Thymic tumors are relatively rare neoplasms arising from the epithelial thymic cells. They show a significant histological heterogeneity and clinical behavior ranging from an indolent non-invasive attitude to a highly infiltrative and metastasizing one. Prognosis is affected by the Masaoka-Koga staging, the World Health Organization (WHO) histological classification, completeness of resection, the diameter of the lesion and the presence of vascular invasion (1-8).
Complete surgical resection, remains the gold standard for cure at any stage. Chemotherapy (CH) is usually administered as an induction before surgery or as definitive treatment when the tumor is deemed unresectable. Radiotherapy (RT) is indicated in selected patients, particularly as adjuvant treatment. A multimodality approach is beneficial for a selected group of patients with invasive tumors (9-11).
According to the Masaoka-Koga staging system, thymic tumors are classified as stage IIA when they show microscopic trans-capsular invasion and IIB in case of macroscopic invasion of the surrounding mediastinal fat tissue or gross adherence to the mediastinal pleura (12,13). Although complete resection can be easily achieved at this stage, local recurrence and metastatic spread may be observed, particularly in case of B2, B3 and thymic carcinoma (6,7,14,15). For this reason, some authors suggest the administration of adjuvant RT to improve local control (16-20). However, the clinical benefit of adjuvant RT in this setting still remains controversial; in fact, not only local recurrence, but also distant metastatic spread may occur. We have previously described our initial experience with adjuvant CH-RT for stage III tumors to prevent local recurrence and distant spreading (9,21-25). Up to 1988 we have treated stage II thymic tumors with surgical resection only; post-operative RT was rarely administered and without standardized indications. We observed a relatively high number of recurrences (33%) and most of them were outside the mediastinum (21,23); for this reason, since 1989 we administer adjuvant CH-RT for stage II—WHO type B thymoma and thymic carcinoma. The aim of this study is to assess the potential benefit of this approach.
Eighty-eight patients prospectively entered the database between 1989 and 2013. The study was approved by the ethical committee of our institution (prot. 116/10). All tumors were staged according to the Masaoka-Koga system. Histology was assessed according to the WHO histological classification (25).
Forty-seven patients were male (53.4%); the mean age was 57±16 years (range, 22–87 years) and 32 (36%) were affected by Myasthenia Gravis; one patient had pemphigus and one had hypogammaglobulinemia. Eighteen patients (20.4%) referred tumor-related symptoms as chest pain and tightness; 22 patients (25%) presented comorbidities including arrhythmias (6%), diabetes (9%) and chronic obstructive pulmonary disease (10%). Three patients (3.4%) had a previous history of cancer (breast, prostate and leukemia). Histology and stage are reported in Table 1. The median follow-up was 107±83 months, ranging from 8 to 280 months. No patient was lost to follow-up.
According to our protocol, patients with stage IIA tumors and B2, B3 or C histology received adjuvant CH-RT; in case of B1 thymoma adjuvant therapy was administered only for lesions with a diameter >5 cm. In case of stage IIB, all patients with B or C histology underwent adjuvant treatment. CH was administered with three cycles of PAC (cisplatinum 50 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide 500 mg/m2); mediastinal RT was administered at a dose between 45 and 55 Gy.
Descriptive statistics were reported as means with ranges and standard deviation for continuous variables and as frequencies and proportions for categorical variables. Disease-free survival (DFS) was defined as the time from surgery to recurrence. Overall survival (OS) was defined as the time from surgery to death by any cause. The Kaplan-Meier method was used to estimate DFS and OS. Results were considered significant for a P value less than 0.05. The statistical analysis was performed with SPSS Statistics 17.0 (IBM®-ITALIA).
Complete resection was achieved in all patients and no perioperative mortality was observed. Surgical data are reported in Table 2. Twenty-six patients (29.5%) had type A or AB thymoma and they did not receive any adjuvant treatment. Fifty-four patients (61%) received post-operative CH-RT, including one B1/IIA patient (tumor diameter >5 cm) (Table 2); 2 (2%) received adjuvant CH only and 3 (3%) postoperative RT only. Two patients with B2 histology refused any adjuvant treatment. One patient with B3 histology did not receive any adjuvant treatment due to her advanced age (87 years).
Hematologic toxicity was observed in 5 patients with mild temporary leukopenia; non-hematologic toxicity included stomatitis, alopecia, nausea and vomiting. There were no infectious complications. Post RT esophagitis was observed in one patient.
OS and DFS are reported in Figures 1,2. Recurrence was observed in 5 patients (5.7%) 105±83 months (range, 8–280 months) after surgery (Table 1). One patient had mediastinal recurrence and he was treated with CH; two patients had extrathoracic recurrence (retroperitoneal and liver); two showed intrathoracic recurrence (pleural after thoracoscopic thymectomy and lung), both of them underwent re-resection.
During follow-up 13 patients died (15%): 4 of them (4.5%) for disease progression; the others died for non-thymoma related complications [one cardiac failure, two acute myocardial infarction (AMI), one herpetic encephalitis, one metastatic melanoma, four “senectus”]. We did not observe any statistically significant difference in terms of OS between stage IIA and IIB after 1989 (P=0.1).
The Masaoka-Koga staging system is based on the detection of microscopic or macroscopic invasion into the capsula of the tumor and adjacent structures and on the presence of metastatic disease. Although for stage II tumors complete resection is always feasible, incomplete resection has been reported and local or distant recurrence may occur. Furthermore, the literature supports the assumption that thymic tumors show a morphologic continuum: some of them may progress from B1 to B3 and even to thymic carcinoma (5,22). These data are sustained also by the finding of different histologies in the same specimen.
In a previous study, in a population of 27 stage IIB patients we observed a relatively high recurrence rate (33%) in the subgroup IIB (21); most of those recurrences were outside the mediastinum (pleura, lung, liver, bone), confirming that even at this stage thymoma can recur and metastasize. For this reason, at that time we postulated that also stage II thymic tumors might benefit from adjuvant treatment. Thus, RT and CH were administered with the aim of reducing local and distant recurrence respectively. The results of our study show that the recurrence rate is decreased and DFS seems improved after adjuvant treatment, when compared to our previous data (23) and the international literature (also when postoperative RT only is administered) (Table 3).
Bae showed a recurrence rate of 11.4% (13 out of 114 patients) (2); Detterbeck reported an average recurrence rate of 11% for stage II (31). Both studies included stage II patients and only RT was administered after surgery. Other studies are much more difficult to interpret since a thorough analysis is not always reported: in other words, it is not always clear how many tumors are at stage IIA or IIB as well as the distribution of histology, particularly the incidence of thymic carcinoma; also the exact number of patients at this stage receiving adjuvant RT is difficult to extrapolate. Furthermore, recurrence is not always well reported at this stage. In the present study the overall recurrence rate was 5.7% while it was 33% in our previous series with surgery alone. Recurrence was observed only in type C (1), B3 (2) and B2 (2) (Table 1). This finding supports that adjuvant CH-RT might contribute to reduce the recurrence rate also at this stage and particularly for more aggressive histological subtypes. It also confirms that the WHO classification has a prognostic impact on this variable: as a matter of fact recurrence occurs only in type B2-3 and thymic carcinoma patients. In the present series OS is influenced by other causes than tumor (cardiac ischemia or failure, encephalitis, second malignancies, older age) and only 4 patients (4.5%) died for disease progression. The consistency of this data is supported by the long follow-up (107±83 months).
We have observed 9 (10.2%) metachronous extra-thymic malignancies (thyroid, breast, liver, lung, skin, prostate and leukemia); they were associated with B2 and B3 histology. This finding supports the hypothesis that more aggressive histological subtypes are associated with a higher risk of developing other malignancies and poorer survival (32). The potential role of adjuvant treatment in the development of other malignancies deserves further investigation.
Thymic carcinoma is relatively rare (15% to 20% of all thymic tumors) (1,3) and it shows a spectrum of 11 subtypes (25). In most of the cases it behaves aggressively and it is discovered at an advanced stage, with a lower survival rate (30–60% at 5 years; 17% if unresectable) (33). It is now considered as a separate entity. In our early stage series, we observed only 7 (8%) patients with thymic carcinoma. Considering this group separately, only 1 (14.2%) patient had recurrence; this incidence is low when compared with the current literature (7,27,30) (Table 3). On the other side, excluding type C, the recurrence rate (4/81) was further reduced respect to our previous series not including this histological subtype (4.9% vs. 33%). These results contribute to support a multidisciplinary approach also at this stage. Although the 2015 ESMO guidelines support the administration of postoperative RT only (34), we believe that also CH should be added in this specific subset of patients since in the literature, and also in our previous experience, distant metastases have been observed and reported.
In conclusion, we confirm that A and AB thymoma show an excellent prognosis with no recurrence, whereas B and C tumors are usually more aggressive also at early stage; postoperative CH-RT might contribute to improve prognosis. Nonetheless, this study does not allow definitive conclusions due to the limitations related to the small number of patients, particularly those with thymic carcinoma; however, with all the limitations of this report, it should serve as “food for thought” for future investigations.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Ethical Statement: The study was approved by the Ethical Committee of the University of Rome Sapienza - Policlinico Umberto I (prot. 116/10). Written informed consent was obtained from the patient.
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