced/recurrent mucoepidermoid carcinoma (MEC) have a poor prognosis. This study aimed to establish and characterize human mucoepidermoid carcinoma cell lines from the initial surgical specimen and biopsy specimen upon recurrence from the same patient to provide a resource for MEC research. MEC specimens from the initial surgical procedure and biopsy upon recurrence were used to establish cell lines. The established cell lines were cytogenetically characterized using multi-color fluorescence in situ hybridization and detection, and the sequence of the CRTC1-MAML2 chimeric gene was determined. Furthermore, the susceptibility of head and neck mucoepidermoid carcinoma to standard treatment drugs such as cisplatin, 5-fluorouracil, and cetuximab was investigated. We successfully established unique MEC cell lines, AMU-MEC1, from an initial surgical specimen and AMU-MEC1-R1 and AMU-MEC1-R2 from the recurrent biopsy specimen in the same patient. These cell lines exhibited epithelial morphology and developed in vitro-like cobblestones. They shared eight chromosomal abnormalities, including der(19)ins(19;11)(p13;?), which resulted in a chimeric CRTC1-MAML2 gene, indicating the same origin of the cell lines. The susceptibility of all cell lines to cisplatin and 5-fluorouracil was low. Interestingly, EGFR dependency for cell growth decreased in AMU-MEC-R1 and AMU-MEC-R2 but was retained in AMU-MEC1. These cytogenetic and biochemical findings suggest that the established cell lines can be used to investigate the disease progression mechanisms and develop novel therapeutics for MEC.
Assuntos
Carcinoma Mucoepidermoide , Neoplasias das Glândulas Salivares , Humanos , Proteínas de Ligação a DNA/genética , Transativadores/genética , Carcinoma Mucoepidermoide/patologia , Hibridização in Situ Fluorescente , Cisplatino , Fatores de Transcrição/genética , Biópsia , Linhagem Celular Tumoral , Fluoruracila/farmacologia , Neoplasias das Glândulas Salivares/patologia , Proteínas de Fusão Oncogênica/genéticaRESUMO
Patients with plasma cell type idiopathic multicentric Castleman disease (PC-iMCD) often show elevated serum IgG4 levels and IgG4-positive cell infiltration in tissues due to overproduction of interleukin-6, and may meet the diagnostic criteria for IgG4-related disease (IgG4-RD). Although PC-iMCD has been listed as a major exclusion disease for IgG4-RD, distinguishing between these diseases is challenging due to a lack of highly specific diagnostic biomarkers. In 2020, we proposed exclusion criteria of IgG4-RD mimickers. In this paper, we validated the accuracy of the criteria in excluding one of the mimickers, PC-iMCD, from IgG4-RD. Validation was performed on 57 PC-iMCD patients (39 presenting lymph node lesions and 19 with lung lesions) and 29 IgG4-RD patients (22 presenting lymph node lesions and seven with lung lesions). According to our results, 20.5% of the PC-iMCD patients with lymph node lesions and 42.1% of those with lung lesions met the diagnostic criteria for IgG4-RD. All these patients with PC-iMCD were excluded from a diagnosis of IgG4-RD by the proposed criteria. Additionally, 6.9% of IgG4-RD patients met the exclusion criteria. Thus, if the exclusion criteria are met, diagnosis should be made based on a combination of findings including organ distribution of disease, response to steroid therapy, and other pathological findings.
Assuntos
Hiperplasia do Linfonodo Gigante , Diagnóstico Diferencial , Doença Relacionada a Imunoglobulina G4 , Imunoglobulina G/sangue , Adulto , Idoso , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/patologia , Feminino , Humanos , Doença Relacionada a Imunoglobulina G4/diagnóstico , Doença Relacionada a Imunoglobulina G4/patologia , Pulmão/patologia , Linfonodos/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
The expression of programmed death ligand-1 (PD-L1) is controlled by complex mechanisms. The elucidation of the molecular mechanisms of PD-L1 expression is important for the exploration of new insights into PD-1 blockade therapy. Detailed mechanisms of the in situ expression of PD-L1 in tissues of oral squamous cell carcinomas (OSCCs) have not yet been clarified. We examined the mechanisms of PD-L1 expression focusing on the phosphorylation of downstream molecules of epidermal growth factor (EGF) and interferon gamma (IFN-γ) signaling in vitro and in vivo by immunoblotting and multi-fluorescence immunohistochemistry (MF-IHC), respectively. The in vitro experiments demonstrated that PD-L1 expression in OSCC cell lines is upregulated by EGF via the EGF receptor (EGFR)/PI3K/AKT pathway, the EGFR/STAT1 pathway, and the EGFR/MEK/ERK pathway, and by IFN-γ via the JAK2/STAT1 pathway. MF-IHC demonstrated that STAT1 and EGFR phosphorylation was frequently shown in PD-L1-positive cases and STAT1 phosphorylation was correlated with lymphocyte infiltration and EGFR phosphorylation. Moreover, the phosphorylation pattern of the related molecules in PD-L1-positive cells differed among the cases investigated. These findings indicate that PD-L1 expression mechanisms differ depending on the tissue environment and suggest that the examination of the tissue environment and molecular alterations of cancer cells affecting PD-L1 expression make it necessary for each patient to choose the appropriate combination drugs for PD-1 blockade cancer treatment.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Fator de Crescimento Epidérmico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Interferon gama/uso terapêutico , Neoplasias Bucais/metabolismo , Fosfatidilinositol 3-Quinases , Receptor de Morte Celular Programada 1 , Carcinoma de Células Escamosas de Cabeça e PescoçoRESUMO
Immunotherapy with immune-checkpoint therapy has recently been used to treat oral squamous cell carcinomas (OSCCs). However, improvements in current immunotherapy are expected because response rates are limited. Transforming growth factor-ß (TGF-ß) creates an immunosuppressive tumor microenvironment (TME) by inducing the production of regulatory T-cells (Tregs) and cancer-associated fibroblasts and inhibiting the function of cytotoxic T-lymphocytes (CTLs) and natural killer cells. TGF-ß may be an important target in the development of novel cancer immunotherapies. In this study, we investigated the suppressive effect of TGF-ß on CTL function in vitro using OSCC cell lines and their specific CTLs. Moreover, TGFB1 mRNA expression and T-cell infiltration in 25 OSCC tissues were examined by in situ hybridization and multifluorescence immunohistochemistry. We found that TGF-ß suppressed the function of antigen-specific CTLs in the priming and effector phases in vitro. Additionally, TGF-ß inhibitor effectively restored the CTL function, and TGFB1 mRNA was primarily expressed in the tumor invasive front. Interestingly, we found a significant negative correlation between TGFB1 mRNA expression and the CD8+ T-cell/Treg ratio and between TGFB1 mRNA expression and the Ki-67 expression in CD8+ T-cells, indicating that TGF-ß also suppressed the function of CTLs in situ. Our findings suggest that the regulation of TGF-ß function restores the immunosuppressive TME to active status and is important for developing new immunotherapeutic strategies, such as a combination of immune-checkpoint inhibitors and TGF-ß inhibitors, for OSCCs.
Assuntos
Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia Adotiva/métodos , Neoplasias Bucais/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Linfócitos T Citotóxicos/efeitos dos fármacos , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Fibroblastos Associados a Câncer/citologia , Fibroblastos Associados a Câncer/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Interferon gama/análise , Interferon gama/metabolismo , Antígeno Ki-67/metabolismo , Células Matadoras Naturais/citologia , Células Matadoras Naturais/imunologia , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , RNA Mensageiro/metabolismo , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Sais de Tetrazólio/farmacologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta1/análise , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismo , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/metabolismo , Adulto JovemRESUMO
Recent studies of tumor microenvironments have revealed that clonal B cells reacting to tumor-derived antigens play an important role in anti-tumor immunity. We report a case of a 72-year-old Japanese man with a complaint of fever for 1 month. Computed tomography revealed a 48 mm mass in his right kidney. The patient underwent a right nephrectomy and histology revealed clear cell renal cell carcinoma (ccRCC) of Fuhrman Grade 4 with rhabdoid morphology. Focally, marked plasmacytoid cell infiltration was detected in the carcinoma. These plasmacytoid cells were immunohistochemically positive for immunoglobulin (Ig) G, and kappa light chain restriction was confirmed using mRNA in situ hybridization. Programmed death-ligand 1 (PD-L1) immunostaining and RNA in situ hybridization of transforming growth factor beta (TGF-ß) revealed that both PD-L1 and TGF-ß were highly expressed in the area with clonal plasmacytoid cell infiltration. The patient developed bone metastasis 3 months after surgery, and plasmacytoma was not detected during the observation period. We identified a potential link between an immunosuppressive microenvironment and clonal B cell proliferation. The latter posed a differential diagnosis problem between reactive and neoplastic clonal B cell proliferation vis-à-vis a plasmacytoma complicating carcinoma.
Assuntos
Carcinoma de Células Renais , Plasmocitoma , Idoso , Linfócitos B , Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/patologia , Proliferação de Células , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Hibridização In Situ , Neoplasias Renais/diagnóstico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Plasmocitoma/diagnóstico , Plasmocitoma/patologia , Fator de Crescimento Transformador beta/análise , Microambiente TumoralRESUMO
Histiocytic and dendritic cell (H/DC) neoplasms are heterogeneous, originating from myeloid- or stromal-derived cells. Multiple reports describe the cross-lineage transdifferentiation of neoplastic B cells into H/DC neoplasms. Most such cases are from Western countries, and rarely from Japan or East Asia. Here we report 17 cases of H/DC neoplasms in Japanese patients, with analysis of t(14;18) by fluorescence in situ hybridization, and of neoplastic programmed death-ligand 1 (PD-L1) expression by immunostaining (clones SP142, E1J2J, and 28-8). These 17 cases were diagnosed according to the 2017 World Health Organization (WHO) classification, and included two histiocytic sarcomas (HS), two interdigitating cell (IDC) sarcomas, one Langerhans cell sarcoma, two dendritic cell sarcomas, and 10 follicular dendritic cell (FDC) sarcomas. No case had any past history of follicular lymphoma (FL). Two cases of HS and one IDC sarcoma, all of which were myeloid-driven, were found to exhibit t(14;18). In the latter case, at 30 months after IDC sarcoma diagnosis, FL development was detected. Three (30%) FDC sarcoma cases exhibited neoplastic PD-L1 expression with all the three PD-L1 antibody clones. This is the first report of t(14;18) and neoplastic PD-L1 expression on H/DC neoplasms among Japanese patients, each of which appeared to be associated with HS and FDC sarcoma, respectively.
Assuntos
Antígeno B7-H1/metabolismo , Sarcoma de Células Dendríticas Foliculares , Sarcoma Histiocítico , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Sarcoma de Células Dendríticas Foliculares/imunologia , Sarcoma de Células Dendríticas Foliculares/metabolismo , Sarcoma de Células Dendríticas Foliculares/patologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Feminino , Histiócitos/metabolismo , Histiócitos/patologia , Sarcoma Histiocítico/imunologia , Sarcoma Histiocítico/metabolismo , Sarcoma Histiocítico/patologia , Humanos , Imuno-Histoquímica , Imunofenotipagem , Hibridização in Situ Fluorescente , Japão , Sarcoma de Células de Langerhans/imunologia , Sarcoma de Células de Langerhans/metabolismo , Sarcoma de Células de Langerhans/patologia , Linfoma Folicular/imunologia , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Linfócitos T/metabolismoRESUMO
Primary central nervous system lymphomas (PCNSLs) rarely exhibit intratumoral hemorrhage. The differential diagnosis of hemorrhagic neoplasms of the central nervous system (CNS) currently includes metastatic carcinomas, melanomas, choriocarcinomas, oligodendrogliomas, and glioblastomas. Here we present the clinical, radiological, pathological, and molecular genetic features of six cases of PCNSL associated with intratumoral hemorrhage. The median age of patients was 75 years, with male predominance. While conventional PCNSLs were associated with low cerebral blood volume (CBV), perfusion magnetic resonance imaging (MRI) revealed elevated CBV in three cases, consistent with vascular proliferation. All six cases were diagnosed pathologically as having diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell-like (non-GCB) phenotype; marked histiocytic infiltrates and abundant non-neoplastic T-cells were observed in most cases. Expression of vascular endothelial growth factor and CD105 in the lymphoma cells and the small vessels, respectively, suggested angiogenesis within the neoplasms. Neoplastic cells were immunohistochemically negative for programmed cell death ligand 1 (PD-L1), while immune cells in the microenvironment were positive for PD-L1. Mutations in the MYD88 gene (MYD88) (L265P) and the CD79B gene (CD79B) were detected in five and one case, respectively. As therapeutic modalities used for PCNSLs differ from those that target conventional hemorrhagic neoplasms, full tissue diagnoses of all hemorrhagic CNS tumors are clearly warranted.
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Neoplasias do Sistema Nervoso Central , Linfoma Difuso de Grandes Células B , Idoso , Sistema Nervoso Central , Neoplasias do Sistema Nervoso Central/complicações , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/genética , Hemorragia , Humanos , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/genética , Masculino , Microambiente Tumoral , Fator A de Crescimento do Endotélio VascularRESUMO
Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNS-DLBCL) is rare. Thirty-nine patients consecutively diagnosed as having PCNS-DLBCL were analyzed to highlight the prognostic value of the expression of programmed cell death ligand-1 (PD-L1) by neoplastic cells and immune cells in the microenvironment. They were positive for CD20 in all (100%), CD5 in two (5%), CD10 in nine (23%), BCL-2 in 27 (69%), BCL-6 in 34 (87%), and MUM-1 in 37 (95%). Only one case was positive for neoplastic PD-L1, with an unexpectedly long clinical course of 92 months. The remaining 38 cases were further divided into three groups based on the percentage of PD-L1+ cells among microenvironmental immune cells. Cutoffs of < 5%, 5-40%, and ≥ 40% successfully stratified mean prognoses with three-year overall survival (OS) of 21%, 63%, and 100% (P = 0.009), respectively. Progression-free survival (PFS) and OS were different between the groups with and without methotrexate (MTX)-containing chemotherapy (P = 0.007 and P < 0.001, respectively). Multivariate analysis identified three independent adverse factors of OS: PD-L1 negativity (< 5%) on microenvironmental immune cells (P = 0.027), deep structure involvement (P = 0.034), and performance status (PS) 2-4 (P = 0.009). The study showed that PD-L1 expression on immune cells in the microenvironment was associated with prognosis among patients with PCNS-DLBCL.
Assuntos
Antígeno B7-H1/metabolismo , Sistema Nervoso Central/patologia , Linfoma Difuso de Grandes Células B/metabolismo , Microambiente Tumoral/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/metabolismo , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfoma Difuso de Grandes Células B/imunologia , Masculino , Pessoa de Meia-Idade , Microambiente Tumoral/fisiologiaRESUMO
Sphingolipids constitute a class of bio-reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non-small-cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR-101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1-positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis.
Assuntos
Movimento Celular , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Proteínas de Membrana/metabolismo , Esfingosina N-Aciltransferase/metabolismo , Animais , Sequência de Bases , Linhagem Celular Tumoral , Ceramidas/metabolismo , Humanos , Masculino , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Modelos Biológicos , Metástase Neoplásica , Pseudópodes/metabolismo , Resultado do TratamentoRESUMO
IgG4-related disease (RD) is a relatively new entity, which was first proposed in 2001. Since then, clinical and pathological characteristics of the disease have been investigated. As IgG4-RD has been studied extensively, the diagnostic criteria for IgG4-RD of each organ and the comprehensive diagnostic criteria for IgG4-RD have also been developed. However, one of the biggest challenges in the field is distinguishing between IgG4-RD and mimickers, which show overlapping features with IgG4-RD. It is now known that some non-IgG4-RDs may meet the diagnostic criteria of IgG4-RD and can be misdiagnosed as IgG4-RD. However, accurate diagnosis is crucial, as the treatments for IgG4-RD and those for other diseases that may be misdiagnosed as IgG4-RD are different. This prompted us to create and propose comprehensive exclusion criteria for IgG4-RD. In this review, we have described the comprehensive exclusion criteria for IgG4-RD, with a historical overview of the disease. These exclusion criteria were recently created by the Research Program for Intractable Disease of the Ministry of Health, Labor, and Welfare of Japan, All Japan IgG4 team, to support correct and accurate diagnosis of IgG4-RD.
Assuntos
Doença Relacionada a Imunoglobulina G4/diagnóstico , Doenças Autoimunes/diagnóstico , Diagnóstico Diferencial , HumanosRESUMO
Management of advanced hormone-naïve prostate cancer (HNPC) is a critical public health issue. Useful prognostic markers are thus needed to select patients who will benefit from recently introduced upfront therapies. p16 expression is an adverse prognostic marker in prostate cancer. The present study aimed to determine whether p16 expression would serve as an adverse prognostic marker in advanced HNPC. A total of 79 patients diagnosed by needle biopsy with adenocarcinoma Gleason score ≥8 between 2010 and 2013 at Aichi Medical University were included in this study. The median patient age was 73 (range 52-87) years. The median follow-up was 62 months (range 2-98). Fourteen patients had p16-positive samples. Fifteen patients died from prostate cancer, 10 of whom were in the p16-positive group. p16 positivity was associated with clinical T stage (P < 0.001), presence of IDC-P (P < 0.001), distant metastasis (P < 0.001) and lymph node metastasis (P < 0.001). These results indicate that p16 expression is associated with adverse prognostic factor of prostate cancer and suggest that p16 expression may provide useful information for treatment planning and identifying suitable candidates for upfront chemotherapy or androgen receptor axis-targeted therapy.
Assuntos
Adenocarcinoma/diagnóstico , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Inibidor p16 de Quinase Dependente de Ciclina/genética , Humanos , Imuno-Histoquímica , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Próstata/metabolismo , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologiaRESUMO
Inhibitors of programmed cell-death 1 (PD-1) and programmed cell-death ligand 1 (PD-L1) have revolutionized cancer therapy. Nodal cytotoxic T-cell lymphoma (CTL) is characterized by a poorer prognosis compared to nodal non-CTLs. Here we investigated PD-L1 expression in 50 nodal CTL patients, with and without EBV association (25 of each). We identified seven patients (14%) with neoplastic PD-L1 (nPD-L1) expression on tumor cells, including three males and four females, with a median age of 66 years. One of the seven cases was TCRαß type, three were TCRγδ type and three were TCR-silent type. Six of the seven cases exhibited a lethal clinical course despite multi-agent chemotherapy, of whom four patients died within one year of diagnosis. Morphological findings were uniform, with six cases showing centroblastoid appearance. Among nPD-L1+ cases, two of three examined had structural variations of PD-L1 disrupting 3'-UTR region. Notably, all of the TCRγδ-type nodal CTL cases showed nPD-L1 or miPD-L1 positivity (3 and 10 cases, respectively). TCRγδ-type cases comprised 42% of nPD-L1+ cases (P = 0.043 vs. PD-L1- ), and 35% of miPD-L1+ cases (P = 0.037 vs. PD-L1- ). The results indicate that PD-L1+ nodal CTL cases, especially of the TCRγδ type, are potential candidates for anti-PD-1/PD-L1 therapies.
Assuntos
Antígeno B7-H1/metabolismo , Linfoma de Células T Periférico , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/patologia , Feminino , Humanos , Linfoma de Células T/diagnóstico , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Composite lymphoma is a well-known diagnostic entity exhibiting the synchronous occurrence of two or more distinct types of lymphomas in the same specimen. Here we report two patients, a 14-year-old female (Case 1) and a 45-year-old male (Case 2), with mediastinal composite lymphoma, comprising nodular sclerosis classic Hodgkin lymphoma (NSCHL) and primary mediastinal large B-cell lymphoma (PMBL). Both patients had a mediastinal mass, and manifested two different histologic components in the same biopsy, one characteristic of NSCHL and the other PMBL. The NSCHL areas included Hodgkin and Reed-Sternberg (HRS) cells with typical immunophenotypic features (CD30-positive and CD20-negative), whereas the sheets of large tumor cells characteristic of PMBL were strongly and uniformly CD20-positive. Interestingly, although both cases showed neoplastic PD-L1 (nPD-L1) positivity on the HRS cells of NSCHL, they differed regarding nPD-L1 expression on the PMBL tumor cells. In Case 1, the nPD-L1-negative PMBL component was anatomically situated outside the NSCHL lesion. On the other hand, in Case 2, the nPD-L1-positive PMBL component was characterized by transitional or continuous areas with the NSCHL component. These findings suggested that nPD-L1 expression may define two subtypes of PMBL that are more similar to or distinct from classic Hodgkin lymphoma.
Assuntos
Antígeno B7-H1/metabolismo , Linfoma Composto/diagnóstico , Doença de Hodgkin/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Neoplasias do Mediastino/diagnóstico , Adolescente , Biomarcadores Tumorais/metabolismo , Feminino , Doença de Hodgkin/metabolismo , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
Although several reports have highlighted neoplastic PD-L1 (nPD-L1) expression in classic Hodgkin lymphoma (CHL), some have addressed associations between its expression and detailed histopathologic features. Here we describe four cases of syncytial variant of CHL (SV-CHL), with and without Epstein-Barr virus (EBV) association, and highlight the diagnostic utility of PD-L1 (clone SP142) immunohistochemistry. The patients were a 61-year-old male, 45-year-old male, 85-year-old female, and 89-year-old female. All presented with cervical or axillary lymphadenopathy, which on biopsy had the established histopathologic features of SV-CHL with a biphasic pattern of cohesive sheets of large tumor cells and typically scattered distribution of Hodgkin and Reed-Stenberg (HRS) cells. These tumor cells showed identical immunophenotypic findings for CD15, CD30, Fascin, PAX5, OCT2, BOB1 and EBV harboring, regardless of location. The exception was absent or decreased expression of nPD-L1 from tumor cells in the confluent sheets, contrasting with HRS cell positivity in typical areas of CHL. These findings offer the first suggestion of possible downregulation of nPD-L1 expression in association with the histopathologic progression of CHL. The results may be relevant for recognizing 'confluent' sheets in the diagnostic workup for SV-CHL.
Assuntos
Antígeno B7-H1/biossíntese , Biomarcadores Tumorais/metabolismo , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/patologia , Idoso de 80 Anos ou mais , Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-IdadeRESUMO
Epstein-Barr virus (EBV) is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age-related EBV-associated B-cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency-associated ones. These LPDs may be associated with immune senescence and are now incorporated into the revised 4th edition of 2017 WHO lymphoma classification as EBV-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS). These EBV+ B-cells often have a Hodgkin/Reed-Sternberg (HRS)-like appearance and are shared beyond the diagnostic categories of mature B-cell neoplasms, mature T-cell neoplasms, classic Hodgkin lymphoma, and immunodeficiency-associated LPD. In addition, peculiar new diseases, such as EBV+ mucocutaneous ulcer and EBV+ DLBCL affecting the young, were recognized. On the other hand, lymphoma classification is now evolving in accord with deeper understanding of the biology of programmed death ligand 1 (PD-L1). Assessing PD-L1 positivity by staining with the anti-PD-L1 monoclonal antibody SP142 provides new insight by discriminating between immune evasion and senescence or immunodeficiency. The aim of the present review is to briefly summarize the diagnostic use of immunostaining with SP142 in malignant lymphomas and/or LPDs that feature tumor and nonmalignant large B-cells harboring EBV.