DISCUSSION
TETs are a rare and heterogeneous entity. Whereas for the lower stages of disease, complete surgical resection has become the accepted standard and mainstay of treatment, little data exist about the value of surgical resection in advanced stages. Especially for Masaoka–Koga Stage IVA, which is defined by the presence of pleural spread and metastasis, the value of surgical resection remains in question. The reason for this lies in the low number of cases that are usually seen in single institutions as well as in the heterogeneity of the clinical presentation. Whereas some patients present with only one or few well-defined and localized pleural lesions, others have a diffuse pattern of pleural involvement and few patients have the combination of pleural and intraparenchymal tumour spread in the lung. Accordingly, surgical attempts for radical resection vary from LP over TP to EPP (complete en bloc removal of pleura, diaphragm and lungs).
The intention of this retrospective study among members of the ESTS Thymic Working Group was therefore to accumulate a sufficiently large cohort of patients that would allow for meaningful statistical analysis and provide better insight and understanding of the role of surgical resection for TETs in Stage IVA.
The most important finding of this study was that complete surgical R0 resection, regardless of which surgical method was applied, as well as the histology of thymomas compared with TCs, was predictive for improved OS at multivariable analysis.
Certainly the choice of the surgical procedure is dependent from the underlying situation and extent of spread of disease. It therefore appears evident that patients undergoing EPP were in an even more advanced tumour situation, compared with patients in whom complete resection was achieved by TP or simple LP. It is therefore even more remarkable that with the extended surgical procedure of EPP, a similar positive effect on OS was achieved in more advanced tumour situations, as with the somewhat more limited procedures in less advanced situations.
Better survival was evident in patients with surgery for recurrent disease to the pleura (first pleural surgery/Scenario 1). In this patient cohort, 18.2% EPPs, 2.2% TCs and 6.8% incomplete resections were performed in contrast to 29.9% EPPs, 15.0% TCs and 29.9% incomplete resections in patients with primary pleural surgery (Scenario 2). There is an obvious bias in disease severity and the resulting invasiveness of the necessary surgical procedure that may not allow a fair comparison of these patient cohorts. Nevertheless, it demonstrates again the excellent outcome of surgery for recurrent disease to the pleura [10]. One might also speculate about different biology of TETs presenting with pleural involvement at first diagnosis or that patients in institutional follow-up programmes after thymic surgery (tertiary prevention) are diagnosed earlier with recurrence than patients with TETs with pleural involvement without prior thymic surgery (no primary prevention).
Different treatments and different reasons to treat the diaphragm in patients with TETs and pleural involvement can be distinguished. For metastases to the diaphragm, partial or complete resection of the diaphragm or just pleurectomy of the diaphragm can be performed. The reason to perform diaphragmatic surgery is purely oncologic: metastasis to the diaphragmatic pleura with our without involvement of diaphragmatic musculature. Despite the respectable number of patients with this rare disease entity and the multicentre nature of this work, no recommendation can be given on whether just pleurectomy or full-thickness resections will result in different outcomes concerning recurrence rates or survival. Since patients with diaphragmatic involvement had concurrent nodules on other pleural sites, the isolated analysis of the issue of diaphragmatic resection or pleurectomy cannot be selectively answered (46.1% recurrences [12 of 26 R0 resections] after complete or partial diaphragmatic resections vs 44.4% recurrences [4 of 9 R0 resections] after diaphragmatic pleurectomy only). Another indication for treatment of the diaphragm in this patient cohort is in patients with tumour infiltration or inseparable tumour adherence to the phrenic nerve. In cases with obligatory demand for oncologic resection of the phrenic nerve, diaphragmatic plication is performed to flatten the paralyzed dome of the diaphragm and thus provide sufficient space for the lung to expand (functional reason).
Five-year OS of patients undergoing resection for pleural dissemination of TETs in studies with 5 to 21 patients was recently reviewed and ranges from 43.1 to 92.3% [3]. In a recent retrospective study on behalf of the Japanese Association for Research on the Thymus on 136 patients who underwent surgical resection for TETs with pleural dissemination, Masaoka Stage IVA (n = 118) and IVB (n = 18), 5-year OS was 83.5% [11]. OS of the entire patient cohort in the current study compares favourably with 87.2%.
A study of 229 patients with TC (Masaoka Stage I–IV, ESTS database) identified 5- and 10-year OS rates of 0.61 and 0.37 and 5- and 10-year FFR rates of 0.60 and 0.43. At multivariate analysis, incomplete resections and advanced stage (Masaoka–Koga Stage III–IV) had a negative impact on OS, P < 0.0001 and P = 0.02, respectively. The authors concluded that surgical resection of TC should be undertaken whenever possible [9]. Five- and 10-year OS of patients with TC (n = 17) with pleural involvement in the current study was comparable, 56.0% and 0% (6 deaths by the end of 10 years), respectively.
Masaoka–Koga Stage III–IV, incomplete resection and non-thymoma histology were identified to have a significant impact on increasing recurrences and worsening survival in an ESTS cohort study (2030 patients). Administration of adjuvant therapy after complete resection was associated with improved survival [8]. Conversely, in a Japanese study on 1320 patients the value of adjuvant therapy after complete resection was in doubt [2]. Masaoka Stage IVA patients (n = 118) with 10 or fewer pleural nodules and macroscopic complete resection were reported to have better prognosis (Japanese Association for Research on the Thymus). In Stage IVA patients with complete resection, there were no supportive data on the efficacy of ChT and/or RT [11].
Better OS and CSS of patients with MG may be explained by looking at diagnosis, resection status and type of surgery (MG+: 2.1% TCs, 17.4% incomplete resections and 10.6% EPPs in comparison with MG−: 15.2% TCs, 25.0% incomplete resections and 33.7% EPPs). There was an obvious difference in disease severity between the 2 study groups. In a study on 797 thymoma patients, a slight protective effect of MG on OS was observed that was not confirmed by multivariate analysis [12]. In patients with thymoma (Masaoka–Koga Stage I–IV), MG had an influence on histology and stage presentation, but only stage had a prognostic significance on OS and DFS [13]. Reasons for these observations may be associated with earlier diagnosis of TETs in MG patients (because of closer follow-up) or improvements in MG management [13].
Ninety percent of patients (64 of 71) underwent extended thymectomy at the time of primary pleural surgery (recurrence rate: 49.0%). Six patients had thymomectomy only (50% recurrences). Only 20.6% of patients undergoing extended thymectomy at primary pleural surgery had MG. Thus, general practice among thymic surgeons in primary surgery of TETs with pleural involvement is to add extended thymectomy. No conclusions on the value of added basic or extended thymectomy to thymomectomy at primary surgery for pleural disease of TETs for FFR can be drawn from this study.
The large number of patients that could be collected on this rare disease entity is one of the strengths of this study. Its retrospective nature is one of the weaknesses. The long study period necessary for collecting this large cohort of patients with this rare presentation of TETs is another limitation of this study. Innovations in diagnostic and therapeutic modalities may change institutional treatment practices influencing outcomes. Prospectively collected data on all patients with TETs and pleural involvement by ESTS/International Thymic Malignancies Interest Group and Japanese Association for Research on the Thymus are warranted. Nevertheless, this collaborative effort gives detailed insights into current diagnostic and therapeutic practices of European and Canadian thoracic surgery and underlines again the incontestable importance of surgery for patients with primary and recurrent TETs with pleural involvement. We recommend close follow-up after surgery for pleural disease of TETs.
In summary, complete surgical resection is the mainstay for treatment of patients with TETs even in Masaoka–Koga Stage IVA. The type of resection, i.e. EPP, TP, LP, is dependent from the extent and distribution of tumour. However, even in more advanced tumour situations with the combination of pleural and intraparenchymal tumour spread, EPP provides equally as good results as the less complex procedures (TP or LP) for pleural metastasis only.