Thymoma is a rare tumor entity and clinical management is very often based on observations of only a few patients in a single center. Surgery is considered the mainstay of therapy and recurrence is described as a typical nature of this tumor [1, 3, 7–11]. Presence of a pseudocapsula influences therapy regime and clinical outcome. Thymomas vary in its biological behaviour; also biology of this malignancy is still not fully understood. Two major classifications for thymomas are important and help to find the best therapy adapted to the prognosis.
In this series we found an overall survival of 88.1% which is representative to described data in the literature [1–3, 5, 7–12]. Vessel infiltration as well as Masaoka stage, WHO classification, R-status and an encapsulated tumor were of prognostic significance. Multivariate analysis was carried out to analyze possible joint-effects of prognostic parameter and only R-status and Masaoka stage appeared to be of independent prognostic significance in our series.
Even though being of strong significance in the univariate survival analysis WHO classification was not independent in the Cox-regression analysis. For clinical use and estimation of the patients' prognosis WHO classification is not as useful as the Masaoka classification which was shown before . The reason for these is based in a couple of problems. First, there is a significant interobserver variability in histological typing [2, 6]. Second, determination of precise cut-off points between different categories (e.g. B1 to B2, or B2 to B3) may lead to different categorisation, especially in highly biological active tumors such as B3 thymomas . Third, proportion of the invasive tumors is not reflected in the WHO classification, and therefore, prognostic value is not preciously mirrored [4, 13].
Kim reported a simplification classifying thymomas into different groups; A-B2 on the one side and B3 and C thymomas on the other side . We used this simplification for statistical analysis and presentation of clinical features (Table 1). It better reflects real survival rates and prognosis, as shown previously [1, 3, 14]. There is a significant difference between cancer-related survival for patients according to WHO classification A-B2 and B3-C. Prognosis is good in patients with type A to B2 thymomas with no tumor related death. In our cohort survival rate was over 95% for WHO A-B2 and only 68% for B3-C. Several investigators have also reported poor prognosis of type B3 thymoma [1–3, 10], whereas no difference is found in others reports in the literature concerning B2 and B3 thymomas [15–17]. In our study group 84% of patients in WHO A to B2 were classified into Masaoka stage I or II. Therefore, the shown joint effect in multivariate analysis due to a large overlap between different subgroups of WHO and early Masaoka stages is easily explained.
Masaoka staging system was the strongest independent factor for survival additional to the R-status in our study group. Large thymomas in advanced Masaoka stages are not very likely to be resected R0 and thus having a decreased outcome .
In our study population an encapsulated tumor is associated with a decreased cancer-related survival compared to a thymoma without a capsula. In complete or incomplete encapsulated thymomas survival rate is 97% and 92%, respectively, while survival rate without a capsula is lightly over 60%. Also being of strong significance in the univariate analysis, presence of a pseudocapsula fales as independent prognostic parameter in the multivariate analysis due to its narrow correlation with the clinical Masaoka stage. However, correlation with Masaoka can easily be explained. A pseudocapsula borders the tumor and limits local infiltration and reflects a less aggressive behaviour. Thus, less lymph node or distant metastases and infiltration of adjacent structures like pericardium or vessels are found (Table 3). Therefore, intraoperative presence of an encapsulated tumor is a good technical marker for the surgeon to evaluate resectability and estimate patient's prognosis including recurrence. This reason emphasizes the importance of a capsula for Masaoka staging.
In our population 26 patients were additionally treated with radiation, out of these 2 patients in stage IV were taken into combined radiochemotherapy after surgery. Subgroup analysis showed significant favourable outcome through adjuvant therapy only for patients with thymic tumors staged Masaoka III. Thymomas are radiosensitive, and radiotherapy (RT) is generally accepted for advanced stages after partial resection [19–22]. However, strong evidence for this is still missing and efficacy is hard to define because of small numbers of patients in the presented studies. Therefore, whether adjuvant RT should be given after resection remains controversial, especially all series addressing postoperative RT involve retrospective reviews including many decades rather than an experience with a defined treatment plan and selection criteria . In complete resected thymomas recurrence rate for stage I and II is so low without adjuvant RT, that the use of RT after surgery can not be recommended . For sure, adjuvant radiation is compulsory for incomplete resection also not showing a better survival. But adjuvant radiation was found to result in lower recurrence rate in patients with incomplete resected thymomas in stage IV [23, 24].
In our study chemotherapy was given in 5 cases only in stage IV and recurrence rate was 7%. No patients in Masaoka stage I-III received neoadjuvant or adjuvant chemotherapy. We did not find any survival advantage for patients with either neoadjuvant or adjuvant systemic treatment. These findings reflect results presented in the literature. Generally, thymomas in stage III and IV do not appear to have a better outcome for adjuvant chemotherapy compared to surgery alone, but in the biggest presented study so far by Kondo a survival advantage was seen for thymic carcinomas .
Multimodality treatment consisting of preoperative chemotherapy, surgery and adjuvant RT was carried out in 2 patients in our study group. There was no survival benefit for this subgroup also the number of patients is extremely small. Interestingly, 2 patients in stage IV were resected R0 after neoadjuvant chemotherapy. Adjuvant treatment was carried on with chemotherapy and therefore leads to a better survival through multimodal therapy. Generally, the position of a multimodality treatment is still discussed controversially because of only small heterogeneous number of patients in the presented literature. A possible resection and survival might be improved in patients with stage III and IV thymomas as reported in the literature [11, 25]. Prospective studies showed increased resectability up to 72% with an average 5-year survival rate of 78% [7, 11, 14]. Therefore, a multimodal treatment regime appears to have a slightly better survival for patients in stage III and IV than for patients with surgery alone, independent, if postoperative RT alone or combined radio chemotherapy is used [7, 11, 14, 25].
Summarized, the shown data confirm the published results on the clinical prognosis of different histological subtypes and the difficulties with the staging systems. Further more, our data point out a difference in survival and prognosis when tumor is complete or incomplete encapsulated stressing the importance of knowledge of presence. According to our opinion, differentiated pathological assessment for pseudocapsula can surely improve clinical evaluation of surgical outcome and is therefore compulsory. The strongest impact on survival is surely a complete resection, which is dependent on Masaoka staging. Prognosis can be evaluated best by carrying out the Masaoka staging. Moreover, WHO classification is not as precise as the Masaoka classification for prediction of prognosis of the patient which is for clinical management still the best. To our opinion pathologically confirmed complete encapsulated tumors do not require any neo- or adjuvant treatment after complete resection. The worse survival results for the higher Masaoka stages support a combined therapy with neoadjuvant chemotherapy and adjuvant radiotherapy which is supported by the literature . More prospective randomized trials are essential to clarify possible beneficial effects for advanced thymomas or thymuscarcinomas.