Immune dysregulation in thymoma: a potential mechanistic link to secondary lung cancer—a case report

Introduction

Thymoma is a rare epithelial neoplasm of the anterior mediastinum, with an incidence of approximately 2 cases per million annually (1). While thymomas are often indolent, they are strongly associated with autoimmune and paraneoplastic syndromes such as myasthenia gravis, pure red cell aplasia, and hypogammaglobulinemia. These associations reflect the central role of the thymus in T-cell maturation and immune tolerance. Architectural disruption within thymomas may impair negative selection of autoreactive T-cells, leading to systemic immune dysregulation (2).

Beyond classical autoimmune manifestations, increasing evidence suggests that thymomas may contribute to a chronic pro-inflammatory state. Cytokine release from immature thymocytes and disorganized thymopoiesis can create an aberrant immune microenvironment, which has been implicated in both tissue injury and oncogenesis. Experimental and clinical observations indicate that patients with thymic lesions may exhibit elevated inflammatory mediators such as interleukin (IL)-6, IL-8, tumor necrosis factor-alpha (TNF-α), and C-X-C motif ligand 13 (CXCL13) in adjacent lung tissue, supporting the concept of a thymoma-driven paracrine inflammatory niche. This inflammatory dysregulation may compromise tumor immunosurveillance and contribute to the development of secondary malignancies (3) (Figure 1).

Figure 1 Proposed mechanistic pathway linking thymoma-associated immune dysregulation to secondary lung cancer. NSCLC, non-small cell lung carcinoma.

The synchronous occurrence of thymoma and non-small cell lung carcinoma (NSCLC) is exceedingly rare and poses diagnostic as well as therapeutic challenges. Moreover, it raises important mechanistic questions about whether thymic dysfunction can directly contribute to lung carcinogenesis.

Here, we present the case of a patient with synchronous thymoma and NSCLC, complicated by unexplained systemic inflammation. We discuss potential immunologic mechanisms linking thymoma to secondary cancer development and review relevant literature highlighting this underrecognized association. We present this article in accordance with the CARE reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-25-43/rc).

Case presentation

A 71-year-old male with a significant smoking history underwent routine lung cancer screening, which initially revealed a 5-mm right apical pulmonary nodule with unremarkable physical examination. Serial imaging at an outside facility a year and a half later demonstrated progressive enlargement of the lesion, reaching 23 mm in diameter (Figure 2). The nodule was plural-based and located in the posterior segment of the right upper lobe. Concurrently, mediastinal lymphadenopathy was noted, raising concern for malignancy.

Figure 2 CT chest without IV contrast 12/27/2024 showed evidence of (A) soft tissue nodule in the anterior mediastinum measuring 2.3 cm and (B) 2.9 cm × 1.9 cm pleural-based mass in the posterior right upper lobe with mediastinal lymphadenopathy. CT, computed tomography; IV, intravenous.

A diagnostic bronchoscopy with transbronchial biopsy of the right upper lobe lesion confirmed NSCLC, favoring adenocarcinoma. Mediastinal lymph node sampling revealed metastatic adenocarcinoma in stations 4R and 11R, while contralateral and subcarinal nodes (stations 4L, 7, and 11L) were negative. Immunohistochemistry showed programmed death ligand 1 (PD-L1) expression of 0% and identified an ERBB2 mutation.

Positron emission tomography-computed tomography (PET-CT) imaging revealed avid fluorodeoxyglucose (FDG) uptake along the periphery of a subpleural nodule located in the apical segment of the right upper lobe (Figure 3). There was bulky FDG-avid lymphadenopathy involving both the right upper and lower paratracheal regions, with extension into the right hilum. Additional FDG uptake was noted in several non-enlarged lymph nodes, including the right supraclavicular, contralateral left upper paratracheal, prevascular, and right internal mammary nodes. A 3-cm anterior mediastinal soft tissue mass demonstrated mild FDG uptake. Based on these findings, the patient was staged as having stage IIIA NSCLC (cT1c, cN2b, cM0) according to the American Joint Committee on Cancer (AJCC) 9th edition.

Figure 3 Avid FDG uptake along the periphery of the subpleural nodule in the apical segment of the right upper lobe and bulky FDG-avid right upper and lower paratracheal lymphadenopathy extending into the right hilum. FDG, fluorodeoxyglucose.

After extensive discussion at a multidisciplinary tumor board, the decision was made to proceed with anterior mediastinal biopsy for completion of staging of NSCLC, and to assist with treatment planning. To our surprise, the histopathologic analysis of the CT-guided biopsy of the anterior mediastinal mass revealed nests of spindle-shaped epithelial cells (AE1/AE3⁺, p40⁺) in background rich in CD3⁺ T-cells, TdT⁺ and CD1a⁺ immature thymocytes, and CD20⁺ B-cell aggregates. The diagnosis was consistent with type A thymoma and micronodular thymoma with lymphoid stroma, both of which are known to preserve but disorganize thymopoiesis.

Based on these findings, the patient was diagnosed with synchronous NSCLC and thymoma. Notably, that the enlarged thymus had been radiographically present since 2021 but remained undiagnosed until staging workup for NSCLC in 2025.

After discussion with the patient, he was initiated on systemic chemotherapy with carboplatin and pemetrexed. After four cycles, repeat imaging demonstrated stable disease in both the lung and mediastinal lesions. He transitioned to maintenance pemetrexed. The case was reviewed again in a multidisciplinary thoracic tumor board, which recommended against surgical resection or stereotactic body radiation therapy (SBRT) for the thymoma. Immunotherapy was avoided due to the presence of thymoma, which carries a high risk of severe immune-related adverse events with checkpoint inhibitors.

Local therapy for the thymoma was deferred because it represented an indolent subtype (type A micronodular thymoma with lymphoid stroma) and had demonstrated long-standing radiographic stability since 2021. Management priorities focused on the unresectable stage IIIA NSCLC, and there was concern that local intervention could exacerbate inflammation, particularly given the patient’s prior thymoma-associated pericarditis. As the thymoma was stable and asymptomatic, local treatment was unlikely to alter short-term outcomes. Systemic therapy for NSCLC adhered to current standards: first-line platinum-pemetrexed was selected based on nonsquamous histology and the presence of an ERBB2 mutation, while PD-L1 expression of 0% minimized the expected benefit of immunotherapy and raised concerns about thymoma-related toxicity with immune checkpoint inhibitors (ICIs). Second-line docetaxel plus ramucirumab was chosen in accordance with guideline-supported evidence for previously treated nonsquamous NSCLC.

The patient was subsequently admitted with features of acute pericarditis with elevated inflammatory markers [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)], which was treated with colchicine. The infectious and autoimmune etiologies for pericarditis were excluded. Flow cytometry and T-cell receptor (TCR) gene rearrangement studies were negative, suggesting unexplained systemic inflammation in the context of a type A thymoma. Imaging raised concern for progressive disease, given the increase in pleural fluid and questionable lymphangitic carcinomatosis and pericarditis (Figure 4). A temporary treatment holiday was given to allow the patient to recover, after which he was started on docetaxel/ramucirumab as second-line treatment for lung cancer. The acetylcholine receptor antibody was 0 (negative).

Figure 4 Mildly increased mild pericardial thickening and increased prominence of adjacent epipericardial fat stranding. Increased mild smooth interlobular septal thickening in the lower lungs. Differential considerations include interstitial edema as well as lymphangitic carcinomatosis.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Thymomas are rare anterior mediastinal neoplasms arising from thymic epithelial cells, with an annual incidence of approximately 2 per million in the United States (1). They are classically associated with autoimmune and paraneoplastic syndromes such as myasthenia gravis, pure red cell aplasia, and hypogammaglobulinemia, reflecting the thymus’ central role in T-cell development and immune tolerance (2,3). While the relationship between thymoma and autoimmunity is well established, the potential oncogenic consequences of thymic dysfunction is not fully understood.

Literature context

The synchronous occurrence of thymoma and NSCLC is exceedingly rare. Only a handful of cases have been reported in the literature, with most identified incidentally during staging workup for lung cancer (4-8). In contrast, our patient’s thymic changes had been radiographically present for at least 5 years before NSCLC diagnosis, suggesting a temporal sequence in which thymic dysfunction preceded the development of lung cancer. This observation supports the hypothesis that thymoma is not merely a coincidental finding but may actively contribute to secondary carcinogenesis via chronic inflammatory process.

Pathophysiologic links

Several immunologic mechanisms may explain this association. Immature thymocyte–mediated inflammation may contribute to chronic cytokine release, particularly IL-7 and IL-2, creating a pro-inflammatory milieu in adjacent lung parenchyma (9,10). Paraneoplastic immune dysregulation was evident in our case, manifested by unexplained pericarditis with markedly elevated CRP and ESR in the absence of infection or autoimmunity. This systemic inflammation may represent early manifestations of thymoma-driven immune activation preceding overt tumor progression. In addition, loss of central tolerance is a well-described feature of thymoma. Architectural distortion and impaired autoimmune regulator (AIRE)-mediated negative selection allow autoreactive T-cell clones to escape, leading not only to autoimmune syndromes but also to reduced tumor immunosurveillance (11,12).

Experimental evidence supports this link. Chorro et al. reported that patients with coexisting thymic lesions and lung cancer demonstrated elevated IL-6, IL-8, TNF-α, and CXCL13 in tumor-adjacent lung tissue, suggesting a thymoma-driven paracrine inflammatory niche that shapes the tumor microenvironment (13). CXCL13 in particular promotes ectopic germinal center formation, perpetuating chronic immune activation and stromal remodeling. Similarly, age-related thymic involution results in the accumulation of atypical thymic epithelial cells through loss of FOXN1 and activation of epithelial-to-mesenchymal transition (EMT) pathways, generating epithelial-rich, immune-poor zones that foster chronic inflammation and impaired tumor surveillance (14). These processes provide a biologic rationale for why thymoma and thymic dysfunction may predispose to secondary cancers.

In addition to mechanistic insights, review of the literature underscores the rarity and complexity of managing patients with synchronous thymoma and NSCLC (Table 1). Song et al. (4), Liu et al. (5), Patella et al. (6), Moorjani et al. (7), and Dolci et al. (8) have described cases with variable histologic subtypes and clinical outcomes. Most underwent surgical resection, sometimes in combination with chemotherapy or radiotherapy, and achieved short-term disease control. Our case differs in that the NSCLC was locally advanced and unresectable, while the thymoma was indolent but associated with systemic inflammation, complicating management. Furthermore, the presence of thymoma limited the use of ICIs, which carry a high risk of severe immune-related adverse events in this population (15,16).

Clinical implications

Clinically, this case has several implications. First, thymic dysfunction may predate and contribute to secondary malignancies, highlighting the importance of long-term surveillance in patients with thymic abnormalities, even when radiographically stable. Second, clinicians should consider thymic dysfunction as a driver of chronic inflammation and impaired immunosurveillance in cancer patients. Finally, therapeutic planning should account for the dual risks of tumor progression and immune-related complications, particularly when considering immunotherapy.

This case adds to the limited literature suggesting that thymoma-associated immune dysregulation extends beyond autoimmunity to oncogenesis. Further studies are needed to clarify the incidence, mechanisms, and risk factors for secondary cancers in thymoma patients. Collaborative registries and translational studies will be essential to determine whether surveillance strategies or preventive interventions can mitigate this risk.

Conclusions

This case may suggest a possible immunologic association between thymoma or thymic dysfunction and the development of secondary malignancies, though further studies are needed to clarify this potential relationship. These findings support further investigation into the thymic dysregulation or occult thymoma as a contributor to extrathymic malignancies. This may merit further study or collaborative exploration.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-25-43/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-25-43/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-25-43/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. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

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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