Thymic adenocarcinoma accompanied by type A thymoma and pulmonary minimally invasive adenocarcinoma and harboring distinct gene alterations: A case report.

RATIONALE: Thymic adenocarcinoma is an extremely rare thymic carcinoma. The exact genetic alteration associated with thymic adenocarcinoma is unclear. Here, we report a case of thymic adenocarcinoma accompanied by type A thymoma and pulmonary minimally invasive adenocarcinoma (MIA). PATIENT CONCERNS: A 53-year-old woman presented with multiple nodules in the mediastinum and lung. Thoracic computed tomography revealed nodules in the anterior superior mediastinum and anterior mediastinum near the right pericardium and ground-glass opacity (GGO) in the right superior lobe of the lung. DIAGNOSIS: The tumor in the anterior superior mediastinum was diagnosed as primary thymic papillary adenocarcinoma. The tumor in the anterior mediastinum near the right pericardium was diagnosed as type A thymoma. The GGO of the right superior lobe of the lung was diagnosed as a MIA. INTERVENTION: The patient underwent thoracoscopic mediastinal tumor resection and partial lobectomy in our hospital. OUTCOMES: The postoperative course was uneventful. The patient is alive and free of the disease for 22 months after diagnosis. LESSONS: Thyroid transcription factor 1 (TTF-1) was positive in this case of thymic adenocarcinoma, which indicated that a thymic adenocarcinoma with TTF-1-positive may not necessarily be a metastasis of lung or thyroid adenocarcinoma. The positive staining of CD5 and CD117 can help us to confirm the thymic origin. Molecular genetic analysis indicated that these tumors harbored different mutations. The thymic adenocarcinoma and type A thymoma both had the mutation of KMT2A, but the mutation sites were different. KMT2A mutation may be a common genetic change in thymic tumorigenesis. The genetic alterations disclosed in this study will help expand the understanding of thymic tumors.

Nkx2.1 downregulation is involved in brain abnormality induced by excess retinoic acid.

Abnormal development of central nervous system (CNS) caused by neural tube defects is not only a major contributor in the prevalence of stillbirths and neonatal deaths but also causes lifelong physical disability in surviving infants. Due to insufficient known investigated causes, CNS developmental abnormality has brought sever burden on health around the world. From previous results of high throughput transcriptome sequencing, we selected transcription factor Nkx2.1 as a candidate to investigate its role on brain abnormalities induced by excessive retinoic acid. The result of in situ hybridization showed that Nkx2.1 was mainly expressed in mouse brain. After the Nkx2.1 gene was silenced, retarded proliferation and accelerated apoptosis were found in mouse Neuro-2a (N2a) cells. Furthermore, our results indicated that the main components of sonic hedgehog (Shh) signaling pathway were affected in Nkx2.1-silenced cells, implying that Nkx2.1 plays an important role in the development of mouse brain by regulating Shh signaling pathway.

Epigenetic Changes During Human Thyroid Cell Differentiation.

Objective: It has been demonstrated that the transcription factors TAZ (transcriptional coactivator with PDZ-binding motif), paired box gene 8 (PAX8), and NK2 homeobox 1 (NKX2-1) are coexpressed in the nucleus of thyroid cells. Furthermore, TAZ is known to enhance the transcriptional activity of PAX8 and NKX2-1 as well as the key thyroid-specific gene, thyroglobulin (TG), suggesting a critical role for TAZ in the control of thyroid cell speciation. We previously reported that the small molecule ethacridine, identified as a TAZ activator, was able to induce thyroid-specific transcription in endodermal cells differentiated from human embryonic stem (hES) cells using activin A. Since transcription factors are epigenetically regulated in cell differentiation, we investigated the epigenetic changes in the promoter regions of these key transcription factors during in vitro differentiation of hES cells into thyrocytes. Methods: We initially profiled chromatin accessibility using the technique of Assay for Transposase Accessible Chromatin sequencing (ATAC-seq), and then examined DNA methylation and histone acetylation in the promoter regions of the three selected thyroid transcription factors and the thyroid-specific genes during hES cell differentiation. Results: ATAC-seq analysis showed enriched chromatin accessibility of TAZ, NKX2-1, and PAX8 after exposure to activin A and ethacridine. There were no methylation changes found in the NKX2-1, PAX8, and TAZ promoters by bisulfite sequencing. In contrast, acetylation of histone H4, specifically acetylation of lysine 16, was observed in each of the promoters when measured by chromatin immunoprecipitation polymerase chain reaction assays, which correlated with the activity and expression of NKX2-1 and PAX8 as well as sodium/iodide symporter, thyroid stimulating hormone receptor, and TG genes. Conclusions: These results indicate that ethacridine treatment of activin A-derived endodermal hES cells leads to enhanced chromatin accessibility, which, in turn, allows histone H4 acetylation in the regulation of active genes for speciation of thyroid follicular cells from hES cells.

Immunohistochemistry Profile Predicts EGFR Mutation Status in Lung Adenocarcinoma.

Significant advances in targeted therapy have been made in recent years for patients with lung adenocarcinoma. These targeted therapies have made molecular testing of paramount importance to drive therapeutic decisions. Material for testing is often limited, particularly in cytology specimens and small core biopsies. A reliable screening tool is invaluable in triaging limited tissue and selection for epidermal growth factor receptor (EGFR) mutation testing. We hypothesized that the immunohistochemistry (IHC) profile of lung adenocarcinoma predicts EGFR mutation status. In this retrospective study, we evaluated the thyroid transcription factor-1 (TTF-1)/napsin A IHC profile and EGFR mutation status in 339 lung adenocarcinomas at our academic institution. In our cohort, we found that 92.3% of cases were positive for TTF-1 and/or napsin A by IHC with an EGFR positivity rate of 17.3%. Importantly, 7.7% of the cases were dual TTF-1/napsin A negative, and none of these cases contained EGFR mutations. This finding supports the use of TTF-1 and napsin A IHC to identify cases where EGFR mutation status will be negative, thus preserving limited tissue for other ancillary testing.

Correlation of Thyroid Transcription Factor-1 Expression with EGFR Mutations in Non-Small-Cell Lung Cancer: A Meta-Analysis.

OBJECTIVES: This meta-analysis investigated the relationship between thyroid transcription factor-1 (TTF-1) expression and epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) to clarify whether TTF-1 can be a potential surrogate marker for EGFR mutation status in advanced NSLCL. METHODS: A systematic searching of databases, including PubMed, EMBASE, Cochrane Library, and Google Scholar, was performed to identify studies assessing the correlation of TTF-1 expression with EGFR mutations. From 17 studies, 9764 patients were included in the combined analysis of odds ratio (OR) for the correlation between TTF-1 expression and EGFR mutations. RESULTS: Compared with NSCLCs showing negative TTF-1 expression, tumors harboring TTF-1 overexpression showed a significantly higher rate of EGFR mutations (OR = 5.19, 95% confidence interval: 3.60⁻7.47, p < 0.00001). This correlation was observed in both subgroups of East Asian (OR = 4.33, 95% CI: 3.46⁻5.41, p < 0.00001) and European patients (OR = 4.64, 95% CI: 1.41⁻15.28, p < 0.01). In addition, TTF-1 expression was significantly associated with EGFR mutations in exon 19 (OR = 4.63, 95% CI: 2.89⁻7.41, p < 0.00001) as well as exon 21 (OR = 3.16, 95% CI: 1.04⁻9.60, p = 0.04). CONCLUSIONS: This meta-analysis demonstrates a significant correlation between TTF-1 expression and EGFR mutations in patients with NSCLC. The status of TTF-1 expression may be a biomarker to guide anticancer treatment in patients with NSCLC and unknown EGFR mutation status.

Cytokeratin 7 and thyroid transcription factor - 1 levels in patients with lung cancer complicated with superior vena cava syndrome and their correlation with clinicopathological characteristics.

PURPOSE: This study aimed to detect the levels of cytokeratin 7 (CK7) and thyroid transcription factor -1(TTF-1) in serum of patients with non-small cell lung cancer (NSCLC) complicated with superior vena cava syndrome (SVCS), and to explore their prognosis and relationship and correlation with pathological characteristics. METHODS: 68 patients with non-small cell lung cancer (NSCLC) complicated with SVCS treated in Shaoxing Second Hospital from July 2014 to May 2018 were selected as the experimental group, 60 normal healthy persons as the control group, and 60 patients with lung cancer as the lung cancer group. The levels of CK7 and TTF-1 in the three groups were determined by enzyme-linked immunosorbent assay (ELISA), and the differences were compared. The relationship between the expression levels of CK7 and TTF-1 and clinicopathological characteristics of patients, the correlation between CK7 and TTF-1 in lung cancer patients complicated with SVCS, and their 3-year survival rate were analyzed. RESULTS: CK7 and TTF-1 levels in experimental group were significantly higher than those in control group (P<0.05). The levels in lung cancer group were significantly higher than those in control group (P<0.05). In experimental group, the expression of CK7 and TTF-1 was not related to gender, age, weight, histological classification and tumor size (P>0.05)). CK7 expression was positively correlated with TTF-1 expression in lung cancer patients (P<0.001). The 3-year survival rate in CK7 and TTF-1 high expression group was significantly lower than that in low expression group (P<0.05). CONCLUSION: The expressions of CK7 and TTF-1 are increased in patients with lung cancer complicated with SVCS, and are related to TNM stage, lymph node metastasis and differentiation degree. The high expressions of CK7 and TTF-1 in serum of patients are expected to be potential prognostic indicators for lung cancer complicated with SVCS.

Thyroid transcription factor-1 promotes lymph node metastasis by inducing lymphangiogenesis in ovarian carcinoma.

AIMS AND BACKGROUND: Thyroid transcription factor-1 (TTF-1) expression is widely considered a specific marker for lung and thyroid carcinomas and plays an important role in angiogenesis in lung cancer. However, it can occasionally be expressed in other malignancies, including ovarian carcinomas, and the mechanism of TTF-1 in lymphatic metastasis of ovarian carcinomas is still unclear. This study aimed to define the TTF-1 expression and lymph vessel density (LVD) in ovarian carcinomas and look for their correlations with clinicopathological features. METHODS: We examined the incidence of thyroid transcription factor 1 expression (clone SPT24) and lymph vessel density (LVD) quantified through D2-40 by immunohistochemistry from 110 primary ovarian carcinomas and 40 benign ovarian tumor as controls in Chinese patients. RESULTS: Thyroid transcription factor 1 was detected in 28 primary ovarian carcinomas (25.5%), which was significantly higher than its expression in benign ovarian tumor. TTF-1 expression was correlated with tumor FIGO stage,T stage and lymphatic metastasis. Moreover, LVD was associated with tumor FIGO stage, TNM stage. Furthermore, the LVD counts in group of TTF-1 positive expression were higher than in group of TTF-1 negative expression. CONCLUSIONS: These findings indicated the occasional expression of TTF-1 immunoreactivity of ovarian carcinomas should be considered in the evaluation of neoplasms of unknown primary origin and TTF-1 might be involved in lymph node metastasis of ovarian carcinomas in the presence of lymphangiogenesis.

Inverse correlation between galectin-4 and TTF-1 in lung adenocarcinoma.

We have previously shown that galectin-4 expression is an independent predictor for lymph node metastasis and serves as an adverse prognostic indicator in patients with acinar adenocarcinoma of the lung. In contrast, thyroid transcription factor-1 (TTF-1) expression in non-small cell lung carcinoma has been shown to be associated with a favorable prognosis. In the present study, 208 cases of acinar adenocarcinoma of the lung and 36 cases with distant metastatic lesions of lung adenocarcinoma were immunohistochemically examined for expression of galectin-4 and TTF-1 to elucidate their correlation with clinicopathological factors. TTF-1 expression was observed in 145 cases (69.7%) and associated with smaller tumor size, infrequent pleural invasion, and lower TNM stage. Galectin-4 expression was observed in 86 cases (41.3%). Furthermore, galectin-4-positive carcinoma cells and TTF-1-positive carcinoma cells existed exclusively within the same lesion. Expressions of TTF-1 and galectin-4 were favorable and adverse prognostic factors, respectively. Approximately 40% (15/36 cases) of lung adenocarcinoma at the distant metastatic sites were immunohistochemically negative for TTF-1. Four out of five galectin-4-positive metastatic lesions were negative for TTF-1. We found an inverse correlation between galectin-4 and TTF-1 expressions in acinar adenocarcinoma, and this phenomenon was also found to be present in metastatic sites. These findings suggest that we should not exclude the possibility of metastatic adenocarcinoma of the lung, even if the tumor cells are immunohistochemically negative for TTF-1 in the primary unknown tumor, because aggressive lung adenocarcinomas often lack TTF-1 expression.