Long-term survival and prognosis after surgical treatment of patients with thymic carcinoma: a retrospective analysis

Introduction

Thymic epithelial tumors are a group of rare tumors (1.7 cases per 1 million people). However, thymic carcinoma is even rarer, accounting for only 15–20% of all thymic epithelial tumors (1,2). Thymic carcinoma is an extremely malignant tumor originating in the thymic epithelium, typically characterized by aggressive growth, invasion of surrounding tissues and organs, and the risk of pleural and distant metastases. Notably, most patients present with pleural dissemination at diagnosis, and typical imaging findings include tumor invasion into vital adjacent structures, such as the pericardium, major blood vessels, and lungs. The prognosis of thymic carcinoma is significantly worse than that of thymoma. Furthermore, there has recently been increasing international attention toward thymic malignancy, including thymic carcinoma, due to the establishment of organizations such as the International Thymic Malignancy Interest Group (3), and various research groups have focused on thymic tumors in Europe, America, and Asia. Given its low incidence rate both domestically and internationally, there are relatively few reports regarding operable cases of thymic carcinoma; thus, its clinicopathological features and treatment approaches have not been well-established.

Retrospective studies of thymic carcinoma have been reported previously (4-6); however, these databases have limitations, such as long periods covered by data collection sources with incomplete information or inconsistent inclusion criteria and low follow-up rates. Therefore, in this study, we aimed to retrospectively analyze the clinicopathological features and survival outcomes of 87 patients with thymic carcinoma from a single Chinese institution. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1056/rc).

Methods

Study population

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The present retrospective study did not involve any sensitive personal information, commercial interests, or inflict harm on human subjects. It solely utilized publicly available and anonymized data from the hospital system for research purposes. Thus, the Ethics Committee of the First Medical Center of the Chinese PLA General Hospital waived the need for ethics approval. Written informed consent was obtained from all patients involved in this study. The clinical data and pathological results of patients with thymic carcinoma who underwent surgical treatment at the First Medical Center of the Chinese PLA General Hospital between January 2010 and October 2023 were collected. The inclusion criteria were as follows: (I) undergoing surgical treatment, including complete or incomplete resection; (II) histopathological diagnosis confirming thymic carcinoma; (III) reclassification according to the 5^th edition of the World Health Organization (WHO) pathological classification system for thymic epithelial tumors; (IV) staging performed based on the Masaoka-Koga staging system; (V) complete clinical and follow-up data; and (VI) no history of other malignant tumors. Ultimately, 87 patients with thymic carcinoma were enrolled in this study.

Observation index

The following observation indices were utilized: patient demographics, paraneoplastic syndromes, tumor size of the surgical specimen, pathologic diagnosis, disease staging, surgical procedure, resection status, perioperative therapy, and follow-up status. Intraoperative findings and postoperative pathology were used to re-stage patients with thymic carcinoma according to the Masaoka-Koga staging system (7). The Masaoka stage I was defined as an intact gross capsule without microscopic infiltration; stage II included peripheral fat or pleural invasion in general or microscopic capsule infiltration; stage III involved invasion of adjacent organs such as the pericardium and large blood vessels; stage IVA, pleural or pericardial spread; and stage IVB encompassed lymphatic or blood metastases extending beyond the chest (with bone metastases being the most common). To confirm the diagnosis of thymic carcinoma, all patients underwent pathological immunohistological examinations performed by two or more physicians with associate senior titles or higher in the Department of Pathology. Postoperative histopathological diagnoses were made based on the 5th edition of the WHO classification system (8). Surgical procedures were performed for all patients with an excision status categorized as follows: R0 excision, no residual tumor present after excision; R1 excision, microscopic residual tumor remaining; R2 excision, locally visible residual tumor, or other features of residual tumor after excision. Notably, some patients underwent additional treatments, including thymus radiotherapy, platinum-based chemotherapy, or chemoradiotherapy.

Follow-up

Patients were followed up for 4–164 months in outpatient clinics and via telephone. The follow-up period was defined as the interval between postoperative pathological diagnosis and recurrence, death, or the last follow-up visit. The survival time was recorded monthly, with overall survival (OS) and disease-free survival (DFS) being the primary outcomes of interest. OS was calculated from the date of surgery to death from any cause, whereas DFS was calculated from the date of surgery to recurrence or death from any cause. Patients who survived without recurrence or were lost to follow-up were included in the final dataset analyzed during the last follow-up assessment (9).

Statistical analysis

Statistical analysis was conducted using SPSS (version 26.0; IBM Corp., Armonk, NY, USA). Measurement data were presented as mean and standard deviation, and t-tests or corrected t-tests were used for analysis. The ratio or composition of the counting data was expressed accordingly. Group comparisons were performed using the Chi-squared or Fisher’s exact tests. OS and DFS were calculated using the Kaplan-Meier method, and survival curves were compared between the groups using the log-rank test. Univariate and multivariate analyses using the Cox proportional risk model were used to evaluate the prognostic factors for OS and DFS, including sex, age, preoperative symptoms, tumor size, histology, Masaoka-Koga stage, surgical method, resection status, and postoperative adjuvant therapy. Statistical significance was set at P<0.05.

Results

Clinical features

The clinicopathological characteristics of the patients are summarized in Table 1. Among the 87 patients diagnosed with thymic carcinoma, 62 were males, resulting in a male-to-female ratio of 2.48:1. Patient age ranged from 28 to 76 years, with an average age of 54.2±10.3 years. Tumor size ranged from 1.5 to 20 cm, with a median of 5.0 cm. Among these patients, 37 had a tumor size <5.0 cm, while 50 had tumors ≥5.0 cm. Initial symptoms included cough, chest tightness, and chest pain in 30 cases; myasthenia gravis (MG) in eight cases; ectopic adrenocorticotropic hormone (ACTH) syndrome in one case; and incidental findings during health examinations in 48 cases. Notably, all patients underwent surgical intervention: 38 cases (43.7%) via median sternotomy, 49 (56.3%) via thoracoscopic surgery, and five (5.7%) involved conversion to thoracoscopy. R0 resection was performed in 75 patients (86.2%), R1 resection in 1 patient (1.1%), and R2 resection in 11 patients (12.6%). Thymic squamous cell carcinoma was the most prevalent histological subtype, accounting for 74 cases (85.1%). Other subtypes included neuroendocrine carcinoma in eight cases (9.2%), lymphoepithelioid carcinoma in three (3.5%), and mucoepidermoid and adenosquamous carcinoma, each in one case (1.1%). According to the Masaoka-Koga staging system, 21 cases (24.1%) were stage I, 23 (26.4%) were stage II, 38 (43.7%) were stage III, and 5 cases were stage IV (5.7%), comprising 2 cases of stage IVA and 3 cases of stage IVB. MG coexisted with thymic carcinoma in eight cases (9.2%), whereas ectopic ACTH syndrome occurred in one case (1.1%). Following surgery for thymic carcinoma, 55 patients received postoperative adjuvant therapy. Among them, 37 patients underwent radiotherapy alone, 3 received chemotherapy alone, and 15 opted for combined chemoradiotherapy. Thirty-two patients did not receive any postoperative treatment.

Follow-up results

The follow-up period ranged from 4 to 164 months (median, 74 months; interquartile range, 36–102 months). During follow-up, disease recurrence and metastasis were observed in eight of the 75 patients who underwent R0 resection. However, disease progression occurred in three of the 12 patients who underwent R1/R2 resection. At the end of the follow-up period, 17 patients had died, with mortality rates of 14.7% for those who underwent R0 resection and 50% in those who underwent R1/R2 resection. No deaths occurred within the first 90 days postoperatively.

Survival and prognostic factor analysis

The 5-year and 10-year OS rates were 85.6% and 69.9%, respectively, and the DFS rates were 76.4% and 58.6%, respectively. Univariate analysis revealed no significant correlation between OS or DFS and sex, age, tumor size, preoperative MG, surgical method, or histological type (P>0.05). However, OS was significantly associated with the Masaoka-Koga stage (P=0.03), resection status (P=0.005), and postoperative adjuvant radiotherapy (P=0.009). Similarly, the Masaoka-Koga stage (P=0.03) was significantly correlated with DFS (Table 2). Patients in the early Masaoka stages had a significantly better prognosis than those in later stages (OS, P=0.03; DFS, P=0.03). The 5-year OS and DFS rates for the Masaoka stages I/II and III/IV were 92.2% and 79.3%, and 86.3% and 74.2%, respectively. The 10-year OS rates for the two groups were 83.8% and 58.1%, whereas the 10-year DFS rates were 78.5% and 47.5%, respectively (Figure 1). Notably, patients who underwent R0 resection had significantly higher survival rates than those who underwent R1/R2 resection (OS, P=0.005). The 5-year OS rate for R0 and R1/R2 resections was 89.5% and 64.2%, respectively. The 10-year OS rate was 76.3% and 38.5%, respectively (Figure 2).

Figure 1 The survival curve of the Masaoka-Koga staging system. (A) Overall survival and (B) disease-free survival according to the Masaoka-Koga staging system (stage I/II vs. stage III/IV).

Figure 2 Overall survival according to resection status (R0 resection vs. not R0 resection).

No significant correlation was observed between chemotherapy and prognosis in patients with thymic carcinoma (P=0.35). Further stratified analysis revealed that chemotherapy did not result in a statistically significant difference in survival among patients with different Masaoka stages and resection statuses. Overall, patients who underwent radiotherapy or chemoradiotherapy postoperatively demonstrated a higher cumulative survival rate than those who did not receive radiotherapy (P=0.009). The 5-year OS rates were 93.9% and 73.7% in patients who received radiotherapy and those who did not, respectively. The 10-year OS rates were 87.4% and 47.4 %, respectively (Figure 3).

Figure 3 Overall survival according to postoperative RT status (post-RT vs. no post-RT). RT, radiotherapy.

Factors that demonstrated statistical significance in the univariate analysis were incorporated into the Cox proportional risk model for multivariate analysis. The findings revealed that the Masaoka stage, resection status, and postoperative radiotherapy significantly influenced the survival of patients with thymic carcinoma postoperatively. Specifically, early Masaoka stage [hazard ratio (HR): 3.690; 95% confidence interval (CI): 1.043–13.049; P=0.043] and postoperative radiotherapy (HR=0.319; 95% CI: 0.102–0.999; P=0.049) were associated with improved OS in patients with thymic carcinoma postoperatively. Furthermore, early Masaoka stage (HR=2.719; 95% CI: 1.032–7.163; P=0.043) was associated with enhanced postoperative DFS in patients with thymic carcinoma (Table 3).

Discussion

We conducted a retrospective analysis of 87 patients with thymic carcinoma at a single center to identify the associated features and prognostic factors. Our findings provide evidence that can guide the evaluation and treatment of this rare malignancy. Thymic carcinoma has a 5-year survival rate ranging from 58% to 80%, with rare occurrences of postoperative complications and mortality (4,6,10). However, chemotherapy or radiotherapy alone yields only a 0–24% 5-year survival rate (11,12). Among the 87 patients who underwent surgery in our study, the 5-year and 10-year OS rates were 85.6% and 69.9%, respectively. Furthermore, no deaths occurred within the first three months postoperatively. These findings strongly support surgery as a safe and effective therapeutic approach for the treatment of thymic carcinoma.

Notably, most studies have indicated that R0 resection is an independent prognostic factor in patients undergoing surgical treatment for thymic carcinoma. Previous studies have reported 5-year survival rates of 67%, 30%, and 24% in patients who underwent complete, incomplete, and unresected resection, respectively (13). Weksler et al. reported a 5-year OS rate of 58% in patients who underwent complete resection, compared with only 16% in patients who underwent incomplete resection (14). Similarly, Ruffini et al. found that the 5-year OS rates were 80%, 36%, and 19% in patients who underwent complete resection, incomplete resection, or biopsy, respectively (10). In contrast to previous reports, our study revealed that while total resection remains an independent prognostic factor for DFS, it does not significantly affect the OS. In this study, >50% of the patients were diagnosed through health examination, including 44 cases (50.58%) at Masaoka stages I and II. A higher proportion of patients with early-stage thymic carcinoma had limited tumor growth and with no evident external invasion, enabling complete surgical resection and a favorable prognosis to be achieved to the maximum extent. Furthermore, owing to the recent increase in the popularity of physical examinations, early-stage thymic carcinomas have been promptly detected for timely diagnosis and treatment. Therefore, improving the R0 resection rate is the most important strategy for the surgical treatment of thymus cancer, depending on the improvement of surgical skills and early detection of the disease.

Owing to the absence of a complete envelope in most thymic carcinomas, invasion of the mediastinum, both internally and externally, is facilitated, with the pericardium, pleura, lungs, major blood vessels, and phrenic nerves being particularly vulnerable. In cases where external invasion is evident, a median thoracotomy incision should be made to achieve maximal tumor removal. In addition, pericardial resection and vascular replacement may be necessary when the pericardium and large blood vessels are involved. A thoracoscopic lateral incision is an alternative approach for relatively localized tumors without obvious external invasion. This study’s distribution of surgical approaches was as follows: 43.7% of the patients underwent a median thoracotomy incision, 56.3% underwent thoracoscopic surgery, and 5.7% underwent conversion to thoracoscopy; however, their survival rates did not significantly differ from those of patients who underwent various surgical approaches. This observation may be attributed to factors such as the Masaoka-Koga staging and completeness of resection. Thoracoscopic surgery offers a complete tumor resection option for patients in the early Masaoka stage. With technological advancements and updated incision protection devices, thoracoscopic surgery can yield comparable or even superior long-term outcomes compared with open-chest surgery. Therefore, adopting individualized surgical approaches based on Masaoka staging principles and prioritizing complete resection are recommended. Previous studies have demonstrated that the combined removal of invasive tissues does not increase perioperative complications or mortality in patients with cancer with adjacent tissue invasion. Successful complete resection is associated with an improved chance of survival (15).

Numerous studies have consistently demonstrated the significant impact of the Masaoka staging on the survival and prognosis of patients diagnosed with thymic carcinoma (16). The onset of thymic carcinoma is gradual. As the tumor progresses, it exerts pressure on adjacent organs and major blood vessels or impinges on nerves, leading to symptoms such as chest and back pain and chest tightness. Notably, most patients diagnosed with thymic carcinoma were already classified as Masaoka stage ≥III. In the present study, the 5-year OS rates for patients classified as Masaoka stages I/II and III/IV were 92.2% and 79.3%, respectively, whereas the corresponding 10-year OS rates were 83.8% and 58.1%, respectively (P=0.029). These findings strongly suggest a poor prognosis for individuals diagnosed at advanced stages based on the Masaoka classification system. Furthermore, Ruffini et al.’s retrospective analysis of clinical data from a cohort of 229 surgically treated patients with thymic carcinoma examined the influence of tumor size on prognosis (10). The tumor size of the surgical specimens ranged from 1.0 to 25.0 cm, with a median value of approximately 5.0 cm. Univariate analysis showed that the tumor size was not an important factor affecting the survival of patients with thymic carcinoma and that there was no significant association between the tumor size and survival prognosis in these patients (P=0.84). Furthermore, the Masaoka stage of thymic carcinoma has greater prognostic significance than tumor size. The 9th TNM staging for thymus tumor, which includes tumor size in the T staging for the first time, proposed by the International Association for the Study of Lung Cancer and ITMIG may better reflect the correlation among thymoma staging, clinical treatment, and prognosis (17). Nevertheless, the Masaoka staging remains the predominant approach in current practice.

Thymic squamous cell carcinoma is the predominant histological subtype of thymic carcinoma (4). Regarding the impact of histological subtypes on the prognosis of patients with thymic carcinoma, Zhai et al. (18) conducted a retrospective analysis of clinical data from 135 patients, including 59 thymic squamous cell carcinoma cases and 76 cases of other special types of thymic carcinoma, revealing 5-year OS rates of 54.5% and 36.8%, respectively (P=0.09). In this study, there were 74 cases classified as thymic squamous cell carcinoma and additional diagnoses such as neuroendocrine (n=8), lymphoepithelioid (n=3), mucoepidermoid (n=1), and adenosquamous carcinomas (n=1). The cumulative DFS rates at the 5-year and 10-year marks were higher for patients with thymic squamous cell carcinoma at approximately 80.2% and 60.2%, respectively. However, for other special types of tumors, they were approximately 87.5% (P=0.41). Consistent with previous research findings regarding survival trends, it can be inferred that there is no significant correlation between histological subtypes and the prognostic outcomes of thymic carcinoma. Owing to the low incidence rate of thymic carcinoma, further confirmation of the significance of histologic type on prognosis is required through multicenter studies with larger sample sizes.

The incidence of MG is highest among patients with thymoma, with approximately 30–50% of them being affected by MG (19). However, the prevalence of MG in patients with thymic carcinoma was significantly lower than that in those with thymoma. In this study, eight cases (9.2%) of thymic carcinoma were complicated by MG, predominantly presenting with ocular muscle involvement. Following tumor resection, myasthenic symptoms improved in most cases, and only one patient experienced myasthenic crisis postoperatively. None of the remaining 79 patients (90.8%) had concurrent MG. The 10-year OS rates were 70.0% and 69.1%, respectively, demonstrating no significant difference between the two groups (P=0.95). In the present study, MG was not a prognostic factor for patients with thymic carcinoma. There is limited research on patients with concomitant thymic cancer and MG; however, early detection and diagnosis of MG allow for timely intervention through complete surgical resection, thereby potentially extending patient survival.

Due to the rarity of thymic carcinoma and the limited availability of high-level evidence-based medical research, the establishment of a well-defined, comprehensive treatment model for post-surgical thymus carcinoma has been challenging. However, some researchers have indicated that perioperative chemotherapy is promising for the comprehensive management of thymic carcinoma. According to the National Comprehensive Cancer Network Guidelines (version 2.2023), radiotherapy is not necessary after Masaoka stage I for patients with R0-resected thymic carcinoma. However, it is recommended for stage II to III cases. Okereke et al.’s study (20) supports this conclusion, whereas Fu et al.’s research (6,21) indicates that postoperative radiotherapy benefits all patients who undergo R0 resection; however, they differed in their interpretation of its impact on OS. The former believes that radiotherapy improves OS, whereas the latter suggests that radiotherapy only enhances DFS without improving OS. However, optimal postoperative adjuvant therapy for thymic carcinoma remains controversial. In our study cohort, postoperative adjuvant therapy was found to have a significant impact on OS, whereas no significant effect was observed on DFS. Significantly higher cumulative survival rates were observed at both the 5-year (93.9% vs. 73.7%) and 10-year (87.4% vs. 47.4%) follow-up periods (P=0.009) in the 52 patients who received postoperative radiotherapy than in those who did not.

Furthermore, multivariate analysis identified postoperative radiotherapy as an independent protective factor for OS in surgically treated patients with thymic carcinoma. Therefore, radiotherapy may have greater significance than chemotherapy or chemoradiotherapy, as supported by several studies (6,22). Komaki et al. (23) propose an optimal radiotherapy regimen of 50 Gy over 5 weeks, with the recommended irradiation focused on the thymus region while discouraging the routine irradiation of the lymph node region. The specific range of irradiation should be determined based on the malignant level of the tumor.

Thymic carcinoma exhibits lower sensitivity to chemotherapy than to radiotherapy. Previous studies have demonstrated that chemotherapy can improve the prognosis of patients with thymic carcinoma, particularly with respect to prolonged progression-free survival (24). Kim et al. (25) reported that chemoradiotherapy was associated with better outcomes in patients with Masaoka stage III thymic carcinoma. In addition, platinum-based multidrug combination chemotherapy or the use of a single platinum drug as a sensitizer during radiation therapy has shown some efficacy (26). In this study, over 50% of patients received chemotherapy or chemoradiotherapy. However, an effective statistical analysis could not be performed due to the small sample size and stratification issues. Overall, for patients with thymic carcinoma, radiotherapy or chemotherapy should be administered to improve the prognosis.

Similar to other pertinent studies, there are some limitations in this study, including the small sample size and absence of clinical observation indicators. Therefore, to enhance the treatment efficacy for thymic carcinoma, it is imperative to expand the sample size and conduct multi-regional and prospective clinical investigations to further elucidate the correlation between relevant factors and prognosis among patients with thymic carcinoma, thereby providing improved treatment guidance.

Conclusions

Thymic carcinoma is a rare mediastinal malignancy in clinical practice, with thymic squamous cell carcinoma being the most prevalent histological subtype. Surgical resection remains the primary treatment for thymic carcinoma. Early Masaoka-Koga staging and postoperative radiotherapy are crucial postoperative prognostic factors. The main components of comprehensive postoperative treatment include radiotherapy and chemoradiotherapy.

Acknowledgments

We thank the patients for their participation in this study as well as their families and caregivers. We are also grateful to Lu Li for her assistance with the statistical analysis in this study.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1056/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1056/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1056/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1056/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. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The present retrospective study did not involve any sensitive personal information, commercial interests, or inflict harm on human subjects. It solely utilized publicly available and anonymized data from the hospital system for research purposes. Thus, the Ethics Committee of the First Medical Center of the Chinese PLA General Hospital waived the need for ethics approval. Written informed consent was obtained from all patients involved in this study.

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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