Surgical therapy of thymic tumours with pleural involvement: an ESTS Thymic Working Group Project.

OBJECTIVES: Surgery for thymic epithelial tumours (TETs) with pleural involvement is infrequently performed. Thus, the value of surgical therapy for primary or recurrent TETs with pleural involvement is not sufficiently defined yet.
METHODS: Twelve institutions contributed retrospective data on 152 patients undergoing surgery (1977-2014) on behalf of the ESTS Thymic Working group. Outcome measures included overall (OS), cause-specific (CSS) and disease-free (DFS) survival as well as freedom from recurrence (FFR).
RESULTS: In 70.4% of cases, pleural involvement was present at the time of primary intervention, whereas 29.6% had surgery for recurrent disease involving the pleura. Pleural involvement resulted from thymomas (88.8%) and thymic carcinomas (11.2%). Forty extrapleural pneumonectomies (EPPs), 23 total pleurectomies (TPs), and 88 local pleurectomies (LPs) were performed (completeness of resection in 76.8%). OS for the entire patient population at 1, 3, 5 and 10 years was 96.4%, 91.0%, 87.2% and 62.7%, respectively. There was no statistically significant difference regarding FFR and OS for patients with local or advanced disease undergoing EPP, TP or LP. Thymic carcinomas in comparison with thymomas had a negative impact on OS [hazard ratio 6.506, P  = 0.002], CSS and FFR. Incomplete resections predicted worse OS [hazard ratio 6.696, P  = 0.003].
CONCLUSIONS: Complete resection remains the mainstay of treatment for TETs with pleural involvement. Study populations treated with EPP, TP and LP had similar survival that may be factual as observed, but in the presence of selection bias, we can further conclude from the results that EPP, TP and LP are equally effective procedures. Procedural choice depends upon the extent of tumour distribution. EPPs, TPs and LPs performed within a multimodality setting seem to be efficient procedures for local control of disease, as they yield excellent results regarding OS, DFS, CSS and FFR.

INTRODUCTION

Thymic epithelial tumours (TETs), namely thymomas and thymic carcinomas (TCs), are rare neoplasms of thymic epithelial origin. TETs present in different clinical stages and show a variety of histological patterns. They are being treated in small numbers in many different centres worldwide with heterogeneous diagnostic and therapeutic algorithms. Advanced-stage TETs with pleural or pericardial dissemination (Masaoka-Koga Stage IVA [1]) are encountered in only 6.8% of all patients with TETs [1-3]. The best treatment for Stage IVA TETs still has to be defined. Complete surgical resection is the mainstay of treatment for patients with TETs. For patients with metastases of TETs to the visceral or parietal pleura, different surgical techniques are employed. Surgical techniques vary from extrapleural pneumonectomy (EPP) to total pleurectomy (TP) or local pleurectomy (LP), and frequently resections are combined with chemotherapy (ChT) and/or radiotherapy (RT) [4, 5]. In general, the indication to perform EPP is the finding of numerous visceral and parietal pleural and pericardial implants (and pulmonary nodules) that cannot be locally resected [6]. TP is the removal of all parietal, mediastinal and diaphragmatic pleural surfaces and pericardium with or without resection of the diaphragm. The decision to perform TP is made when visceral pleura and lung are not affected by malignant disease. LP is metastasectomy (local resection) of pleural implants without removal of all pleural surfaces. It is performed for mono- or oligometastatic disease.

The value of surgical therapy with or without ChT and/or RT for primary or recurrent thymic tumours with pleural involvement is not sufficiently defined yet, due to limitations in the available data. In this collaborative effort, members of the European Society of Thoracic Surgeons (ESTS) Thymic Working Group retrospectively collected data on patients undergoing thoracic surgical procedures for primary and recurrent thymic tumours with pleural involvement. The current work reflects the former and current practice patterns of European and Canadian thoracic surgery institutions treating TETs with pleural and/or pericardial involvement.

MATERIALS AND METHODS

On behalf of the ESTS Thymic Working Group, emails were sent to ESTS members to ask for participation on this retrospective data collection in the treatment of patients with TETs with pleural involvement. Respondents received a detailed standardized questionnaire (Supplementary Material, Table S1). In this collaborative effort, a total of 152 patients with pleural disease of TETs were reported by 12 institutions from 8 countries. All institutions were specialized thoracic surgery centres routinely performing surgery on patients with TETs. The reported patients were diagnosed and operated between February 1977 and November 2014 (90% of patients between 1 January 2001 and 30 November 2014, Supplementary Material, Table S2).

Each institution obtained ethical approval from its ethics committee.

Study flow

There were coherent data for survival analysis on all 152 patients and on 115 patients with complete resection for analysis of freedom from recurrence (FFR; Fig. 1).

Figure 1

Flow chart illustrating the assignment of patients to different end-points. TETs: thymic epithelial tumours.

Statistics/outcome analysis

Definitions of recurrence and outcome measures were reported as recommended by the International Thymic Malignancies Interest Group [7]. Overall survival (OS) was calculated as the primary outcome from the date of surgery (first pleural surgery, Fig. 1) to the date of death of any cause. Patients without an event were censored at the last time point known to be alive. Disease-free survival was analysed from the date of surgery (first pleural surgery) to the date of recurrence or death from any cause (DFS) [8]. The end-point of interest for cause-specific survival (CSS) was defined as death from TET (censored observations: unrelated deaths and unknown cause of death) [7]. FFR was calculated only in patients after complete surgical resection (R0) from the date of surgery (first pleural surgery) to the date of recurrence and full information on recurrence status [9]. Log-rank tests were employed to compare whole Kaplan–Meier curves. Differences at 1, 3, 5 and 10 years were reported descriptively. Statistical methods are detailed further in the Supplementary Material.

RESULTS

Institutions contributed a median of 11 patient cases (range 2–38; Supplementary Material, Table S2).

The median follow-up time for the entire patient cohort was 52 months [range 0–265; 95% confidence interval: 32.0–72.0].

The study cohort consists of 2 types of patients undergoing surgery for pleural disease of TETs. Patients with pleural disease at primary diagnosis (70.4%) as well as patients with pleural disease who had previous surgery for a TET (without involvement of the pleura [29.6%]) were included in the study (Fig. 2). Mean age at surgery for pleural disease was 47.3 years for the cohort undergoing primary surgery for pleural disease of TETs and 54.6 years for patients with surgery for their first recurrent disease to the pleura. Forty patients (26.3%) had 1 TET resection before the first surgery of pleural disease (3 patients had 2 surgeries, 1 patient had 3 surgeries and 1 patient had 4 surgeries before pleural dissemination, respectively).

Figure 2

Primary pleural surgery and surgery for recurrent pleural disease. TETs: thymic epithelial tumours.

Clinical data

Basic demographic data are presented in Table 1. For initial symptoms (51.3%), diagnostic imaging, tumour location and preoperative biopsy (68.4%), see Supplementary Material, Table S3. Myasthenia gravis (MG) was reported in 47 patients (30.9%); for other autoimmune diseases (7.2%) and other malignancies, see Supplementary Material. Seventeen patients (11.2%) were diagnosed with TC and 135 (88.8%) with thymoma. Patients were reported in pathological Masaoka–Koga Stages I (3.4%), II (6.1%), III (20.5%), IVA (65.0%) and IVB (4.8%) at their first surgery. The frequency of thymomas and TCs according to World Health Organization histology was B2 (33.6%), B3 (23.9%), B1 (13.0%), combined B2/B3 (11.6%), TC (10.3%), AB (4.1%), B1/B2 (2.0%), A (0.7%) and combined B3/TC (0.7%) (Supplementary Material, Table S4).

Table 1

Basic demographic and clinical parameters

	n (%)
Total number of cases	152 (100)
female:male ratio	76:76 (50:50)
Age in years mean/median [range]	50.4/51.0 [22–75]
Pleural surgery for thymic epithelial tumours
Surgery for pleural recurrence	45 (29.6)
Primary pleural surgery	107 (70.4)
Diagnosis
Thymoma	135 (88.8)
Thymic carcinoma	17 (11.2)

Surgery

Thymectomy information

Primary surgery for thymic epithelial tumours without involvement of the pleura (Scenario 1): There were 3 TET resections (thymomectomies) without thymectomy, 5 thymomectomies combined with basic thymectomies (removal of thymic lobes) and 22 thymomectomies in conjunction with extended thymectomies (basic thymectomy plus resection of mediastinal and cervical fatty tissue). All patients had a recurrence to the pleura (Fig. 2).

Primary pleural surgery (Scenario 2): There was 6 thymomectomies, 1 thymomectomy combined with basic thymectomy (removal of the thymic lobes) and 64 thymomectomies in conjunction with extended thymectomies. There were 3 recurrences after thymomectomy only (50%), after thymomectomy plus basic thymectomy 1 (100%) and thymomectomy combined with extended thymectomy 26 (49.0%).

Surgery for pleural disease of thymic epithelial tumours: surgical approach, type and completeness of resection

Different surgical approaches were chosen to resect TETs with pleural involvement (Table 2). For the resection of pleural disease, EPP was performed in 26.5%, TP in 15.2% and LP in 58.3% of patients. EPP, TP and LP were performed in 32 cases (29.9%), 13 cases (12.1%, including 1 case of pleurectomy/decortication [P/D]) and 62 cases (57.9%) for primary pleural surgery (Scenario 2), respectively. In patients with pleural surgery for recurrence (Scenario 1, first pleural surgery) EPP, TP and LP were carried out in 8 patients (18.2%) and 10 patients (22.7%, including 3 patients with P/D) and 26 patients (59.1%), respectively (missing information: 1 patient). Completeness of resection was pathologically confirmed in 76 (71%, R0), incomplete resection in 16 (15%, R1) and 15 (14%, R2) for primary pleural surgery. Completeness of resection for recurrent pleural surgery was reported as: 40 (90.9%, R0), 1 (2.3%, R1) and 2 (4.5%, R2), respectively (missing information: 2 patients).

Table 2

Treatment modalities

n = 152	n (%)
Preoperative treatment
Neoadjuvant	67/107 (62.6)
Chemotherapy	59/67 (88.1)
Radiotherapy	5/67 (7.5)
Radiotherapy and chemotherapy	3/67 (4.4)
Pseudo-neoadjuvant	15/45 (33.3)
Chemotherapy	14/15 (93.3)
Radiotherapy	1/15 (6.7)
Radiotherapy and chemotherapy	0/15 (0.0)
Response to preoperative therapy
Neoadjuvant
Stable disease	5 (7.5)
Partial response	48 (71.6)
Progression	3 (3.9)
No information	11 (16.4)
Pseudo-neoadjuvant
Stable disease	1 (6.6)
Partial response	7 (46.6)
Progression	0 (0.0)
No information	7 (46.6)
Postoperative treatment
Adjuvant	68/107 (63.6)
Chemotherapy	5/68 (7.3)
Radiotherapy	49/68 (72.1)
Radiotherapy and chemotherapy	14/68 (20.6)
Pseudo-adjuvant	10/45 (22.2)
Chemotherapy	5/10 (50.0)
Radiotherapy	4/10 (40.0)
Radiotherapy and chemotherapy	1/10 (10.0)
Surgical approach
Thoracotomy	61 (40.4)
Sternotomy	65 (43.0)
Clamshell	6 (4.0)
Hemi-clamshell	16 (10.6)
Video-assisted thoracic surgery	3 (2.0)
Type of pleural surgery
Extrapleural peumonectomy	40 (26.5)
Local pleurectomy	88 (15.2)
Total pleurectomy	23 (58.3)
Invasion
Lung	91 (65.9)
Pericardium	76 (53.9)
Pleura
Parietalis	40 (28.2)
Visceralis	6 (4.2)
Diaphragmatic	11 (7.7)
Parietal/visceral/diaphragmatic	67 (47.2)
Diaphragm muscle	39 (27.7)
Superior vena cava	10 (7.1)
Thoracic wall	9 (6.4)
Phrenic nerve	33 (23.4)
Adherence
Lung	68 (47.6)
Pericardium	56 (39.2)
Diaphragmatic musculature	41 (28.7)
Aorta	8 (5.6)
Great vessels other than aorta	12 (8.4)
Residual tumour
R0	116 (77.3)
R1	17 (11.3)
R2	17 (11.3)
Recurrencea	115 (100)
No	56 (48.7)
Yes	59 (51.3)
Recurrence type	59 (100)
Local	15/59 (25.4)
Regional	30/59 (50.8)
Distant	9/59 (15.3)
Regional and distant	5/59 (8.5)

Recurrences only after R0 resection were included in the analysis.

The mean number of resected pleural nodules was 7.7 [range 1–90]. Tumour invasion/adherence (Table 2).

Treatment of the diaphragm in patients with thymic epithelial tumours and pleural involvement

In non-EPP patients, there were 52 patients with metastasis of TETs to the diaphragm. Diaphragmatic resection was performed in 34 cases: 6 complete and 28 partial resections of the diaphragm (missing information on the extent of resection in 2 cases). There were 16 pleurectomies of the diaphragm without resection of the diaphragm.

Diaphragmatic plication was performed in 5 patients due to paralysis of the diaphragm as a result of oncologic phrenic nerve resection.

Multimodal therapy

Neoadjuvant therapy was administered in 67 patients (62.2%), pseudo-neoadjuvant therapy before surgery for recurrence in 15 patients (33.3%), adjuvant therapy in 68 patients (63.6%) and pseudo-adjuvant therapy after surgery for recurrence in 10 patients (22.2%), respectively (Table 2). Neo- and pseudo-neoadjuvant PAC ChT (planned protocol: cisplatin 50 mg/m2, doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2) was administered in 45 patients of the 76 (59.2%) patients who received ChT. For induction therapy (n = 65), the mean number of administered ChT cycles was 4.15 (median 4, range 2–8).

Radiotherapy was administered in a neoadjuvant (8 patients), pseudo-neoadjuvant (1 patient), adjuvant (63 patients) or pseudo-adjuvant (5 patients) setting. The administered mean radiation dose was 40.9 G [median 45 G, range 20–56 G] for neoadjuvant therapy and 50.3 G [median 50 G, range 24–60 G] for adjuvant therapy.

Recurrence after surgery with or without chemo- and radiotherapy for pleural disease of thymic epithelial tumours

The median time from primary surgery for a TET without involvement of the pleura to surgery for recurrence of disease to the pleura (first pleural surgery, Scenario 1) was 55.0 months.

The median time to recurrence after the first pleural surgery (second recurrence in Scenario 1 and first recurrence in Scenario 2, see Fig. 2) was 46 months. Recurrence after complete resection (R0) with or without ChT and/or RT for TETs with pleural involvement occurred in 59 patients (51.3%). See Table 2 for type of recurrence. The mean total number of recurrences after surgery for pleural disease was 1.47 (median 1, range 1–9).

Mortality during the first postoperative year

Two patients died during the first 30 days (perioperative mortality) after pleural surgery for TETs (patients with TC suffered from pneumonia and acute respiratory distress syndrome after EPP; patient with TC undergoing total pleurectomy died due to acute pulmonary embolism and prolonged air leak). One patient with B2 thymoma undergoing EPP died between 30 and 90 days postoperatively (cause of death not tumour related). Two more patients died between 90 days and 1 year. A patient with TC after EPP died related to progression of metastatic disease at 8 months, and another patient with B2 thymoma after EPP died from pneumonia resulting in acute respiratory distress syndrome 10 months after surgery.

Complications

There were documented data on 103 patients on complications or follow-up without complications. Of these, 59 patients had no surgical complications. Complications allocated to their respective type of surgery (Supplementary Material, Table S5).

Survival analysis

Outcome: overall survival, cause-specific survival, disease-free survival and freedom from recurrence

The number of events for survival analyses (n = 152) and analyses of FFR (n = 115) is indicated in Fig. 1 (number of events for the respective subgroup analyses is indicated in Figs 2 and 3). OS of the entire patient cohort at 1, 3, 5 and 10 years was 96.4%, 91.0%, 87.2% and 62.7%, respectively. Accordingly, DFS, CSS and FFR were calculated: DFS: 84.3%, 60.9%, 44.9% and 15.2%; CSS: 97.8%, 94.9%, 92.3% and 79.7%; FFR (n = 115) at 1, 3, 5 and 10 years was 83.1%, 57.9%, 43.0% and 22.2%, respectively (Fig. 3).

Figure 3

Survival analysis: entire patient cohort. Overall survival (A), disease-free survival (B), cause-specific survival (C) and freedom from recurrence (D).

Analysis of OS at 3, 5 and 10 years revealed statistically significant differences between primary pleural surgery and surgery for pleural recurrence (P = 0.028, P = 0.023, P = 0.027, respectively). Comparably, the analysis of OS at 3, 5 and 10 years revealed statistically significant differences between complete and incomplete resections: R0 vs R1/R2 (P = 0.032, P = 0.003, P = 0.001, respectively). While there were no statistically significant differences in FFR for the type of surgery: EPP vs TP vs LP, there were differences in OS [1-year: P = 0.010], DFS [3-year: P = 0.021 and 5-year: P = 0.037] and CSS [1-year: P = 0.012 and 3-year: P = 0.041]. The calculation of OS, DFS, CSS and FFR for thymomas versus TCs at 1, 3, 5 and 10 years revealed statistical significance for all analysis. Analysis of OS and CSS revealed a statistically significant survival advantage for patients with MG (10-year OS: P = 0.010; the 5 and 10-year CSS: P = 0.047 and P = 0.014, respectively; Fig. 4 and Supplementary Material, Table S6). In non-EPP patients with pericardial resection (n = 52), there was significantly worse survival at 10 years (OS at 1, 3, 5 and 10 years for pericardial resection yes (n = 52) vs no (n = 52): 98.0% vs 100.0% (P = 0.322), 93.3% vs 100.0% (P = 0.082), 86.7% vs 97.0% (P = 0.082), and 55.1% vs 87.2% (P = 0.010), respectively.

Figure 4

Survival analysis: comparison of primary pleural surgery and pleural surgery for recurrence: OS (A), FFR (B), type of surgery: EPP vs TP vs LP: OS (C), FFR (D), thymoma vs TC: OS (E), FFR (F), and completeness of resection: OS (G), FFR (H). EPP: extrapleural pneumonectomy; TP: total pleurectomy; LP: local pleurectomy; TC: thymic carcinoma.

Prognostic factors

Table 3 illustrates the analysis of predictors (univariable and multivariable analysis) using 3 end-points: OS, CSS and FFR.

Table 3

Univariable and multivariable analysis

	Univariable				Multivariable
			95% CI				95% CI
	HR	P-value	Lower	Upper	HR	P-value	Lower	Upper
Overall survival
Sex (male)	1.508	0.322	0.669	3.397	2.438	0.092	0.865	6.871
Age (continuous)	1.026	0.161	0.990	1.063	1.017	0.395	0.978	1.058
Myasthenia gravis (yes)	0.234	0.019	0.069	0.790	0.551	0.459	0.114	2.666
TC vs thymoma	6.315	0.000	2.652	15.040	6.506	0.002	1.956	21.646
Incomplete resection	3.916	0.001	1.727	8.882	6.696	0.003	1.944	23.060
Pleural surgery
Primary pleural surgery vs pleural surgery for recurrencea	4.392	0.017	1.302	14.813	1.493	0.603	0.330	6.757
Type of pleural surgery
EPP vs LP + TP	2.351	0.040	1.041	5.312	2.491	0.122	0.784	7.913
Preoperative therapy (yes)b	3.086	0.013	1.271	7.463	1.495	0.427	0.554	4.032
Postoperative therapy (yes)c	2.558	0.030	1.093	5.988	1.733	0.293	0.622	4.831
Cause-specific survival
Sex (male)	1.740	0.331	0.569	5.325	3.206	0.128	0.715	14.372
Age (continuous)	1.041	0.108	0.991	1.093	1.039	0.197	0.980	1.101
Myasthenia gravis (yes)	0.022	0.110	0.000	2.387	0.000	0.952	0.000	171.39
TC vs thymoma	12.129	0.000	3.867	38.044	13.144	0.001	2.726	63.370
Incomplete resection	2.004	0.255	0.606	6.628	2.053	0.387	0.402	10.487
Pleural surgery
Primary pleural surgery vs pleural surgery for recurrencea	2.198	0.239	0.593	8.130	1.213	0.836	0.194	7.576
Type of pleural surgery
EPP vs LP + TP	2.301	0.155	0.729	7.265	1.063	0.934	0.252	4.488
Preoperative therapy (yes)b	2.179	0.180	0.697	6.803	1.072	0.914	0.593	3.788
Postoperative therapy (yes)c	2.066	0.203	0.675	6.329	1.020	0.976	0.288	3.613
Freedom from recurrenced
Sex (male)	1.541	0.096	0.926	2.566	1.800	0.033	1.050	3.086
Age (continuous)	1.007	0.523	0.985	1.031	1.009	0.504	0.983	1.036
Myasthenia gravis (yes)	0.623	0.090	0.361	1.077	0.661	0.208	0.346	1.260
TC vs thymoma	2.748	0.006	1.330	5.676	2.442	0.027	1.106	5.388
Pleural surgery
Primary pleural surgery vs pleural surgery for recurrencea	1.138	0.629	0.002	1.919	1.131	0.676	0.633	2.024
Type of pleural Surgery
EPP vs LP + TP	1.491	0.165	0.849	2.618	1.467	0.241	0.773	2.784
Preoperative therapy (yes)b	0.852	0.542	0.508	1.427	0.577	0.068	0.319	1.042
Postoperative therapy (yes)c	0.750	0.270	0.450	1.250	0.849	0.578	0.476	1.513

TC: thymic carcinoma; LP: local pleurectomy; TP: total pleurectomy; EPP: extrapleural pneumonectomy.

Analysis of primary pleural surgery versus pleural surgery for recurrence.

Patients received (pseudo-)neoadjuvant therapy, including chemotherapy ± radiotherapy.

Patients received (pseudo-)adjuvant therapy, including chemotherapy ± radiotherapy.

Freedom from recurrence was analysed only for patients after R0 resection.

At univariable analysis, the presence of MG was beneficial at increasing OS [hazard ratio (HR) 0.234; P = 0.019], while TC, incomplete resection, TC vs thymomas, primary pleural surgery vs surgery for pleural recurrence, type of pleural surgery (EPP vs TP/LP), preoperative and postoperative therapy had a negative impact on OS.

TCs in comparison with thymomas at multivariable analysis had a negative impact on OS [HR 6.506; P = 0.002], CSS [HR 13.144; P = 0.001] and FFR [HR 2.442; P = 0.027], respectively. Further, incomplete resections predicted worse OS [HR 6.696; P = 0.003] and male sex predicted worse FFR [HR 1.800; P = 0.033] at multivariable analysis. In order to eliminate the potential strong bias of incomplete resection on other predictors, we also performed multivariable analysis only on patients after complete resection (R0): negative impact on OS male sex [HR 3.176; P = 0.025], TC [HR 3.988; P = 0.013], primary pleural surgery compared with surgery for pleural recurrence [HR 4.132; P = 0.040]; no effect was found for MG, age, type of surgery, preoperative or postoperative treatments. Analysis of multimodality therapy (all patients with [pseudo-]neo- and [pseudo-]adjuvant therapy combined: n = 126) vs surgery alone (n = 26) revealed no statistically significant differences.

Univariable analysis for the number of resected nodules (n = 122) with a cut-off value of 4 (median number of resected nodules) for dichotomizing groups revealed no statistically significant differences.

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.

SUPPLEMENTARY MATERIAL

Supplementary material is available at EJCTS online.

Conflict of interest: none declared.

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