Evolving paradigms in thymoma surgery and multidisciplinary care: a narrative review

Introduction

Background

Thymic epithelial tumors (TETs), which encompass thymomas and the more aggressive thymic carcinomas, are the most prevalent primary malignancies of the anterior mediastinum (1). Although rare—with an estimated incidence of 0.15–0.25 cases per 100,000 person-years—their unique biology and high propensity for recurrence necessitate specialized management (2,3).

A crucial aspect of thymoma’s clinical significance is its strong association with paraneoplastic syndromes (PNSs), most notably myasthenia gravis (MG). This condition is observed in up to one-third of patients and often influences both the diagnostic workup and perioperative management (4-7). Clinical decision-making is further guided by the World Health Organization (WHO) histopathologic classification (Types A, AB, B1–B3, and thymic carcinoma) and established staging systems. The recent adoption of the Tumor-Node-Metastasis (TNM) classification, including the 8th and emerging 9th editions, has improved prognostic stratification and treatment planning (1,2).

The fundamental principle of curative intent for resectable thymoma remains complete surgical resection (R0) (2). Historically, this was achieved via a median sternotomy, but the field has undergone a rapid technical evolution toward minimally invasive approaches (8). Video-assisted thoracoscopic surgery (VATS) and particularly robotic-assisted thoracic surgery (RATS) have emerged as preferred options for early-stage disease, offering benefits like reduced trauma and faster recovery without compromising oncological outcomes (1,9).

Several recent narrative reviews have summarized the epidemiology, pathology, staging systems, and general management of TETs, including the roles of surgery, radiotherapy (RT), and standard chemotherapy. While these publications provide valuable overviews of established practice and guideline-based recommendations, many focus on isolated domains such as surgical techniques, systemic therapy advances, or staging updates. As a result, they place less emphasis on how emerging technologies, evolving surgical platforms, and multidisciplinary strategies are influencing contemporary clinical decision-making in thymoma management.

This review adopts a multidisciplinary, surgery-centered framework that integrates imaging, staging, surgical strategy, and systemic therapy within a unified clinical decision-making pathway. Particular emphasis is placed on developments in clinical practice between 2010 and 2025, including the expanding role of minimally invasive surgery (MIS) in selected advanced cases, the integration of radiomics and artificial intelligence (AI) to improve preoperative assessment and prediction of resectability, and the evolving role of molecular profiling and immunologic therapies. By focusing on areas where evidence is actively reshaping clinical practice, this review aims to provide a forward-looking perspective on how contemporary innovations are influencing thymoma management and how care may evolve over the coming decade in specialized multidisciplinary centers. By integrating surgical, diagnostic, and systemic treatment perspectives within a single framework, this review provides a practical synthesis of emerging evidence and highlights areas where future research and technological innovation are most likely to influence clinical practice.

Rationale and knowledge gap

The technical feasibility and oncologic safety of RATS are now being increasingly explored and confirmed even in selected cases of locally advanced tumors (TNM Stage II–IV) and for larger tumors (≥5 cm), challenging traditional surgical boundaries (8,9). For locally advanced or metastatic thymoma, curative management transitions into a demanding multimodal strategy, integrating surgery with systemic neoadjuvant and/or adjuvant chemotherapy and RT (1). Despite the advancements in surgical technique and multimodal approaches, significant challenges persist in managing recurrent, refractory, and advanced disease, necessitating novel therapeutic strategies (1,8). The latest frontiers are centered on molecular profiling and precision oncology, with research illuminating distinct molecular signatures and genomic alterations in thymoma and thymic carcinoma (10). These insights are paving the way for targeted agents, such as tyrosine kinase inhibitors, and immunotherapy, which have shown promising results in clinical trials, particularly for thymic carcinoma (10). Ultimately, successful navigation of these complex diagnostic and therapeutic pathways is critically dependent on robust multidisciplinary collaboration, involving thoracic surgery, oncology, neurology, and pathology, as championed by international bodies like the International Thymic Malignancy Interest Group (ITMIG) (3,11).

Objective

This comprehensive review aims to synthesize the evolving paradigms in the surgical and multidisciplinary management of thymoma, with a focus on recent data published between 2010 and 2025. We will discuss updates in pathologic classification and staging, the contemporary evidence comparing various surgical platforms, the optimized integration of multimodal therapy for locally advanced disease, and the exciting emerging trends in molecular diagnostics and personalized treatment. We present this article in accordance with the Narrative Review reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-2025-1-68/rc).

Methods

This article is a narrative review designed to provide a comprehensive and interpretive overview of current evidence on thymoma management, with a focus on evolving clinical paradigms rather than exhaustive systematic synthesis. A targeted literature search was performed using PubMed, MEDLINE, and Google Scholar, supplemented by reviews of guideline-based resources such as the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (Version 2.2025) and consensus statements from the ITMIG. The detailed search strategy, including databases, keywords, and combinations of search terms used, is provided in Table S1. Search terms broadly covered thymoma diagnosis, staging, surgical approaches, multimodality therapy, and emerging systemic and imaging-based strategies. Both clinical and translational studies were included. Priority was given to contemporary data from prospective cohorts, multi-institutional trials, large retrospective databases [National Cancer Database (NCDB), Surveillance, Epidemiology, and End Results (SEER), ITMIG Registry], and systematic reviews, while case reports and small single-institution series were used selectively to illustrate rare clinical scenarios or emerging techniques. Relevant studies were selected based on their contribution to key thematic areas. These included staging and histopathologic classification, advances in imaging and diagnostic workup, comparisons of surgical platforms, multimodal management of locally advanced disease, treatment of recurrent or metastatic thymoma, and emerging domains such as targeted therapies, immunotherapy, and radiomics-assisted planning. Findings were synthesized qualitatively to identify consistent patterns, highlight areas of consensus and controversy, and integrate real-world evidence from large databases with emerging prospective data. Given the heterogeneity of study designs, predominance of retrospective series, and the exploratory nature of emerging topics discussed, this review was conducted as a narrative review rather than a systematic review. Accordingly, formal PRISMA guidelines were not applied, as the primary objective was to synthesize trends, contextualize evidence, and highlight areas of evolving practice rather than to perform quantitative comparison or meta-analysis. The structure and reporting of this review were informed by established principles for narrative reviews, including the SANRA (Scale for the Assessment of Narrative Review Articles) framework, to ensure clarity, transparency, and balance in study selection and interpretation. No formal quantitative assessment of study quality or risk of bias was performed; however, studies were appraised qualitatively based on design, sample size, and clinical relevance when synthesizing conclusions.

Pathologic classification and staging updates

The core of thymoma management starts with accurate pathologic classification and staging, both of which have been substantially refined in recent years. The current standard is the WHO Classification of Tumors of the Thymus (5th edition, 2021/2022), which retains the five primary thymoma subtypes (A, AB, B1, B2, B3) and thymic carcinoma (12-14). This classification holds profound independent prognostic weight, demonstrating a stepwise increase in malignant behavior and recurrence risk from Type A/AB to B3 and thymic carcinoma (13,14). Critically, this subtyping is now correlated with distinct molecular profiles, such as the frequent GTF2I missense mutation found in indolent Type A and AB thymomas, distinguishing them from higher-risk thymoma subtypes and thymic carcinomas, which have shown comparatively greater molecular complexity, although thymomas overall retain a relatively low tumor mutational burden and few consistently actionable alterations (12,14-16). The identification of these subtypes, however, still presents challenges in reproducibility, highlighting the need for pathologist training and adherence to the refined morphological criteria in the latest WHO edition (13,14,17,18). The updated WHO histopathologic classification and the TNM staging framework are summarized in Table 1, highlighting key morphologic features, associated molecular profiles, and corresponding prognostic implications.

Despite these advances in molecular characterization, the clinical applicability of molecular profiling in thymoma remains limited. Large-scale genomic studies have demonstrated that thymomas generally exhibit a low tumor mutational burden and relatively simple genomic landscape, with few recurrent alterations that can be directly targeted therapeutically. Although the GTF2I mutation is highly characteristic of Type A and AB thymomas and has improved understanding of thymoma biology, it currently does not translate into actionable targeted therapies. Consequently, molecular profiling has primarily contributed to refining tumor classification and biological insight rather than substantially altering treatment strategies in routine clinical practice (15,16).

Despite its widespread adoption, the WHO histopathologic classification of TETs is subject to interobserver variability, even among experienced pathologists. This variability is most pronounced in tumors with overlapping histologic features, particularly at the interfaces between Type AB and B1 thymomas and between B2 and B3 subtypes. Differences in the interpretation of epithelial-to-lymphocyte ratios, cellular atypia, and architectural patterns can lead to discrepancies in subtype assignment, which may affect reported prognostic correlations and complicate comparisons across studies. As a result, expert pathologic review and multidisciplinary discussion are often recommended, especially in cases where histologic subtype may influence treatment decisions. Ancillary studies, including immunohistochemistry and emerging molecular data, may provide supportive information but do not currently replace morphologic assessment as the foundation of thymoma classification (18).

Throughout this review, the TNM staging system is presented as the current preferred framework for thymoma staging in contemporary clinical practice. The Masaoka-Koga system is referenced selectively to provide historical context and facilitate comparison with earlier studies that continue to inform the literature.

The move toward a universal oncologic language is exemplified by the adoption of the TNM staging system (8th and emerging 9th editions), which was proposed by the International Association for the Study of Lung Cancer (IASLC)/ITMIG as a standardized, anatomically based alternative to the longstanding Masaoka-Koga system (17). The TNM system provides a more anatomically precise classification. Its adoption has been associated with a degree of stage migration compared with the Masaoka-Koga system, largely due to differences in how capsular invasion, pleural involvement, and nodal disease are categorized. As a result, some tumors previously classified as Masaoka-Koga Stage II or III may be reclassified into earlier TNM stages, which can complicate direct comparison with historical outcome data (13,17). This change better reflects modern surgical curability, as these structures can be safely resected en bloc. Furthermore, the TNM system provides crucial, granular details for advanced disease by clearly defining N1/N2 nodal involvement (anterior vs. deep intrathoracic/cervical) and M1a/M1b metastatic spread (pleural/pericardial vs. distant organ), which are essential for guiding multimodal therapy. While the prognostic curves of Masaoka-Koga and TNM can sometimes overlap in certain stages, the ITMIG/European Society of Thoracic Surgeons (ESTS) collaborative efforts continue to leverage large global datasets to refine the TNM system—such as the upcoming 9th edition—to improve its predictive power and reproducibility, ultimately harmonizing management guidelines worldwide (17,19). The TNM classification system for TETs, including tumor extent (T), nodal involvement (N), metastatic spread (M), and stage grouping, is described in detail in the literature (20).

As a result, contemporary guidelines and clinical discussions frequently reference both systems, creating a degree of staging duplicity that can complicate cross-study comparisons and treatment interpretation. In this review, TNM staging is emphasized for contemporary anatomic and prognostic assessment, while Masaoka-Koga terminology is referenced where necessary for historical context and alignment with existing literature.

The Masaoka-Koga staging system has historically served as the cornerstone for thymoma staging due to its simplicity and strong correlation with prognosis, particularly in surgical series. Its emphasis on capsular invasion and local spread aligns well with operative findings and has facilitated consistent reporting across decades of retrospective studies. However, Masaoka-Koga staging lacks granularity in defining nodal involvement and distant metastasis, limiting its utility for modern multimodal treatment planning and cross-institutional comparison (21).

In contrast, the TNM staging system offers a more anatomically precise and standardized framework, clearly distinguishing tumor extent (T), lymph node involvement (N), and metastatic disease (M). This structure improves prognostic stratification, supports harmonization with other solid tumor staging systems, and enhances applicability to advanced disease and clinical trials. Nonetheless, this stage migration has been gradually adopted due to the continued reliance on historical data reported using Masaoka-Koga criteria (22).

Clinical presentation and comprehensive diagnostic workup

The clinical presentation of thymoma is highly diverse, reflecting its origin as a tumor of the thymus gland. While an increasing number of thymomas are discovered incidentally (up to 50%) on routine chest imaging, the remaining patients often present with symptoms that necessitate a thorough diagnostic workup (23,24). Symptoms typically fall into two categories: those caused by the local mass effect of the tumor and those resulting from associated PNS (23). Local symptoms arise from the tumor’s expanding bulk in the anterior mediastinum, leading to nonspecific complaints like persistent chest pain, chronic cough, and dyspnea (24). In advanced stages, direct invasion or compression of major structures can lead to potentially life-threatening conditions such as superior vena cava syndrome (SVCS) or unilateral diaphragmatic paralysis due to phrenic nerve involvement (24). The most defining clinical characteristic of thymoma is its association with a wide array of autoimmune PNSs, occurring in 30–50% of patients (25,26). The most common and clinically relevant is MG, a postsynaptic neuromuscular disorder causing fluctuating, fatigable muscle weakness (e.g., ptosis, diplopia, difficulty swallowing) (23,27). MG results from the tumor promoting T-cell dysregulation and the subsequent production of autoantibodies, primarily against the acetylcholine receptor (AChR) (26,27). The presence of MG is a critical finding, as it is associated with an increased likelihood of diagnosing the thymoma at an earlier, more resectable stage (Masaoka-Koga I or II), although it adds considerable complexity to the preoperative management. Less common but serious PNSs include pure red cell aplasia (PRCA), a severe form of anemia, and Good syndrome (hypogammaglobulinemia), which increases the risk of recurrent infections (25). Initial laboratory assessment often includes screening for AChR antibodies and a serum protein electrophoresis to identify hypogammaglobulinemia (27).

The diagnostic workup centers on cross-sectional imaging: contrast-enhanced chest computed tomography (CT) is the cornerstone of diagnosis and initial clinical staging. It provides essential information regarding the tumor’s size, its lobulated or smooth morphology, and its relationship to the heart, great vessels, and pleura (17,28). CT images are primarily used to apply the Masaoka-Koga staging system, which determines the extent of invasion (28). Magnetic resonance imaging (MRI) is also often employed secondarily for superior soft-tissue delineation. It is particularly valuable when assessing potential invasion into the chest wall, diaphragm, or vascular structures, as it can more clearly distinguish tumor tissue from surrounding edema or fibrosis (28). It can also aid in differentiating thymoma from thymic hyperplasia, a benign condition, through specific chemical-shift protocols (28). The utility of ¹⁸F-FDG positron emission tomography-CT (PET/CT) is primarily reserved for aggressive disease (high-risk WHO Types B2/B3 or suspected thymic carcinoma) or to rule out Stage IVB distant metastasis (24,28). While FDG avidity can vary, higher SUVmax values typically correlate with more aggressive histology and a poorer prognosis (28).

The decision regarding tissue diagnosis via biopsy is one of the most critical and debated steps. For a mass that is highly suggestive of a low-grade thymoma and appears resectable on imaging, a pretreatment biopsy is generally discouraged (27,28). The consensus is to proceed directly to surgery, as a complete surgical resection (R0) is both diagnostic and potentially curative, while a percutaneous biopsy carries a small but clinically significant risk of capsular violation and tumor seeding onto the pleura or mediastinum (29). A core-needle biopsy is required only in specific scenarios: when the diagnosis is uncertain and differentiation from entities that require immediate non-surgical treatment, such as lymphoma or germ cell tumor, is necessary, or when the tumor is locally advanced (Stage III/IV) and neoadjuvant chemotherapy or chemoradiation is planned to downsize the mass prior to surgery (29).

Prior to treatment, all patients undergo a thorough preoperative assessment, focusing on cardiac and pulmonary function, especially in MG patients (27). The ultimate therapeutic strategy—which includes the sequence of surgery, chemotherapy, and radiation—must be determined by a multidisciplinary tumor board (MTB) evaluation to ensure adherence to evidence-based guidelines and optimize the patient’s individual outcome (29).

Surgical management: principles and technical evolution

The fundamental principle guiding surgical treatment of thymoma is achieving complete resection (R0) of the tumor and the entire thymus gland (extended thymectomy), as this remains the most important prognostic factor for long-term survival across disease stages (29-31). Due to the tumor’s malignancy potential, the resection must be performed en bloc with the tumor capsule intact, minimizing the risk of intraoperative capsular violation and subsequent pleural or mediastinal tumor seeding (1,29). The choice of surgical approach should be individualized based on tumor characteristics, surgeon experience, and institutional volume, as high-quality randomized comparisons between open and minimally invasive thymectomy remain limited (31,32).

The extent of surgical resection in thymoma remains a subject of ongoing debate, particularly for early-stage disease. Total thymectomy, involving en bloc removal of the thymus and surrounding mediastinal fat, has traditionally been considered the standard approach due to its association with reduced local recurrence and its importance in patients with or at risk for MG. Partial thymectomy or limited thymic resection may be considered in carefully selected patients with small, well-encapsulated early-stage tumors, especially when complete resection with negative margins can be achieved. Tumor resection alone, without removal of residual thymic tissue, is generally discouraged due to higher recurrence rates and limited oncologic control, except in highly selected cases where patient comorbidities or anatomical constraints preclude more extensive surgery (5,27,29,33).

Minimally invasive approaches—particularly VATS and RATS—have emerged as effective alternatives to median sternotomy for carefully selected early-stage thymomas. These techniques allow complete thymectomy while preserving capsular integrity and minimizing surgical trauma (30,33). While perioperative outcomes such as blood loss, complication rates, and hospital length of stay have been widely compared in the literature, key comparative metrics are summarized in Table 2. Beyond perioperative advantages, minimally invasive approaches require careful patient selection and adherence to oncologic principles to ensure safe en bloc resection and adequate mediastinal fat clearance (30,33). Comparative studies suggest similar or improved perioperative outcomes with RATS relative to VATS, with equivalent oncologic results in early-stage disease and selected larger tumors (9). Although available data remain largely retrospective and subject to selection bias, an ongoing multicenter randomized trial is expected to provide higher-level evidence comparing robotic-assisted and video-assisted thymectomy in early-stage thymoma (1). Accordingly, careful patient selection, surgeon experience, and institutional volume remain critical determinants of success, and total thymectomy continues to be preferred when feasible to optimize long-term disease control.

Surgical techniques for thymectomy have evolved significantly from traditional open methods to advanced minimally invasive procedures:

Median sternotomy (open surgery)

Historically, median sternotomy has been the reference approach for thymoma resection across stages. It provides the best exposure of the anterior mediastinum, the great vessels, and both phrenic nerves, which is essential for ensuring complete resection and meticulous margin control (30,31). Median sternotomy remains the gold standard for large, locally invasive tumors (Masaoka-Koga Stage III/IV) where combined resection of adjacent structures or vascular reconstruction is anticipated (29,31).

MIS

For early-stage, non-invasive thymomas (Masaoka-Koga Stage I and II), minimally invasive techniques—VATS and RATS—have gained wide acceptance (30,32).

VATS: VATS, typically performed via a uniportal or multiportal approach, offers reduced blood loss, decreased postoperative pain, shorter chest tube duration, and significantly shorter hospital stays compared to open sternotomy (32,33). Oncological outcomes (recurrence and long-term survival) appear comparable to open surgery for these early stages (33).

RATS: RATS offers superior technical advantages over conventional VATS, including a three-dimensional magnified view and articulated instruments, which aid in precise dissection in the narrow retrosternal space (30). Comparative studies suggest RATS provides benefits over open surgery in terms of less blood loss, fewer complications, and shorter hospital stays, while being comparable to VATS in terms of short-term oncological outcomes (30,32). RATS is increasingly adopted in experienced centers for limited-stage thymoma and in selected patients with MG, where complete removal of all anterior mediastinal fat is critical (29,30). However, evidence remains largely retrospective, and outcomes are closely linked to surgeon experience and institutional volume.

Robotic-assisted thymectomy can be performed using lateral thoracic, subxiphoid/subcostal, or bilateral approaches. The lateral thoracic approach offers familiar port placement and efficient unilateral exposure, making it suitable for small, laterally located tumors. Subxiphoid and subcostal approaches provide improved midline visualization and facilitate bilateral mediastinal fat dissection, which is particularly advantageous in patients with MG requiring extended thymectomy. Bilateral approaches may be selected for large anterior mediastinal tumors or cases requiring extensive bilateral dissection. Current comparative evidence is limited and largely retrospective, and approach selection should be individualized based on tumor characteristics, need for bilateral access, and surgeon experience (4-7).

In patients with MG, complete thymectomy with en bloc removal of mediastinal and perithymic fat is recommended to optimize neurologic outcomes. While MIS techniques can achieve extended resections in experienced hands, concerns remain regarding the completeness of ectopic thymic tissue clearance, and sternotomy may still be preferred in selected cases requiring maximal exposure (27,28).

Minimally invasive approaches are most appropriate for well-encapsulated, early-stage thymomas without radiologic evidence of invasion into adjacent structures. Tumor size alone is not an absolute contraindication, but larger tumors may limit visualization and specimen extraction, particularly in centers with limited MIS experience. Careful preoperative imaging is essential to exclude invasion of the innominate vein, superior vena cava (SVC), aorta, pulmonary artery, or pericardium requiring complex reconstruction, as these findings generally favor an open approach (5,30,32).

Median sternotomy remains the safest and most versatile approach in cases of suspected great vessel invasion, extensive pericardial involvement requiring reconstruction, bulky tumors with unclear planes of dissection, or when en bloc resection of adjacent lung or phrenic nerve is anticipated. It also provides optimal exposure in reoperative fields and in situations where rapid vascular control may be necessary (5,29,31). For locally invasive thymoma (Stage III), management is complex and often involves multimodality therapy (neoadjuvant chemotherapy followed by surgery) (31). Surgical resection of these tumors frequently requires the combined resection of involved adjacent structures, such as the pericardium, lung tissue, or major blood vessels (31). Minimally invasive approaches for locally invasive thymomas remain controversial. While limited pericardial or lung wedge resections may be feasible via MIS in specialized centers, suspected invasion of the innominate vein, SVC, aortic arch, pulmonary artery, or myocardium generally constitutes a contraindication to MIS and favors an open approach to ensure oncologic safety and vascular control (5,30,31).

Although retrospective studies and registry data have reported favorable outcomes with robotic-assisted thymectomy in experienced centers, high-level prospective evidence is still emerging. A multicenter randomized trial (NCT06029621) comparing robotic-assisted versus video-assisted thoracoscopic thymectomy for early-stage (Stage I–II) thymomas is currently ongoing and will provide more definitive data on perioperative outcomes, oncologic efficacy, and functional recovery (34).

Vascular reconstruction: Invasion of major vascular structures like the brachiocephalic veins or the SVC often necessitates their resection and subsequent reconstruction, typically using autologous or synthetic grafts (31). This complex procedure is usually performed via median sternotomy to ensure adequate exposure, though advanced surgeons are exploring RATS for select less-complex invasive cases (29,31). The paramount goal is always achieving an R0 resection, even if it requires extensive vascular work or the use of techniques like cardiopulmonary bypass (31).

Intraoperative considerations and margin control: Regardless of the approach, meticulous intraoperative margin control is essential. The tumor must be resected en bloc with a cuff of surrounding normal tissue (pericardium or mediastinal fat) (31). If the integrity of the tumor capsule is violated, or if invasion is identified, the operative plan may be converted from a minimally invasive to an open approach to facilitate safe and complete resection (30).

Prospective comparative studies and registry-based analyses are ongoing to better define the relative benefits of robotic, thoracoscopic, and open thymectomy, but current evidence remains largely retrospective and subject to selection bias.

The role of multimodal therapy

The management of locally advanced and metastatic thymoma (Masaoka-Koga stages III and IV) relies heavily on a multimodal therapy approach, strategically combining surgery with radiation and systemic agents to maximize the likelihood of achieving an R0 resection and improving long-term survival (29,35). Management strategies discussed in this section align with contemporary recommendations from the NCCN (v2.2025) and the ITMIG, which emphasize stage, resection status, and histology (thymoma vs. thymic carcinoma) in guiding perioperative and systemic therapy decisions. Systemic and radiation therapies are employed in both the neoadjuvant (preoperative) and adjuvant (postoperative) settings:

Neoadjuvant therapy (induction): Neoadjuvant chemotherapy is recommended for patients with potentially resectable but locally advanced thymomas (typically TNM Stage III or IVA) where upfront complete resection is unlikely. The goal is tumor downstaging to facilitate R0 resection. This approach is supported by NCCN and ITMIG consensus guidance, particularly for tumors with radiologic invasion of adjacent mediastinal structures. It is often combined with radiation and is indicated for patients with locally advanced disease (Stage III or IVA) that is initially deemed unresectable due to invasion of vital structures (36). The primary goal of neoadjuvant therapy is tumor downsizing, which increases the probability of achieving a complete R0 surgical resection (36).

Adjuvant therapy (postoperative radiotherapy, PORT): The role of PORT depends on histology, stage, and margin status. For completely resected (R0) early-stage thymoma (Stage I), PORT is generally not recommended. In Stage II thymoma with R0 resection, the benefit of PORT remains controversial and is typically considered only in the presence of high-risk features. For Stage III–IVA thymoma after R0 resection, PORT is more commonly considered to reduce local recurrence risk. In cases of microscopically (R1) or macroscopically (R2) positive margins, PORT is generally recommended. For thymic carcinoma, indications for PORT are broader due to higher recurrence risk (29,37). Even after R0 resection, adjuvant RT is frequently recommended for Stage II–III disease, and it is strongly advised in the presence of R1/R2 margins. These distinctions reflect the more aggressive biology and higher local recurrence rates observed in thymic carcinoma compared with thymoma (29).

The recommended multidisciplinary management pathways for Stage I–IV thymoma—including surgical selection, induction therapy, adjuvant radiation, and surveillance—are outlined in Figure 1.

Figure 1 Multidisciplinary treatment algorithm for thymic epithelial tumors. Figure created by the authors based on contemporary guidelines and consensus recommendations for thymic epithelial tumors (20,21,37). PORT, postoperative radiotherapy; RATS, robotic-assisted thoracic surgery; SBRT, stereotactic body radiotherapy; VATS, video-assisted thoracoscopic surgery.

RT is crucial for local control. Standard adjuvant RT doses typically range from 50 to 60 Gy (29). The target volumes must encompass the primary tumor bed plus generous margins to cover potential microscopic invasion, while simultaneously minimizing the dose delivered to critical surrounding organs like the heart, lungs, and spinal cord (29). Studies consistently show that RT significantly decreases the local recurrence rate in patients with invasive thymoma (Stages II and III). Furthermore, preoperative RT may be used as part of induction therapy, often achieving better tumor conformity with less toxicity than postoperative RT (36).

Chemotherapy is the foundation of systemic treatment for unresectable, metastatic, or recurrent thymic malignancies:

First-line regimens: The standard first-line regimen typically involves platinum-based combinations (36,37). Common combinations include cisplatin/carboplatin plus etoposide (PE) or cisplatin plus doxorubicin and cyclophosphamide (PAC) (36). Response rates to these regimens are generally favorable, ranging from 40% to 70% in thymoma (36,37).

Advanced/recurrent disease (Stage IV): Systemic therapy strategies also differ between thymoma and thymic carcinoma. In thymoma, platinum-anthracycline combinations remain a common first-line approach, with subsequent options including pemetrexed, gemcitabine-based regimens, or targeted therapies in selected cases. In thymic carcinoma, carboplatin–paclitaxel is frequently used as first-line therapy, with second-line options including pembrolizumab (in selected patients), sunitinib, or other targeted agents, although immune-related toxicity is a particular concern in thymoma (37-40). For recurrent or refractory Stage IV disease, therapeutic options include dose-dense chemotherapy, single-agent options (e.g., pemetrexed), and, increasingly, novel agents such as targeted therapy (e.g., sunitinib for c-Kit-positive tumors) and immunotherapy (36,37). The principal systemic therapy regimens used in thymic malignancies, along with their indications and key clinical considerations, are summarized in Table 3.

The integrated management of Stage III and IVA disease epitomizes the multimodal approach:

Initially unresectable Stage III/IVA: These cases are frequently discussed in a case-based manner by the MTB. The standard sequence often involves neoadjuvant chemotherapy (PE/PAC), followed by meticulous re-staging, then definitive surgery to achieve R0 resection, and finally, adjuvant RT if margins were close (R1) or if the initial stage was highly invasive (36). This sequential approach has demonstrated improved long-term outcomes compared to single-modality therapy for advanced stages (36).

Importantly, treatment response differs by histology. Thymomas are generally more chemosensitive, with higher response rates to platinum-based combinations such as PAC. Thymic carcinomas, in contrast, tend to demonstrate lower response rates and more aggressive behavior, often requiring alternative platinum doublets such as carboplatin–paclitaxel in the first-line setting (38).

Selected patients with recurrent thymoma may achieve durable disease control with local therapies. Surgical re-resection, when feasible for isolated mediastinal or pleural recurrence, has been associated with 5-year overall survival (OS) rates exceeding 70% in retrospective series. Stereotactic body radiation therapy (SBRT) has demonstrated high local control rates, often greater than 80%, for oligometastatic pleural or nodal recurrences, with acceptable toxicity. Re-irradiation (Re-RT) may also provide meaningful local control in carefully selected patients, although cumulative dose constraints and proximity to critical structures limit its applicability (41-43).

Management of recurrent and advanced thymoma

The management of recurrent and advanced thymoma (Masaoka-Koga Stage IV) is highly individualized, reflecting the tumor’s rarity and often indolent, yet unpredictable, course. Treatment is determined by an MTB and focuses on local control and systemic disease management (39,42).

Thymoma recurrence occurs in 5% to 30% of radically resected cases, often years after the initial surgery (median time to recurrence is around 5 years, but can stretch past a decade) (39,41). The predominant pattern of recurrence is loco-regional within the chest cavity, most commonly involving the pleura (pleural implants) or the mediastinum; distant (hematogenous) spread is less frequent (41).

Due to the risk of late recurrence, surveillance strategies require long-term follow-up. Guidelines, such as those from the NCCN, recommend chest CT scans with contrast every 6 months for the first 2 years, followed by annual CT scans for up to 10 years, with some experts advocating for even longer or lifelong surveillance (44). Early detection of recurrence allows for potential curative re-intervention. Surveillance following definitive treatment typically includes contrast-enhanced chest CT every 6 months for the first 2 years, followed by annual imaging thereafter, consistent with NCCN recommendations. Given the potential for late recurrence, long-term or lifelong surveillance may be appropriate, particularly in patients with advanced-stage disease or aggressive histological subtypes (37,44).

For recurrent disease that is still localized (typically pleural or mediastinal), complete re-resection (R0) remains preferred whenever technically feasible (41). Meta-analyses suggest that a surgical approach for recurrence is associated with a significantly better 5-year OS compared to non-surgical treatments (41).

RT plays a critical role in local control in patients unsuitable for surgery or as a consolidation measure:

SBRT: SBRT delivers high-dose, targeted radiation in a few fractions. It is increasingly utilized for treating isolated, small recurrent lesions, particularly pleural metastases, in non-surgical candidates, showing promising local control with acceptable toxicity (43).

Re-RT: Conventional Re-RT may be employed for larger, locally advanced recurrences or residual disease after incomplete re-resection (43).

Treatment selection for recurrent thymoma is individualized and depends on disease distribution, prior therapies, patient performance status, and anticipated treatment-related toxicity. Surgical re-resection is generally favored for localized, resectable recurrence in patients with good functional status. Radiation-based approaches, including SBRT or Re-RT, are typically considered for unresectable but limited-volume disease or in patients who are poor surgical candidates. Systemic therapy is reserved for multifocal, unresectable, or progressive disease, particularly when local therapies are unlikely to achieve durable control. Multidisciplinary evaluation is essential to optimize outcomes in this setting. For unresectable, widespread, or metastatic disease, systemic therapy is the primary treatment modality (37,41,42).

Platinum-based chemotherapy: This remains the standard of care for first-line treatment. Regimens such as PE or PAC are commonly used, yielding objective response rates in thymoma ranging from 40% to 70% (39).

Targeted therapy: For refractory or second-line treatment, agents targeting specific molecular pathways may be considered. For example, sunitinib and everolimus have demonstrated modest activity in previously treated thymic carcinoma, with reported response rates ranging from 15% to 30% and median progression-free survival of approximately 5–10 months (45,46). Lenvatinib has also shown promising activity in small prospective studies and is emerging as a potential option in refractory disease (39).

Immunotherapy: Immune checkpoint inhibitors (ICIs) like programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors (e.g., pembrolizumab or avelumab) have demonstrated efficacy in thymic malignancies, with reported objective response rates of approximately 20–25% in thymic carcinoma across phase II studies (39). However, their use in thymoma is complicated by the tumor’s unique immune biology. Thymomas are associated with defects in immune self-tolerance, leading to a high risk of severe, sometimes life-threatening, immune-related adverse events (irAEs) such as myocarditis or MG, with grade 3–4 irAEs reported in approximately 30–70% of thymoma patients treated with ICIs (39). Notably, these toxicity rates are substantially higher than those observed in other solid tumors and in thymic carcinoma. Therefore, ICIs are generally used with extreme caution and high-dose corticosteroids are often required to manage irAEs (39). Given this risk profile, ICIs in thymoma are typically reserved for refractory disease and are ideally administered within clinical trials or at experienced centers with multidisciplinary expertise.

The recommended treatment strategies for recurrent thymoma include surgical re-resection, SBRT, Re-RT, and systemic therapy is provided in Table 4.

Managing long-term toxicity and autoimmune complications requires vigilance for two major issues:

Treatment-related toxicity: Chemotherapy and RT can cause long-term cardiovascular and pulmonary toxicity, necessitating careful surveillance (39).

Autoimmune complications: Thymomas are strongly linked to PNSs, most commonly MG, which can be present at diagnosis or manifest later (39). The use of ICIs significantly elevates the risk of these autoimmune conditions. Management requires close collaboration with a neurologist and often involves systemic immunosuppression (e.g., high-dose corticosteroids) to control symptoms and prevent crises, particularly before and during the use of immunotherapy (39).

Progress in systemic therapy for thymoma has been comparatively limited, reflecting the tumor’s low mutational burden and complex immune biology. While molecular profiling has identified recurrent alterations, most thymomas lack clearly actionable targets, constraining the immediate clinical impact of precision oncology. This limitation underscores the importance of investigational strategies, including combinatorial approaches integrating chemotherapy, targeted agents, and carefully selected immunotherapy in specialized centers. Future advances are likely to depend more on biomarker-guided patient selection and collaborative clinical trials than on single-agent targeted therapies.

Multidisciplinary collaboration and institutional experience

The optimal management of thymoma demands a high degree of multidisciplinary collaboration and is significantly impacted by institutional experience and expertise due to the tumor’s rarity and clinical complexity (29,30,36,47). The treatment standard for thymoma necessitates review by an MTB, ensuring that decisions integrate the expertise of thoracic surgery, medical oncology, radiation therapy, and pathology (29,36). Collaboration with a neurologist is also crucial, given the high prevalence of associated MG, which complicates anesthesia, surgery, and especially the use of certain systemic therapies like immunotherapy (39). Because therapeutic strategies often involve a sequence of surgery, chemotherapy, and radiation, the MTB is essential for consensus on the sequencing and delivery of multimodal therapy (29). Consequently, patients should be treated at specialized centers with documented experience in thymic malignancies, rather than general oncology centers (36). Evidence from large datasets confirms that institutional volume and expertise significantly impact patient outcomes:

Improved survival: Studies show that patients treated at high-volume centers—those performing a greater number of thymectomies annually—demonstrate superior OS compared to those treated at low-volume centers (44). This benefit is often attributed to the greater likelihood of achieving complete surgical resection (R0) and having experienced pathology review and planning for multimodal therapy (43).

Reduced complications: High-volume centers tend to have lower rates of perioperative complications and better management of rare but severe side effects, particularly the autoimmune flare-ups associated with MG (44).

Insights from large-scale data initiatives, such as the ITMIG database and national databases like the NCDB and SEER, provide crucial real-world lessons that shape guidelines (42,43):

Validation of staging: These databases have been instrumental in validating the prognostic value of the Masaoka-Koga staging system and the newer TNM system in predicting prognosis (42).

Prognostic factors: They reinforce that the completeness of resection (R0) and the Masaoka-Koga stage are the strongest independent prognostic factors (43).

Multimodality efficacy: Real-world data confirms the value of adjuvant therapy, particularly radiation, in improving local control for invasive thymoma (42).

These findings underscore that adherence to specialized, multidisciplinary care is not merely an ideal but a necessary component for optimizing treatment and improving long-term outcomes for thymoma patients (39).

Emerging trends and future directions in thymoma management

The field of thymoma management is continuously evolving, focusing on refining surgical precision, personalizing systemic therapies through molecular insights, and leveraging AI for improved planning and collaborative research (29,39,40). Despite these advances, progress remains constrained by the rarity of thymoma, which limits large prospective trials, the predominance of retrospective data, and the absence of validated predictive biomarkers to support individualized treatment decisions.

Advances in surgery and imaging

Technological evolution is making surgery less invasive and more precise, particularly through robotic and image-guided surgical platforms. RATS is increasingly adopted in experienced centers for early-stage thymoma due to its high dexterity, superior visualization, and minimally invasive benefits (29,39). The integration of image-guided surgery (IGS), which overlays real-time imaging data such as CT or MRI, promises to enhance the precision of R0 resection, particularly in identifying and excising small pleural implants or close margins that are difficult to see (39).

Radiomics and surgical planning

Radiomics, which extracts high-dimensional quantitative imaging features from medical images, is increasingly being integrated with AI-based analytical tools to support surgical planning. These approaches are being investigated for their ability to predict tumor invasiveness, resectability, and surgical complexity, particularly in Stage III thymoma where operative decision-making is often challenging. Early studies suggest that AI-assisted analysis of CT and MRI features may improve preoperative risk stratification, inform surgical approach selection, and reduce unexpected intraoperative findings. Although these tools remain largely investigational, they represent a promising shift toward data-driven surgical planning and may ultimately help standardize preoperative assessment across institutions (36,44).

Molecular profiling and targeted strategies

Molecular understanding is gradually expanding opportunities for more personalized therapeutic strategies in thymic malignancies, particularly in advanced disease where conventional platinum-based chemotherapy has limited efficacy. Molecular profiling is increasingly being explored to identify potentially actionable alterations and improve biological characterization of thymic tumors. However, unlike many other solid malignancies, thymomas typically exhibit a relatively low tumor mutational burden and a limited number of recurrent actionable driver mutations. Recurrent mutations in the GTF2I gene, most commonly observed in Type A and AB thymomas, represent one of the most characteristic genomic findings, although these alterations are generally associated with low proliferative activity and currently lack direct targeted therapeutic options. Additional alterations involving signaling pathways such as RAS or PI3K/AKT/mTOR have been described, but their clinical utility remains under investigation. Consequently, molecular profiling currently plays a limited role in routine treatment selection for thymoma and is most relevant in advanced, recurrent, or treatment-refractory disease, where it may support enrollment in biomarker-driven clinical trials or experimental targeted therapy approaches (10,15,29).

Emerging systemic therapies

Novel systemic agents and ongoing clinical trials are increasingly shifting the focus beyond traditional chemotherapy. Targeted agents such as sunitinib, a multi-kinase inhibitor, and everolimus, an mTOR inhibitor, are being investigated for their ability to disrupt key cell-signaling pathways in aggressive thymomas and thymic carcinomas (29). Immunotherapy is also being explored; although ICIs like PD-1/PD-L1 blockers have shown promise in thymic carcinoma, their use in thymoma remains challenging due to the high risk of severe irAEs, particularly myocarditis and MG (39). Ongoing trials are therefore focused on identifying biomarkers that can predict ICI response while reducing irAE risk (39).

Collaborative research and data integration

Given the rarity of thymoma, collaborative efforts are essential for progress. The ITMIG continues to advance data harmonization by standardizing terminology, staging systems such as TNM, and data-collection practices, which are critical for combining datasets across institutions and continents to support robust analyses and clinical trials (40). Additionally, AI tools are being leveraged to analyze large, heterogeneous datasets from multiple centers, uncover subtle prognostic patterns, and optimize clinical trial design, ultimately accelerating the development of precision therapies (36).

Ultimately, future progress will rely on prospective collaborative studies that integrate clinical, radiologic, molecular, and immunologic data to develop truly risk-adapted and precision-based treatment strategies.

Limitations

This review has several inherent limitations due to its narrative design. Because studies were selected based on relevance rather than a strict systematic protocol, the possibility of selection bias cannot be excluded. The available literature on thymoma remains limited by the rarity of the disease, resulting in small sample sizes, retrospective designs, and significant heterogeneity between studies in terms of staging systems, treatment protocols, and follow-up duration. The transition from the Masaoka-Koga staging system to the TNM classification further complicates comparisons among older and newer studies. Additionally, high-level evidence such as randomized controlled trials is scarce, particularly regarding comparative surgical approaches or optimal multimodal sequencing, limiting the strength of conclusions. Emerging areas such as molecular profiling, targeted therapy, immunotherapy, and radiomics are supported primarily by early-phase studies or small cohorts, making long-term outcomes uncertain. Finally, because the field is rapidly evolving—especially in robotic surgery and immunotherapy—recent advancements may outpace the currently available published data.

Conclusions

The landscape of thymoma management is characterized by continuously evolving paradigms centered on personalized, team-based care and driven by international research. While complete surgical resection (R0) remains the absolute cornerstone of curative intent across all stages, the decision-making process has become highly stratified. Surgical management is increasingly utilizing minimally invasive techniques (VATS/RATS) for early-stage tumors, while maintaining the open approach (median sternotomy) for locally invasive disease, often requiring complex vascular reconstruction. For advanced (Masaoka-Koga III/IV) and recurrent disease, treatment relies heavily on a multidisciplinary approach, integrating neoadjuvant chemotherapy, definitive surgery, and adjuvant RT to optimize local control and survival.

The path forward emphasizes personalized, team-based approaches delivered at specialized, high-volume centers. The management of systemic disease is rapidly shifting toward precision therapy, moving beyond traditional platinum-based chemotherapy to targeted agents and cautiously implementing immunotherapy, always balancing efficacy with the unique and severe risk of irAEs associated with this tumor’s autoimmune background. Ultimately, progress depends on continued international collaboration through initiatives like ITMIG and harmonized data collection, which are essential for powering the clinical trials necessary to establish new standards of care for this rare malignancy.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-2025-1-68/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-2025-1-68/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-2025-1-68/coif). The authors have no 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.

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