Ephrin Receptors (Ephs) Expression in Thymic Epithelial Tumors: Prognostic Implications and Future Therapeutic Approaches

Ephrin receptors (Ephs) are receptor tyrosine kinases (RTKs) implicated in tissue development and homeostasis, and they are aberrantly expressed in tumors. Here, immunohistochemical Eph type-A and -B expression in thymic epithelial tumors (TETs) was assessed and correlated with clinicopathological parameters. Tissue microarrays from 98 TETs were stained for EphA1, -A2, -A4 -A6, -B1, -B2, -B4 and -B6. The relationship between neoplastic and lymphoid cell immunoreactivity score (H-score), histopathological parameters (Pearson’s test) and survival of 35 patients (Mantel-Cox model) was explored. Epithelial-rich subtypes showed higher EphA6 cytoplasmic H-score (B2/B3, carcinoma) (p < 0.001) and stronger EphA4 H-score (B3, carcinoma) (p = 0.011). The immature T-cells, especially in subtypes AB/B1, had higher EphB6 H-score than carcinoma-associated mature lymphocytes (p < 0.001); carcinomas had higher lymphocytic EphB1 H-score (p = 0.026). Higher lymphocytic and lower epithelial EphB6 H-score correlated with Masaoka stage ≤II (p = 0.043, p = 0.010, respectively). All cases showed variable epithelial and lymphocytic EphA2 expression, but clinicopathological associations were not reached. Our study confirmed that Eph type-A and -B expression in TETs is associated with established prognostic parameters, i.e., tumor subtype and Masaoka stage, although correlation with patient survival was not reached. Such findings suggest involvement of these RTKs in thymic neoplasia, as well as their potential utility as treatment targets.

The Expression of PD-L1 and B7-H4 in Thymic Epithelial Tumor and Its Relationship With Tumor Immune-Infiltrating Cells

BackgroundPD-L1 and B7-H4 have been reported to be expressed in various malignancies and are considered as promising prognostic factors and potential immunotherapy targets.MethodsWe analyzed the correlation between the expression of PD-L1 and B7-H4 transcriptomes and clinicopathological characteristics in 121 TET patients from The Cancer Genome Atlas (TCGA) database. The immune-infiltration levels in the TET microenvironment were estimated using ssGSEA and quanTiseq algorithms. We collected 80 TET cases from 2008 to 2015. PD-L1、B7-H4、FOXP3 and CD163 protein expression in tumor tissues were detected by immunohistochemistry.ResultsTCGA database showed PD-L1 mRNA levels can predict the OS (P = 0.018) and DFS (P = 0.033) of TET patients. B7-H4 mRNA levels were positively related to the World Health Organization (WHO) pathological classification (P = 0.003) but not correlated with patient prognosis. Immune infiltration analysis showed PD-L1 is positively correlated with Tregs and M2 macrophages, B7-H4 is positively correlated with Tregs. Patients with high PD-L1 and Tregs or M2 macrophages, high B7-H4 and Tregs had a worse prognosis. Immunohistochemistry showed PD-L1 expression was positively correlated with the WHO pathological classification and Masaoka stage (P = 0.025, 0.003) and high PD-L1 expression can predict the poor OS of patients (P = 0.043); B7-H4 was also positively correlated with WHO pathological classification and Masaoka stage (P = 0.036, 0.049). However, B7-H4 expression did not correlate with patient prognosis. Evaluation of co-expression patterns showed TET patients with a high-grade WHO pathological classification harbored a 44.4% co-expression of PD-L1 and B7-H4. In addition, we found the expression level of PD-L1 is positively correlated with FOXP3 and CD163 (P = 0.004, P = 0.029) and B7-H4 is positively correlated with FOXP3 (P = 0.037). High PD-L1 combined with High FOXP3 and High CD163, High B7-H4 combined with High FOXP3 can be used to predict the poor prognosis of TET patients (P = 0.026, 0.031, 0.028, respectively).ConclusionPD-L1 and B7-H4 were related to the aggressiveness of TET and their expression level can indicate the suppressive immune microenvironment. Combined with FOXP3 and CD163, PD-L1 and B7-H4 can indicate a poor prognosis of TET.

Prognostic Value of Systemic Inflammatory Markers and the Nutrition Status in Thymic Epithelial Tumors with Complete Resection

BackgroundRecent studies have shown that several systemic inflammatory markers and the nutrition status, including the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI), are useful prognostic factors in several malignant tumors. The present study explored the prognostic value of the NLR, MLR, PLR, and PNI in thymic epithelial tumor (TET) patients who underwent complete resection.MethodsA total of 158 TET patients who underwent complete resection were involved in the analysis. Their NLR, MLR, PLR, and PNI values were obtained from a blood examination within one month before the initiation of treatment. A receiver operating characteristic curve analysis was conducted to determine the optimal cut-off values. ResultsThe enrolled patients were stratified by cut-offs of 4.35 for the NLR, 0.22 for the MLR, 130.18 for the PLR, and 44.02 for the PNI. A univariate analysis revealed that high-grade malignant TET, including type B2 and B3 thymoma, thymic carcinoma, and thymic neuroendocrine tumor; an advanced Masaoka stage; a high NLR; a high MLR; and a low PNI were significant predictors of a poor disease-free survival (DFS). A multivariate analysis confirmed that an advanced Masaoka stage (HR = 5.5557, P = 0.0007) and a high MLR (HR = 3.3371, P = 0.0264) were independent predictors of a poor DFS.ConclusionsOur study demonstrated that the pretreatment MLR was an independent predictor of the DFS in patients with TETs who underwent complete resection.

Prognostic Significance of Metabolic Parameters by 18F-FDG PET/CT in Thymic Epithelial Tumors

Background: Imaging tumor FDG avidity could complement prognostic implication in thymic epithelial tumors. We thus investigated the prognostic value of volume-based 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT parameters in thymic epithelial tumors with other clinical prognostic factors. Methods: This is a retrospective study that included 83 patients who were diagnosed with thymic epithelial tumors and underwent pretreatment 18F-FDG PET/CT. PET parameters, including maximum and average standardized uptake values (SUVmax, SUVavg), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), were measured with a threshold of SUV 2.5. Univariate and multivariate analysis of PET parameters and clinicopathologic variables for time-to-progression was performed by using a Cox proportional hazard regression model. Results: There were 21 low-risk thymomas (25.3%), 27 high-risk thymomas (32.5%), and 35 thymic carcinomas (42.2%). Recurrence or disease progression occurred in 24 patients (28.9%). On univariate analysis, Masaoka stage (p < 0.001); histologic types (p = 0.009); treatment modality (p = 0.001); and SUVmax, SUVavg, MTV, and TLG (all p < 0.001) were significant prognostic factors. SUVavg (p < 0.001) and Masaoka stage (p = 0.001) were independent prognostic factors on multivariate analysis. Conclusion: SUVavg and Masaoka stage are independent prognostic factors in thymic epithelial tumors.

Effect of Postoperative Radiotherapy in Thymoma Patients: A SEER-Based Study

<b><i>Introduction:</i></b> The role of postoperative radiation therapy (PORT) for thymoma is under debate, especially in patients aged ≥60 years with an advanced stage (Masaoka stages III and IV). We aimed to evaluate the efficacy of PORT for thymoma in a population-based registry. <b><i>Methods:</i></b> A retrospective analysis of the Surveillance, Epidemiology, and End Results (SEER) database was conducted to compare the outcomes of thymoma patients with or without PORT. The primary outcomes were overall survival (OS) and cancer-specific survival (CSS). Conditional inference tree analyses were performed for risk classification according to the study variables. Cox regression was performed to evaluate the prognostic effect of PORT in the specific subgroups. <b><i>Results:</i></b> A total of 2,236 patients were included. The conditional inference tree analysis identified that an age ≥60, a Masaoka stage ≥3, and the year of diagnosis were important factors when classifying patients into prognostic subgroups. PORT was found to be a protective predictor of OS in patients aged ≥60 years, those with a Masaoka stage III—IV, and those diagnosed after 2005. Further subgroup analyses revealed that PORT was significantly associated with a better OS (HR = 0.77) in patients aged ≥60 years, whereas it was not significantly associated with CSS. <b><i>Conclusions:</i></b> An older age (≥60 years) is critical for predicting survival outcomes in thymoma patients. Moreover, patients aged ≥60 years could benefit from PORT in terms of OS.

Relationship of possible biomarkers with malignancy of thymic tumors: a meta-analysis

Background Role of biomarkers for promotion of tumor proliferation (BPTPs) and for promotion of apoptosis (BPAs) in thymic malignant tumors is still unclear. The purpose of this study was to evaluate the relationship between BPTPs and/or BPAs and malignancy of thymic malignant tumors. Methods Studies on thymic malignant tumors and biomarkers were searched in PubMed, ISI Web of Knowledge, and Embase databases, and all statistical analyses were conducted using Review Manager. Results Twelve articles related to biomarkers and thymic malignant tumors were selected and analyzed. A relationship between BPAs and Masaoka stage was demonstrated for four markers, namely Bax, p73, Casp-9 and Bcl-2, included 138 stage I/II patients and 74 stage III/IV patients, and BPAs were significantly correlated with high Masaoka staging (P = 0.03). We further found a relationship between BPAs and degree of malignancy for four markers, namely Bax, p73, Casp-9 and Bcl-2, included 176 thymoma patients and 36 thymic carcinoma patients, and BPAs were significantly correlated with thymic carcinoma (P = 0.010). In addition, a relationship between BPTP and Masaoka staging was demonstrated for seven markers, namely Podoplanin, Glut-1, Muc-1, Egfr, Igf1r, c-Jun, and n-Ras, included 373 patients with stage I/II and 212 patients with stage III/IV, and BPTPs were significantly correlated with high Masaoka staging (P < 0.001). We also found a relationship between BPTPs and degree of malignancy for ten markers, namely Mesothelin, c-Kit (CD117), Egfr, Lat-1, Muc-1,Ema, Glut-1, Igf1r, c-Jun, and n-Ras, included 748 thymoma patients and 280 thymic carcinoma patients, and BPTPs were significantly correlated with thymic carcinoma (P < 0.001). Conclusion These findings show that high levels of BPTPs or BPAs are more closely related to thymic carcinoma and Masaoka stage III/IV, suggesting that BPTPs and BPAs may play an important role in the occurrence and development of thymic malignant tumors.