Normal Thymic Tissue Research Articles

Conventional dendritic cells are more activated in the hyperplastic Thymus of myasthenia gravis patients

IntroductionDendritic cells (DCs) are crucial to form ectopic germinal centers (GCs) in the hyperplastic thymus (HT), which are typically found in anti-acetylcholine receptor autoantibody-positive myasthenia gravis (MG) patients. However, the characteristics of such DCs in the HT and their roles in thymic hyperplasia formation remain unclear. MethodsWe collected thymic tissue from MG patients and patients who underwent cardiac surgery. The tissues were cut into sections for immunohistochemistry and immunofluorescence or digested into a single cell suspension for flow cytometry. ResultsIn addition to formation of ectopic GCs, we found that the proportion of the medulla in the thymic parenchyma was higher than that in the cortex (areacortex/areamedulla, 1.279 vs. 0.6576) in the HT of MG patients. The density of conventional dendritic cells (cDCs) in the HT was 131 ± 64.36 per mm2, whereas in normal thymic tissue, the density was 59.17 ± 22.54 per mm2. The more abundant cDCs expressed co-stimulatory molecules (CD80 and CD86) strongly. Moreover, the more abundant subset was mainly CD141+ DCs (cDC1s), accounting for an increase from 15% to 29%. However, these increased cDC1s appeared to be unrelated to Hassall's corpuscles and ectopic GCs. ConclusionThymic hyperplasia in MG patients is manifested as an increase in the proportion of the thymic medulla accompanied by increases in the density and functional activation as well as changes in the subset composition of cDCs.

Targeted Metabolomics of Tissue and Plasma Identifies Biomarkers in Mice with NOTCH1-Dependent T-Cell Acute Lymphoblastic Leukemia.

While the genomics era has allowed remarkable advances in understanding the mechanisms driving the biology and pathogenesis of numerous blood cancers, including acute lymphoblastic leukemia (ALL), metabolic studies are still lagging, especially regarding how the metabolism differs between healthy and diseased individuals. T-cell ALL (T-ALL) is an aggressive hematological neoplasm deriving from the malignant transformation of T-cell progenitors characterized by frequent NOTCH1 pathway activation. The aim of our study was to characterize tumor and plasma metabolomes during T-ALL development using a NOTCH1-induced murine T-ALL model (ΔE-NOTCH1). In tissue, we found a significant metabolic shift with leukemia development, as metabolites linked to glycolysis (lactic acid) and Tricarboxylic acid cycle replenishment (succinic and malic acids) were elevated in NOTCH1 tumors, while metabolites associated with lipid oxidation (e.g., carnitine) as well as purine and pyrimidine metabolism were elevated in normal thymic tissue. Glycine, serine, and threonine metabolism, glutathione metabolism, as well as valine, leucine, and isoleucine biosynthesis were enriched pathways in tumor tissue. Phenylalanine and tyrosine metabolism was highly enriched in plasma from leukemia-bearing mice compared to healthy mice. Further, we identified a metabolic signature consisting of glycine, alanine, proline, 3-hydroxybutyrate, and glutamic acid as potential biomarkers for leukemia progression in plasma. Hopefully, the metabolic differences detected in our leukemia model will apply to humans and contribute to the development of metabolism-oriented therapeutic approaches.

Metabolic signatures of thymomas: potential biomarkers and treatment targets.

A study of tumour metabolic reprogramming has revealed disease biomarkers and avenues for therapeutic intervention. Metabolic reprogramming in thymoma is currently understudied and largely unknown. This study utilized metabolomics and isotope tracing with 13C-glucose to metabolically investigate thymomas, adjacent thymic tissue and benign thymic lesions. From 2017 to 2021, 20 patients with a suspected thymoma were recruited to this prospective Institutional Review Board approved clinical trial. At the time of surgery, 11 patients were infused with 13C-glucose, a stable, non-radioactive tracer which reports the flow of carbon through metabolic pathways. Samples were analysed by mass spectrometry to measure the abundance of >200 metabolites.13C enrichment was measured in patients who received 13C-glucose infusions. Histological analysis showed that 9 patients had thymomas of diverse subtypes and 11 patients had benign cysts. In our metabolomic analysis, thymomas could be distinguished from both adjacent thymus tissue and benign lesions by metabolite abundances. Metabolites in pyrimidine biosynthesis and glycerophospholipid metabolism were differentially expressed across these tissues.13C-glucose infusions revealed differential labelling patterns in thymoma compared to benign cysts and normal thymus tissue. The lactate/3PG labelling ratio, a metabolic marker in aggressive lung tumours correlated with lactate uptake, was increased in thymomas (1.579) compared to normal thymus (0.945) and benign masses (0.807) (thymic tissue versus tumour P = 0.021, tumour versus benign P = 0.013). We report metabolic biomarkers, including differential 13C labelling of metabolites from central metabolism, that distinguish thymomas from benign tissues. Altered glucose and lactate metabolism warrant further investigation and may provide novel therapeutic targets for thymoma.

High levels of expression of Trop-2 in thymic epithelial tumors

BackgroundTrophoblastic antigen 2 (Trop2) is a cell surface glycoprotein expressed in multiple types of cancers, including breast cancer, non-small cell lung cancer, and gastrointestinal cancers. Trop2 expression and the use of Trop2-directed therapy such as antibody-drug conjugate (ADC) have not yet been investigated in thymic epithelial tumors (TETs). MethodsPatients with TETs treated at MedStar Georgetown University Hospital were retrospectively identified. Of the patients for whom tumor samples and normal thymus tissue were available, immunohistochemistry (IHC) membranous staining for Trop2 and PD-L1 were performed. Positivity for Trop2 required at least 10% of the tumor cells to be stained, with an intensity scored of 1+ (weak), 2+ (moderate), and 3+ (strong). Cases with CPS ≥ 5% were considered positive for PD-L1. Results30 TET samples from 29 patients (17 patients with thymoma and 12 patients with thymic carcinoma) were identified. One patient with thymic carcinoma had two samples from different time points. From the same set of patients, 13 samples of normal thymus tissue were available. In normal thymus tissue, eight samples (62%) showed no positivity of Trop2, while five samples (38%) showed 1 + IHC staining. In the thymoma samples, four (24%) showed 0 or 1 + IHC staining, while 13 (76%) showed 2 + or 3 + staining. Of the 13 thymic carcinoma samples, three samples (23%) showed 1 + IHC staining while seven (54%) showed 2 + staining and three (23%) showed 3 + staining. There was no statistically significant correlation found between PD-L1 expression and Trop-2 expression in thymoma or thymic carcinoma. ConclusionsTrop2 is readily expressed in TETS with a higher degree of expression in thymic carcinoma. The expression of Trop-2 was lower in normal thymic tissue compared with TETs. The increased expression of Trop-2 in TETs suggests that Trop2 is an attractive therapeutic target for Trop-2 directed therapy.

A “no-touch” neck “mass” in a child

Aberrant cervical thymus is a rare cause of pediatric neck masses related to the embryological development. In most of the cases, this condition is asymptomatic and essentially benign in nature. Here, we describe the sonological and magnetic resonance imaging (MRI) features of cervical thymus in a 2-month-old baby who presented with the left submandibular swelling. The unique imaging findings on ultrasound and MRI paralleling that of the normal thymus tissue were helpful in confidently establishing the diagnosis. Therefore, the radiologist must be aware of the condition and the typical normal appearance of thymus which can obviate the need for biopsy or surgical intervention.

Brief Report: High Levels of CD47 Expression in Thymic Epithelial Tumors

IntroductionCD47 is a tumor antigen that inhibits phagocytosis leading to immune evasion. Anti-CD47 therapy is a promising new immunotherapy across numerous tumor types, but it has not been tested in thymic epithelial tumors (TETs): thymomas and thymic carcinomas. TETs are rare tumors that are difficult to treat, especially with programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors, owing to the excessive rates of immune-related adverse events. This study investigated the levels of CD47 expression in TETs to explore the possibility of anti-CD47 therapy. MethodsA total of 67 thymic tumors (63 thymomas and 4 thymic carcinomas) and 14 benign thymus controls and their clinical data were included. Samples were stained for CD47 expression (rabbit monoclonal antibody SP279, Abcam, Waltham, MA) and scored for both intensity and H-score (intensity multiplied by the percentage of tumor involved). Intensity was defined as follows: 0 = none, 1 = weak, 2 = moderate, and 3 = strong. H-scores ranged from 0 to 300. Samples with an intensity score below 2 or an H-score below 150 were considered CD47low, whereas the rest were CD47high. ResultsCompared with normal thymic tissues, TETs were more frequently CD47 positive and had significantly higher levels of CD47 expression. CD47 was positive in 79.1% of TETs compared with 57.1% of normal thymus. The level of CD47 expression was 16-fold higher in TETs (mean H-score 75.0 versus 4.6, p = 0.003). Multivariate analysis adjusted for age, sex, stage, resection status, and performance status revealed that CD47-high tumors were highly correlated with WHO histology type (p = 0.028). The most frequent CD47high tumors, in contrast to CD47low tumors, were types A (28.6% versus 7.5%) and AB (57.1% versus 13.2%), and the least frequent were B1 (7.1% versus 24.5%), B2 (0% versus 35.8%), B3 (7.1% versus 11.3%), and C (0% versus 7.5%). ConclusionsIn contrast to normal thymus, TETs had significantly higher levels of CD47 expression. Tumor samples with high CD47 expression were mostly WHO types A and AB. This is the first study to explore CD47 expression in thymic cancers and lends support for ongoing investigation of anti-CD47 macrophage checkpoint inhibitor therapy in these tumors.

A Knock-In Mouse Model of Thymoma With the GTF2I L424H Mutation

IntroductionThe pathogenesis of thymic epithelial tumors remains largely unknown. We previously identified GTF2I L424H as the most frequently recurrent mutation in thymic epithelial tumors. Nevertheless, the precise role of this mutation in tumorigenesis of thymic epithelial cells is unclear. MethodsTo investigate the role of GTF2I L424H mutation in thymic epithelial cells in vivo, we generated and characterized a mouse model in which the Gtf2i L424H mutation was conditionally knocked-in in the Foxn1+ thymic epithelial cells. Digital spatial profiling was performed on thymomas and normal thymic tissues with GeoMx-mouse whole transcriptome atlas. Immunohistochemistry staining was performed using both mouse tissues and human thymic epithelial tumors. ResultsWe observed that the Gtf2i mutation impairs development of the thymic medulla and maturation of medullary thymic epithelial cells in young mice and causes tumor formation in the thymus of aged mice. Cell cycle-related pathways, such as E2F targets and MYC targets, are enriched in the tumor epithelial cells. Results of gene set variation assay analysis revealed that gene signatures of cortical thymic epithelial cells and thymic epithelial progenitor cells are also enriched in the thymomas of the knock-in mice, which mirrors the human counterparts in The Cancer Genome Atlas database. Immunohistochemistry results revealed similar expression pattern of epithelial cell markers between mouse and human thymomas. ConclusionsWe have developed and characterized a novel thymoma mouse model. This study improves knowledge of the molecular drivers in thymic epithelial cells and provides a tool for further study of the biology of thymic epithelial tumors and for development of novel therapies.

CD47 expression patterns in thymic epithelial tumors.

8586 Background: Blockade of CD47, an immunoglobulin overexpressed on solid tumor cells that inhibits macrophage phagocytosis, is a promising anti-cancer immunotherapy which has not yet been explored in thymic epithelial tumors (TETs). TETs, including thymomas and thymic carcinomas, are rare tumors with limited immunotherapy treatment options due to the high rates of immune-related adverse effects observed with PD-1/PD-L1 checkpoint inhibitors. This study aimed to examine CD47 protein expression in TETs. Methods: A clinically annotated tissue microarray of 67 TETs consisting of 64 thymomas and 3 thymic carcinomas, as well as 14 thymic controls were included. Each sample with an average of 3 cores was stained for CD47 epithelial expression (rabbit monoclonal antibody SP279, Abcam, USA). Samples were scored for intensity as follows: 0 = none, 1 = weak, 2 = moderate, and 3 = strong. An H-score, defined as intensity x percentage of tumor involved, was also assigned and ranged from 0 to 300. Samples with an intensity score of < 2 or an H-score of < 150 were categorized as CD47low, while the rest as CD47high. Multivariate linear regression analysis accounted for WHO subtype, stage, resection status and presence of paraneoplastic syndrome (Prism 9, Graphpad). Results: Compared to normal thymic tissue, TETs were more frequently CD47 positive and had significantly higher levels of CD47 expression. CD47 was present in 91% of TETs, compared to 64.3% of normal thymus. Importantly, the level of expression was significantly higher in TETs by 16-fold (mean H-score 75.0 vs 4.6, p = 0.003). Among tumors, univariate analyses showed that higher CD47 expression was correlated with a lower stage (p = 0.032) and more complete resection (p = 0.058). A multivariate analysis accounting for these factors showed that CD47 expression by both H-score and intensity were each highly correlated with WHO histology subtype (p = 0.0005; p = 0.0017 respectively) with lower grade subtypes more frequently found in CD47high tumors. The most frequent subtype in CD47high, when compared to CD47low tumors, was AB (61.5% vs 13.7%) and the least frequent was B2 (0% vs 37.3%). Tumors with the highest grade (subtype C, thymic carcinomas) were exclusively CD47low. CD47high tumors were associated with an increased incidence of paraneoplastic syndromes (52.4% vs 12.0%, p = 0.0014). Conclusions: CD47 expression was found in the vast majority of TETs, and in significantly higher levels than normal thymic tissue. Among tumors, those with higher CD47 expression tended to have lower grade and stage, as well as higher frequency of paraneoplastic syndromes. This study is the first to examine CD47 expression in TETs. Given the prevalent expression of CD47 found in TETs and current available CD47 targeted agents, this study lends support for further investigation of this novel therapeutic approach.

Developmental dynamics of the neural crest-mesenchymal axis in creating the thymic microenvironment.

The thymic stroma is composed of epithelial and nonepithelial cells providing separate microenvironments controlling homing, differentiation, and selection of hematopoietic precursor cells to functional T cells. Here, we explore at single-cell resolution the complex composition and dynamic changes of the nonepithelial stromal compartment across different developmental stages in the human and mouse thymus, and in an experimental model of the DiGeorge syndrome, the most common form of human thymic hypoplasia. The detected gene expression signatures identify previously unknown stromal subtypes and relate their individual molecular profiles to separate differentiation trajectories and functions, revealing an unprecedented heterogeneity of different cell types that emerge at discrete developmental stages and vary in their expression of key regulatory signaling circuits and extracellular matrix components. Together, these findings highlight the dynamic complexity of the nonepithelial thymus stroma and link this to separate instructive roles essential for normal thymus organogenesis and tissue maintenance.

Characterization of thymic epithelial cell and thymocyte function and development in patients with thymic defects using scRNAseq profiling

Abstract The interaction between thymocytes and thymic epithelial cells (TEC) in the thymus is critical for the correct function and maturation of both cell populations and for the development of a diverse repertoire of non-self-reactive T-cell lymphocytes. Limited information is available on lympho-stromal crosstalk in the thymus of patients carrying thymic defects. We have previously shown that thymic tissues from DiGeorge syndrome (DGS) and Down syndrome (DS) patients have alterations in architecture and TEC composition, leading to altered T-cell development. Based on these results, we are performing single cell RNAseq (scRNAseq) to explore the transcriptional landscape of both stromal and hematopoietic components in the human thymus. Thanks to a collaboration with the pediatric cardiothoracic surgery center at the Children’s National Medical Center in Washington D.C., we have access to discarded thymic samples obtained from pediatric patients with partial DGS and DS, and from patients without immune defects. Preliminary results of scRNAseq analysis comparing tissues from normal donors and DS patients revealed a different distribution of cell subsets in both hematopoietic and stromal compartments, with several pathways differentially regulated, such as stress and metabolic processes. Additionally, we established a collaboration with the Thoracic and Gastrointestinal Malignancies Branch at the National Cancer Institute and are evaluating samples obtained from resected thymic epithelial tumors. Integration of data obtained from normal and diseased thymic tissue will provide novel insights into the function and development of the human thymus that could be helpful in the clinical management of patients with thymic defects. This research was supported by the Intramural Research Programs of the NIAID and the NCI (Center for Cancer Research), NIH

A large anterior mediastinal mass in a young infant

Abstract Funding Acknowledgements Type of funding sources: None. TITLE A large anterior mediastinal mass in a young infant Case Report A 4 week old male neonate, KS was referred to the emergency department with a 24 hour history of increased work of breathing, two brief episodes of apnoeas and inspiratory stridor. There was no infective symptoms or changes to his usual feeding pattern. There was no significant past medical history and he was on no regular medications. A chest x-ray demonstrated a large mediastinal mass and suspicion of cardiomegaly. A transthoracic echocardiogram demonstrated a structurally and functionally normal heart. However, there was a large anterior homogenous soft tissue mass extending to the left ventricular apex which was separate from the pericardium. This mass did not cause any heart chamber compression or compromise. Further cross-sectional imaging with cardiac computed tomography (CT) showed a non-enhancing uniform soft tissue mass occupying the superior and anterior mediastinum without evidence of calcification or fatty components. The lesion was seen to be extending from the root of the neck down to the left cardiac apex region with the total dimensions of the mass being 5.2 x 3.5 x 5cm. There was no compression of the great arteries or the airway. Parasternal ultrasound of the chest showed a starry sky appearance compatible with normal thymic tissue. Overall, the appearances were felt to be compatible with a prominent normal thymus. Discussion The differential diagnosis of an anterior mediastinal mass in young infants includes germ cell tumours (mainly teratomas), congenital thymic cysts and true thymic hyperplasia(1). These can be difficult to distinguish from the normal large neonatal thymus. The normal thymus can take on a variety of shapes and sizes and still be considered normal. One of the most important features of a normal thymus is the lack of mass effect or compression on the airway or vascular structures(2). True thymic hyperplasia is characterised by an increase in the size and shape of the thymus while preserving thymic architecture. If the anterior mass has a bipyramidal morphology with the presence of gross intercalated fat on CT, these findings are pathognomonic for thymic hyperplasia(3). Thymomas are rare in children and appear as well-defined, rounded or lobulated soft tissue density mass with mild enhancement on CT. It can demonstrate irregular borders with extension into adjacent structures and approximately 30% will have necrosis and internal cystic foci(4). The most common germ cell tumour in the mediastinum is a teratoma with the hallmark being fat, fluid and calcified components on CT(2). Lymphomas are the most common anterior mediastinal mass in children but are usually seen in children older than 5 years. They often cause mass effect with displacement of the trachea. CT scan demonstrates larger nodal areas with hypodense and cystic areas suggestive of necrosis(1). Abstract Figure 1 Abstract Figure 2

GHSR methylation-dependent expression of a variant ligand and receptor of the ghrelin system induces thymoma tumorigenesis.

Our previous study reported that the DNA methylation of growth hormone secretagogue receptor (GHSR) was significantly higher in thymoma or thymic carcinoma (TC) than in normal thymic tissue samples. Thymic epithelial tumors (TETs) with higher GHSR DNA methylation were associated with significantly worse prognosis than those with lower levels of DNA methylation. Diversified components of the ghrelin-GHSR axis may exert opposing effects in cancer progression, depending on the cancer type in question. However, the precise function of the axis remains unclear. In the present study, the mRNA expression of five key components of the ghrelin system [native ligand ghrelin, variant ligand In-1 ghrelin, native receptor GHSR1a, variant receptor GHSR1b and acylation enzyme ghrelin O-acyltransferase (GOAT)] were examined in 58 TET samples by reverse transcription-quantitative PCR, and protein expression of GHSR1a and GHSR1b was assessed in 20 TETs using immunohistochemistry. The results revealed that In-1 ghrelin, GHSR1b (variant forms) and GOAT were more strongly expressed in thymoma compared with thymic-adjacent tissue. By contrast, no significant differences were observed in the expression of ghrelin and GHSR1a (native forms) between thymoma and thymic tissue. The mRNA expression of In-1 ghrelin and GHSR1b (variant forms) was positively associated with GHSR methylation in thymoma tissue samples. However, a relationship was not found between ghrelin, GHSR1a or GOAT expression (native forms) and GHSR methylation in thymoma. Immunohistochemical analysis revealed that mRNA expression of GHSR1a and GHSR1b generally correlated with expression of the corresponding protein, and that the expression of GHSR1b was increased in advanced-stage TETs. These results indicate that the DNA methylation of GHSR is associated with a shift from native expression (ghrelin and GHSR1a) to variant expression (In-1 ghrelin and GHSR1b), which induces the tumorigenesis of thymoma, but not TC.

GAD1 expression and its methylation as indicators of malignant behavior in thymic epithelial tumors.

Thymic epithelial tumors (TETs) comprise thymomas and thymic carcinoma (TC). TC has more aggressive features and a poorer prognosis than thymomas. Genetic and epigenetic alterations in thymomas and TC have been investigated in an attempt to identify novel target molecules for TC. In the present study, genome-wide screening was performed on aberrantly methylated CpG islands in thymomas and TC, and the glutamate decarboxylase 1 gene (GAD1) was identified as the 4th significantly hypermethylated CpG island in TC compared with thymomas. GAD1 catalyzes the production of γ-aminobutyric acid from L-glutamic acid. GAD1 expression is abundant in the brain but rare in other tissues, including the thymus. A total of 73 thymomas and 17 TC tissues were obtained from 90 patients who underwent surgery or biopsy at Tokushima University Hospital between 1990 and 2017. DNA methylation was examined by bisulfite pyrosequencing, and the mRNA and protein expression levels of GAD1 were analyzed using reverse transcription-quantitative PCR and immunohistochemistry, respectively. The DNA methylation levels of GAD1 were significantly higher in TC tissues than in the normal thymus and thymoma tissues, and GAD1 methylation exhibited high sensitivity and specificity for discriminating between TC and thymoma. The mRNA and protein expression levels of GAD1 were significantly higher in TC tissues than in thymomas. Patients with TET with high GAD1 DNA hypermethylation and high mRNA and protein expression levels had significantly shorter relapse-free survival rates than those with low levels. In conclusion, significantly more epigenetic alterations were observed in TC tissues compared with in thymomas, which may contribute to the clinical features and prognosis of patients.

Identification of differentially expressed circular RNAs associated with thymoma.

BackgroundThymomas and thymic carcinomas are the most common tumor types among anterior mediastinal lesions. However, the relationship between molecular aberrations and thymoma patients are poorly understood, especially abnormal changes in the expression profiles of circRNAs. The purpose of the present study was to investigate the expression profiles of circRNAs in thymoma patients and their possible roles in the pathogenesis of thymoma.MethodsDiseased tissues and surrounding normal thymic tissues in two thymoma patients were collected for circRNA sequencing. The top four upregulated circRNAs were selected as candidates and further validated with RT‐PCR in 20 thymoma patients. Gene ontology and signal transduction network analyses of circRNA‐related mRNAs were performed to analyze the functional properties. Survival analysis of their parental genes were also carried out to evaluate the clinical value of differentially expressed circRNA.ResultsA total of 73 circRNAs were differentially expressed in thymoma tissues using high‐throughput sequencing. Among these circRNAs, hsa_circ_0001173, hsa_circ_0007291, hsa_circ_0003550, and hsa_circ_0001947 were significantly upregulated in thymoma tissues compared with normal thymic tissues. We identified that these four circRNA‐related mRNAs were involved in cell–cell adhesion, MAPK pathways, and TNF pathway, which may contribute to the pathological immune disorder in thymoma. Finally, we also found that SCAP (hsa_circ_0007291 parental gene) and AFF2 (hsa_circ_0001947 parental gene) were all significantly related with progression‐free survival (PFS) of thymoma patients in a Kaplan‐Meier plot (p‐value <0.05).ConclusionsThe expression levels of hsa_circ_0001173, hsa_circ_0007291, hsa_circ_0003550, and hsa_circ_0001947 were significantly upregulated and positively correlated with immune imbalance in thymoma patients.

Mediastinal teratoma presenting as a cervical tumor: images.

Benign extra-gonadal germ cell tumors, known as teratoma or dermoid cysts, are commonly found in the anterior mediastinum in association with the thymic gland. This association is due to their common site of embryological origins, from the third and the fourth pharyngeal pouches. Since it is not unusual to find normal thymic tissue in the neck, germ cell tumors arising from here will present as a cervical tumor. We submit the typical images of one such tumor in a young adult. Intraoperatively, the tumor was well encapsulated and was connected to the mediastinal thymus by a long pedicle of thymic tissue. It was not related to the thyroid gland unlike a primary cervical teratoma. We present these typical images of a mediastinal dermoid in this unusual cervical location. The differential diagnoses to be considered clinically are primary cervical teratomas, thyroid tumors, lymph nodal pathologies, and branchial cyst.

Significance and expression of X chromosome linked inhibitor of apoptosis protein, B-cell lymphoma-2 and Survivin in thymoma

Objective To explore significance and expression of X chromosome linked inhibitor of apoptosis protein (XIAP), B-cell lymphoma-2 (bcl-2) and survivin in thymoma. Methods The expressions of XIAP, bcl-2 and Survivin in 19 cases of thymic hyperplasia, 45 cases of thymoma and 13 cases of thymic adenocarcinoma were detected by immunohistochemical method, and the relationship between the expression of XIAP, bcl-2 and Survivin and age, sex, histological type, clinical stage, ymph node metastasis and myasthenia gravis was analyzed. Results The positive rate of XIAP in normal thymic tissue (2/19), thymoma (26/45) and thymic adenocarcinoma (10/13) increased in turn, and the difference was statistically significant (P<0.05). The positive rates of bcl-2 in normal thymic tissue (2/19), thymoma (29/45) and thymic adenocarcinoma (11/13) increased in turn (P<0.05). The positive rates of Survivin in normal thymic tissue (1/19), thymoma (23/45) and thymic adenocarcinoma (11/13) increased in turn (P<0.05). The positive rates of XIAP, bcl-2 and Survivin in thymoma tissues were correlated with histological type, clinical stage, ymph node metastasis, and was not correlated with age, sex and myasthenia gravis. The expressions of XIAP was correlated wih the expression of bcl-2 (r=0.568, P<0.01), the expression of XIAP was correlated with the expression of the expression of Survivin (r=0.671, P<0.01), the expression of bcl-2 was correlated with Survivin in thymoma tissues (r=0.529, P<0.01). Conclusion XIAP, bcl-2 and Survivin were highly expressed in thymoma tissues, which could be used as predictors of the occurrence and malignancy of thymoma. Key words: X chromosome linked inhibitor of apoptosis protein; B-cell lymphoma-2; Survivin; Thymoma

Age-stratified Patterns of Thymic Involution on Multidetector CT.

The aim of this study was to better assess the prevalence and appearance of thymic tissue in adults stratified by age using multidetector computed tomography (MDCT) in order to prevent misinterpretation of normal thymic tissue as pathology. This study examined the CT appearance of the thymus in 597 trauma patients aged 30 to 69 years (M=48.0 y, SD=11.3). Three body fellowship-trained attending radiologists independently reviewed the CT scans. Reviewers assigned one of 5 grades on the basis of the relative proportions of fat and soft tissue in the thymic bed: complete fatty replacement (grade 0), predominantly fat (grade 1), even mix of soft tissue and fat (grade 2), predominantly soft tissue (grade 3), and discrete confluent thymic tissue (grade 4). Objectively, fixed-area region of interest values of the thymic bed were obtained. Interrater reliability was calculated. Increased fatty replacement of the thymus occurred with increasing age. We found residual thymic tissue (≥grade 1) in the following age categories: 30 to 39 years (83.0%), 40 to 49 years (71.9%), 50 to 59 years (52.6%), and 60 to 69 years (34.8%). Kappa comparisons for the entire sample were excellent (κ=0.86). Higher grades had higher region of interest values. Residual thymic tissue in adults on MDCT is both more prevalent and more prominent than that reported in earlier studies and can be visible into the seventh decade. We recommend that radiologists and clinicians familiarize themselves with the normal range appearances of the thymus on MDCT, in order to prevent misinterpretation of normal thymic tissue as pathology, which may result in unnecessary procedures.

Issue Highlights-May 2018 (94B3).

Issue Highlights-May 2018 (94B3).

Detection of human parvovirus B19 infection in the thymus of patients with thymic hyperplasia-associated myasthenia gravis

ObjectiveTo investigate the association between myasthenia gravis (MG) and human parvovirus B19 (B19V) infection in the thymus. MethodsThe presence of human B19V DNA and protein was assessed in 138 samples—including 68 thymic hyperplasias (39 with MG), 58 thymomas (23 with MG), and 12 normal thymus tissues—using a nested polymerase chain reaction, immunohistochemistry, laser capture microdissection, and sequencing in a double-blinded manner. ResultsB19V DNA was detected mainly in thymic hyperplasia, and the positivity rate (41.18%, 28/68) was significantly higher than that in thymoma (3.45%, 2/58) (p <0.001) but not that in normal thymic tissues. Correspondingly, the positivity rate in thymic hyperplasia with MG (30.77%, 12/39) was significantly higher than that in thymoma with MG (4.35%, 1/23) (p=0.021). However, it was higher in thymic hyperplasia without MG (55.17%, 16/29) than in thymic hyperplasia with MG (30.77%, 12/39) (p=0.043). Cells in thymic hyperplasia positive for B19V VP1/VP2 protein (63.24%, 43/68) were identified mainly in ectopic germinal centres and thymic corpuscle epithelial cells, but were rare in thymomas (1.72%, 1/58) (p <0.001). Moreover, the positivity rate was significantly higher in thymic hyperplasia with MG (74.36%, 29/39) than in thymic hyperplasia without MG (48.28%, 14/29) (p=0.027). ConclusionsTo our knowledge, the present study is the first to show that human B19V infection is closely associated with thymic hyperplasia and thymic-hyperplasia-associated MG, but is not related to thymoma or thymoma-associated MG. The findings reveal a previously unrecognized aetiopathogenic mechanism of thymic-hyperplasia-associated MG, evoking numerous questions that require further investigation.

Direction of further investigation into microscopic thymoma

Thymoma plays an important role in the initiation of the autoimmune response to acetylcholine receptor (AchR), which leads to myasthenia gravis (MG) (1). Because thymoma, unlike normal thymus tissue, does not have medullary epithelial function and lacks autoimmune regulator expression, negative selection for T cells does not work efficiently. Consequently, many types of autoantibody including anti-AchR antibody are produced.