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The thymus is the central organ involved with T-cell development and the production of naïve T cells. During normal aging, the thymus undergoes marked involution, reducing naïve T-cell output and resulting in a predominance of long-lived memory T cells in the periphery. Outside of aging, systemic stress responses that induce corticosteroids (CS), or other insults such as radiation exposure, induce thymocyte apoptosis, resulting in a transient acute thymic involution with subsequent recovery occurring after cessation of the stimulus. Despite the increasing utilization of immunostimulatory regimens in cancer, effects on the thymus and naïve T cell output have not been well characterized. Using both mouse and human systems, the thymic effects of systemic immunostimulatory regimens, such as high dose IL-2 (HD IL-2) with or without agonistic anti-CD40 mAbs and acute primary viral infection, were investigated. These regimens produced a marked acute thymic involution in mice, which correlated with elevated serum glucocorticoid levels and a diminishment of naïve T cells in the periphery. This effect was transient and followed with a rapid thymic "rebound" effect, in which an even greater quantity of thymocytes was observed compared to controls. Similar results were observed in humans, as patients receiving HD IL-2 treatment for cancer demonstrated significantly increased cortisol levels, accompanied by decreased peripheral blood naïve T cells and reduced T-cell receptor excision circles (TRECs), a marker indicative of recent thymic emigrants. Mice adrenalectomized prior to receiving immunotherapy or viral infection demonstrated protection from this glucocorticoid-mediated thymic involution, despite experiencing a substantially higher inflammatory cytokine response and increased immunopathology. Investigation into the effects of immunostimulation on middle aged (7-12 months) and advance aged (22-24 months) mice, which had already undergone significant thymic involution and had a diminished naïve T cell population in the periphery at baseline, revealed that even further involution was incurred. Thymic rebound hyperplasia, however, only occurred in young and middle-aged recipients, while advance aged not only lacked this rebound hyperplasia, but were entirely absent of any indication of thymic restoration. This coincided with prolonged deficits in naïve T cell numbers in advanced aged recipients, further skewing the already memory dominant T cell pool. These results demonstrate that, in both mice and humans, systemic immunostimulatory cancer therapies, as well as immune challenges like subacute viral infections, have the potential to induce profound, but transient, glucocorticoid-mediated thymic involution and substantially reduced thymic output, resulting in the reduction of peripheral naive T cells. This can then be followed by a marked rebound effect with naïve T cell restoration, events that were shown not to occur in advanced-aged mice.

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INTRODUCTION: Dendritic 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. METHODS: We 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. RESULTS: In 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. CONCLUSION: Thymic 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.

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PURPOSE: Abnormal liver blood tests (ALBTs), neutropenia (NEU) and thymic hyperplasia (TH) are new features of Graves' disease (GD). Our objectives were: (a) to calculate the accuracy of TH in discriminating between Graves' and non-Graves' thyrotoxicosis, compared to ALBTs, NEU and Graves' orbitopathy (GO); (b) to explore the outcome of GD-associated TH and non-GD-associated TH. METHODS: We prospectively analyzed consecutive adult patients with newly diagnosed thyrotoxicosis from January 2018 to June 2023. TH was detected via neck ultrasound (nUS) then confirmed and followed by magnetic resonance imaging (MRI). For GD vs non-GD clinical sensitivity (SE) and specificity (SPEC), accuracy, positive predictive value (PPV) and negative predictive value (NPV) of GO, TH, ALBTs and NEU were calculated. RESULTS: 264 thyrotoxic patients were included. TH was found in 16.4% (20/122) of GD vs 1.4% (2/142) in non-GD (p < 0.001). SE, SPEC, accuracy, PPV and NPV of the four extrathyroidal manifestations of GD were as follows, respectively: GO 26%, 100%, 66%, 100%, 61%; ALBTs 41%, 89%, 69%, 76%, 66%; NEU 5%, 100%, 56%, 100%, 55%; TH 16%, 98%, 61%, 91%, 98%. In 18 of them, TH regressed within 12 months after achieving euthyroidism under anti-thyroid drug therapy, while in the remaining 2, TH regressed 6 months after thyroid surgery. In the two non-GD patients with TH, thymus disappeared along with euthyroidism. CONCLUSIONS: TH in the hyperthyroidism scenario provides a high PPV for GD. A conservative approach for the diagnostic work-up and initial management of thyrotoxicosis-associated TH should be adopted.

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OBJECTIVE: To determine whether histogram analysis based on unenhanced CT can play a role in the differential diagnosis of thymoma and lymphoma from thymic hyperplasia and cyst (mean CT attenuation > 10 HU). MATERIALS AND METHODS: This retrospective study included consecutive asymptomatic participants who have prevascular mediastinal lesions incidentally detected by unenhanced CT between December 2013 and August 2020, and with definitive diagnosis by pathology or additional radiologic work-ups. A total of thirteen histogram parameters on enhanced CT were calculated for each lesion, then were compared between tumor (thymoma + lymphoma) and non-tumor (hyperplasia + cyst). Receiver operating characteristic analysis was conducted to investigate the performance of histogram parameter for identifying tumor. RESULTS: The study population included 192 patients (106 men and 86 women) with a mean age of 50.5 years at the time of CT examination. Of them, 94 patients have tumor (87 thymomas and 7 lymphoma) and 98 have non-tumor (48 thymic hyperplasia and 50 cysts). Nine of the thirteen histogram parameters revealed significant difference between the two groups, including median, minimum, range, 10th percentile, 90th percentile, kurtosis, skewness, uniformity and entropy. No significant difference was observed in the mean CT attenuation between groups. Higher median was found to be independent predictors for distinguishing tumor from non-tumor, and can achieve an area under the curve (AUC) of 0.785 (95% confidence interval [95% IC], 0.720-0.841). CONCLUSIONS: Histogram analysis based on unenhanced CT may be able to provide some help in the differential diagnosis of incidental lesions in prevascular mediastinal. GRAND SUPPORT: This study was sponsored by Natural Science Foundation of Shanghai (No. 21ZR1459700).

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BACKGROUND: Graves' disease increases bone resorption in hyperthyroidism, leading to elevated serum calcium levels and a negative bone balance. Thymic hyperplasia is observed in some Graves' disease patients. What's more, there have been a few reports of increased serum calcium and severe osteoporosis induced by Graves' disease with thymic hyperplasia. It remains unclear whether Graves' disease with thymic hyperplasia is associated with higher serum calcium levels. Our study aimed to investigate the possibility of elevated serum calcium levels and aggravated bone mobilization in Graves' disease patients with thymic hyperplasia. METHODS: Newly diagnosed and untreated patients with Graves' disease (n = 96) were enrolled. They were divided into two groups based on the incidental detection of thymic hyperplasia during imaging. Albumin, alkaline phosphatase, calcium, free triiodothyronine, free thyroxine, thyroid-stimulating hormone, and thyrotrophin receptor antibody (TRAb) were measured, and a computerized tomography of the chest was obtained. RESULTS: Patients with Graves' disease who had thymic hyperplasia were notably younger (P=0.018) and exhibited higher serum calcium levels (P=0.001) compared to those with Graves' disease without thymic hyperplasia. In the multiple regression analysis, thymic hyperplasia, TRAb, and female gender were significant variables associated with elevated serum calcium levels in patients with Graves' disease, collectively accounting for 31.7% of the variation in serum calcium. CONCLUSIONS: Graves' disease patients with thymic hyperplasia showed higher serum calcium levels. thymic hyperplasia, TRAb, and female gender were found to be correlated with increased serum calcium levels in Graves' disease, suggesting a potential association between thymic hyperplasia and bone mobilization in Graves' disease.

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Mediastinal tumours represent a heterogeneous group of entities derived from the manifold structures located in or adjacent to the mediastinum. Due to the occurrence of some of these tumours in characteristic mediastinal compartments, an anatomical subdivision of the mediastinum in the prevascular (anterior), visceral (middle), and paravertebral (posterior) is helpful for the differential diagnosis. Benign anterior mediastinal tumours linked to an enlargement of the thymic gland mainly consist of thymic cysts and several types of thymic hyperplasia: true thymic hyperplasia, rebound hyperplasia, lymphofollicular hyperplasia, and so-called thymic hyperplasia with lymphoepithelial sialadenitis (LESA)-like features. Mature teratomas, ectopic (para)thyroid tissue, and benign thymic tumours such as thymolipoma or thymofibrolipoma represent further typical tumours of the anterior mediastinum. Pericardial, bronchogenic, or oesophageal duplication cysts predominate in the middle mediastinum, whereas neurogenic tumours and myelolipomas are characteristic findings in the posterior compartment. Vascular tumours, lipomas, adenomatoid tumours, Castleman disease, or mediastinitis are further examples of less frequent tumours or tumorous lesions affecting the mediastinum. This review focuses on benign mediastinal lesions with an emphasis on benign tumours of the thymus. Besides histology, characteristic epidemiological and clinical aspects prerequisite for the correct diagnosis and patient management are discussed.

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OBJECTIVES: Graves' disease (GD) is a rare auto-immune disorder in pediatric population. The association between GD and thymic hyperplasia was rarely reported in children. Diagnosis and management of GD are challenging in children. CASE PRESENTATION: This report presents the case of a 5-year-old girl with a personal history of asthma and congenital bilateral isolated clinical anophthalmia who presented with acute congestive heart failure, sinus tachycardia and atypical signs of orbitopathy with edema and erythema of the lower right eyelid and excessive tearing. The diagnosis of GD was based on detecting a suppression of serum TSH level and the presence of high titers of TRAbs. Relapse occurred after 10 months of antithyroid drugs with chief complaints of palpitations, dyspnea and dysphagia. Computed tomography showed heterogeneous anterior mediastinal mass with no invasion into the surrounding tissue. The marked shrinkage of the mass after radioiodine therapy supported the diagnosis of thymic hyperplasia associated with GD. CONCLUSIONS: The presence of clinical anophthalmia may be a confusing factor for the diagnosis of Graves' ophthalmopathy. Recognition of the association between GD and thymic hyperplasia would avoid invasive diagnostic procedures and unnecessary surgical resection. Radioiodine therapy may be used in young children with repeated relapses of GD.

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BACKGROUND: Thymic hyperplasia with lymphoepithelial sialadenitis-like features (LESA-like TH) is a rare form of thymic hyperplasia, characterized by a prominent expansion of the thymic medulla containing hyperplastic lymphoid follicles with germinal centers, while an almost total absence of thymic cortex. Since the first report in 2012, only a few cases of LESA-like TH have been reported in the literature to date. Due to the rarity of LESA-like TH and the tumor-like morphology, it is easy to be misdiagnosed as other common diseases of the thymus in routine practice, such as thymoma and lymphoma. CASE PRESENTATION: Herein, we present a case report of a 52-year-old Chinese female patient with LESA-like TH, without any discomforting symptoms. Computer-tomography imaging revealed a cystic solid mass in the anterior mediastinum, with well-defined boundaries and multiple internal septa. Histologically, prominent features were florid lymphoid follicles containing germinal centers, as well as hyperplasia of thymic epithelial cells and proliferation of Hassall bodies. However, the thymic cortex rich in immature T cells was almost completely absent. Furthermore, mature plasma cells, lymphoepithelial lesions, and cholesterol clefts were frequently seen. CONCLUSION: We made a diagnosis of LESA-like TH and performed a literature review to better understand the clinicopathological features of LESA-like TH and reduce misdiagnosis.

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PURPOSE: To explore the efficiency of a contrast-enhanced CT-based radiomics nomogram integrated with radiomics signature and clinically independent predictors to distinguish mass-like thymic hyperplasia (ml-TH) from low-risk thymoma (LRT) preoperatively. METHODS: 135 Patients with histopathology confirmed ml-TH (n = 65) and LRT (n = 70) were randomly divided into training set (n = 94) and validation set (n = 41) at a ratio of 7:3. The least absolute shrinkage and selection operator (LASSO) algorithm was used to obtain the optimal features. Based on the selected features, four machine learning models, support vector machine (SVM), logistic regression (LR), extreme gradient boosting (XGBOOST), and random forest (RF) were constructed. Multivariate logistic regression was used to establish a radiomics nomogram containing clinically independent predictors and radiomics signature. Receiver operating characteristic (ROC), DeLong test, and calibration curves were used to detect the performance of the radiomics nomogram in training set and validation set. RESULTS: In the validation set, the area under the curve (AUC) value of LR (0.857; 95% CI: 0.741, 0.973) was the highest of the four machine learning models. Radiomics nomogram containing radiomics signature and clinically independent predictors (including age, shape, and net enhancement degree) had better calibration and identification in the training set (AUC: 0.959; 95% CI: 0.922, 0.996) and validation set (AUC: 0.895; 95% CI: 0.795, 0.996). CONCLUSION: We constructed a contrast-enhanced CT-based radiomics nomogram containing clinically independent predictors and radiomics signature as a noninvasive preoperative prediction method to distinguish ml-TH from LRT. The radiomics nomogram we constructed has potential for preoperative clinical decision making.

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BACKGROUND: To describe the clinical features of patients with childhood-onset myasthenia gravis (MG) (CMG) and explore predictors affecting the treatment outcomes. METHODS: A retrospective observational cohort analysis of 859 patients with CMG with disease onset before age 14 years was performed at Tongji Hospital. RESULTS: Patients in the pubertal-onset group (n = 148) had a worse disease course than those in the prepubertal group (n = 711), including a higher incidence of generalized MG (GMG) at presentation, generalization of ocular MG (OMG), and more severe Myasthenia Gravis Foundation of America (MGFA) classification. All patients were initially treated with pyridostigmine, 657 with prednisone, and 196 with immunosuppressants (ISs). However, 226 patients were resistant to prednisone treatment. Multivariate analysis revealed that thymic hyperplasia, higher MGFA class, disease duration before prednisone administration, and thymectomy before prednisone administration were independent predictors of prednisone resistance. At the last visit, 121 of the 840 patients with OMG had developed GMG after a median of 10.0 years from symptom onset and 186 patients (21.7%) achieved complete stable remission (CSR). In multivariable analysis, age at onset, thymic hyperplasia, prednisone, and IS treatment were associated with generalization, whereas age at onset, disease duration, anti-acetylcholine receptor antibodies (AChR-ab), MGFA class II, short-term prednisone treatment, and IS treatment were associated with CSR. CONCLUSIONS: The majority of patients with CMG have mild clinical symptoms and favorable outcomes, especially those with earlier onset age, shorter disease duration, and negative AChR-ab. In addition, early prednisone and ISs are shown to be effective and safe for most patients with CMG.

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Myasthenia gravis (MG) is an autoimmune disease (AD), and patients with MG often have other types of ADs. We analyzed the prognosis of patients with MG complicated by AD after thymectomy. A retrospective analysis was performed for patients with MG complicated by ADs treated surgically in our center over the past 22 years, and their general condition and follow-up data were collected and analyzed. 33 patients were included totally. 28 patients displayed improvement or even complete recovery of MG, and 23 of 36 ADs revealed improvement or even complete recovery. The prognosis of MG is significantly correlated with the duration of postoperative follow-up time (p = 0.028), and in patients with thymoma, the larger the tumor diameter, the better the prognosis of MG (p = 0.026). Thymic hyperplasia patients were predominantly female (p = 0.049) and young (p < 0.001). The most common concomitant AD in this study was a thyroid-associated AD, which was associated with thymic hyperplasia (p < 0.001), Osserman type I MG (p < 0.001), and young age (p < 0.001). Thymectomy had a good therapeutic effect on MG complicated by AD, and there was a close correlation between surgery, thymus, MG, and ADs.

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RATIONALE: Thymoma is a rare malignant tumor but it is the most common primary tumor of the anterior mediastinum. The current imaging methods for thymoma screening suffer from false positive rate problems, and thymoma pathogenesis remains elusive. Study of thymoma metabolic characteristics could provide clues for improving the diagnosis and understanding the pathogenesis of thymoma. METHODS: Metabolic profiling of plasma from thymoma and thymic hyperplasia patients was performed using ultrahigh-performance liquid chromatography combined with high-resolution mass spectrometry in both positive and negative ionization modes. After pre- and post-processing, the dataset was divided into three age groups and statistical analysis was performed to select differential metabolites of thymoma. For feature identification, experimental tandem mass spectra were matched to those of databases and available chemical standards, and also manually annotated with plausible chemical structures to ensure high identification confidence. RESULTS: A total of 47 differential metabolites were identified in thymoma. Significantly higher levels of histidine, sphinganine 1-phosphate, lactic acid dimer, phenylacetylglutamine, LPC (18:3) and LPC (16:1), and significantly lower levels of phenylalanine, indole-3-propionic acid (IPA), hippuric acid and mesobilirubinogen were associated with thymoma. Tryptophan level in thymoma-associated myasthenia gravis (TAMG) was significantly lower than that of the MG(-) group. IPA and hippuric acid abundances exhibited increasing trends from indolent to aggressive thymoma. CONCLUSIONS: Our study revealed aberrant aromatic amino acid metabolism and fatty acid oxidation might be associated with thymoma. The identified unique metabolic characteristics of thymoma may provide valuable information for study of the molecular mechanism of thymoma pathogenesis, and improvement of diagnosis and discovery of new therapeutic strategies for thymoma.

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Thymic hyperplasia is a rare condition generally caused by lymphoid follicular hyperplasia associated with autoimmune disorders. True thymic parenchymal hyperplasia unassociated with lymphoid follicular hyperplasia is extremely rare and may give rise to difficulties in diagnosis. We have studied 44 patients with true thymic hyperplasia (38 females and 6 males) aged 7 months to 64 years (mean, 36 years). Eighteen patients presented with symptoms of chest discomfort or shortness of breath; in 20 patients, the lesions were discovered incidentally. Imaging studies demonstrated enlargement of the mediastinum by a mass lesion suspicious for malignancy. All patients were treated with complete surgical excision. The tumors measured from 3.5 to 24 cm (median, 10 cm; mean, 10.46 cm). Histologic examination showed lobules of thymic tissue displaying well-developed corticomedullary architecture, with scattered Hassall corpuscles separated by mature adipose tissue and bounded by a thin fibrous capsule. No cases showed evidence of lymphoid follicular hyperplasia, cytologic atypia, or confluence of the lobules. Immunohistochemical studies showed a normal pattern of distribution for keratin-positive thymic epithelial cells against a background rich in CD3/TdT/CD1a+ lymphocytes. Twenty-nine cases had an initial clinical or pathological diagnosis of thymoma or thymoma vs thymic hyperplasia. Clinical follow-up in 26 cases showed that all patients were alive and well between 5 and 15 years after diagnosis (mean, 9 years). Thymic parenchymal hyperplasia causing significant enlargement of the normal thymus that is sufficient to cause symptoms or worrisome imaging findings should be considered in the differential diagnosis of anterior mediastinal masses. The criteria for distinguishing such lesions from lymphocyte-rich thymoma are presented.

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BACKGROUND: Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum. METHODS: After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated. RESULTS: After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth. CONCLUSION: Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH.

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INTRODUCTION/AIMS: Descriptions of the clinical characteristics of anti-AChR-MuSK-LRP4 antibody-negative myasthenia gravis (triple-negative myasthenia gravis, TNMG) are lacking in the current literature. Therefore, we investigated the clinical characteristics of TNMG in Chinese patients. METHODS: We retrospectively analyzed 925 patients with MG registered in the Department of Neuroimmunology, Henan Institute of Medical and Pharmaceutical Sciences from January 2015 to March 2021. RESULTS: One hundred six patients diagnosed with TNMG were included in the study. The average age of onset was 32.4 y, with a male-to-female ratio of 1:1. The age of onset showed a bimodal distribution: 0-9 y and 40-49 y. Adult patients were more likely to have weakness of limb and bulbar muscles (p < .05). Thymic hyperplasia was found in 20.2% of the patients. Younger patients were more likely to relapse. The rate of adult early-onset myasthenia gravis reaching complete stable remission and pharmacological remission was 47.6%, and the prognosis was better than that in juvenile-onset myasthenia gravis (p = .019). Older age of onset was the only risk factor for the development of generalized TNMG from ocular TNMG (R = 1.046, p = .002, 95% confidence interval 1.017-1.077). DISCUSSION: This study showed that the clinical characteristics of patients with TNMG varied among the different age groups. Significant findings included a bimodal distribution of onset age, coexisting thymic hyperplasia, and a generally favorable prognosis.

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Thymic hyperplasia with lymphoepithelial sialadenitis-like features is characterized by thymic hyperplasia with lymphocytic infiltrates in the thymic epithelium. The lesion differs from other forms of thymic hyperplasia, including true and follicular thymic hyperplasia, in that it presents at an advanced age and has been reported to be unassociated with autoimmune diseases. We report a case of thymic hyperplasia with lymphoepithelial sialadenitis-like features in a 55-year-old male patient with a history of an immunoglobulin G4 (IgG4)-related disorder. Histologically, the resected mediastinal mass showed features consistent with those of thymic hyperplasia with lymphoepithelial sialadenitis-like features. In addition, the IgG4/IgG ratio was elevated in the polyclonal plasmacytoid infiltration. Thymic hyperplasia with lymphoepithelial sialadenitis-like features has not been reported to be associated with IgG4-related disorders; however, as shown in our report, it is crucial to include it in the differential diagnosis of a mediastinal mass in a patient with IgG4-related disorders.

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