• TYME network
• basaloid thymic carcinoma
• thymic cancer

• small molecule multitarget antiangiogenic inhibitors
• thymic carcinoma
• thymic epithelial tumor
• thymoma

• Humans
• Retrospective Studies
• Thymus Neoplasms/pathology
• Thymoma/pathology
• Neoplasms, Glandular and Epithelial/drug therapy

• Not applicable.

• cellular signaling network
• genomic
• molecular
• thymic carcinoma
• thymic epithelial tumors
• thymoma

• Humans
• Thymoma/genetics
• Thymus Neoplasms/diagnosis
• Thymus Neoplasms/genetics
• Thymus Neoplasms/pathology
• Neoplasms, Glandular and Epithelial/diagnosis
• Neoplasms, Glandular and Epithelial/genetics
• Prognosis
• Tumor Microenvironment/genetics

• classification
• mediastinum
• staging
• thymoma
• thymus

• Humans
• Thymoma/genetics
• Transcriptome/genetics
• Exome/genetics
• Clonal Evolution
• Thymus Neoplasms/diagnosis
• Thymus Neoplasms/drug therapy
• Thymus Neoplasms/genetics

• clinicopathologic characteristics
• prognosis
• progression-free survival (PFS)
• thymoma
• treatment

• ZZ22006 Beijing Association for Science and Technology's "Golden-Bridge Seed Funding Program"
• 2021YJJPY011 Hospital Founding of Beijing Tongren Hospital

• Digital spatial profiling
• GTF2I mutation
• Mouse model
• Thymic epithelial tumors

• Animals
• Humans
• Mice
• Mutation
• Neoplasms, Glandular and Epithelial/genetics
• Neoplasms, Glandular and Epithelial/pathology
• Thymoma/genetics
• Thymoma/pathology
• Thymus Neoplasms/genetics
• Thymus Neoplasms/pathology
• Transcription Factors, TFII/genetics
• Transcription Factors, TFIII/genetics

• P30 CA008748 NCI NIH HHS

• Thymic epithelial tumors
• Thymomas and Thymic carcinomas
• anti-angiogenic drugs
• immune checkpoint inhibitors
• phase I and II trials

Thymic epithelial tumors are rare tumors frequently associated with paraneoplastic syndromes, the most common being myasthenia gravis and pure red cell aplasia. While patients with limited-stage cancer can often undergo resolutive surgery, advanced surgically unresectable and metastatic tumors can be refractory to first-line platinum-based treatment and represent a medical challenge. Somatostatin receptor expression was documented in thymic tumors both in vivo and in vitro and represents the rationale for therapeutic use. Despite single-case reports and three single-arm phase II studies, as well as the inclusion of somatostatin analogs in National Comprehensive Cancer Network guidelines, the role of these drugs in thymic epithelial tumors is still rather undefined.

Thymic epithelial tumors are rare tumors usually presenting as a mass located in the anterior mediastinum and/or with symptoms deriving from associated paraneoplastic syndromes. Unresectable platinum-refractory tumors are often treated with alternative regimens, including chemotherapeutic agents as well as chemo-free regimens. The most popular unconventional therapy is represented by the somatostatin analog octreotide, which can be used alone or with prednisone. The in vivo expression of somatostatin receptors documented by imaging with indium-labeled octreotide or gallium-68 Dotapeptides, the successful use of octreotide and prednisone in a chemo-refractory patient, and, thereafter, the experiences from a case series have enforced the idea that this treatment merits consideration—as proved by its inclusion in the National Comprehensive Cancer Network guidelines. In the present review, we analyze the preclinical basis for the therapeutic use of somatostatin and prednisone in refractory thymic tumors and discuss the available studies looking at future perspectives.

• octreotide
• prednisone
• somatostatin
• targeted therapy
• thymic carcinoma
• thymic epithelial tumors
• thymoma

• Pleural thymoma
• extrapleural pneumonectomy (EPP)
• multimodality treatment
• thymoma

• biomarkers
• cerna network
• prognostic
• thymic epithelial tumors

• Biomarkers, Tumor/genetics
• Cohort Studies
• Computational Biology/methods
• Computational Biology/statistics & numerical data
• Datasets as Topic
• Disease Progression
• Gene Expression Regulation, Neoplastic/genetics
• Gene Ontology
• Gene Regulatory Networks
• Humans
• MicroRNAs/analysis
• Neoplasms, Glandular and Epithelial/genetics
• Predictive Value of Tests
• Prognosis
• Proportional Hazards Models
• RNA, Long Noncoding/analysis
• RNA, Messenger/analysis
• ROC Curve
• Thymus Neoplasms/genetics

• Genomic alterations
• PD-L1 expression
• thymoma

• biomarkers
• oncology

• Adult
• Aged
• Aged, 80 and over
• Antigens, Neoplasm/genetics
• Antigens, Neoplasm/immunology
• Biomarkers, Tumor
• Carcinoma, Squamous Cell/diagnosis
• Carcinoma, Squamous Cell/etiology
• Diagnosis, Differential
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Immunophenotyping
• Male
• Melanoma/diagnosis
• Melanoma/etiology
• Middle Aged
• Thymoma/diagnosis
• Thymoma/etiology
• Young Adult

• Ono Pharmaceutical Co., Ltd.
• Roche
• MSD
• AstraZeneca

• next-generation sequencing
• somatic profiling
• thymoma

• Indel
• Mutation
• Pathway
• Survival
• Thymic carcinomas
• Thymomas

Thymic epithelial tumors (TETs) belong to a group of tumors that rarely occur, but have unresolved mechanisms and heterogeneous clinical behaviors. Current care of TET patients demands biomarkers of high sensitivity and specificity for accurate histological classification and prognosis management. In this study, 134 fresh‐frozen tissue samples (84 tumor, 40 tumor adjacent, and 10 normal thymus) were recruited to generate a quantitative and systematic view of proteomic landscape of TETs. Among them, 90 samples were analyzed by data‐independent acquisition mass spectrometry (DIA‐MS) leading to discovery of novel classifying molecules among different TET subtypes. The correlation between clinical outcome and the identified molecules was probed, and the prioritized proteins of interest were further validated on the remaining samples (n = 44) via parallel reaction monitoring (PRM) as well as immunohistochemical and confocal imaging analysis. In particular, two proteins, the cellular mRNA deadenylase CCR4 (carbon catabolite repressor 4)‐NOT (negative on TATA) complex subunit 2/9 (CNOT2/9) and the serine hydroxymethyltransferase that catalyzes the reversible interconversions of serine and glycine (SHMT1), were found at dramatic low levels in the thymic epithelia of more malignant subtype, thymic squamous cell carcinoma (TSCC). Interestingly, the mRNA levels of these two genes were shown to be closely correlated with prognosis of the TET patients. These results extended the existing human tissue proteome atlas and allowed us to identify several new protein classifiers for TET subtyping. Newly identified subtyping and prognosis markers, CNOT2/9 and SHMT1, will expand current diagnostic arsenal in terms of higher specificity and prognostic insights for TET diagnosis and management.

• WHO classification
• molecular profiling
• protein classifiers
• targeted proteomics
• thymic epithelial tumors

The molecular pathogenesis of thymoma remains largely unknown. It has been recently demonstrated, that activation of Wnt signaling pathway leads to increased incidence of thymoma in murine models. The present study investigated the activation of molecules of the Wnt signaling pathway in human thymoma. A total of 112 thymoma cases with complete clinical and follow-up data and 8 controls were included in the present study. Patients with thymoma and controls were examined immunohistochemically for β-catenin and E-cadherin. The mRNA expression levels of CTNNB1, CCND1, MYC, AXIN2 and CDH1 were analyzed by reverse transcription-quantitative PCR. Immunohistochemically, β-catenin and E-cadherin were overexpressed in neoplastic cells of all thymomas. In type A, B1 and non-invasive type B2 thymoma, both molecules were located in the cytoplasm, in contrast to invasive type B2 and B3 thymoma, where membranous immunopositivities were observed. mRNA expression levels of genes involved in the Wnt pathway and of E-cadherin were significantly increased in both type A and B thymoma compared with controls; increasing gradually from type B1 to B3, and with higher stage of disease. In recurrent type B thymoma, the mRNA expression of the molecules was significantly higher. Despite the activation of Wnt pathway in indolent type A thymoma, the negative feedback of the pathway was preserved by overexpression of inhibitory molecule axin2, which was not overexpressed in type B thymoma. In summary, the Wnt pathway was activated in human thymoma and may contribute to oncogenesis. Detection of molecules of the Wnt pathway may be of diagnostic and prognostic value.

• E-cadherin
• Wnt
• axin2
• thymoma
• β-catenin

• Thymic carcinoma
• mutations
• targeted therapy
• thymic epithelial tumors

A thymoma is a tumor arising from the epithelium of the thymus, mostly occurring in the anterior mediastinum. The incidence of this disease is low and research progress in this field is slow. Consequently, there is an urgent need to investigate the correlation between molecular regulation and the prediction of survival and prognosis in patients with thymoma.

We collected thymoma datasets from The Cancer Genome Atlas (TCGA). Differentially expressed genes (DEGs) of TCGA datasets were then determined using R software. A gene signature was obtained by screening prognostic DEGs from the TCGA datasets using univariate and multivariate Cox survival analysis. The summation of the weighted expression levels was calculated as a risk score, which could then be used to predict the survival rate and prognosis of patients with thymoma. The validity of this model was verified by the analysis of receiver operating characteristic (ROC) curves and area under the curve (AUC).

In total, 297 DEGs were identified from the integrated results of TCGA datasets. A seven-gene signature, along with a regression model of prognostic risk, was obtained by Cox survival analysis. The expression levels of the seven genes were then weighted and summed to calculate the risk score for each sample. Patients were effectively divided into high- and low-risk groups using the median risk score (P < 0.05). ROC analysis showed that this Cox regression model was effective in predicting the prognosis of patients with thymus tumors (AUC = 0.983, P < 0.05).

For the first time, we identified an effective seven-gene signature in patients with thymic tumors. In the future, the risk and prognosis of patients can be preliminarily assessed using this model, although further testing is required to improve rigor.

• Gene signature
• Prognostic signature
• Risk score
• Thymoma

Currently, four immunohistochemical assays are registered with the US Food and Drug Administration to detect the expression of PD-L1. We investigated the PD-L1 expression in thymic carcinomas using these four diagnostic assays. The cases of 53 patients were reviewed and their specimens were subjected to four PD-L1 assays with different antibodies (SP142, SP263, 22C3, and 28-8). The PD-L1 expression in tumor cells (TCs) and immune cells (ICs) was evaluated. In TCs, the four assays showed similar scores in each case. Histopathologically, high TC scores were observed in squamous cell carcinomas (SqCCs). Meanwhile, there were no significant relationships among the IC scores in the four assays. In SqCCs, the high expression of PD-L1 (defined as ≥50% TC score) in TCs tended to be associated with early stage cancer. The patients with high expression levels of PD-L1 tended to show longer overall survival in the 22C3 assays (p=0.0200). In thymic carcinomas, the staining pattern showed high concordance among the four assays when TCs – rather than ICs – were stained. High PD-L1 positivity in TCs, especially in SqCCs, indicated that PD-1/PD-L1 targeted therapy may be a promising therapeutic approach.

• immunohistochemistry
• programmed death 1 (PD-1)
• programmed death ligand 1 (PD-L1)
• squamous cell carcinoma
• thymic carcinoma

• Animals
• Apoptosis/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Female
• Humans
• Hydrazines/pharmacology
• Karyopherins/antagonists & inhibitors
• Karyopherins/metabolism
• Mice
• Mice, Inbred NOD
• Mice, Nude
• Mice, SCID
• Neoplasms, Glandular and Epithelial/drug therapy
• Neoplasms, Glandular and Epithelial/metabolism
• Neoplasms, Glandular and Epithelial/pathology
• Random Allocation
• Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors
• Receptors, Cytoplasmic and Nuclear/metabolism
• Thymus Neoplasms/drug therapy
• Thymus Neoplasms/metabolism
• Thymus Neoplasms/pathology
• Triazoles/pharmacology
• Xenograft Model Antitumor Assays
• Exportin 1 Protein

• ZIA BC011410 Intramural NIH HHS

• Epigenetic regulation
• Thymic carcinoma
• Thymic epithelial tumors
• Thymoma
• miR-145-5p
• microRNA

The anti-apoptotic cellular FLICE-like inhibitory protein cFLIP plays a pivotal role in normal tissues homoeostasis and the development of many tumors, but its role in normal thymus (NT), thymomas and thymic carcinomas (TC) is largely unknown.

Expression, regulation and function of cFLIP were analyzed in biopsies of NT, thymomas, thymic squamous cell carcinomas (TSCC), thymic epithelial cells (TECs) derived thereof and in the TC line 1889c by qRT-PCR, western blot, shRNA techniques, and functional assays addressing survival, senescence and autophagy. More than 90% of thymomas and TSCCs showed increased cFLIP expression compared to NT. cFLIP expression declined with age in NTs but not in thymomas. During short term culture cFLIP expression levels declined significantly slower in neoplastic than non-neoplastic primary TECs. Down-regulation of cFLIP by shRNA or NF-κB inhibition accelerated senescence and induced autophagy and cell death in neoplastic TECs.

The results suggest a role of cFLIP in the involution of normal thymus and the development of thymomas and TSCC. Since increased expression of cFLIP is a known tumor escape mechanism, it may serve as tissue-based biomarker in future clinical trials, including immune checkpoint inhibitor trials in the commonly PD-L1^high thymomas and TCs.

• NF-κB
• autophagy
• cFLIP
• senescence
• thymic tumors

Combined thymic carcinoma is a malignant neoplasm of the thymus recently added to the 4th edition of the World Health Organization (WHO) classification of tumors of the lung, pleura, thymus and heart. It involves at least one type of thymic carcinoma and another thymic epithelial tumor. The previously used term “combined thymic epithelial tumor” has been abandoned.

Here, we present an unusual case of combined thymic carcinoma of the thymus in a 44-year-old male who had suffered from fever, chest pain, chest tightness and shortness of breath. Magnetic resonance imaging (MRI) detected a mass approximately 6.4 cm × 4.2 cm in the anterior mediastinum, and a nonencapsulated tumor approximately 5.0 cm × 3.5 cm × 2.5 cm with an irregular shape was resected. The morphological features and the immunostaining pattern of the tumor revealed it to be an unusual combined thymic carcinoma consisting of type AB thymoma and squamous cell carcinoma. There were cysts of various sizes, some of which had crack-like structures, in the type AB thymoma area. A gradual transition could be seen between these structures and the squamous cell carcinoma, indicating that the carcinoma portion may have originated from the composition of the thymoma.

Combined thymic carcinoma composed of type AB thymoma and squamous cell carcinoma is rare, and the carcinoma portion may have originated from epithelial structures in the type AB thymoma.

• Combined thymic carcinoma
• Mediastinum
• Squamous cell carcinoma
• Type AB thymoma

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Delayed-Action Preparations
• Female
• Humans
• Male
• Middle Aged
• Neoadjuvant Therapy
• Neoplasm Recurrence, Local/drug therapy
• Octreotide/administration & dosage
• Octreotide/adverse effects
• Prednisone/administration & dosage
• Prednisone/adverse effects
• Thymoma/drug therapy
• Thymoma/pathology
• Thymus Neoplasms/drug therapy
• Thymus Neoplasms/pathology
• Treatment Outcome

• Immune checkpoint inhibitors
• Malignant pleural mesothelioma
• SCLC
• Thymic epithelial tumors

Thymoma is the most commonly identified cancer in the anterior mediastinum. To date, the causal mechanism that drives thymoma progression is not clear. Here, we generated K5-ΔN64Ctnnb1/ER^T2 transgenic mice, which express an N-terminal deletion mutant of β-catenin fused to a mutated ligand-binding domain of estrogen receptor (ER^T2) under the control of the bovine cytokeratin 5 (K5) promoter. The transgenic mouse lines named Tg1 and Tg4 were characterized. Forced expression of ΔN64Ctnnb1/ER^T2 in the Tg1 and Tg4 mice developed small thymoma lesions in response to tamoxifen treatment. In the absence of tamoxifen, the Tg1 mice exhibited leaky activation of β-catenin, which activated the TOP-Gal transgene and Wnt/β-catenin-targeted genes. As the Tg1 mice aged in the absence of tamoxifen, manifest thymomas were found at 10-12 months. Interestingly, we detected loss of AIRE and increase of p63 in the thymomas of Tg1 mice, similar to that observed in human thymomas. Moreover, the β5t protease subunit, which was reported as a differential marker for human type B3 thymoma, was expressed in the Tg1 thymomas. Thus, the Tg1 mice generated in this study accurately mimic the characteristics of human thymomas and may serve as a model for understanding thymoma pathogenesis.

• AIRE
• cytokeratin 5
• p63
• thymic epithelium
• thymus
• β5t

• Thymic epithelial tumor (TET)
• histology
• reporting

• Mutation
• PI3K
• PI3K inhibitor
• Thymic epithelial tumor

• Programmed cell death-1
• Targeted therapy
• Thymic carcinoma
• Thymic epithelial tumors
• Thymoma

The World Health Organization (WHO) has classified thymic carcinoma and other thymomas (types A, AB, and B) as different neoplasms. Myasthenia gravis (MG) is an early sign of thymoma and theoretically does not accompany thymic carcinoma; however, cases of thymic carcinoma with MG have been reported. Whether thymic carcinoma can accompany MG has yet to be established.

The medical records of patients who underwent thymectomy for MG between 1990 and 2011 in a single hospital were reviewed. All cases with the diagnostic code of "thymic carcinoma" or "thymoma type C" (old terminology) were selected. A pathologist re-reviewed the pathologic specimens using the new WHO criteria. The rate of thymic carcinoma among these MG patients was then calculated.

A total of 81 patients with MG had thymic tumors, 10 of whom had thymic carcinomas or thymoma type C. Seven cases of well-differentiated thymic carcinomas (type B3) were excluded, leaving three (3.7%) cases of thymic carcinoma with MG. All three of these cases were type B3 thymoma with a focal squamous cell carcinoma component that was very small and well demarcated. In addition, two out of the three tumors were found to be at an early clinical stage. All of the cases survived without recurrence over follow-up periods of at least 5 years.

Thymic carcinoma transformation from thymoma can occur during the early stages of thymoma. The association of this condition with MG is not as rare as was previously thought. Thymic carcinomas accompanying MG had a predominant B3 thymoma component with a focal thymic carcinoma area (squamous cell carcinoma).

• myasthenia gravis
• thymectomy
• thymic carcinoma
• thymic squamous cell carcinoma
• thymoma

• Carcinomes thymiques
• Chirurgie
• Radiotherapy
• Radiothérapie
• Surgery
• Thymic carcinomas
• Thymic epithelial tumors
• Thymomas
• Thymomes
• Tumeurs épithéliales thymiques

Thymomas and thymic carcinoma are rare tumors with no approved therapies. Our purpose was to analyze the molecular features and outcomes of patients referred to the Clinical Center for Targeted Therapy (Phase I Clinic).

We retrospectively reviewed the medical records of consecutive referred patients with advanced/metastatic thymoma or thymic carcinoma

Twenty-one patients were identified (median age 52 years; 10 women; median number of prior systemic therapies = 2). Six of 10 patients (60%) treated with mTOR inhibitor combination regimens achieved stable disease (SD) ≥12 months or a partial response (PR). For patients treated on mTOR inhibitor regimens (N = 10), median time to treatment failure (TTF) was 11.6 months versus 2.3 months on last conventional regimen prior to referral (p=0.024). Molecular analyses (performed by next generation sequencing in seven patients and single polymerase chain reaction (PCR)-based assays in an additional six patients) showed diverse actionable mutations: PIK3CA (1 of 12 tested; 8%); EGFR (1 of 13; 8%); RET (1 of 7; 14%); and AKT1 (1 of 7; 14%). Of two patients with PIK3CA or AKT1 mutations, one was treated with an mTOR inhibitor-based regimen and achieved 26% regression with a TTF of 17 months.

Patients with advanced/metastatic thymoma or thymic carcinoma demonstrated prolonged TTF on mTOR inhibitor-based therapy as compared to prior conventional treatment. Heterogeneity in actionable molecular aberrations was observed, suggesting that multi-assay molecular profiling and individualizing treatment merits investigation.

• classification
• cortex
• differentiation
• medulla
• stem cell
• thymoma
• thymus

• Biomarkers, Tumor/metabolism
• CD40 Antigens/metabolism
• Carcinoma, Squamous Cell/classification
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Cell Differentiation
• Cell Lineage
• Claudin-4/metabolism
• Epithelial Cells/pathology
• Humans
• Immunohistochemistry
• Keratin-10/metabolism
• Neoplasms, Glandular and Epithelial/classification
• Neoplasms, Glandular and Epithelial/metabolism
• Neoplasms, Glandular and Epithelial/pathology
• Neoplastic Stem Cells/pathology
• Thymoma/classification
• Thymoma/metabolism
• Thymoma/pathology
• Thymus Neoplasms/classification
• Thymus Neoplasms/metabolism
• Thymus Neoplasms/pathology
• Transcription Factors/metabolism
• Young Adult
• AIRE Protein

Thymic epithelial cells (TECs) are the key components in thymic microenvironment for T cells development. TECs, composed of cortical and medullary TECs, are derived from a common bipotent progenitor and undergo a stepwise development controlled by multiple levels of signals to be functionally mature for supporting thymocyte development. Tumor necrosis factor receptor (TNFR) family members including the receptor activator for NFκB (RANK), CD40, and lymphotoxin β receptor (LTβR) cooperatively control the thymic medullary microenvironment and self-tolerance establishment. In addition, fibroblast growth factors (FGFs), Wnt, and Notch signals are essential for establishment of functional thymic microenvironment. Transcription factors Foxn1 and autoimmune regulator (Aire) are powerful modulators of TEC development, differentiation, and self-tolerance. Dysfunction in thymic microenvironment including defects of TEC and thymocyte development would cause physiological disorders such as tumor, infectious diseases, and autoimmune diseases. In the present review, we will summarize our current understanding on TEC development and the underlying molecular signals pathways and the involvement of thymus dysfunction in human diseases.