Pathogenesis of thymoma-associated myasthenia gravis: a narrative review

Introduction

Normal thymus function

T cell development in the normal thymus

The thymus, an organ in which T cells differentiate and mature, enables immune cells to defend against infection while avoiding autoimmunity. The cellular mechanisms of immune tolerance in the thymus involve thymic epithelial cells (TECs), dendritic cells (DCs), and B cells. The thymus structure comprises the cortex, medulla, and perivascular spaces (PVSs) (1). Bone marrow-derived T cell progenitors mature within the thymus and differentiate into CD4⁺ single-positive (SP) or CD8⁺ SP T cells, which subsequently exit to the periphery. Key events that occur during intrathymic T cell differentiation include the following:

• Generation of thymocytes expressing a wide variety of T cell receptors (TCRs) by rearrangement of the TCR genes within the thymic cortex;
• Positive selection in the cortex, achieved by inducing apoptosis of T cells that fail to recognize the self-major histocompatibility complex (self-MHC), thereby selecting T cells capable of recognizing self-antigens;
• Chemokine-mediated migration of thymocytes from the cortex to the medulla;
• Negative selection in the medulla, eliminating T cells expressing TCRs that strongly recognize self-antigens;
• The appearance of CD8⁺ and CD4⁺ SP thymocytes.

In essence, the thymus uses a purposeful mechanism that initially produces T cells with an extensive repertoire of TCRs beneficial to the host defense, before eliminating those with potentially autoreactive TCRs (negative selection). Errors in these processes result in autoreactive T cells, ultimately leading to the development of autoimmune diseases.

Tissue-restricted self-antigens (TRAs) in the thymus

The expression of TRAs by medullary TECs (mTECs) is an important mechanism for eliminating autoantigen reactive T cells in the thymus. Autoimmune regulator (AIRE), a transcriptional modulator mainly expressed in mTECs, is the most well-known molecule involved in this process (1). In mTECs, AIRE is part of a multimeric complex that includes proteins related to nuclear transport, chromatin binding/structure, transcription, and pre-messenger RNA processing (2). AIRE induces “promiscuous gene expression” of more than 3,000 TRAs (1,3). The mechanism by which AIRE promotes tissue TRA expression has been elucidated in terms of the DNA and chromatin structure (4). Researchers used Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) analysis to identify Z-DNA motifs (left-handed double-helical DNA structures) and transcription factors nuclear factor erythroid 2-musculoaponeurotic fibrosarcoma oncogene homolog (NFE2-MAF) binding sites which play important roles in selecting AIRE target genes (5). In addition to AIRE, approximately 400 other TRAs are regulated by forebrain embryonic zinc finger-like protein 2 (Fezf2) (6), whereas approximately 1,000 TRAs are co-regulated by Fezf2 and AIRE or Fezf2 and chromodomain helicase DNA-binding protein 4 (Chd4) (1,7,8). Recent multi-omics studies have revealed TRA-related mechanisms. The fine classification and spatial proximity of post-AIRE mTECs have been reported (9,10). For example, neuroendocrine cells have been identified and located in close proximity to Hassall’s corpuscles (9,10). Single-cell ATAC-seq has revealed that post AIRE mTECs possess diverse chromatin accessibility states. These cells, termed “mimetic cells”, exhibit characteristics of peripheral tissues such as the skin, lung, liver, intestinal cells, and neuroendocrine cells (11,12), and can induce immune tolerance.

Histologic thymoma classification and its T cell differentiation potential

Histologic thymoma classification

A thymoma is a tumor composed of TECs and lymphocytes. Thymoma local extension and metastasis is generally described using the Masaoka-Koga Staging system. The recently introduced tumor, lymph nodes, metastasis (TNM) staging system is being used in parallel with the Masaoka-Koga system (13). Additionally, the histopathological classification follows the World Health Organization (WHO) system, which categorizes thymomas into types A, AB, B1, B2, and B3 based on epithelial cell characteristics and lymphocyte proportions.

T cell differentiation potential of thymoma

Most lymphocytes in thymomas are CD4⁺CD8⁺ double-positive (DP) T cells, whereas TCRαβ-positive CD4⁺ SP and CD8⁺ SP cells have also been identified in patients with thymomas. Tumor epithelial cells in thymomas have functions similar to those of normal TECs and induce the differentiation of bone marrow-derived T cell progenitors into CD4⁺ SP and CD8⁺ SP cells (14,15).

Thymoma and autoimmune diseases

Prevalence of autoimmune diseases associated with thymoma

Thymomas are frequently associated with myasthenia gravis (MG). Indeed, approximately 10–20% of patients with MG have thymomas, and MG is the most common autoimmune disease associated with thymomas (30–44%) (16). In terms of the frequency of MG according to histologic subtype, MG is rare in patients with type A, but relatively more common in those with type B2, accounting for 24–71% of cases. Type B1 and B3 account for 7–70% and 25–65% of cases, respectively (15,17). Thymomas are not only associated with MG but also with pure red cell aplasia (approximately 4%), Isaac’s syndrome (approximately 3%), systemic lupus erythematosus (approximately 2%), hypo-γ-globulinemia, myositis, stiff-person syndrome, rippling muscle disease, Morvan’s syndrome, dermatomyositis, encephalitis, Hashimoto’s thyroiditis, Graves’ disease, Cushing’s syndrome, Addison’s disease, type 1 diabetes, paraneoplastic pemphigus, colitis, hepatitis, rheumatoid arthritis, and Sjögren’s syndrome (16,18,19).

Pathogenic mechanisms of autoimmune diseases associated with thymoma

Common tumor-related paraneoplastic autoimmune diseases, such as Lambert-Eaton Myasthenic syndrome associated with small cell lung carcinoma, possess autoantibodies that target autoantigens that are common to both tumor cells and target organs of autoimmunity (20). Given that the thymus was originally a tissue that expressed self-antigens, thymomas likely cause autoimmune diseases because of self-antigen expression (20,21). Indeed, thymoma-associated MG (TAMG) is sometimes accompanied by anti-striational and synaptic autoantibodies, whereas thymomas express muscle antigens such as titin and ryanodine receptors, as well as neural antigens such as gamma-aminobutyric acid (GABA) receptor and leucine-rich glioma inactivated 1 (LGI-1) protein (22,23). However, considering that autoimmune phenomena associated with thymomas occur at a notably high frequency (>50% compared to <5% in other tumors), mechanisms other than self-antigen expression within the thymoma microenvironment possibly contribute to autoimmunity induction (20). Many studies have focused on self-antigens and T cells in elucidating TAMG pathogenesis. The following sections provide an overview of these findings. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-25-28/rc).

Methods

In this narrative review, we aimed to summarize and interpret the immunopathological mechanisms underlying TAMG, based on a selection of key published studies. We prioritized original research that contributed significantly to the understanding of self-antigen expression, T cell kinetics, and impaired negative selection in TAMG, including both classical findings and recent immunological insights.

In particular, we placed special emphasis on studies involving bioinformatic analysis. While a wide range of molecular and cellular investigations were reviewed, we focused our in-depth discussion on bulk RNA-sequencing (RNA-seq), single-cell RNA-seq (scRNA-seq), and spatial transcriptomic data obtained from our original studies of patients with TAMG. These data-driven approaches enabled us to identify novel cell populations and spatial niches that may be critical for MG onset in thymoma.

The selected studies were not systematically screened from all available literature but rather chosen based on their clinical relevance, mechanistic insight, and citation impact. Our goal was to provide a balanced and conceptually integrative view of TAMG pathogenesis, supported by both historical and state-of-the-art data (Table 1).

Results

Autoantigen expression

The acetylcholine receptor (AChR) is the target antigen in MG (24). In MG with thymic hyperplasia, thymic myoid cells express fetal and adult-type AChRs (25-27). However, thymomas do not contain myoid cells (28); thus, the precise nature of the target antigens in thymomas continues to be debated. Neoplastic epithelial cells express various AChR subunits but not whole receptors (29-31). Due to the lack of strong evidence that the AChR itself acts as an autoantigen in thymomas, the mechanism of molecular mimicry has also been investigated. Midsize neurofilament (NF-M) overexpression within the neoplastic epithelial cells of type B thymomas (32) and five identical, repetitive AChR-like epitopes on NF-M recognized by monoclonal anti-AChR antibody have been demonstrated (33). NF-Ms have also been found to be expressed and share epitopes with titin (32). Therefore, T cells from patients with TAMG react to NF-Ms (33) and trigger an autoimmune response to muscular antigens, including AChR and titin (Figure 1) (34). Taken together, these observations indicate that, in thymomas, the mechanism of molecular mimicry may be more pivotal than the direct expression of the AChR itself. However, since the region of AChR that shares molecular homology with neurofilament is considered to be within its intracellular domain (33), intrathymic autoantigen expression alone is probably insufficient to fully explain the onset of TAMG.

Figure 1 Previously reported pathogenesis of TAMG. Several factors have been implicated in TAMG pathogenesis, including ectopic expression of autoantigens in thymomas, immature T cell production, Treg decrease, and impaired negative selection due to AIRE deficiency, reduced HLA expression, and CTLA-4 overexpression. AIRE, autoimmune regulator; CTLA-4, cytotoxic T-lymphocyte antigen 4; HLA, human leukocyte antigen; TAMG, thymoma-associated myasthenia gravis.

Aberrant T cell kinetics in thymoma

T cell production in MG-associated thymoma

T cell kinetics have been extensively investigated in patients with TAMG. TCR excision circles (TRECs), which are circular DNA fragments formed during TCR gene rearrangement in developing T cells within the thymus, have been examined as an indicator of recent thymic emigrants in patients with TAMG. The TREC levels in CD4⁺ and CD8⁺ peripheral blood lymphocytes in patients with TAMG are significantly higher than those in healthy individuals (14), indicating active thymic output and a robust generation of new T cells in patients with TAMG. Consistently, in contrast to thymomas without MG, MG-associated thymomas shed large numbers of mature CD4⁺CD45RA⁺ cells into the blood (Figure 1) (35). Moreover, thymic carcinomas (type C) that do not exhibit thymocyte proliferation rarely develop into MG (36). Collectively, these data indicate that robust T cell production from thymomas increases the likelihood of developing MG.

Dysregulated helper T cell differentiation in TAMG

The aberrant differentiation of effector helper T cells has been reported in patients with TAMG. Indeed, in these patients, the proportion of T follicular helper (TFH) cells (CD4⁺CXCR5⁺ T cells), which facilitate antibody production from B cells, was significantly higher than that in healthy controls and patients with thymomas without MG (37). In addition, the expression levels of TFH cell surface markers, such as C-X-C chemokine receptor type 5 (CXCR5), programmed cell death protein 1 (PD-1), inducible costimulatory molecule (ICOS), and the transcription factor B-cell lymphoma 6 protein (Bcl-6), were significantly elevated in thymomas from patients with MG compared to both control groups and patients with thymomas without MG. These molecules correlate with TFH cell functions and are involved in the pathogenesis of autoimmune diseases (38). Another study confirmed increased interleukin (IL)-21 and IL-4 production in TAMG, along with an increased proportion of peripheral helper T (Tph) cells in peripheral blood. In addition, increased ICOS expression and higher T helper type 17 (Th17) cells frequency were observed in both patients with TAMG and those with thymomas without MG (39). We performed scRNA-seq analysis of peripheral CD4⁺ T cells from patients with autoimmune disease and demonstrated through meta-analysis that Th17 and T helper type 1 (Th1) cells are characteristic of MG (40). Regarding regulatory T cells (Tregs), the promotion of intratumoral CD4⁺CD25⁺FoxP3⁺ Tregs in thymocytes was found to be reduced in thymomas [TAMG (+) and TAMG (−)] compared to normal thymus (Figure 1) (41,42). Taken together, these data indicate that patients with TAMG have dysregulated Th cell differentiation, which leads to autoantibody production.

Negative selection

Accumulating evidence suggests that negative selection is dysregulated in MG-associated thymomas. Although thymomas express a variety of autoantigens, AIRE expression is reduced in thymoma (43,44). Since both MG (+) and MG (−) thymomas show deficiencies in AIRE, AIRE deficiency alone is clearly insufficient to elicit MG (20). However, AIRE deficiency may impair negative selection, potentially contributing to MG development (Figure 1) (45,46). MHC class II molecules play an important role in the negative selection of thymocytes by presenting peptides. Many studies have reported that thymomas exhibit low levels of MHC class II molecules (1), whereas TECs exhibit MHC haploinsufficiency (1). These abnormalities may disrupt proper T cell development (Figure 1) (1,47-49). Genetic abnormalities that alter T cell activation have been reported in TAMG. Some patients with TAMG have gain-of-function mutations in cytotoxic T-lymphocyte antigen 4 (CTLA4) and protein tyrosine phosphatase non-receptor type 22 (PTNP22), suggesting their involvement in disease development (50-52). Signaling through CTLA4 and PTPN22 is generally immunosuppressive and prevents autoimmune diseases; however, in the thymus, it increases the risk of autoimmunity by inhibiting negative selection (Figure 1).

Working hypothesis on TAMG development and ongoing issues

Several hypotheses have been proposed to explain the mechanism of TAMG development. Based on findings regarding the loss of self-tolerance in TAMG, Shelly et al. posited ‘The immature T cell theory’ hypothesis, which states that, in thymoma, thymocytes are immature and develop MG because they do not have sufficient self-tolerance (53). Marx et al. integrated findings from thymoma and peripheral immunity data in TAMG and proposed a pathway from thymoma to the onset of MG. According to their hypothesis, naïve effector T cells that fail to acquire self-tolerance are exported from thymomas without undergoing appropriate negative selection (20). When these T cells encounter relevant epitopes presented by antigen-presenting cells outside the thymus, they become activated, potentially triggering autoantibody production through B cell stimulation.

These hypotheses have been derived from studies focusing on specific molecules, cells, or signaling pathways involved in TAMG. However, they are largely based on targeted observations and do not necessarily represent an unbiased sampling of the highly heterogeneous cellular composition within thymomas. As such, it remains possible that key cellular players or pathogenic mechanisms have been overlooked.

To comprehensively elucidate the pathogenesis of TAMG, high-resolution, data-driven, and unbiased approaches are needed to capture the full complexity of the thymoma microenvironment. scRNA-seq is essential for a thorough understanding of the mechanisms underlying thymoma development (54,55). These techniques have the potential to provide an unbiased analysis and landscape of the complex process involved in MG pathogenesis in thymoma. Here, we attempted to introduce our recent data regarding TAMG by using a bioinformatic approach.

Application of bioinformatic analysis for MG-associated thymoma

scRNA-seq for thymoma: neuromuscular mTEC (nmTEC) identification using multi-omics analysis

Initially, we re-analyzed publicly available thymoma datasets, particularly focusing on The Cancer Genome Atlas (TCGA) dataset, which includes bulk RNA-seq data from 116 thymoma cases annotated with MG status and histologic classifications. By comparing the gene expression profiles of MG-associated and non-MG-associated thymomas, we identified MG-specific differentially expressed genes, including ryanodine receptors, GABA receptors, glycine receptors, and neurofilaments (Figure 2). These proteins have previously been implicated as target antigens in thymoma-associated autoimmune neuromuscular diseases (18,56).

Figure 2 Gene expression signature of MG-associated thymoma identified using bulk RNA-seq. Volcano plot displaying DEGs between thymomas with and without MG based on bulk RNA-seq analysis of open data source. Red and green dots indicate significantly upregulated and downregulated genes in MG, respectively (FDR corrected P<1e−5 and |log₂fold change| >2.5). Black dots represent genes that did not show significant differential expression. Representative MG-related genes including NF-M, RYR3, and GABRA5 were among the upregulated genes (56). DEG, differentially expressed gene; FDR, false discovery rate; GABA, gamma-aminobutyric acid; GABRA5, GABA receptor 5; MG, myasthenia gravis; NF-M, midsize neurofilament; RNA-seq, RNA-sequencing; RYR3, ryanodine receptor 3.

To identify specific cell populations expressing MG-related molecules, we performed scRNA-seq on thymoma and peripheral blood mononuclear cell samples obtained from four patients with TAMG (Figure 3A). This analysis revealed a previously uncharacterized TEC subset that was distinct from known subsets (Figure 3A). Although this novel cell subset did not express AIRE, immunohistochemical analysis confirmed specific expression of neuromuscular antigens such as neurofilaments and GABA receptors at the protein level (Figure 3B). We termed this novel cell population “nmTECs” (Figure 3A) (56).

Figure 3 scRNA-seq analysis revealed that MG-specific molecules are neuromuscular antigens expressed in nmTECs. (A) UMAP plot (left) showing the distribution of 65,935 cells obtained from thymoma tissue and PBMCs of four anti-AChR antibody-positive patients, identifying 49 transcriptionally distinct clusters, including T cells, B cells, innate lymphoid cells, myeloid cells, stromal cells, and TECs. UMAP plot (middle) shows subclustering of TECs including a novel cluster of nmTECs. Violin plots (right) depict the mean expression levels of REACTOME pathway gene sets related to the neuronal (left) and muscular (right) system across TEC subsets. nmTECs exhibited unique upregulation of neuromuscular gene programs compared to other TEC populations. (B) Immunostaining confirmed that neuromuscular antigens such as NF and GABA receptor are present at the protein level in thymoma. Scale bar: 20 µm. The black arrows indicate the stained regions. (C) TCR similarity between peripheral blood and thymoma. The thickness of edges represents TCR similarity. This figure was reproduced from Yasumizu et al. (56). AChR, acetylcholine receptor; cTECs, cortical TECs; GABA, gamma-aminobutyric acid; GABRA5, GABA receptor 5; MG, myasthenia gravis; mTECs, medullary TECs; NEFL, neurofilament light chain; NEFM, neurofilament medium chain; NF, neurofilament; nmTECs, neuromuscular medullary TECs; PBMCs, peripheral blood mononuclear cells; RNA-seq, RNA-sequencing; scRNA-seq, single-cell RNA-seq; Tcm, central memory T cells; TCR, T cell receptor; TECs, thymic epithelial cells; Tem, effector memory T cells; Th1, T helper type 1; Th17, T helper type 17; Treg, regulatory T cell; UMAP, Uniform Manifold Approximation and Projection.

Gene set enrichment analysis (GSEA) suggested that nmTECs are actively involved in antigen processing and presentation through both MHC class I and II pathways, indicating that they play a significant role in the induction of TAMG and other thymoma-associated autoimmune neuromuscular diseases (56). Furthermore, nmTECs showed strong interactions with lymphocytes, monocytes, and DCs, highlighting their potential key role in MG pathogenesis (56). In addition, C-X-C motif chemokine ligand 12 (CXCL12), a chemokine critical for angiogenesis and lymphocyte recruitment, was highly expressed in nmTECs, whereas its receptor C-X-C chemokine receptor type 4 (CXCR4) was identified in thymic B cells, TFH cells, and Tregs (56). These findings suggest that nmTECs contribute to distinct thymoma microenvironment formation that promotes immune cell recruitment and activation within tumors (56).

We also observed TFH cells and germinal center (GC) B cells within thymomas, along with evidence of B cell activation and differentiation of naive B cells into GC B, memory B, and plasma cells (56). Interestingly, when we analyzed TCR similarity between the thymus and the periphery for each cluster, we found that T cells, including Tregs, displayed high levels of TCR similarity (Figure 3C).

These findings suggest that antigen presentation by nmTECs, modulated by extrathymomal CD4⁺ T cells, may initiate an immune response within the thymoma that ultimately leads to autoantibody production. Thus, nmTECs appear to not only present antigens but also to actively shape a microenvironment that facilitates lymphocyte recruitment and antibody production within thymomas (56).

Spatial transcriptomics for thymoma: localization and associated niche of nmTECs

To visualize the autoimmune responses in the TAMG, we used spatial transcriptome analysis on paraffin-embedded thymoma sections, which allowed for the collection of spatially resolved messenger RNA expression data. This approach facilitated clustering of the cortical, medullary, and border regions, validating the distinct structural organization observed in the thymic tissue. Comparative analyses revealed structural differences between the normal thymus, MG-associated thymoma, and non-MG thymomas. In the normal thymus, the cortex is located peripherally and surrounds a large central medulla. However, in type B1 MG-associated thymomas, the medullary region was enlarged and located peripherally compared to non-MG thymomas (Figure 4). C-C chemokine receptor type 7 (CCR7) staining, a medullary marker, confirmed that the medullary regions were enlarged in MG-associated type B1 thymomas compared to non-MG thymomas (Figure 4). These observations led us to hypothesize that disruption of the corticomedullary architecture and significant medullary expansion are critical for autoimmune responses. The medulla harbors disease susceptibility genes, as identified by genome-wide association studies, suggesting that it is a key site for autoimmune activation in MG (57).

Figure 4 Spatial transcriptomic profiling and Immunostaining of thymomas with or without MG. FFPE sections from thymomas were analyzed using the CytAssist Visium spatial transcriptomics platform and immunostaining. The left and middle are Visium-based spatial transcriptome maps annotated by Leiden clustering and spatial domain classification, and the right shows immunostaining for CCR7. Spots are colored according to tissue regions: cortex (blue), junction (orange), medulla (green), medulla_FN (medulla-specific clusters characterized by FN1 expression) (red), medulla_GC (purple), and stroma (brown). Thymomas are primarily composed of cortical regions with reduced medullary areas. MG-associated thymomas (anti-AChR antibody positive) show relatively enlarged medullary regions located at the periphery and contain ectopic GC-like structures (arrowheads). Spatial domain annotation and nmTEC prediction indicate that nmTECs are enriched at the boundary between cortex and medulla. This figure was reproduced from Yasumizu et al. (57). Immunostaining for CCR7, a medullary marker, revealed that MG-associated type B1 thymomas had significantly larger medullae than those without MG. Scale bar: 500 µm. AChR, acetylcholine receptor; CCR7, C-C chemokine receptor type 7; FFPE, formalin-fixed, paraffin-embedded; FN, fibronectin; GC, germinal center; MG, myasthenia gravis; nmTECs, neuromuscular medullary TECs; TECs, thymic epithelial cells.

Finally, we investigated the spatial localization of nmTECs. These cells were identified at the corticomedullary junction, a region that is abundant in DP (CD4⁺CD8⁺) T cells (Figure 4) (57). Chemokine expression patterns in thymomas closely resemble those in the normal thymus (57), suggesting that DP cells may be activated by neuromuscular antigens and subsequently migrate to the medulla. The adjacent areas contained antigen-presenting DCs, effector T cells, including TFH and antibody-producing B cells. These findings suggest that the cascade from antigen presentation to autoantibody production is initiated in the medulla adjacent to nmTECs (Figure 5) (57).

Figure 5 Graphical abstract. This schematic summarizes the spatial immunopathology of MG-associated thymoma. In seropositive cases, the medullary region is relatively enlarged and structurally remodeled. At the cortico-medullary junction, nmTECs expressing neuromuscular autoantigens are enriched and may contribute to the development of autoreactive T cells. Ectopic lymphoid structures are observed in the medulla, where TFH, dendric, and B cells interact, potentially driving autoantibody production. DP, double-positive; MG, myasthenia gravis; MHC, major histocompatibility complex; nmTECs, neuromuscular medullary TECs; SP, single-positive; TAMG, thymoma-associated myasthenia gravis; TECs, thymic epithelial cells; TFH, T follicular helper.

Conclusions

By integrating bulk RNA-seq, scRNA-seq, spatial transcriptome analysis, pathological information, and clinical information related to thymomas, we found that TECs expressing neuromuscular antigens and medullary structures may be involved in TAMG pathogenesis. The medullary-like structures were larger in MG-associated type B1 thymomas than in non-MG-associated B1 thymomas, suggesting that the involvement of nmTECs and adjacent medullary structures may be particularly important in type B1 TAMG development. However, there was no significant difference in the area of medullary-like structures between cases with and without MG, despite the presence of nmTECs in type B2 thymomas. Therefore, microenvironments other than medullary-like structures may contribute to MG development in type B2 thymomas, highlighting the need for further studies to identify them.

Bioinformatic methods have the potential to comprehensively capture the thymoma microenvironment, which cannot be analyzed by conventional pathological examination or flow cytometry. Given that such research approaches are conducted in combination with conventional pathological examination and immune cell analysis, new discoveries will be made.

Acknowledgments

Figure 3 is reproduced from the article “Myasthenia gravis-specific aberrant neuromuscular gene expression by medullary thymic epithelial cells in thymoma” by Yasuimizu et al., published in Nature Communications [2022], licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0). Figure 4 is reproduced from the article “Spatial transcriptomics elucidates medulla niche supporting germinal center response in myasthenia gravis-associated thymoma” by Yasumizu et al., published in Cell Reports [2024], available under a CC BY license. The original authors and publishers are duly acknowledged, and appropriate citations are provided.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Malgorzata Szolkowska) for “The Series Dedicated to the 14th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2024)” published in Mediastinum. The article has undergone external peer review.

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-25-28/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-25-28/prf

Funding: This work was supported by JSPS KAKENHI (Nos. 23K27517 and 25H01863 to T.O.) and by AMED (No. 23gm1810003h0002 to A.K.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-25-28/coif). “The Series Dedicated to the 14th International Thymic Malignancy Interest Group Annual Meeting (ITMIG 2024)” was commissioned by the editorial office without any funding or sponsorship. T.O. reported supports from JSPS KAKENHI (Nos. 23K27517 and 25H01863), and AMED (No. 23gm1810003h0002). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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