Thymic epithelial tumors (TETs) are rare malignancies originating from thymic epithelial cells, displaying a range of behaviors from indolent to highly aggressive. This heterogeneity is evident in their histological subtypes and staging, which greatly influence prognosis and treatment approaches [1]. Complete surgical resection is the primary treatment for early-stage TETs. However, for cases with adverse postoperative pathological features, a multimodal approach, including adjuvant radiotherapy (RT) and sometimes chemotherapy, is recommended to improve outcomes [2,3]. Despite advancements in management of TETs, predicting recurrence and long-term survival remains difficult, as traditional indicators like histopathology and staging may not fully capture disease complexity. This highlights the need for reliable biomarkers to better stratify patients by prognosis. Recently, inflammatory markers, including the systemic immune-inflammation index (SII), have gained interest as prognostic tools in oncology research, with high SII levels linked to poor outcomes in multiple tumors [4]. Elevated SII levels are thought to reflect a pro-tumor inflammatory state, which can drive tumor progression and metastasis. While the prognostic significance of pre-operative SII has been demonstrated in patients with resected thymomas, the impact of its value in the postoperative, pre-RT period on prognosis has not yet been investigated [5]. This study aims to assess the prognostic significance of postoperative, pre-RT SII in patients with resected TETs receiving adjuvant RT.

The cohort consisted of 13 (35.1%) male and 24 (64.9%) female patients. The median age of the patients was 56 years (range, 25 to 75 years). Remaining patient, tumor, and treatment characteristics are summarized in Table 1. Based on the American Joint Committee on Cancer/Union for International Cancer Control 8th edition staging system, 72.9% (n=27) were classified as stage group I, 16.3% (n=6) as stage group II, and 10.8% (n=4) as stage group IIIA. All patients with stage group I disease received adjuvant RT due to adverse postoperative risk factors such as capsular invasion or positive surgical margins.

Prior to RT, the median neutrophil count was 5.6 × 10³/µL (range, [1.2 to 19.3] × 10³/µL), median lymphocyte count was 1.9 × 10³/µL (range, [0.6 to 8.2] × 10³/µL), and median platelet count was 279 × 10³/µL (range, [105–675] × 10³/µL). The median SII was calculated to be 722 (range, 398 to 6,672).

The median follow-up was 90 months (range, 12 to 230). A total of 35 patients (94.5%) had a follow-up duration of more than 1 year, and 31 patients (83.7%) were followed for more than 2 years. During the follow-up period, one patient (2.7%) experienced local recurrence, one (2.7%) had regional recurrence in the perithymic lymph nodes, and three patients (8.1%) developed distant metastasis, all of which were pleural metastases. Table 2 summarizes the characteristics of patients who experienced disease recurrence. The 5- and 10-year OS rates were 97.1% and 92.7%, respectively, while the DFS rates were 90.7% at both 5 and 10 years.

The ROC analysis identified an optimal SII cut-off value of 916, with an area under the curve of 0.74, specificity of 67%, and sensitivity of 71% for predicting recurrence (Fig. 1). In results of univariate analysis, patients with an SII ≥916 showed significantly lower 5-year OS (92.3% vs. 100%, p=0.028) and DFS (73.1% vs. 100%, p=0.011) compared to those with an SII <916 (Fig. 2). Additionally, univariate analysis demonstrated that early Masaoka stage, and the presence of myasthenia gravis at diagnosis were also significant positive prognostic factors for DFS (Table 3). To further evaluate the independent prognostic impact of SII and other relevant variables, we performed multivariable Cox regression analysis. However, none of the included variables—including SII—retained statistical significance, likely due to the limited number of events and small sample size (Table 4).

No grade 3 or higher acute toxicities were observed. Grade 1 acute esophagitis was noted in four patients (10.8%), and grade 2 acute esophagitis in one patient (2.7%). Subacute-late toxicity included grade 2 radiation pneumonitis in three patients (8.1%), with no cases of grade 3 or higher late toxicities reported.

This single-center retrospective study indicates that postoperative, pre-RT SII may be associated with survival outcomes in patients with TETs receiving adjuvant RT, suggesting a potential prognostic role that warrants further investigation. TETs are rare neoplasms that generally exhibit higher survival rates compared to other thoracic malignancies, with 5-year survival rates reaching up to 90% even in advanced stages after complete resection [7,8]. Additionally, cases of recurrence often respond favorably to salvage treatments, with a significant proportion of patient mortality attributed to non-tumor-related factors, such as myasthenia gravis [9]. Despite these encouraging survival rates, TETs represent a heterogeneous patient group; even among patients with similar clinicopathological profiles and receiving standardized treatment regimens, some display more aggressive disease course and higher disease-specific mortality rates. This highlights a substantial need for biomarkers that can more accurately stratify TET patients by prognosis, going beyond traditional prognostic factors.

The link between cancer prognosis and inflammation has emerged as a key focus in recent oncology research. Inflammation is recognized as a multifaceted driver in both tumor development and progression, with inflammatory responses in the tumor microenvironment significantly influencing patient outcomes [10]. The SII, derived from peripheral blood parameters, provides an easily accessible and cost-effective biomarker that may serve as an indicator of systemic inflammation. Initially described in 2014, SII has been shown to hold prognostic value, with higher SII values consistently associated with poorer outcomes across multiple cancer types [6,11-18].

Despite its increasing relevance in other malignancies, most studies on SII have not included TETs. Only a limited number of studies have assessed the prognostic implications of SII specifically in TET patients. For instance, a retrospective analysis by Veraar et al. [19], involving 184 surgically treated TET patients, demonstrated that elevated pre-operative SII values were associated with lower cancer-specific survival rates. Similarly, Li et al.’s retrospecive study [5] of 425 surgically treated TET patients revealed that higher pre-operative SII values correlated with worse OS. However, in the first of these two studies, 60% of the patients were reported to have received adjuvant therapy, whereas the second study did not provide details on adjuvant therapy. Since adjuvant RT is widely used in routine practice and is known to improve oncological outcomes for TETs, the prognostic significance of the pre-operative SII value may theoretically vary based on whether patients receive adjuvant RT [20]. Notably, no studies to date have investigated the prognostic value of postoperative, pre-RT SII in patients requiring adjuvant RT due to adverse pathological risk factors, to the best of our knowledge. This study is therefore the first to address this gap, examining the prognostic role of postoperative, pre-RT SII in a cohort of TET patients receiving adjuvant RT. Our findings reveal that patients with elevated postoperative, pre-RT SII values exhibit significantly poorer 5-year OS and DFS rates. These results suggest that SII may serve as a meaningful prognostic biomarker, potentially elucidating some of the heterogeneity observed within TET patient populations undergoing adjuvant RT and aiding in more refined prognostic stratification. Although our univariate analysis demonstrated a significant association between elevated SII and poorer survival outcomes, this finding did not retain statistical significance in the multivariable model. This may be attributed to the inherent limitations of our cohort, particularly the small sample size and low number of events, which likely reduced the statistical power to detect independent prognostic effects. Nonetheless, the consistent directionality of HRs and the biological plausibility of SII as a marker of tumor-promoting inflammation support its continued investigation as a potential prognostic biomarker in TETs. Larger, multi-institutional studies are needed to validate these preliminary observations.

While our study is the first to specifically investigate the prognostic significance of postoperative, pre-RT SII in patients with TETs undergoing adjuvant RT, it is important to acknowledge several limitations. The retrospective nature of the study may inherently introduce selection biases, potentially affecting the robustness of our findings. Additionally, the small sample size and low incidence of disease-related events in our cohort may limit the statistical power and affect the ability to detect subtler associations. However, given the challenges of designing prospective studies due to the rarity of TETs, our study plays a valuable role in filling a significant gap in the literature.

In conclusion, this study suggests that elevated postoperative, pre-RT SII values may be associated with poorer OS and DFS in patients with TETs undergoing adjuvant RT. Given the heterogeneity of TETs, SII may aid in identifying patients who could benefit from more personalized and potentially intensified treatment and follow-up strategies. However, these findings should be interpreted with caution, and validation through larger prospective studies is warranted.