BACKGROUND: Thymic carcinomas (TCs) and thymic neuroendocrine neoplasms (TNENs) are two aggressive subtypes of thymic malignancy. Traditional therapy for advanced TCs and TNENs has limited outcome. New genomic profiling of TCs and TNENs might provide insights that contribute to the development of new treatment approaches. METHODS: We used gene panel sequencing technologies to investigate the genetic aberrations of 32 TC patients and 15 TNEN patients who underwent surgery at Shanghai Chest Hospital between 2015 and 2017. Patient samples were sequenced using a 324-gene platform with licensed technologies. In this study, we focused on clinically relevant genomic alterations (CRGAs), which are previously proven to be pathogenic alterations, to identify the pathology-specific mutational patterns, prognostic signatures of TCs and TNENs. RESULTS: The mutational profiles between TCs and TNENs were diverse. The genetic alterations that ranked highest in TCs were in CDKN2A, TP53, ASXL1, CDKN2B, PIK3C2G, PTCH1, and ROS1 , while those in TNENs were in MEN1, MLL2, APC, RB1 , and TSC2 . Prognostic analysis showed that mutations of ROS1, CDKN2A, CDKN2B, BRAF, and BAP1 were significantly associated with worse outcomes in TC patients, and that mutation of ERBB2 indicated shortened disease-free survival (DFS) and overall survival (OS) in TNEN patients. Further investigation found that the prognosis-related genes were focused on signal pathways of cell cycle control, chromatin remodeling/DNA methylation, phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), and receptor tyrosine kinase (RTK)/RAS/mitogen-activated protein kinase (MAPK) signaling. CONCLUSION We profiled the mutational features of 47 Chinese patients with thymic malignancy of diverse pathologic phenotypes to uncover the integrated genomic landscape of these rare tumors, and identified the pathology-specific mutational patterns, prognostic signatures, and potential therapeutic targets for TCs and TNENs.
Humans ; Thymoma ; Protein-Tyrosine Kinases/genetics* ; Proto-Oncogene Proteins/genetics* ; China ; Thymus Neoplasms/pathology* ; Prognosis ; Neuroendocrine Tumors/pathology* ; Mutation/genetics*

Objective: To investigate the clinicopathological features, and molecular genetic alterations of metaplastic thymoma (MT). Methods: A total of ten MT cases, diagnosed from 2011 to 2021, were selected from the Department of Pathology of Jinling Hospital, Nanjing University Medical School, Nanjing, China for clinicopathological and immunohistochemical (IHC) examination and clinical follow-up. Fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and YAP1 C-terminus (YAP1-CT) IHC were performed to detect YAP1::MAML2 fusions. Results: There were four males and six females, ranging in age from 29 to 60 years (mean 50 years, median 54 years). Microscopically, all tumors showed a typical biphasic morphology consisting of epithelial components and gradually or abruptly transitioning spindle cell components. The two components were present in varying proportions in different cases. Immunophenotypically, the epithelial cells were diffusely positive for CKpan, CK5/6 and p63. The spindle cells were diffusely positive for vimentin and focally positive for EMA. TdT was negative in the background lymphocytes. Ki-67 proliferation index was less than 5%. YAP1 and MAML2 break-apart FISH analyses showed that all ten cases had narrow split signals with a distance of nearly 2 signal diameters and may be considered false-negative. Using YAP1::MAML2 fusion FISH assays, abnormal fusion signals were observed in all the ten cases. NGS demonstrated YAP1::MAML2 fusions in all eight cases with adequate nucleic acids; in two cases the fusions were detected by DNA sequencing and in eight cases by RNA sequencing. All ten cases of MT demonstrated loss of YAP1 C-terminal expression in epithelioid cells. Conclusions: MT is a rare and low-grade thymic tumor characterized by a biphasic pattern and YAP1::MAML2 fusions. Break-apart FISH assays may sometimes show false-negative results due to the proximity of YAP1 and MAML2, while YAP1 C-terminal IHC is a highly sensitive and specific marker for MT. Loss of YAP1 C-terminal expression can also be used to screen YAP1::MAML2 fusions for possible MT cases.
Male ; Female ; Humans ; Adult ; Middle Aged ; Thymoma/genetics* ; In Situ Hybridization, Fluorescence ; Transcription Factors/genetics* ; Mutation ; Thymus Neoplasms/genetics*

Heart Neoplasms/genetics* ; Hemangiosarcoma/genetics* ; Humans ; Mediastinal Neoplasms ; Thymus Neoplasms

OBJECTIVETo explore the role of TNFα induced protein 3 interacting protein 1 (TNIP1) in the pathogenesis of myasthenia gravis (MG) among patients with thymoma.

METHODSFrom December 2014 to March 2015, 11 patients with MG associated thymoma (MGT) and 11 non-MG thymoma (NMGT) patients receiving thymectomy were selected. Thymus specimens were obtained during surgery, and peripheral venous blood samples were obtained before the surgery. For the MGT cohorts, peripheral venous blood samples were also collected at 3-6 months after the surgery. TNIP1 mRNA was determined with quantitative real-time PCR (qPCR), and its protein expression was evaluated by Western blotting.

RESULTSFor both thymus specimen and peripheral blood samples, the levels of TNIP1 mRNA and protein in the MGT group were both significantly lower than those of the NMGT patients (P<0.05). For the MGT group, the levels of TNIP1 mRNA and protein of the peripheral blood samples have increased following thymus resection compared with before the surgery.

CONCLUSIONReduced TNIP1 expression may have a role in the pathogenesis of MG for patients with thymoma. Thymectomy may help to recover the expression of TNIP1 among such patients.

Blotting, Western ; DNA-Binding Proteins ; genetics ; metabolism ; Female ; Gene Expression ; Genetic Predisposition to Disease ; genetics ; Humans ; Male ; Myasthenia Gravis ; complications ; genetics ; Reverse Transcriptase Polymerase Chain Reaction ; Thymectomy ; Thymoma ; complications ; surgery ; Thymus Neoplasms ; complications ; surgery

We previously determined that AKR/J mice housed in a low-dose-rate (LDR) (137Cs, 0.7 mGy/h, 2.1 Gy) gamma-irradiation facility developed less spontaneous thymic lymphoma and survived longer than those receiving sham or high-dose-rate (HDR) (137Cs, 0.8 Gy/min, 4.5 Gy) radiation. Interestingly, histopathological analysis showed a mild lymphomagenesis in the thymus of LDR-irradiated mice. Therefore, in this study, we investigated whether LDR irradiation could trigger the expression of thymic genes involved in the DNA repair process of AKR/J mice. The enrichment analysis of Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways showed immune response, nucleosome organization, and the peroxisome proliferator-activated receptors signaling pathway in LDR-irradiated mice. Our microarray analysis and quantitative polymerase chain reaction data demonstrated that mRNA levels of Lig4 and RRM2 were specifically elevated in AKR/J mice at 130 days after the start of LDR irradiation. Furthermore, transcriptional levels of H2AX and ATM, proteins known to recruit DNA repair factors, were also shown to be upregulated. These data suggest that LDR irradiation could trigger specific induction of DNA repair-associated genes in an attempt to repair damaged DNA during tumor progression, which in turn contributed to the decreased incidence of lymphoma and increased survival. Overall, we identified specific DNA repair genes in LDR-irradiated AKR/J mice.
Animals ; DNA Repair/*radiation effects ; Dose-Response Relationship, Radiation ; Female ; Gene Expression Regulation/*radiation effects ; Gene Regulatory Networks/radiation effects ; Lymphoma/etiology/*genetics ; Mice ; Mice, Inbred AKR ; Oligonucleotide Array Sequence Analysis ; *Radiation, Ionizing ; Reverse Transcriptase Polymerase Chain Reaction ; Thymus Gland/*radiation effects ; Thymus Neoplasms/etiology/*genetics

OBJECTIVETo study the clinicopathologic features of primary thymic extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT).

METHODSThe clinical and pathologic findings were evaluated in 3 cases of biopsy confirmed thymic MALT lymphoma. The clincopathologic features, treatment and prognosis were discussed and literatures reviewed.

RESULTSOne male and two female patients presented with asymptomatic mediastinal masses with a history of Sjögren syndrome. They were aged 36, 35 and 41 years respectively, and only one patient had B symptoms. Grossly, all three tumors were encapsulated and had multiple variable-sized cysts on cut-surface. Histopathologically, the normal thymic lobular architecture was effaced by abnormal dense lymphoid infiltration. Prominent lymphoepithelial lesions were formed by centrocyte-like cells infiltrating and expanding Hassall's corpuscles and epithelial cyst lining. All cases showed apparent plasmacytic differentiation. Immunohistochemically, the tumor cells were positive for CD20, CD79a, bcl-2 and negative for CD3, CD5, cyclin D1, CD43, CD10, bcl-6, and CD23. The plasma cells showed kappa light chain restriction. Immunoglobulin heavy chain rearrangement in three cases was confirmed by PCR. All patients were at early stage and received routine chemotherapy with or without radiotherapy after surgical removal. All patients achieved complete remission with 24, 18 and 3 months follow-up, respectively.

CONCLUSIONSPrimary thymic MALT lymphoma may be a rare distinctive lymphoma. It can be diagnosed by HE and immunohistochemical study and should be differentiated from reactive lymphoid proliferation, other types of lymphoma and mediastinal thymoma.

Adult ; Antibodies, Monoclonal, Murine-Derived ; therapeutic use ; Antigens, CD20 ; metabolism ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Cyclophosphamide ; therapeutic use ; Diagnosis, Differential ; Doxorubicin ; therapeutic use ; Female ; Follow-Up Studies ; Gene Rearrangement, B-Lymphocyte, Heavy Chain ; Humans ; Immunoglobulin Heavy Chains ; genetics ; Keratin-19 ; metabolism ; Lymphoma, B-Cell, Marginal Zone ; drug therapy ; genetics ; metabolism ; pathology ; surgery ; Male ; Prednisone ; therapeutic use ; Pseudolymphoma ; pathology ; Thymus Hyperplasia ; pathology ; Thymus Neoplasms ; drug therapy ; genetics ; metabolism ; pathology ; surgery ; Vincristine ; therapeutic use

OBJECTIVETo observe the effect of the combination of Wenxia Changfu Formula ([see text], WCF) with cisplatin (CDDP) on inhibiting non-small cell lung cancer (NSCLC) in vitro and In Vivo and explore its mechanism from its effect on cell cycle.

METHODSIn vitro, WCF-containing serum was prepared and the rhubarb b1, emodin, and aconitine were detected qualitatively by high-performance liquid chromatogram (HPLC). A549 cell lines were treated with blank control (dimethyl sulfoxide), normal serum, normal serum with CDDP (1.25, 2.5, and 5.0 μg/mL, respectively), WCF-containing serum plus different doses of CDDP (1.25, 2.5, and 5.0 μg/mL, respectively). The inhibitory effect was detected by 3-(4,5)-dimethylthiazo(-zy1)-3,5-diphenylterazolium bromide (MTT). The cell cycle was detected by flow cytometry. The protein and mRNA expressions of cyclin D1, proliferating cell nuclear antigen (PCNA), retinoblastoma (Rb), and p16 were observed with immunofluorescence and RT-PCR, respectively. In Vivo, nude mice xenograft model was established and grouped into the control, CDDP, WCF, and combination groups. The combination's inhibition of tumor growth and influence on the weight, spleen, and thymus gland were observed.

RESULTSThe inhibitory rate of the combination against A549 cell lines excelled the CDDP alone significantly (P <0.05); the combination showed a synergism inhibitory effect (Q=1.19). Compared with the monotherapy, the combination increased the cell percentage in G(0)/G(1) phase and decreased the cell percentage in S phase significantly (P <0.05); the protein and mRNA expressions of cyclin D1, PCNA, and Rb were significantly reduced; the protein and mRNA expressions of p16 were significantly enhanced. Compared with the monotherapy, the combination inhibited the tumor growth significantly In Vivo and reduced the weight of tumor (P <0.05); compared with the CDDP group, the spleen and thymus gland index of the combination group were enhanced significantly (P <0.05).

CONCLUSIONSThe combination of WCF with CDDP significantly inhibited the A549 cell lines proliferation in vitro and the growth of the tumor In Vivo; it inhibited effectively the atrophy of the immune organ caused by chemotherapy. The combination inhibited overproliferation of A549 cell lines by arresting the G(0) /G(1) phase of cell cycle and affecting the protein and mRNA expressions of cell cycle-related proteins, cyclin D1, etc.

Animals ; Antineoplastic Agents ; pharmacology ; therapeutic use ; Antineoplastic Combined Chemotherapy Protocols ; pharmacology ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; pathology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Chromatography, High Pressure Liquid ; Cisplatin ; pharmacology ; therapeutic use ; Drug Synergism ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Flow Cytometry ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; pathology ; Male ; Neoplasm Proteins ; genetics ; metabolism ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Wistar ; Spleen ; drug effects ; pathology ; Thymus Gland ; drug effects ; pathology ; Xenograft Model Antitumor Assays

Carcinoma ; drug therapy ; genetics ; metabolism ; pathology ; radiotherapy ; Desmoplastic Small Round Cell Tumor ; metabolism ; pathology ; Diagnosis, Differential ; Gene Rearrangement ; Head and Neck Neoplasms ; drug therapy ; genetics ; metabolism ; radiotherapy ; Humans ; Keratin-20 ; metabolism ; Keratin-7 ; metabolism ; Lymphatic Metastasis ; Male ; Mediastinal Neoplasms ; drug therapy ; genetics ; metabolism ; radiotherapy ; Melanoma ; metabolism ; pathology ; Neuroectodermal Tumors, Primitive ; metabolism ; pathology ; Nuclear Proteins ; genetics ; metabolism ; Oncogene Proteins ; genetics ; metabolism ; Oncogene Proteins, Fusion ; genetics ; metabolism ; Rhabdomyosarcoma ; metabolism ; pathology ; Thymus Neoplasms ; drug therapy ; genetics ; metabolism ; radiotherapy

OBJECTIVETo study the correlation between amplification of chromosome 1 and histological typing and clinical staging of thymic epithelial tumors according to the WHO classification.

METHODSAmplification of chromosome 1 was detected by interphase fluorescence in-situ hybridization (FISH) in 60 cases of thymic epithelial tumors, including type A thymoma (2 cases), type AB (19 cases), B1 (4 cases), B2 (14 cases), B3 (11 cases), metaplastic thymoma (2 cases), and thymic carcinoma (8 cases) and 11 samples of normal thymus.

RESULTSGain on chromosome 1 was found in 19 cases (31.7%) of thymic epithelial tumors, and none was detected in normal thymic tissues (P < 0.05). The positive rates of gain on chromosome 1 were statistically different among various histological subtypes of thymic epithelial tumors (P < 0.05), in which the highest rate of detection was in thymic carcinoma (6/8), the second, type B3 (6/11), followed by type A (1/2), type AB (4/19), type B2 (2/14) and type B1 (0). The positive rate of gain on chromosome 1 in type B3 had no statistical difference from thymic carcinoma (P > 0.05), but significantly higher than that in other types of thymoma (P < 0.05). In addition, the polysomy rate of chromosome 1 was significantly different among the thymic epithelial tumors at different clinical stages (P = 0.023), and that at stages III and IV was statistically higher than that in stages I and II (P = 0.003) but there was no significant difference between stage I and stage II tumors (P = 0.750).

CONCLUSIONSGain on chromosome 1 is more common in thymic carcinoma and type B3 thymoma than that in other subtypes of thymic epithelial tumors. Thymoma of type B3 may have different genetic features from other subtypes. Detection of gain on chromosome 1 by FISH is helpful in the differential diagnosis and prediction of prognosis in patients with thymic epithelium tumors.

Adult ; Aged ; Carcinoma, Squamous Cell ; genetics ; pathology ; Chromosomes, Human, Pair 1 ; genetics ; Female ; Follow-Up Studies ; Gene Amplification ; Humans ; Male ; Middle Aged ; Neoplasm Staging ; Polyploidy ; Prognosis ; Thymoma ; classification ; genetics ; pathology ; Thymus Neoplasms ; classification ; genetics ; pathology

OBJECTIVETo investigate the correlation of cytokeratin pan (CKP), vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) to spiral CT manifestations of thymoma.

METHODSEighty-four thymoma patients were underwent spiral CT examination, and 40 of the patients also had enhanced CT examination. All the CT findings were carefully reviewed to analyze their correlation to the expressions of CKP, VEGF and MVD.

RESULTSThe enhancement on spiral CT images increased with the levels of VEGF expression and MVD counting (P<0.01). Significant correlations were observed between VEGF expression, MVD counting and such spiral CT findings as lobular contours, cusp-like or sawtooth-like margins and tumor invasions of the pleural membrane, pericardium and great vessels (P<0.05). CKP expression showed no obvious correlation to these findings by spiral CT.

CONCLUSIONSpiral CT can reflect the pathological characteristics of thymoma, and may serve as a noninvasive modality for preoperative evaluation of thymoma.

Adolescent ; Adult ; Aged ; Female ; Humans ; Keratins ; genetics ; metabolism ; Male ; Microvessels ; Middle Aged ; Thymoma ; blood supply ; diagnostic imaging ; metabolism ; Thymus Neoplasms ; blood supply ; diagnostic imaging ; metabolism ; Tomography, Spiral Computed ; Vascular Endothelial Growth Factor A ; genetics ; metabolism ; Young Adult