Stage-related outcome for thymic epithelial tumours

Background Thymic epithelial tumours (TETs) are characterized by a wide variety of biological behaviors. Radical resection and stage are strong prognostic factors. Aim of this study is to review our Single Center Experience. Methods One hundred and seventy-seven patients observed in the period from January 2000 to December 2016 were included in the study. Data regarding clinicopathologic features, treatment, and survival were collected. Stage-related clinical standpoints and therapeutic options were also evaluated. Results Non-surgical treatment was primarily performed in 15 (8.47%), unresectable disease was intraoperatively found in 12 cases (7.4%). The analysis of 150 patients undergoing curative surgery revealed 70 stage I TET (46.66%), 49 stage II (32.66%), 19 stage III (12.66%), 6 stage IVa (4%) and 6 stage IVb (4%) at the first hospital admission. Histology identified 12 A thymoma (8%), 38 AB (25.33%), 24 B1 (16%), 50 B2 (33.33%), 19 B3 (12.66%) and 7 carcinomas (4.66%). The mean follow up time was 84.14 months (sd = 61.68 months). Disease relapse occurred in 13 patients (8.78%) at a mean period of 78.85 months (sd = 60.87 months) after surgery. Exitus due to thymoma happened in 6 cases (4.05%) after a mean survival of 56.02 months (sd = 25.17 months). The 5-year overall survival rate was 0.94 (95%CI 0.88–0.97) and the 5-year disease-free survival rate was 0.90 (95%CI 0.83–0.94). The 5-year overall survival rates were 96.1% (95% CI, 89.9–98.5%) for the early stages and 87.4% (95% CI, 65.6–95.8%) for the advanced stages (p = 0.670). The 5-year disease-free survival rates resulted being 98.8% (95% CI, 92.3–99.8%) for the early stages and 59.8% (95% CI, 37.8–76.2%) for the advanced stages (p < 0.001). Conclusions Advanced stage TETs are characterized by higher mortality and recurrence rates. Although technically demanding, surgery, as part of multimodality therapy, could prolong survival. Iterative surgical treatment of recurrences is a viable option for selected patients. Trial registration The study was approved by the Institutional Review Board of Perugia and Terni University Hospitals [Code T1003] and was retrospectively registered.


Background
Thymic epithelial tumours (TETs) are the most common epithelial neoplasms of the anterior mediastinum whose natural history proves a wide variety of biological behaviors [1][2][3]. Even if they are usually characterized by an indolent course, in some cases TETs can show an aggressive disease trend. [4][5][6]. The large number of scientific contributions did not thoroughly lead to complete agreement so far; this circumstance is mainly due to the retrospective study designs and the relatively low incidence of these particular tumours [7].
We reviewed our experience with TETs, in order to highlight biological and clinical aspects possibly concerning survival, disease progression and treatment.

Methods
The experience with thymoma and thymic carcinoma of the Thoracic Surgery Unit of Perugia and Terni, in the period from January 2000 to December 2016, is retrospectively reviewed. Every patient's workup included computed tomography scanning (CT), electromyogram (EMG), anti-acetylcholine receptor antibodies (ARAb) assay, complete blood count. Bronchoscopy and 18-fluorodeoxiglucose positron emission tomography (18-FDG PET/CT) were performed in particular cases. Magnetic Resonance Imaging (MRI) was occasionally indicated. Suspect diagnosis was usually achieved by imaging and clinical features but 56 cases (31.63%) with non-evocative clinical patterns have been submitted to biopsy as a first invasive procedure. Diagnostic procedures to assess clinical staging, tumour histology and myasthenia gravis occurrence in patients with clinically suspected thymic epithelial tumours are listed in Table 1.
All inpatient records were evaluated as well as the follow up data based on hospital registers, referring physician's reports and family doctor's databases. All patients have been then examined and asked about general condition, tumor-related symptoms and perceived quality of life.
Patients were stratified in subgroups according to the stage (Masaoka I, II, III, IVa and IVb) in order to specifically emphasize stage-related clinical standpoints and the more appropriate therapeutic options.

Statistical analysis
The data are expressed as mean and standard deviation (sd) unless otherwise stated. Survival and time to recurrence were calculated since the day of the primary treatment. Mean follow-up time was calculated using the reverse Kaplan-Meier method. Overall survival and disease-free survival were estimated by the Kaplan-Meier method. Survival curves were compared using the log-rank test. All estimates were achieved using STATA 14.2 (Stata Corp Ltd., College Station, TX, USA).
Two patients were lost during follow up. The mean follow up time was 84.14 months (sd = 61.68 months). Disease relapse occurred in 13 patients (8.78%) at a mean period of 78.85 months (sd = 60.87 months) after surgery.

Recurrences
Recurrent TETs were 13: one in the primary site, 4 pleural-pericardial and 8 distant metastases (5 in the lung, 3 in the nodes). They appeared in one B1 thymoma, 6 B2 and 3 B3 and 3 carcinomas. Seven patients (53.84%) underwent one or more surgical procedures for the treatment of pleural, pericardial, pulmonary or nodal recurrences. Two of them (28.57%) died for TET progression, three (42.85%) are alive with stable disease and two (28.57%) are alive with no evidence of disease. Six patients (43.15%) received chemo-radiation therapy. Four of them (66.66%) died for TET progression and two (33.33%) are alive with stable disease.

Thymoma in cysts
Thymoma in cysts (2 cases) could be a tricky situation. In some cases the diagnosis of thymoma is unexpected after simple thymic cyst removal (no cases in our series). Surgery has to face a really thin cystic wall that needs to be respected. Thymoma in cysts is really rare and cyst-related risk of malignancy is not assessable out of our experience.

Stage I and II
This is the least aggressive pattern that TETs can show: mainly asymptomatic often diagnosed by chance [1,10]. Surgery (thymus gland removal) is the standpoint therapy and proved to be effective and safe [11,12]. If the resection is radical, the complete tumor excision leads to a bright prognosis [10,11]. In Masaoka stage I and II thymoma, surgery is actually a potential method of cure by itself: adjuvant radiotherapy is not of evident help following appropriate surgical resection [1,10]. Sternotomy approach remains the most common technique to be employed but, along with thoracotomy, there are several series describing the minimally invasive surgery as a valuable therapeutic option in the removal of a mediastinal mass suggesting a low-stage thymoma [13][14][15]. The recurrence seems to be frequently related to spillage, malignant residue after suboptimal surgery or possible multifocal malignancy within the mediastinal fat [1,5,12,16]. A careful surgery can safely remove all the neoplastic tissue but must be respectful of the primary lesion integrity [17]. Open surgery represents the standard approach; however, in the last decades, minimally invasive techniques have gained popularity [1,2]. Encouraging results have been reported in large series from high volume centers [13,15,17]. Tumor manipulation during minimally invasive procedures can result in additional risk of drop metastasis that would forward the stage from I-II to IVa with a significant worsening of prognosis [16][17][18]. Therefore, the indication to such operations needs to be balanced against its hazards [15,17,18]. Moreover, the oncological potentials of the robot-enhanced thoracoscopic resections have to be validated by long-term trials [13,19].
Stage I and stage II lesions cannot be separately discussed [1,11]. Preoperative imaging plays an important role not only to distinguish early from advanced stages but it can also be useful to plan the optimal surgical approach for TET [20,21].
Finally, even if a small, round well-incapsulated lesion can hopefully depict a benign tumor, TETs have always to be considered malignant due to their potentials and natural history [3,6].

Stage III
The tumor infiltration of a proximal organ varies largely from minimal lung involvement to extended compromise of great vessels [2,12,20]. The spectrum of possible therapy is dependent on the tumor resectability [22]. Preoperative imaging plays an important role, but the sensibility of the commonly employed technologies (CT, MRI and PET-CT) does not guarantee a complete tumor removal earlier than the time of surgery [20,22]. Although sternotomy is the ordinary approach, it is not the only access available: thoracotomy and other incisions have been successfully employed, but no kind of minimally invasive surgery has a reasonable indication [17]. The difficult preoperative assessment for complete resectability, probably represents the primary pitfall and concurs in producing the substantial rate of subtotal removal [21,23]. This fact underlines that the surgical accuracy is the unique non-biological key point to deal with this disease [1,11,12]. Although the complete resection is the aim to achieve, it remains a macroscopic presumption after any kind of surgery. Considering the potential microscopic spread and the following relapse, minimal tumor remnants after surgery for a stage III thymoma have been reported in different series [24,25]. For this reason, adjuvant treatment can appropriately be indicated [1,2,24].
Preoperative treatment can be performed in order to down-stage the disease and make the resection feasible [22]. Whereas radiotherapy has a valuable post-operative recommendation, neoadjuvant treatment is mainly based on chemotherapy, with multiple therapeutic schemes that can be employed with satisfying results [22,26]. We agree with those who support the theory that, among stage III, there are several different conditions regarding the compromised organs by direct infiltration from the tumour [1,2,27]. According to the new TNM/IASLC staging system, indeed, stage III tumours have been divided in stage IIIa and stage IIIb tumours, in order to better identify patients suitable for surgery. Heart and great vessels, as long as trachea and esophagus involvement, should be considered a more advanced tumor compared to those cases with lung, pericardium, chest wall, phrenic nerve or SVC infiltration [1,27].

Stage IV
Surgery is part of a multimodality treatment and timing for surgery should be indicated in a dedicated multidisciplinary setting where inappropriate therapeutic decisions would be minimized [1,2]. Surgery can manage both primary lesions spreading to pleural space or recurrent metastatic pleuro-pericardial seedings [28]. The aim of surgery does not change at all: debulking or cytoreduction have minimal rationale; surgery has a role in case of possible complete removal [24]. Once decided to submit the patient to surgery for stage IV thymoma, diagnostic and staging information must satisfy technical conditions for a possible macroscopically complete resection; if it is absolutely not achievable, any surgical plan should be abandoned [25,28]. Redo-surgery is not self-limiting and cases of indolent disease can develop multiple metachronous metastasis that can undergo surgery time by time [16,29].
Surgery is represented by a large number of procedures that can be advocated [24,28]. The entire removal of each spot of malignancy can rise from minimal lung resections for visceral pleura seedings to wide pleurectomy and pleuropnemonectomy for extensive disease [1,24].
Extended resections for stage III and IV thymoma can be technically demanding and the high morbidity and possible mortality must be taken into account [24,28]. The balance between risk and effectiveness is indeed crucial [24,25].

Off stage
There are possible situations in which Masaoka staging, histology and ordinary preoperative evaluations are of limited importance. Life-threatening conditions are really rare; however, in these circumstances such as spontaneous rupture, bleeding and possible other emergency conditions, the treatment can be surgical, but sometimes impossibly radical, or decided at the time of surgery for insufficient diagnostic work up [30]. In case of ectopic thymoma or orthotopic tumor grown outside the mediastinum, the Masaoka stage can be even misleading; the principles of surgery for thymoma find in the complete removal of the thymus gland and the surrounding fat the basic procedure to be extended to the neighboring organs in case of infiltration [2]. For ectopic thymoma or orthotopic tumor grown outside the mediastinum, the treatment can be accomplished without total thymectomy [31]. We suggest to look for R0 instead of making a total thymectomy if the tumor is far detached from the thymus gland and to follow the patient up for a supposed enhanced risk of new primary thymic malignancies [31,32].

Thymoma and myasthenia gravis
Our series suggests that MG incidence is not associated to stage. Myasthenic patients presented a trend to a higher 5 year DFS compared to non-myasthenic ones, even if this parameter does not reach a statistical significance. Probably, this trend can be explained considering that the presence of the syndrome can lead to the diagnosis of an otherwise asymptomatic early-stage thymoma [1,2].

Conclusions
Advanced stage TETs are characterized by higher mortality and recurrence rates. Although technically demanding, surgery, as part of multimodality therapy, could prolong survival. Iterative surgical treatment of recurrences is a viable option for selected patients.