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Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.
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INTRODUCTION: Diffuse midline glioma with H3-K27M mutation is an infiltrative high-grade glioma, with predominantly astrocytic differentiation. PATIENT CONCERNS: A 54-year-old Chinese woman presented with memory loss for a month and walking instability for 15 days. DIAGNOSIS: Magnetic resonance imaging showed a mass shadow of isometric T1 and slightly longer T2 with mild mixed signals in the third ventricle of the suprasellar region. Histologically, the tumor was primarily sheet-like, with many "anucleate areas" composed of long and thin fibrillary processes of the bipolar cells, which formed "whorls." The neoplastic nuclei were ovoid and moderate in size. The tumor showed brisk mitotic activity and vascular proliferation, with no necrosis. In addition to histone H3K27M mutation, immunohistochemical staining showed that the tumor cells were positive for glial fibrillary acidic protein, oligodendrocyte transcription factor 2, alpha-thalassemia/mental retardation syndrome X, S-100 and Vimentin. The "anucleate areas" were positive for glial fibrillary acidic protein and negative for synaptophysin. The Ki-67 proliferation index was about 10%. Molecular genetic analyses detected H3F3A K27M mutation, but no mutations in IDH1 or IDH2, TERT promoter mutations, MGMT promoter methylation, KIAA1549-BRAF fusion or deletion of 1p/19q were found. Based on these findings, the patient was diagnosed as diffuse midline glioma with H3-K27M mutation in the third ventricle, corresponding to WHO grade 4. INTERVENTIONS: A craniotomy with total excision of the tumor was performed. OUTCOMES: After surgery, she was routinely treated with temozolomide for chemotherapy and synchronous radiotherapy. It has been 11 months now, and the patient is living well. CONCLUSION: This case report provides information on the microscopic morphological features of diffuse midline glioma with H3K27M mutation, which can help pathologists to make a definitive diagnosis of this tumor.
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Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/patologia , Feminino , Proteína Glial Fibrilar Ácida/genética , Glioma/diagnóstico , Glioma/genética , Glioma/metabolismo , Histonas/genética , Humanos , MutaçãoRESUMO
We report a case of a 26-year-old Chinese man who had experienced three grand mal seizures in the past two months. Magnetic resonance imaging revealed a relatively well-circumscribed lesion in the left frontal lobe. A craniotomy with total excision of the tumor was performed. Histopathological investigations confirmed a grade 2 ependymoma according to the World Health Organization classification. Genetic analysis revealed a tumor harboring FAM118B fusion to YAP1, and no other genetic alterations or methylation of the O6 -methylguanine-DNA methyltransferase gene promoter were detected. This is the second case report of ependymoma with YAP1:FAM118B fusion.
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Ependimoma/genética , Ependimoma/patologia , Lobo Frontal/patologia , Neoplasias Supratentoriais/genética , Neoplasias Supratentoriais/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Ependimoma/diagnóstico , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Convulsões/patologia , Neoplasias Supratentoriais/diagnóstico , Fator de Transcrição RelA/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAPRESUMO
BACKGROUND AND AIMS: Microvascular invasion (MVI) is a key pathological factor that severely affects the postoperative prognosis of patients with hepatocellular carcinoma (HCC). However, no MVI classification schemes based on standardized gross sampling protocols of HCC are available at present. METHODS: 119 HCC specimens were sampled at multiple sites (3-, 7-, and 13 points) for the optimum MVI detection rate. 16,144 resected HCCs were graded as M0, M1 or M2 by adopting three-tiered MVI grading (MVI-TTG) scheme based on the seven-point sampling protocol (SPSP). Survival analyses were performed on 2573 patients to explore the advantages of MVI-TTG. RESULTS: The MVI detection rate determined by SPSP was significantly higher than that determined by the 3-point sampling method (34.5% vs. 47.1%, p = 0.048), but was similar to that determined by the 13-point sampling method (47.1% vs. 51.3%, p = 0.517). Among 16,144 resected HCCs, the proportions of M0, M1 and M2 specimens according to SPSP were 53.4%, 26.2% and 20.4%, respectively. Postoperative survival analysis in 2573 HCC patients showed that the 3-year recurrence rates in M0, M1 and M2 MVI groups were 62.5%, 71.6% and 86.1%, respectively (p < 0.001), and the corresponding 3-year overall survival (OS) rates were 94.1%, 87.5% and 67.0%, respectively (p < 0.001). M1 grade was associated with early recurrence, while M2 grade was associated with both early and late recurrence. MVI-TTG had a larger area under the curve and net benefit rate than the two-tiered MVI grading scheme for predicting time to recurrence and OS. CONCLUSIONS: SPSP is a practical method to balance the efficacy of sampling numbers and MVI detection rates. MVI-TTG based on SPSP is a better prognostic predictor than the two-tiered MVI scheme. The combined use of SPSP and MVI-TTG is recommended for the routine pathological diagnosis of HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Carcinoma Hepatocelular/cirurgia , Humanos , Microvasos , Invasividade Neoplásica , Recidiva Local de Neoplasia , Estudos RetrospectivosRESUMO
High-risk human papillomavirus (HPV) infection play an important role in the development of lung cancer. Our previously study showed that E6 and E7 in HPV16 upregulated the expression of GLUT1 in lung cancer cells. However, whether they can promote the glucose uptake by GLUT1 and the underlying molecular mechanism has not been identified. It has been reported that thioredoxin interacting protein (TXNIP) regulates both the expression of GLUT1 and its glucose uptake. We speculate that high risk HPV16 infection may be closely related to TXNIP expression. Therefore, we associate HPV16 with TXNIP to explore the potential molecular mechanism of their regulation of GLUT1 expression and glucose uptake. Using double directional genetic manipulation in lung cancer cells, we showed that HPV16 E6/E7 proteins downregulated the expression of p-PTEN in lung cancer cells, the knockdown of PTEN further inhibited the expression of TXNIP, the inhibition of TXNIP further promoted the accumulation of HIF-1α by inhibiting the translocation of nuclear HIF-1α to the cytoplasm, and subsequently upregulated the expression of GLUT1 at the protein and mRNA levels. More interestingly, we found that the knockdown of TXNIP played a decisive role to promote the glucose uptake by GLUT1. Together, these findings suggested that the PTEN-TXNIP-HIF-1α axis might be related to the E6/E7-mediated expression of GLUT1 and its glucose uptake.
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BACKGROUND: HPV16 E6/E7 proteins are the main oncogenes and only long-term persistent infection causes lung cancer. Our previous studies have shown that HPV16 E6/E7 protein up-regulates the expression of GLUT1 in lung cancer cells. However, whether E6 and E7 protein can promote the glucose uptake of GLUT1 and its molecular mechanism are unclear. METHODS: The regulatory relationships of E6 or E7, miR-451, CAB39, PI3K/AKT, and GLUT1 were detected by double directional genetic manipulations in lung cancer cell lines. Immunofluorescence and flow cytometry were used to detect the effect of CAB39 on promoting the translocation to the plasma membrane of GLUT1. Flow cytometry and confocal microscopy were performed to detect the glucose uptake levels of GLUT1. RESULTS: The overexpression both E6 and E7 proteins significantly down-regulated the expression level of miR-451, and the loss of miR-451 further up-regulated the expression of its target gene CAB39 at both protein and mRNA levels. Subsequently, CAB39 up-regulated the expression of GLUT1 at both protein and mRNA levels. Our results demonstrated that HPV16 E6/E7 up-regulated the expression and activation of GLUT1 through the HPV-miR-451-CAB39-GLUT1 axis. More interestingly, we found that CAB39 prompted GLUT1 translocation to the plasma membrane and glucose uptake, and this promotion depended on the PI3K/AKT pathway. CONCLUSION: Our findings provide new evidence to support the critical roles of miR-451 and CAB39 in the pathogenesis of HPV-related lung cancer.
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BACKGROUND: There is an immediate need for research on the mechanism underlying telomerase activation and overexpression. MATERIALS & METHODS: A total of 174 patients with lung cancer (n = 106) and benign lung disease (n = 68) were recruited for the current study. The mRNA expression levels of E6, E7, LKB1, Sp1, and hTERC in brushing cells were detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and hTERC amplification was also detected by fluorescence in situ hybridization (FISH). To investigate the potential mechanism, bidirectional genetic manipulation was performed in well-established lung cancer cell lines. RESULTS: Our results indicated that the mRNA expression levels of E6, E7, Sp1, and hTERC and the amplification level of hTERC were significantly increased in the malignant group compared with those of the benign group (p < 0.01). Conversely, the mRNA expression level of LKB1 was significantly decreased in the malignant group (p < 0.01). The correlation between E6, E7, Sp1, and hTERC expression was positive but was negative with LKB1 (p < 0.01). Our results also showed that HPV16 E6/E7 downregulated the expression of LKB1 at both the protein and mRNA levels. The loss of LKB1 upregulated Sp1 expression, and also promoted Sp1 activity. Sp1 further upregulated hTERC at the mRNA and gene amplification levels. Thus, we proposed a HPV-LKB1-Sp1-hTERC axis of E6/E7 upregulation of hTERC expression. CONCLUSION: We demonstrated for the first time that E6 and E7 promoted hTERC mRNA expression and the amplification of hTERC by relieving the effect of LKB1 on the phosphorylation of Sp1. Sp1 further activated hTERC by directly binding to the promoter regions of hTERC.
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Biopsy, brushing, and transbronchial needle aspiration (TBNA) are the most common methods for diagnosis of lung adenocarcinoma and are taken during the same diagnostic bronchoscopic procedure. However, it is not clear what the morphological diagnostic criteria of cytology by brushing or TBNA are. A retrospective analysis was performed on 136 patients who underwent video bronchoscopy examination for diagnostic purposes. All the subjects were performed brushing or TBNA and confirmed as lung adenocarcinoma by biopsy or postoperative pathology. An additional 140 randomly selected patients with benign lung diseases were included in the study and used as a control group. The benign cells usually confused with adenocarcinoma cells were ciliated columnar cells, mucous columnar cells, ciliated cuboid cells, and reactive ciliated cells, respectively. The number of cases diagnosed as adenocarcinoma cells, carcinoma cells, suspicious cancer cells, and atypical proliferative cells by cytology was 101, 11, 20, and 4, respectively. The main basis for the interpretation of adenocarcinoma cells is the enlargement of individual nucleus, the arrangements of multistage papillary, and the general enlargement of nuclei, while the main clue for the interpretation of suspicious cancer cells and dysplasia cells comes from escape cells. The results suggested that the degree of nuclear enlargement, multiple papillary arrangement, and escape cells or escape trend cells are important clues for the interpretation of lung adenocarcinoma cells, while the atypical proliferative cells were similar to escape cells or escape trend cells, which were essentially benign cells beside the cancer.
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Adenocarcinoma de Pulmão/cirurgia , Broncoscopia/métodos , Neoplasias Pulmonares/cirurgia , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Chronic infection of HPV16 E6/E7 is frequently associated with lung cancers, especially in non-smokers and in Asians. In our previous studies, we found that HPV16 E6/E7 up-regulated HIF-1α at protein level and further up-regulated GLUT1 at both protein and mRNA levels in well-established lung cancer cell lines. In one of our further mechanism study, the results demonstrated that HPV16 E6/E7 up-regulated the expression of GLUT1 through HPV-LKB1-HIF-1α-GLUT1 axis. However, there are multiple pathways involved in HPV16 E6/E7 regulation of HIF-1α expression. In current study, using double directional genetic manipulation in well-established lung cancer cell lines, we showed that both E6 and E7 down-regulated the expression of RRAD at both protein and mRNA levels. Like LKB1, RRAD is one of the cancer suppressor genes. The loss of RRAD further activated NF-κB by promoted cytoplasmic p65 translocated to nucleus, and up-regulated the expression level of the p-p65 in nucleus. Furthermore, p-p65 up regulated HIF-1α and GLUT1 at both protein and mRNA levels. Thus, we proposed HPV16 E6/E7 up-regulated the expression of GLUT1 through HPV-RRAD-p65- HIF-1α- GLUT1 axis. In conclusion, we demonstrated for the first time that E6 and E7 promoted the expression of HIF-1α and GLUT1 by relieving the inhibitory effect of RRAD which resulted in the activation of NF-κB by promoting cytoplasmic p65 translocated to nucleus, and up-regulated the expression of the p-p65 in nucleus in lung cancer cells. Our findings provided new evidence to support the critical role of RRAD in the pathogenesis of HPV-related lung cancer, and suggested novel therapeutic targets.
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Transcription factor E3 (TFE3) is a useful marker for tumors with Xp11.2 translocation, including alveolar soft part sarcoma and renal cell carcinoma. Recently, TFE3 overexpression was also found in granular cell tumors (GrCTs). However, the case cohorts of these two studies were limited to only 11 and 6 cases. Whether aberrant TFE3 expression is a common feature of Asian patients with GrCT requires further investigation. In the present study, immunohistochemical staining and TFE3 break-apart fluorescence in situ hybridization (FISH) assay were performed in 45 samples of GrCTs obtained from Chinese patients recruited from three medical centers in northeast China. Diffusive and marked nuclear staining for TFE3 was identified in 11/45 (24%) cases, which was lower than previously reported. Focal or weak TFE3 staining was identified in 13/45 (29%) cases. The remaining 21 cases were negative stained. In addition, GrCTs in subcutaneous tissue exhibited a relatively higher ratio (8/45, 18%) for TFE3 expression, compared with those in other sites. Furthermore, according to FISH data, no rearrangement or amplification of TFE3 was identified in these cases, whether they were positively or negatively stained for TFE3. The results from the present study demonstrated that part of patients GrCTs exhibited TFE3 overexpression, which suggested that this may not be derived from gene rearrangement.
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The cytology of peritoneal washing fluids for gastric cancer is the most basic method for judging peritoneal micrometastasis. However, the clinical value of this method is not clear at present. A retrospective analysis was performed on 277 patients with pathologically proven and surgically treated gastric cancer. The peritoneal washing fluids were collected after opening the abdomen and before the operation, and were sent to the cytology laboratory for screening of occult cancer cells in the collected washing fluids. The number of cases diagnosed as cancer cells, reactive mesothelial cells, serosal balls, and traumatic mesothelial cells were 42, 18, 27, and 190, respectively. Typical adenocarcinoma cell nests were found in eight of 10 T4b samples, whereas 34 cases of cancer cells in T3 and T4a showed that these cell nests usually contained mesothelial cells, and the three-dimensional stereoscopic sense of the nests was not obvious. In the specific subcellular morphological changes of both reactive mesothelial cells and serosal balls, the changes of both the contour of nuclear membrane and the polarity of cell alignment were present only in stage T3 and T4a. The presence or absence of mesothelial cells in the nests of cancer cells and the changes of the contour of nuclear membrane and of the polarity of cell alignment in reactive mesothelial cells or serosal balls may help us to predict the depth of invasion of cancer cells.
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Adenocarcinoma/secundário , Líquido Ascítico/citologia , Neoplasias Mesoteliais/secundário , Neoplasias Gástricas/patologia , Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido Ascítico/patologia , Epitélio/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Mesoteliais/diagnóstico , Neoplasias Mesoteliais/patologia , Neoplasias Mesoteliais/cirurgia , Estudos Retrospectivos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/cirurgiaRESUMO
Liver kinase B1 (LKB1) is a critical tumor suppressor that is frequently mutated in human cancers. LKB1 has serine/threonine protein kinase activity, which regulates gene expression by phosphorylation of Yes-Associated protein (YAP). The phosphorylation-dependent YAP shuttling is critically important intracellular mechanism in the Hippo pathway. In our previous study, we found that the amplification of hTERC was significant higher in the bronchial brushing cells of patients with lung cancer, however, the underlying molecular mechanism is not clear. In this study, we showed that LKB1 overexpression could phosphorylate YAP and promoted its nuclear rejection. Silencing LKB1 could dephosphorylate YAP and promoted its entry into the nucleus. Here, we found that LKB1 inhibited the mRNA expression and the amplification of hTERC. YAP further up-regulated hTERC at mRNA and gene amplification levels. Therefore, we suggest that LKB1 may inhibit the expression and amplification of hTERC through the axis of LKB1-pYAP(YAP)-hTERC.
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BACKGROUND: The cytological diagnosis of a malignant epithelial tumor, i.e., a cancer cell in the body fluid effusions is usually made by cytomorphological examination alone; however, diagnostic challenges can occur when the cancer cells are rare or cytological atypia is minimal. Morphological similarity between the cancer and the reactive mesothelial cell is the most common problem in establishing a clear diagnosis. The aim of this study is to investigate whether the cocktail acid phosphatases (ACP) special staining will be a useful tumor marker in differentiation of the reactive mesothelial cells from the cancer cells in the body fluid effusions. METHODS: The cocktail ACP special staining was performed on 212 body fluid effusion samples, which included 128 pleural effusions, 69 ascites, and 15 pericardial effusions. RESULTS: The mesothelial cells were cocktail ACP positive in 84 out of 84 benign effusion cases, and the sensitivity and the specificity were 100% for the benign effusions which including pleural effusions, ascites, and pericardial effusions. On the other hand, 122 out of 128 cancer cases were cocktail ACP negative, indicating that the sensitivity of using the cocktail ACP staining to rule out the malignant effusions was 95.3%. Thus, the cocktail ACP staining is an excellent marker with high sensitivity and specificity to distinguish the carcinoma from the reactive mesothelial cells in the body fluid effusions. CONCLUSIONS: Our finding provided a new tool for cytopathologists in diagnosing the body fluid effusion that could impact clinical decision making.
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Diffuse midline glioma with histone H3-K27M mutation is a new tumor entity defined by the 2016 WHO Classification of Tumors of the Central Nervous System. A 51-year-old Chinese woman presented with neck pain for a month. Subsequent MRI revealed an intramedullary neoplasm extending from C5 to C7. Histologically, the cellular area of the tumor was composed of primitive, poorly differentiated, small cells with scant cytoplasm, nuclear molding, and brisk mitotic activity, exhibiting PNET-like appearance, while in the hypocellular area, oligodendroglioma-like cells were observed. More importantly, neuropil-like islands were observed in the cellular area. Microvascular proliferation was noted, with no necrosis. Besides histone H3K27M mutation, immunohistochemical staining also showed that the tumor cells were positive for oligodendrocyte lineage transcription factor 2 and ATRX. The neuropil-like areas were positive for synaptophysin, intermingled with scattered neuronal nuclear antigen positive cells. The Ki-67 proliferation index was about 30%, and tumor cells were highly immunopositive for p53. Sequencing for IDH1 codon 132 and IDH2 codon 172 gene mutations showed negative results. Furthermore, fluorescent analysis revealed 1p deletion in the lesion but no 19q deletion. Based on these findings, the tumor was diagnosed as diffuse midline gliomas with histone H3-K27M mutation in the spinal cord, corresponding to WHO grade IV. After 4 months of remission, the tumor recurred; 2 months later, the patient died. Herein, we report an extremely rare case of diffuse midline glioma with histone H3K27M mutation, which was morphologically characterized simultaneously by primitive neuroectodermal tumor-like appearance and neuropil-like islands.
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Glioma/patologia , Histonas/genética , Mutação , Neoplasias da Medula Espinal/patologia , Vértebras Cervicais , Feminino , Glioma/diagnóstico , Glioma/diagnóstico por imagem , Glioma/genética , Humanos , Isocitrato Desidrogenase/genética , Pessoa de Meia-Idade , Tumores Neuroectodérmicos Primitivos/patologia , Neurópilo/patologia , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Oligodendroglioma/patologia , Neoplasias da Medula Espinal/diagnóstico , Neoplasias da Medula Espinal/diagnóstico por imagem , Neoplasias da Medula Espinal/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Thyroid cancer 1 (TC1, C8orf4) plays important roles in tumors. The aim of this study was to examine the protein expression levels, methylation status, and mutational status of TC1 (C8orf4) in lung cancers, and investigate the correlation between TC1, other members of the Wnt signaling pathway, and lung cancer. TC1 expression levels were assessed via immunohistochemical staining in 179 cases of lung cancer. ß-catenin, TCF4, Axin, Disabled-2, Chibby, and DNA methyltransferase-1 (DNMT1) expressions were also examined. Bisulfite sequencing PCR analysis was used to examine the methylation status of the C8orf4 locus, while PCR analysis and direct sequencing were used to determine its mutational status. We found high TC1 expression correlated with poor differentiation, advanced TNM stage, lymphatic metastasis, and poor prognosis in lung cancer patients. TC1 expression also correlated with ß-catenin and DNMT1 expressions. No mutations in C8orf4 were detected. However, methylation levels of C8orf4 in lung cancers were lower than in corresponding normal lung tissues. In conclusion, high TC1 expression is implicated in lung cancer progression and correlates with poor prognosis in lung cancer. Reduced methylation levels might be responsible for the elevated TC1 expression levels. TC1, ß-catenin, and DNMT1 can synergistically activate Wnt/ß-catenin signaling in lung cancers.
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HPV 16 E6 upregulates hTERT expression in lung cancer cells. However, the underlying molecular mechanism is unclear. In this paper, E6, LKB1, SP1, and hTERT mRNA expression levels were detected in brushing cells of patients with lung cancer (n = 106) and with benign lung disease (n = 68) by qRT-PCR. The mRNA expression levels of E6, SP1, and hTERT were significantly increased in the malignant group compared with the benign group (P < 0.01). Conversely, the mRNA expression level of LKB1 was significantly decreased in the malignant group (P < 0.01). Furthermore, the correlation between E6, Sp1, hTERT, and LKB1 was performed, our results indicated that E6, Sp1, and hTERT with positive, but LKB1 with negative correlation (P < 0.01). To investigate the potential relationship between these genes, using double directional genetic manipulation, we showed that overexpression of E6 in H1299 cells down-regulated LKB1 mRNA and protein expression but up-regulated SP1 and hTERT as well as the transcriptional activity of Sp1. In contrast, knockdown of E6 in A549 cells by short-interference RNAs (siRNAs) up-regulated LKB1 expression, but down-regulated SP1 and hTERT expression as well as Sp1 activity. LKB1 loss upregulated both SP1 and hTERT at the protein and mRNA level as well as SP1 activity. To verify that the role of E6 on hTERT was mediated by SP1, siRNA knockdown of SP1 was performed on both H1299 and A549 cell lines. Inhibition of SP1 downregulated hTERT expression. Our results indicate that HPV16 E6 indirectly upregulated the expression of hTERT by inhibition of LBK1 expression and upregulation of Sp1 expression, thus suggesting a HPV-LKB1-SP1-hTERT axis for the tumorigenesis of lung cancer. Our study also provides new evidence to support the critical role of SP1 and LKB1 in the pathogenesis of HPV-related lung cancer, and suggests novel therapeutic targets.
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Neoplasias Pulmonares/metabolismo , Proteínas Oncogênicas Virais/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Telomerase/metabolismo , Fator de Transcrição AP-1/metabolismo , Quinases Proteína-Quinases Ativadas por AMP , Adulto , Idoso , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Oncogênicas Virais/genética , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Proteínas Repressoras/genética , Telomerase/genética , Fator de Transcrição AP-1/genéticaRESUMO
Long-term persistent infection of HPV16 E6/E7 is frequently associated with lung cancers, especially in non-smokers and in Asians. However, molecular mechanisms of HPV16 E6/E7 induction of lung cancer are not fully understood. Using bi-directional genetic manipulation and four well-established lung cancer cell lines, we showed HPV16 E6/E7 downregulated expression of liver kinase B1 at both protein and messenger RNA levels; liver kinase B1 downregulated hypoxia-inducible factor 2α at protein level but not at messenger RNA level, and hypoxia-inducible factor 2α upregulated vascular endothelial growth factor at both protein and messenger RNA levels. This is the first study to show hypoxia-inducible factor 2α as a downstream effector of liver kinase B1 in lung cancer cells. Our results indicate that HPV16 E6/E7 indirectly upregulated the expression of vascular endothelial growth factor by inhibition of liver kinase B1 expression and upregulation of hypoxia-inducible factor 2α expression, thus propose a human papillomavirus-liver kinase B1-hypoxia-inducible factor 2α-vascular endothelial growth factor axis for the tumorigenesis of lung cancer. Our study also provides new evidence to support the critical role of liver kinase B1 in the pathogenesis of human papillomavirus-related lung cancer and suggests novel therapeutic targets.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Papillomavirus Humano 16/genética , Neoplasias Pulmonares/genética , Proteínas Oncogênicas Virais/genética , Proteínas E7 de Papillomavirus/genética , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Repressoras/genética , Fator A de Crescimento do Endotélio Vascular/biossíntese , Quinases Proteína-Quinases Ativadas por AMP , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Papillomavirus Humano 16/patogenicidade , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/virologia , Proteínas Serina-Treonina Quinases/genética , Ativação Transcricional/genética , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Imaging and histology of clear-cell ependymoma and cerebellum-based hemangioblastoma are similar; distinguishing between them is a diagnostic challenge. CASE PRESENTATION: A 62-year-old Chinese woman presented with an intermittent headache of 8 years' duration. Computed tomography and magnetic resonance imaging revealed a mass in the cerebellum. Neurological imaging suggested hemangioblastoma (HB). Histologically, the tumor included cellular and paucicellular areas, in which cells were arranged in nests or diffusely distributed; and a highly vascular area, in which tumor cells were arranged in clusters and separated by capillaries. At low magnification, the tumor mimicked cellular HB, but at high magnification, tumor cells showed clear cytoplasm instead of the vacuolated cytoplasm typically observed in HB. Moreover, spindly, bipolar elements resembling tanycytes were observed within the nest structures. Although these features indicated the possibility of ependymoma, neither true ependymal rosettes nor an ependymal-lined profile was observed. The tumor was characterized by prominent vascularity, but glomeruloid formation was absent. We saw pleomorphism in foci of some tumor giant cells, but pathologic mitosis and palisaded necrosis were absent. Most tumor cells were positive for glial fibrillary acidic protein and S100. Epithelial membrane antigen was expressed with a paranuclear dot-like or a ring-like pattern. The Ki-67 index was approximately 2%. Considering the patient's symptom, neurological imaging, and pathological findings, she was diagnosed as cerebellar ependymoma (WHO grade II). CONCLUSIONS: Here, we report a case of ependymoma with overlapping clear-cell and tanycytic features, and review the literature to evaluate its real incidence. Pathologists should consider this rare diagnosis when confronted with a similar presentation.
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Neoplasias Cerebelares/patologia , Células Ependimogliais/patologia , Ependimoma/patologia , Hemangioblastoma/patologia , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Biópsia , Neoplasias Cerebelares/química , Neoplasias Cerebelares/genética , Angiografia Cerebral/métodos , Deleção Cromossômica , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 19 , Angiografia por Tomografia Computadorizada , Diagnóstico Diferencial , Células Ependimogliais/química , Ependimoma/química , Ependimoma/genética , Feminino , Hemangioblastoma/química , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Gradação de Tumores , Valor Preditivo dos TestesRESUMO
BACKGROUND: Biopsy, brushing, and transbronchial needle aspiration (TBNA) are the most common methods used for the diagnosis of small cell lung cancer during the same diagnostic bronchoscopic procedure. However, it is not clear which method provides better results. PATIENTS AND METHODS: A retrospective analysis was performed of 140 patients who had undergone video bronchoscopy for diagnostic purposes. Bronchial brushings were obtained from all subjects. Biopsy specimens were also obtained from all subjects, except for 6 cases that could not be sampled; the TBNA method was used for some special lesions. The results were analyzed separately by histology and cytology. RESULTS: The diagnostic yield of cytology was significantly greater than that of histology (P < .01) and that of conventional smear preparations in cytology was obviously greater than that of hematoxylin and eosin stains in histology (P < .01). The false-negative results were significantly lower with cytology than with histology (P < .01). Also, the cases of sampling site restriction with cytology were distinctly less than those with histology (P < .05). Stretch deformation of the tissue structure and cell morphology was the main reason for the false-negative results in the histologic diagnosis. The use of TBNA resolved all 4 cases of hilar adenopathy and 2 cases of lesions outside the bronchus. Multiple brushings of the tissue adjacent to cancer tissue and liquid-based preparations of cancerous necrotic tissue can significantly reduce the false-negative results from biopsy. CONCLUSIONS: The diagnostic yield of cytologic examination of brushings and TBNA for small cell lung cancer was superior to that of histologic examination of hematoxylin and eosin stains and immunohistochemistry.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Citodiagnóstico/métodos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Adulto , Idoso , Biópsia , Broncoscopia , Corantes , Amarelo de Eosina-(YS) , Reações Falso-Negativas , Feminino , Hematoxilina , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Coloração e RotulagemRESUMO
Hemangioblastoma is a well-circumscribed, highly vascular, lipid-rich and low-grade tumor of uncertain histogenesis. Its histopathological features have been well established. Herein, we present a case of cerebellar hemangioblastoma in a 43-year-old woman. Histologically, the tumor was predominantly composed of cellular areas showing eosinophilic or vacuolated stromal cells arranged in nests and sheets. Focally, conventional reticular areas could be seen. Additionally, in some areas, the stromal cells were arranged radially around blood vessels, exhibiting perivascular pseudorosette structures, which were similar mostly to those of ependymomas. Immunohistochemically, the stromal cells markedly showed diffused staining for Vimentin, S-100, CD56, NSE, inhibin-a, podoplanin, alpha-Thalassemia/mental retardation syndrome X and carbonic anhydrase IX, and were negative for cytokeratin, epithelial membrane antigen, oligodendrocyte transcription factor 2, neuronal nuclear antigen, synaptophysin, isocitrate dehydrogenase 1 (R132H), P53 and CD34. Interestingly, the reticular and cellular areas either showed no or individual scattering of the GFAP-positive cells, respectively, while, the perivascular pseudorosette areas strongly and diffusely expressed GFAP. Nuclear mitosis and necrosis were not observed. The MIB-1 antibody labeling index was especially low (about 3%). Based on these findings, the patient was diagnosed with cerebellar hemangioblastoma. In the present case, we documented a distinctive histological appearance of perivascular pseudorosettes in hemangioblastoma and provided the evidence for stromal cells with glial differentiation.