Thymoma is a rare epithelial tumor with an annual incidence of 0.17 per 100,000 in China. Thymomas often occur in the anterosuperior mediastinum and have a slow progression, often referred to as “inert” tumors. Because of its low incidence, slow progression, and complex pathology, clinicians have limited knowledge of it. Patients with thymoma of all tissue types and stages can develop distant metastases, and despite its long course and relatively good outcome, thymoma remains a malignant tumor. Due to the lack of prospective randomized controlled studies in clinical practice, there has been controversy about the reasonable comprehensive treatment model for thymoma. According to the morphological characteristics of epithelial cells, the World Health Organization classifies thymic tumors into six pathological types, including A, AB, Bl, B2, B3 and C, among which type C is thymic carcinoma. At present, the clinical staging of thymoma still adopts Masaoka staging criteria. The current status and controversies of thymoma treatment are reviewed and discussed thematically. 1. Surgical treatment of thymoma: Surgery is the basic method of thymoma treatment. Almost all stage I thymomas and most stage II thymomas can be completely resected, and about 50% of stage III thymomas and about 25% of stage IV thymomas can be completely resected. The overall 5-year survival rate of patients with surgically resected thymoma is high. 10-year survival rates are 90% and 70% for stage I and II patients, respectively, and 55% and 35% for stage III and IVa patients, respectively. 15-year overall survival rates are 78%, 73%, 30% and 8% for stage I, II, III and IV patients, respectively. We retrospectively analyzed the outcome of 283 cases of thymoma treated mainly with surgery in our hospital. The 5-year overall survival rates were 94.3%, 86.3%, 71.6% and 39.4% for stage I, II, III and IV patients, respectively, and the 10-year overall survival rates were 84.3%, 75.4%, 56.6% and 29.6%, respectively. The completeness of tumor resection and Masaoka stage were the main prognostic factors for long-term survival of patients with thymoma. Patients with complete resection of thymoma had better survival, and the long-term survival rate after complete resection of stage III thymoma was similar to that of stage I thymoma. 2. Postoperative adjuvant radiotherapy for thymoma: Thymoma is a tumor sensitive to radiation therapy, and radiotherapy plays an important role in the treatment of thymoma. Although there is a lack of clinical randomized controlled studies, the available retrospective analysis of clinical data suggests that selective postoperative radiotherapy can benefit the survival of patients with thymoma. In the 1980s, postoperative radiotherapy was recommended for patients with all stages of thymoma, regardless of whether they were completely resected. More recent studies have focused on which stage of tumor or which resection status patients may benefit from postoperative radiotherapy. One study showed that the recurrence rate for patients with stage I and completely resected thymoma was 2% to 3% at 32 years of follow-up. Thus, it is concluded that patients with stage I thymoma are unlikely to benefit from postoperative radiotherapy. The results of a small randomized clinical trial from the Cancer Hospital of the Chinese Academy of Medical Sciences showed no survival benefit of postoperative radiotherapy for patients with stage I thymoma. A retrospective study (n=901) using SEER registry data also showed no therapeutic benefit of postoperative radiotherapy for patients with stage I thymoma. Adjuvant postoperative radiotherapy significantly improves overall survival in patients with stage II and III thymoma, especially in patients with non-completely resected mouths]. One study showed that the 5-year recurrence rate of those with stage II and III thymoma without radiotherapy after RO resection was 47%, whereas no recurrence was seen in patients who underwent postoperative radiotherapy. In 2009, a Meta-analysis of 592 patients showed no therapeutic benefit of postoperative radiotherapy in reducing recurrence in patients with completely resected stage II and III thymoma. utsumi et al. reported 324 patients treated surgically for thymoma, of whom 119 patients underwent postoperative radiotherapy, and concluded that stage I, II, and A, AB, and Bl patients are not recommended to receive postoperative radiotherapy. AB, and Bl patients were not recommended to receive adjuvant radiotherapy; and there was no statistically significant difference in survival rates for patients with stage III, stage IV, and types B2 and B3 regardless of whether they received postoperative radiotherapy. Although the evaluation of postoperative radiotherapy for thymoma has not been fully supported by evidence-based medicine, the preference in the literature is that postoperative radiotherapy is not recommended for stage I patients; postoperative radiotherapy is still recommended for patients with stage II and above, regardless of whether they are completely resected, as recommended by the National Comprehensive Cancer Network (NCCN) guidelines for the treatment of thymic tumors; for incompletely resected stage III and IV For stage III and IV patients with incomplete resection, postoperative radiotherapy is the standard of care. For patients with complete resection, the recommended dose of postoperative radiotherapy is 50-60 Gy; for patients with incomplete resection and large residual tumors, the total dose of postoperative radiotherapy should be >60 Gy. To reduce normal tissue complications and increase the dose of tumor irradiation, three-dimensional conformal or intensity-modulated radiotherapy techniques are recommended. 3. The role of chemotherapy in thymoma treatment: Patients with progressive thymoma are treated with single-agent chemotherapy at the beginning of chemotherapy. Single-agent chemotherapy drugs include cisplatin, interleukin 2, pemetrexed, isocyclophosphamide, and octreotide. Although, these drugs are effective in thymoma, they are mostly clinical phase II trials and the number of patients in each study is small and inconclusive, but have shown the effectiveness of platinum-based chemotherapy. Since the 1980s, combination chemotherapy has been used for progressive thymomas, with platinum-based regimens being more effective, with efficiencies of 60% to 90%. Currently, the CAP regimen (cyclophosphamide + adriamycin + cisplatin) and the EP regimen (pedialyte glycoside + cisplatin) are recognized as two effective combination chemotherapy regimens. In a group of clinical trials applying CAP regimen chemotherapy, the efficiency rate was 50% and the median survival time was 11.8 months in 30 evaluable patients with metastasis or recurrence. in a prospective study conducted by the EORTC Lung Cancer Cooperative Group, 16 patients with recurrent or metastatic thymoma were treated with EI:regimen chemotherapy and the median survival time was 4.3 years. fomasierc et al. reported that 32 patients with stage III and IV thymoma treated with chemotherapy using the ADOC regimen (adriamycin + cisplatin + vincristine + cyclophosphamide) had an efficiency of 90% and a median survival time of 15 months, while another group of 16 patients had an efficiency of 81%. The EP regimen was also used to treat 16 patients with thymoma, with an efficiency of 56%. Tysol + carboplatin regimen in thymoma treatment was 35%. The above clinical studies showed the effectiveness of combined chemotherapy in the treatment of thymoma. 4. Preoperative induction therapy and radiotherapy for inoperable thymoma: In clinical practice, nearly 1/3 of patients with thymoma are inoperable due to local progression at the time of diagnosis. Preoperative chemotherapy or radiotherapy has been shown to improve the surgical resection rate and long-term survival of patients with locally progressive thymoma. The efficiency of preoperative chemotherapy for locally advanced thymoma is > 50%. One study showed that 21 patients with thymoma treated with preoperative induction chemotherapy using the ADOC regimen had an overall efficiency of 62%, a complete resection rate of 43%, and a pathologic complete remission rate of 14%. It has also been reported that 25 patients with thymoma treated with EP or ADOC regimen for preoperative induction chemotherapy had an efficiency rate of 72%, complete resection rate of 44%, and complete pathological remission rate of 8%. In another group, preoperative induction chemotherapy using the ADOC regimen had an efficiency of 100%, a complete resection rate of 69%, and a pathologic complete remission rate of 31%, and Kim et al. used the CAP+prednisone regimen for preoperative induction therapy with an efficiency of 77%, a complete resection rate of 76%, and a pathologic complete rate of 38%. It is clear that preoperative induction therapy can lead to complete surgical resection in nearly half of patients with locally advanced thymoma, and therefore a multidisciplinary discussion should be held before treating this group of patients to determine the treatment modality. For patients with thymoma that cannot be treated surgically, radiotherapy is undoubtedly the preferred treatment modality, and radiotherapy combined with chemotherapy needs to be supported by more clinical trials. 5. Treatment of thymoma recurrence and distant metastasis: The main reasons for thymoma treatment failure are local recurrence and distant metastasis. The lung and pleura are the main sites of thymoma metastasis and recurrence. We analyzed the treatment outcomes of 48 patients with recurrent metastatic thymoma, including 27 cases of recurrence and 26 sides of metastasis. The treatment of recurrent patients included five treatment modalities including surgical re-excision of recurrent tumor, surgery + postoperative radiotherapy, radiotherapy, radiotherapy + chemotherapy and chemotherapy, and the treatment modalities of metastatic patients included radiotherapy, chemotherapy, radiotherapy + chemotherapy and surgery plus chemotherapy. The 5-year and 10-year survival rates of patients after retreatment were 37.5% and 25.0%, respectively, with a median survival time of 2.7 years, including a median survival time of 4 years after retreatment for patients in the recurrent group and 2 years after retreatment for patients in the metastatic group. the EORTC lung cancer cooperative group reported the results of 16 patients with recurrent metastatic thymoma treated with chemotherapy in combination with the EP regimen, with a median survival time of 4.3 years. Long-term survival outcomes were better in patients with recurrent metastases who were treated with reoperation. In a group of 28 patients with recurrent metastases, complete resection was achieved in 19 cases and partial resection in 9 cases, with overall survival rates of 51% and 43% at 5 and 10 years after retreatment, respectively. The prognosis of patients with metastasis and recurrence of thymoma is relatively poor compared with that of patients with primary treatment, but after active retreatment, they can still obtain more satisfactory treatment results. 6.Molecular targeted therapy for thymoma: The genes related to thymoma are epidermal growth factor receptor (EGFR), human epidermal growth factor receptor-2 (HER-2), Kit, K-ras, Bcl-2, TP53, p16INK4A, vascular endothelial growth factor (VEGF) and tumor invasion factors (matrix metalloproteinases and metalloprotein tissue inhibitors). In addition, high mRNA expression of the c-j un and AL050002 (an unknown gene) genes was associated with progressive thymoma. EGFR is overexpressed in 46% to 100% of thymoma patients. One study showed that 32 patients with thymoma were examined by fluorescence in situ hybridization method ( FISH), and the results showed that 30% of patients had significant amplification of EGFR, especially in patients with B3 thymoma. However, EGFR mutations were rare, with only 2 exon 21 mutations in a group of 29 patients analyzed. the EGFR inhibitors gefitinib and erlotinib had little effect on thymoma. In a clinical trial of 26 patients treated with gefitinib 250 mg/d, the results showed one partial remission, 15 stable cases and no patients in complete remission. Some clinical studies have shown that cetuximab is effective in treating patients with progressive thymoma. A clinical trial on the CAP regimen in combination with cetuximab for locally advanced thymoma is still ongoing (NCT01025089), in which patients received cetuximab for 4 weeks and cetuximab + CAP chemotherapy for 4 cycles, followed by surgery. Imatinib, an oral multikinase inhibitor, was treated in 7 cases of B3 thymoma and thymic carcinoma, with 2 cases stable and 5 cases progressing. Sorafenib is a multitargeted tyrosine receptor inhibitor that inhibits wild-type and V600E mutant Rafl23l in addition to PDGFR, c-Kit, and VEGFR, and case report results of sorafenib suggest that it may be effective in thymoma. belinostat is a histone deacetylase (HDAC ) class I and II enzyme inhibitor. Phase II clinical studies showed that of 32 patients with recurrent and metastatic thymoma or thymic carcinoma, 27 were evaluable, 2 were in partial remission, 15 were stable, and 10 were progressive. Another phase I-II clinical trial is investigating the efficacy of Belinostat -line in combination with CAP regimen applied to progressive or recurrent thymoma (NCT01100944). Another HDAC inhibitor, 4SC-201, has also been shown to be effective in thymoma. In recent years, although scientists have actively explored the molecular pathways of thymoma, the results of clinical studies have been mostly disappointing, and the number of enrolled patients is small, and they are all clinical phase I and II studies, which have not yet had any impact on the clinical treatment strategy of thymoma. 7. The International Thymic Tumor Cooperative Research Organization was established: Thymoma is a rare tumor and there are few prospective randomized controlled clinical studies. In order to accelerate scientific collaboration in thymic tumors and to accumulate more clinical data, the first international thymic tumor cooperative was established in 2010, namely the ITMIG (Intemational Thymic MalignanciesInterest Group), a registered non-profit academic organization whose mission is to promote clinical and basic research in thymic malignancies. In 2009, the Thymic Tumor Research Foundation, in collaboration with the National Institutes of Health (NIH), convened the First International Conference on Thymic Tumors. Recently, ITMIG is standardizing the principles of surgery, chemotherapy and radiotherapy for thymic tumors and the reporting of pathology and imaging. 2011 saw the first World Congress of Thymic Oncology in the Netherlands, and 2012 will see the second World Congress of Thymic Oncology in Japan. It is expected that the clinical and basic research on thymic tumors will make great progress on this basis and make positive contribution to the standardized treatment of thymic tumors. In conclusion, thymoma that can be surgically resected should be treated surgically as much as possible, and tumor stage and completeness of surgical resection are the main prognostic factors for thymoma. Patients with thymoma that cannot be treated surgically should be treated with radiotherapy or combined radiotherapy and chemotherapy. Postoperative radiotherapy can improve the local control rate of patients with stage II-IV thymoma, and combined chemotherapy is effective for progressive thymoma. To further improve the efficacy of thymic tumors and standardize the treatment of thymoma, future clinical studies should focus on (1) treatment modalities of preoperative induction chemotherapy or chemotherapy and radiotherapy for patients who cannot be treated surgically; (2) clarification of the value of postoperative adjuvant radiotherapy and chemotherapy for patients with completely resected stage II and III thymoma using a clinical randomized controlled study; (3) correlation studies from histological typing and clinical staging from the correlation between histological staging and clinical staging to obtain the prognostic factors for each pathological type; and (4) the issue of individualized treatment of metastatic and recurrent thymic tumors. In addition, long-term follow-up remains an important issue because patients with thymoma have a good long-term survival rate, but local recurrence and distant metastases can still occur long after treatment.