Autoimmune diseases and malignancies in patients with thymoma: A 9-year retrospective study

To the Editor: Thymoma, a rare thymic epithelial tumor (1.3–3.2 per million individuals per year),[1] is classified by WHO-2021 into types A, AB, B, micronodular thymoma with lymphoid stroma (MNT-LS), metaplastic, and lipofibroadenoma. Thymoma is found to be associated with autoimmune diseases (ADs) and other malignancies.[2] Nevertheless, previous studies lack a systematic investigation of factors associated with ADs in patients with thymoma, as well as an exploration of the connections between ADs and other malignancies or different pathological classifications; therefore, we conducted this retrospective study. We retrieved the list of patients diagnosed with thymoma from the Department of Pathology at West China Hospital, Sichuan University, from January 1, 2016, to December 31, 2024. Patients with duplicate records and with incomplete clinical information were excluded. Thymoma was diagnosed and classified according to the 2021 WHO classification criteria after pathological biopsy. This study has obtained ethical approval from West China Hospital’s Ethics Committee (No. 2025(434)) and informed consent was waived. Medical records were reviewed to extract patients’ clinical information. Univariate and multivariate logistic regression analyses were conducted to identify potential factors associated with ADs. We included all variables (age, gender, Masaoka–Koga stage, presence of other malignancies, the temporal sequence of diagnosis between thymoma and other tumors or ADs, pathological classification, follow-up duration, and comorbidities) in a univariate logistic regression model. Variables with significant differences (P <0.05) were subsequently incorporated into a multivariate logistic regression. A value of P <0.05 was considered statistically significant. Analyses were performed using SPSS 23.0 (IBM Corp., Armonk, NY, USA) and R 4.4.1 (R Foundation for Statistical Computing, Vienna, Austria). A total of 883 patients with thymoma were included [Figure 1]. The gender distribution was nearly equal (male: 51.2% [452/883], female: 48.8% [431/883]), with a mean age of 45.4 years. Among them, 27.9% [246/883] were diagnosed with ADs, the vast majority (90.2% [222/246]) of whom were diagnosed simultaneously with or before the diagnosis of thymoma. Additionally, 9.2% (81/883) of the patients had primary malignancies other than thymoma, with the majority (76.5%, 62/81) of malignancies being diagnosed simultaneously with or before the diagnosis of thymoma. Lung cancer was the most common malignancy (4.6%, 41/883), followed by thyroid cancer (0.9%, 8/883). Other malignancies included breast cancer, intestinal cancer, esophageal cancer, multiple myeloma, chronic myeloid leukemia, etc [Supplementary Table 1, https://links.lww.com/CM9/C732].Figure 1: Flowchart of thymoma patient inclusion for this study from the Department of Pathology at West China Hospital, Sichuan University, from January 1, 2016, to December 31, 2024.The most prevalent pathological type was type AB (36.1%, 319/883), followed by B2 (19.9%, 176/883), B1 (14.2%, 125/883), and B3 (11.6%, 102/883). Other less frequent types included type A (7.0%, 62/883), atypical type A (1.7%, 15/883), MNT-LS (0.9%, 8/883), and metaplastic thymoma (0.3%, 3/883). Additionally, 73 (8.3%) patients were diagnosed with mixed thymoma (consisting of two or more histological components). The most common AD was myasthenia gravis (MG), identified in 24.1% (213/883) patients. Other ADs included Hashimoto’s thyroiditis (1.4%, 12/883), pure red cell aplasia (0.9%, 8/883), systemic lupus erythematosus (0.6%, 5/883), pemphigus (0.5%, 4/883), etc. The distribution of these ADs varied across different pathological types of thymoma [Supplementary Figure 1 and Supplementary Table 2, https://links.lww.com/CM9/C732]. Regarding the prevalence of ADs across different pathological classifications, the highest was in type B3 thymomas, with 39.2% (40/102) presenting with ADs, followed by type A (37.1%), type B2 (36.9%), and mixed thymoma (31.5%). In contrast, ADs were less frequently associated with other pathological types, such as MNT-LS (25.0%), type B1 (24.0%), type AB (19.4%), atypical type A (13.3%), and metaplastic thymoma (n = 0) [Supplementary Figure 1 and Supplementary Table 2, https://links.lww.com/CM9/C732]. In the multivariate logistic regression model, variables with significant differences in univariate logistic regression were subsequently included [Supplementary Table 3, https://links.lww.com/CM9/C732]. Finally, we found that patients without other malignancies were more associated with concomitant ADs (odds ratio [OR] = 10.21, 95% confidence interval [95% CI]: 3.17–32.86, P <0.001]. Additionally, the pathological classification of thymoma was also associated with the coexistence of ADs (P = 0.001). Using the most common pathological subtype—type AB—as the reference, patients with type B3 (OR = 2.46, 95%CI: 1.51–4.02), type A (OR = 2.45, 95% CI: 1.35–4.44), and type B2 (OR = 2.35, 95% CI: 1.54–3.57) thymomas exhibited a higher relevance accompanied by ADs. In contrast, patients with atypical type A (OR = 0.64, 95% CI: 0.14–2.96) and MNT-LS (OR = 0.83, 95% CI: 0.14-2.96) thymoma might have a lower correlation of accompanied by ADs even without significantly statistical difference, while no concomitant AD was observed in metaplastic thymoma patients. Similar to previous findings,[2] the prevalence of ADs is high in thymoma patients (27.9% in our study), with MG (24.1%) being the most common. The relationship between pathological classifications and ADs is a key focus of our study. Ao et al[5] summarized the ADs associated with different subtypes of thymoma, yet most of the findings were derived from case reports or small-sized case series and the classification criteria were inconsistent, lacking large-scale systematic studies. In this study, we summarized the prevalence of ADs across different subtypes according to the latest WHO classification of thymomas based on a large sample size. The prevalence of ADs differed among various subtypes of thymomas. Lipofibroadenoma is exceedingly rare,[3] thus it was not encountered in our study. The thymus plays a pivotal role in maintaining central immune tolerance by eliminating self-reactive T cells through negative selection, thereby preventing autoimmune reactions.[2] However, the presence of tumor cells may disrupt immune tolerance mechanisms. In patients with thymoma, T helper 17 (Th17) cells increase while the regulatory T cells (Treg) population decreases in tissues and peripheral blood, leading to alterations in the Th17/Treg ratio and destruction of immune tolerance, potentially resulting in paraneoplastic autoimmune diseases. Moreover, different pathological subtypes of thymoma exhibit distinct tumor microenvironments,[4] influencing the infiltration and function of immune cells, with high-risk thymomas (B2, B3) exhibiting lower epithelial cell differentiation.[5] For example, B3 thymomas are characterized by the presence of terminally differentiated cluster of differentiation 4-positive (CD4+) or CD8+ T cells,[4,5] potentially leading to ADs, consistent with our observation that patients with B2 and B3 thymomas have a higher prevalence of ADs. Previous studies have indicated that thymoma patients have a higher probability of developing other malignancies, possibly attributed to altered T-cell immune function or/and genetic predisposition.[1,6] Lung cancer is the most common primary malignancy, which may owe to the anatomical proximity, embryological origin similarities between lung cancer and thymoma, and the presence of shared genetic alterations, etc.[6] Our study findings indicate that among thymoma patients, the prevalence of ADs is higher among those without concurrent malignancies. The mechanism of this phenomenon is not yet clear and may be elucidated by the hypotheses of immune exhaustion and competing risks. Despite a large sample, limitations still remain: retrospective design, short follow-up time, and single-center data. Prospective, long-term, multicenter studies and mechanistic investigation are warranted. In conclusion, we retrospectively investigated the prevalence of ADs and other primary malignancies among thymoma patients. Meanwhile, we summarized the incidence of ADs across different pathological subtypes of thymoma and explored potential associated factors of the co-occurrence of ADs, finding that in patients with thymoma, the prevalence of ADs is higher in those with particular pathological types (type B3, B2, and A) and without concurrent malignant tumors. Acknowledgments We would like to express our gratitude to Research Professor Wen Wang from West China Hospital of Sichuan University for reviewing and providing suggestions on the statistical methods used in this study. Funding This work was supported by the project of National Natural Science Foundation of China (No. 82304062) and the Science and Technology Program of Sichuan Province (No. 24NSFSC1628). Conflicts of interest None.