Clinical characteristics, prognostic factors, and long‐term outcomes associated with epithelial malignancies of the thymus: A 20‐year single‐institution experience

Abstract Background Thymic epithelial tumors are rare and include thymomas and thymic carcinomas. There is scarce literature characterizing prognostic factors and long‐term outcomes in these tumors. Aims This review aims to describe disease features of thymomas and thymic carcinomas and to report clinical differences among thymoma histological subtypes. Methods and Results A retrospective chart review was performed at the University of Florida Shands Hospital, a tertiary care academic medical center in Gainesville, Florida, USA. The review included clinical data of adults with thymic epithelial tumors diagnosed between 2001 and 2021. Significant associations among demographics, histology, stage, and outcomes were investigated. Thymoma subgroup analysis was performed using histological subtype and sex. Forty patients with thymoma and seven patients with thymic carcinoma were included in the final analysis. Among those with thymomas, patients with subtype B1, B2, or B3 tumors were younger, had larger tumors, and presented with higher stage disease when compared to those with subtypes A or AB. Tumor recurrence was most common in subtype B2 and B3 tumors (50.0% and 16.7% vs. 0%; p < .01). However, there was no significant difference in overall survival between histologic subtypes. Compared to females, males with thymomas had superior overall survival (103.0 vs. 62.9 months; p = .021) despite presenting with larger tumors (9.8 vs. 5.8 cm; p = .041). Concomitant myasthenia gravis was associated with increased recurrence but not worsened mortality. Compared to thymomas, patients with thymic carcinoma presented with higher‐stage disease and had poorer 5‐year survival (50.0% vs. 93.1%; p < .01). Conclusion This study affirmed pathologic stage and resectability as prognostic factors for thymic epithelial tumors. New findings include inferior overall survival in female patients and higher recurrence rates in those with thymomas and concomitant myasthenia gravis.

These tumors comprise roughly one-fifth of mediastinal masses and most commonly present between the ages of 40 and 60. 1 Thymomas are generally indolent, albeit malignant, neoplasms with a tendency for local spread and several immunological manifestations such as myasthenia gravis or pure red cell aplasia. 2 Other associated autoimmune pathologies include inflammatory myopathies, systemic lupus erythematosus, and autoimmune bullous dermatoses-autoimmune blistering diseases (e.g., pemphigus vulgaris, paraneoplastic pemphigus, bullous pemphigoid).
Thymic epithelial tumors are histologically arranged according to the World Health Organization (WHO) classification scheme, which identifies type A and B tumors, defined by the presence of spindleoval versus stellate-polygonal epithelial cells, respectively. These tumor types are further divided into subtypes: A, AB, B1, B2, and B3 epithelial thymomas based on organotypical features such as composition of tissue and pattern of growth. 3 Thymic carcinomas (WHO type C) are more aggressive, high-grade cancers identified by cellular atypia and infiltrative growth patterns on histology that present with obstructive symptoms due to tumor extension and metastasis.
Thymic epithelial tumors are staged according to the tumor, node, and metastasis system of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC); however, the alternative Masaoka system stages thymic epithelial tumors by degree of macroscopic and microscopic tissue invasion and has been widely used in descriptive and investigative studies. 4,5 With an incidence of 1-2 cases per 100 000 person-years, thymic cancers are exceedingly rare with exceptionally diverse presentations. 1 Although WHO classification lends credible prognostic significance, as subtype A-B2 tumors are often more localized on presentation than subtype B3-C tumors, features such as patient characteristics (e.g., age of onset, gender predilection) and the combined effect of stage and histologic classification on both prognosis and recurrence are less well described. There is an overall paucity of data on clinical characteristics, prognostic indicators, and management. This institutional retrospective cohort study aimed to address this deficit by describing disease characteristics and long-term outcomes in patients with thymomas and thymic carcinomas.

| Disease characteristics
Tumor characteristics are listed in Table 2. Thymomas were more likely to have been discovered incidentally than thymic carcinomas; however, this result was not statistically significant (42.5% vs. 14.3%; p = .157). p < .01) and, among patients who underwent surgery, were more likely to have microscopically negative margins (84.6% vs. 0.0%; p = <.01).
Tumor recurrence was more common in patients with myasthenia gravis (38.5% vs. 10.7%; p = .037), higher stage disease (p = .026), and positive surgical margins (p = .028). Detailed patient characteristics on the seven patients with thymic carcinomas are provided in Table 3.

| Survival analysis
significant relationship between thymoma subtype and overall survival. There is ultimately insufficient evidence regarding the impact of thymoma histological subtype and overall outcomes, justifying the need for long-term clinical surveillance in all cases.
Due to the rarity of thymomas, prognostic information is limited.
A few investigations have independently identified complete resectability and stage as factors significantly associated with mortality in patients with thymomas as well as thymic carcinoma. [21][22][23][24] A brief review of available published data on thymomas is available in Table 7; this summary is limited to retrospective studies with at least 40 cases detailing prognostic factors and significant associations among individuals with thymomas of any subtype. In our cohort, stage on presentation was similarly associated with increased mortality; however, complete resection was not significantly associated with improved mortality. Several additional prognostic factors were identified within this study. Female sex was associated with increased mortality from thymoma of any subtype, with a mean overall survival of roughly 5 years when compared to over 8 years in males. Contemporary data has suggested that the expression of estrogen receptors in thoracic malignancies may contribute to the gender differential in regard to survivorship. 25  The presence of concomitant autoimmune disease, namely myasthenia gravis, has also been proposed as a negative prognostic factor for thymomas. However, several studies, including a large investigation in 2020, have reported no significant association between the presence of myasthenia gravis and overall outcomes in patients with thymoma. [26][27][28] Myasthenia gravis in thymomas has demonstrated no sex predilection and worsened severity of disease when compared to non-thymoma myasthenia gravis. 29 Therefore, it has been suggested that symptomatic myasthenia gravis may inadvertently promote earlier detection of underlying malignancies, including thymomas. In this study, the presence of myasthenia gravis was not associated with increased mortality but did demonstrate a significant association with higher rates of tumor recurrence. One study investi- confidence interval 0.9-2.2). 31 Over half of patients in our cohort had a history of smoking. While there was not an appropriate control population to allow demonstration of significant association, this striking level of tobacco use is noteworthy.
Data demonstrating the efficacy of various treatment modalities of thymomas and thymic carcinoma has been insufficient. Surgical resection remains the mainstay of treatment for epithelial thymic malignancies. All patients with thymoma in this study received surgical resection except one individual, who did not receive any treatment.
The significance of postoperative radiotherapy and chemotherapy in thymoma remains controversial due to paucity of data. 32,33 Generally, surgical margins and pathologic staging are used to guide postoperative management. 34 Rimner et al., which is by far the largest study, found survival benefit with postoperative radiotherapy in stage II and III thymoma. 35 Survival benefits were found in all histological subtypes, especially thymoma subtypes B1, B2, and B3. In our study, nine patients received radiotherapy (2/3 with subtype A, 1/8 with subtype B2, and 6/6 with subtype B3), which may explain higher recurrence in patients with B2 subtype compared to those with B3 subtype thymomas, where all patients received radiation. Overall, the use of chemotherapy and radiotherapy did not significantly impact survival in this study.
Thymic carcinoma is a more rare, understudied, and aggressive form of epithelial thymic malignancy. In our cohort, patients with thymic carcinoma presented with more advanced disease, which is consistent with the literature. 10  No differences in progression-free, distant metastasis-free, and local-regional relapse-free survival between patients with and without myasthenia gravis