Thymic epithelial tumors are rare, and the primary treatment is surgery [1,2,3]. Decisions regarding adjuvant therapy depend on the type of resection, Masaoka-Koga stage, and histological classification, with no complete consensus available. Recurrence in R0 resected TET has been reported at a rate of 10–15%, typically occurring within an average of 5 years (range 3–7) [1]. Several predictive and prognostic factor-based classifications have been developed to estimate recurrence, and international guidelines have been established since 2015 [1,2,3, 5, 8, 12]. This study involves an analysis of single-center TET patient outcomes in the light of current guidelines.

According to a Japanese study, the incidences of thymoma, TC, and TNET were 88%, 10%, and 2% respectively, while the IASLC staging committee reports these incidences as 84%, 15.5%, and 1.5% based on data from 11,347 patients [2, 18]. In the prospective RYTHMIC study, the frequency of occurrence for WHO types A, AB, B, C, and others are reported as 10%, 25%, 53%, 11%, and 1% respectively [5]. However, the difficulty in distinguishing between WHO B2 and B3 types is also noted [19].

The role of PORT in R0 resected Masaoka-Koga sI cases has not been demonstrated and is not recommended [1, 20]. On the other hand, the role of PORT in R0 resected sII cases is debated. The ITMIG study reported a survival benefit with PORT in R0 resected Masaoka-Koga sII cases [13]. In a study by Jackson et al. involving 4056 cases using 3DCRT/IMRT techniques, no benefit was shown in Masaoka-Koga sIIa, whereas survival benefit was reported in sIIb-III and incompletely resected cases [21]. Conversely, in the SEER analysis, no difference in OS and CSS was found with PORT in Masaoka-Koga sIIb cases [22]. The WHO classification is reported as an independent prognostic factor with A/AB/B1 indicating low risk and B2/B3/TC indicating high risk [23]. In Lee et al.’s study of R0 resected 406 cases, 5‑year freedom from recurrence was reported as 99.3% for Masaoka-Koga sI and A/AB/B1 cases, emphasizing that adjuvant RT is unnecessary [20]. The Italian study group suggests PORT for sIIb and B2-3 cases, whereas the ESMO guidelines recommend PORT for sIIb or sIIa and B2-3 cases [1, 24].

Masaoka-Koga staging is standard for treatment decisions. The TNM staging system was developed to address the need for a universal and consistent classification [11]. The 8th edition of TNM staging can be adapted to all histological types, with incidences reported as 81.4% for sI, 2.7% for sII, 10.5% for sIII, and 5.2% for sIV, and recurrence rates of 5%, 18%, 32%, and 46%, respectively. In the RYTHMIC study, most patients showed stage migration from Masaoka-Koga sII to TNM sI [5]. In their study, PORT was recommended for 4% of Masaoka-Koga sI patients, and 27% of TNM sI patients, with the multidisciplinary board decision aligning 92% with the ESMO recommendations. Factors considered for PORT included TC/B3 histology, Masaoka-Koga stage, TNM stage, and incomplete resection, while performance status, presence of comorbidities, and stage discordance were taken into consideration in cases where PORT was not recommended. In a recent study of R0 resected 445 cases, TNM staging was highlighted as better predictive of recurrence than Masaoka-Koga staging [12].

Patients with TC and TNET are often at advanced stages and have a worse prognosis compared with thymoma [16]. In a study by Rimner et al., involving 462 TC cases, survival benefit with PORT was reported in incompletely resected or sIII-IV cases [25]. SEER analysis reported that Masaoka-Koga stage, type of resection, lymph node or distant metastasis, tumor size, and receiving RT are predictive of survival [26]. The aggressive nature and high recurrence rates of TNET cases suggest that adjuvant RT and chemotherapy are necessary even for R0 resected cases [16].

In our study, the incidence rates of thymoma, TC, and TNET were 91%, 6%, and 3% respectively, consistent with published data. 95% of our Masaoka-Koga sII cases were classified as TNM sI. The low incidence of Masaoka-Koga sI cases in our study (5%) is due to fact that they were not referred to our department because there was no indication for PORT. Due to high risk, only 3 Masaoka-Koga sI cases underwent PORT. 5‑year OS for Masaoka-Koga sI-II and sIII-IV were 81.6% and 61%, and for TNM sI-II and sIII-IV were 81.6% and 54.1%, showing compatibility (p = 0.001, r = 0.881).

In TET patients, older age, larger tumor size, and the presence of MG are also reported as independent poor prognostic factors [6, 23]. On the other hand, MG was associated with favorable features (i.e. earlier stage, complete resection status) in many studies [2, 6]. Significant threshold values for tumor size are reported as 5 to 10 cm in different studies [1, 27]. Lopez et al. reported that poor performance status was associated with worse survival in 192 patients who received PORT and were followed for 10 years [9]. Recent studies emphasize that organ invasion indirectly reflects advanced stage and poor prognosis [8, 15]. Funaki et al. reported 35% organ invasion in R0 resected 306 thymoma cases, with single organ, two organs, and three or more organs involvement rates of 13.7%, 16.5%, and 14.1% respectively [8]. We identified older age and poor performance status were significant prognostic factors in terms of OS demonstrating that prognosis is influenced not only by tumor-related factors but also by patient-related factors. We did not identify significant difference for presence of MG because of overlap with other prognostic factors. A total of 37.5% organ invasion was seen in our study, with rates of 1, 2, and ≥ 3 organs involvement were 16%, 9%, and 12.5%, respectively, consistent with the literature. The presence of organ invasion was significant for all survival groups in univariate analysis.

The first site of recurrence in TET is often the pleura, pericardium, or lung, with predictive factors for recurrence including advanced stage, large tumor size, non-thymoma histology, and incomplete resection [9, 20, 28]. Lopez et al. reported 38% locoregional recurrence and 16% distant recurrence in 192 cases receiving PORT, with 22% of local recurrences being in-field recurrences [9]. In our study, a total of 23% recurrences occurred, 17% of which were within the field. The 5‑year LC was 82.4%, whereas the 5‑year intrathoracic control was 78.9%. While there was a significant relationship between LC and Masaoka-Koga stage, no significant relationship was found between LC and TNM stage, and this was attributed to stage migration.

The frequency of MG in thymoma patients is reported as 30%, often associated with early diagnosis and good prognosis [1, 6, 28]. In contrast, other autoimmune diseases occur in 10% of cases and have a worse prognosis. Opportunistic respiratory infections are common in these patients [29]. Additionally, since TET patients are relatively young and may live longer, treatment-related side effects must be considered. High death rates due to lung and heart toxicity in TET patients highlight the importance of RT dose and technique [1, 5, 13]. Gomez et al. reported dose-volume threshold values for organ at risk in patients with TET [30]. Current guidelines emphasize starting adjuvant RT within 3 months, using at least 3DCRT/IMRT techniques, and selecting the RT dose based on the type of resection [1,2,3]. The Delphi consensus report recommends 4DCT simulation at 82% and VMAT technique at 88% [17]. It is emphasized that secondary primary cancers are seen in 17–28% of TET patients at diagnosis and follow-up, with the age of diagnosis being crucial rather than treatment [28]. In our study, 33% of patients had autoimmune diseases at diagnosis, which increased to 40% during follow-up, consistent with literature. RT was initiated within 3 months in all but one patient who received treatment on the 95th day after biopsy. Patients received a median of 5040 cGy RT. Dose constraints were not exceeded in any patients. Among patients treated before 2015, two patients died of pneumonia who had also MG, and other two patients died of cardiac disorder during follow-up. These patients received between 4140 to 6000 cGy RT and the doses to organs at risk were unknown. After 2015, 3 out of 30 patients developed new cardiac disorder, all were alive at the last follow-up, and no relationship was found in terms of heart doses. There was no survival difference based on RT technique or year of treatment. Second primary cancers were present in a total of 14% of cases, and their median age at diagnosis was 61 years, consistent with literature.

Advances in surgical techniques have reduced perioperative complications and improved survival, and also the skills and experiences of the surgeon are important [31]. PFS and CSS were significantly better in those who underwent surgery in our center.

Advancements in the diagnosis, staging, and treatment of TET continue. A recent development is the use of radiomics for preoperative differentiation of low or high risk with a reported accuracy of 92%, sensitivity of 96%, and specificity of 90% [32]. The genetic profile of TET cases is heterogeneous, and research is ongoing into the use of targeted agents and immunotherapy in systemic treatment [1,2,3]. Studies including new prognostic factor-based TNM staging (9th edition) are underway [18, 27]. Mediastinal pleural invasion is a pathological finding that is not easily recognized and is difficult to detect in clinical staging, suggesting its exclusion from staging. Furthermore, because survival differences have been demonstrated, it is planned to include tumor size with a 5 cm threshold in staging, and to place lung and phrenic nerve invasion in T2 rather than T3. Despite the shown relationship between nodal staging and survival, issues with pathological and clinical nodal staging discrepancies and the significance of the number of metastases remain unresolved.

The limitations of the study are the inclusion of patients with TC, TNET and unresectable patients, and the heterogeneity in RT techniques. Strengths of the study include the long follow-up period and demonstration of the importance of current prognostic factors.

In conclusion, in this single-center study of 64 TET patients treated with RT, a 5-year LC rate of 82.4% was achieved with a follow-up of 70 months. 20% of recurrences occurred after 5 years and long follow-up is required. In univariate analysis, the presence of invasive organs and TNM stages were identified as significant new prognostic factors for survival. In multivariate analysis, the prognostic significance of KPS, histology, Masaoka-Koga stage, risk group, and surgical center experience was confirmed. Advances in the diagnosis, staging, and treatment of TET will enable more personalized treatment approaches.