Long-term outcomes of 307 patients after complete thymoma resection

Thymic epithelial tumors, including thymoma and thymic carcinoma, are the most common tumors in the anterior mediastinum [1], with an incidence of 0.17 cases/100,000 annually in China [2]. Thymoma presents with an indolent course and a favorable prognosis. The 5-year overall survival (OS) rate of patients with thymoma is approximately 90.0% [3–5]. Complete resection is the gold-standard treatment of operable thymoma; radiotherapy and chemotherapy appear to benefit patients with inoperable or incompletely resected tumors [3–5].

Unfortunately, although indolent, the recurrence of thymoma is not infrequent after complete resection. Long-term follow-up is therefore required to determine recurrence rates of thymoma patients who undergo complete resection. The possibility of recurrence associates with disease stage upon diagnosis. The average recurrence rates of primary thymoma after resection are as follows: 4.0%, stage I; 14.0%, stage II; 26.0%, stage III; and 46.0%, stage IV [6]. Recurrence is generally confined to the intrathoracic regions, including locoregional recurrence and intrathoracic dissemination; distant metastases are rare.

Owing to the rarity and indolent nature of thymoma, there is limited and inconsistent information related to patients’ long-term outcomes and possible prognostic factors, particularly those associated with recurrent thymoma. The objective of our study was to analyze the long-term outcomes of a large number of patients with thymoma who underwent complete resection. For this purpose, we evaluated clinicopathologic characteristics of the patients with primary thymoma, investigated the types of treatment of recurrent thymoma after initial resection, and estimated independent predictors of disease-free survival (DFS) and OS.

In the present study, we found that Masaoka stage and WHO histological classification were the primary determinants of patients’ outcomes and that these factors effectively predicted DFS and OS of patients who underwent complete resection of primary thymoma. Postoperative radiotherapy reduced recurrence rate and was significantly associated with DFS, although it did not serve as an independent predictor. The recurrence pattern of thymoma was an independent predictor of PRS. Although not statistically significant, the type of therapy may be a prognostic factor for patients with recurrent thymoma.

The Masaoka staging system was proposed in 1981 [10], and a modified version was suggested in 1994 [11]. Although the WHO TNM staging system was subsequently proposed, it is not widely used to stage thymoma because of the low frequency of lymph node metastasis [12]. The difference between the Masaoka and WHO TNM staging systems is the classification of N1 disease, which is included into the criteria of stage IVb disease in the Masaoka staging system and stage III disease in the WHO TNM staging system, respectively [13]. Furthermore, the lymph node metastasis rate in patients with thymoma is <2.0%, and the TNM system may therefore be unsuitable for staging thymoma [14]. Similarly, lymph node metastasis was not detected in the thymoma patients studied in the present study. By contrast, the Masaoka staging system, which is most commonly used, focuses on the primary tumor and classifies lymph node metastasis as stage IVb disease. We found that the Masaoka stage served as a perfect predictor of prognosis in the present study, which is consistent with the findings of other studies [3, 15, 16].

The WHO histological classification was first recommended in 1999, and a modification was introduced in 2004. According to the morphology of epithelial cells and the lymphocyte-to-epithelial cell ratio, thymoma is pathologically stratified into types A, AB, B1, B2, and B3 [13]. Interestingly, the prognostic value of WHO histological classification for thymoma is inconsistent in previous studies. Some studies found that the WHO histological classification is an excellent prognostic factor for thymoma and helps clinicians to stratify patients and therefore administer the most appropriate treatment [16, 17]. However, other studies found that the WHO histological classification does not predict DFS and OS [3, 18]. Our results demonstrate that the WHO histological classification was significantly associated with recurrence rate and predicted the DFS and OS of patients with thymoma.

Surgery plays a vital role in the management of thymoma. Compared with thymoma patients who receive conservative therapies, those who undergo complete resection achieve the maximum survival advantage [19]. New and novel surgical techniques such as VATS and the da Vinci Surgical System are now used in clinic. Compared with open surgery, VATS thymectomy shortens postoperative hospitalization, reduces blood loss, and reduces restriction of patients’ activities. These advantages hasten recovery, which was demonstrated by our short-term study [9]. Furthermore, a recent meta-analysis showed that, compared with patients who underwent open surgery, those who underwent minimally invasive surgery (VATS and da Vinci robotic surgery) had less blood loss and shorter hospitalization [20]. For selected thymoma patients, minimally invasive surgery is safe and can achieve survival and recurrence rates comparable with those of open surgery [20]. However, the present long-term study shows that surgical approaches were not significantly associated with survival of patients with thymoma and that DFS and OS did not differ significantly between patients who underwent VATS and those who underwent open surgery (sternotomy and thoracotomy), which may be due to the small size of the patients with recurrent thymoma.

Although complete resection is recognized as curative treatment for patients with resectable thymoma, the role and benefit of postoperative radiotherapy are controversial. The patients treated with surgical resection alone and those treated with postoperative radiotherapy showed significant, though conflicting, results [21], which may be due to heterogeneous subject populations and therapeutic regimens. Our results suggest that postoperative radiotherapy reduced the recurrence rate and prolonged DFS after complete resection of thymoma. We hypothesize, therefore, that patients eligible for postoperative radiotherapy were selected according to the surgeon’s judgment of high risk factors such as invasiveness or intraoperative adhesiveness as well as Masaoka stage and WHO histological classification. Based on our present results and clinical experience, we propose that type B2 or type B3 encapsulated thymoma and invasive thymoma should be treated with adjuvant radiotherapy after complete resection.

Because of the indolent biological behavior of thymoma, long-term follow-up is required for patients who undergo resection. The most frequent site of recurrence (≤92.0%) is the pleura [22–24], which is consistent with the findings of the present study (40%). Locoregional recurrence is the most common reported recurrence pattern [25, 26], which is also consistent with our present findings. The recurrence site was not associated with survival, although here the recurrence pattern was an independent predictor of PRS.

Due to the infrequence of thymoma recurrences, the data about recurrent thymoma are limited, and related studies are rare; the optimal management of recurrent disease is inconsistent and not identified. Surgical resection for recurrent thymoma is recommended because of its feasibility and low postoperative morbidity [27]. In the present study, patients with recurrent thymoma who underwent surgery had a longer PRS compared with those treated with other strategies. Patients who did not undergo surgery had disseminated disease; therefore, the significant differences in survival after recurrence might be explained by disseminated disease that was more extensive. Although the multivariate analysis results of survival after recurrence were not statistically significant, treatment modalities trended as independent prognostic factors of recurrent thymoma (P = 0.051). Moreover, prolonged PRS of patients treated with surgery suggests that debulking surgery may play a positive role in the management of recurrent thymoma. To our knowledge, no data are available on the benefit of adjuvant treatment of recurrence. Nevertheless, we recommend the administration of adjuvant therapy to patients with recurrent thymoma after resection because the surgeons cannot intraoperatively find the residual lesions or microscopically recurrent sites.

This study has limitations because of its retrospective nature and the experience of a single center. In a retrospective study, the follow-up schedule could not be made uniform, which may cause bias when assessing the survival time. Even if substantial number of patients underwent complete resection, a randomized large-scale trial is required to further validate our conclusions. Because of the primary selection bias in treatment allocation, it may not be possible to precisely define the role of adjuvant therapy. Furthermore, patients with recurrent thymoma who were eligible for surgery might have survived longer compared with those who were not because of limited dissemination of the tumor.

In the present study, our results reiterate that Masaoka stage and WHO histological classification are reliable predictors of DFS and OS of patients with thymoma who undergo initial complete resection. The recurrence pattern is an independent predictor of PRS in patients with recurrence. Repeated surgical resection is recommended for patients with recurrent thymoma, along with the possible use of adjuvant therapy.