Thymic tumors are the most common tumor arising in the thymus, which include both thymomas and thymic carcinomas. Thymic carcinomas account for less than 1% of thymic malignancies [1]. Thymomas grow very slowly and act like benign tumor. Even after thymomas had become invasive and invaded adjacent organ of thorax, hematogenous or lymphogenous metastasis is still very infrequent [2]. Pleural or pericardial dissemination is a common pattern of progression in this disease [3]. In contrast, thymic carcinomas have more aggressive natures. Thymic carcinomas invade surrounding structures frequently and have early metastasis to intrathoracic lymph nodes and distant organs. Thus, most patients with thymic carcinomas have advanced disease, resulting inferior survival compared with that of thymomas [4].

The pathologic classification of thymic carcinomas had been somewhat confused until World Health Organization (WHO) pathologic classification system was published in 2004, and thus, most of previous studies reporting treatment outcomes of thymic carcinoma had included well-differentiated thymic carcinoma (WHO type B3) and thymic carcinoma (WHO type C) together and regarded them as one disease category, thymic carcinoma. Given that histologic type of the carcinoma is one of the crucial determinants of prognosis, it is necessary to evaluate treatment outcomes of thymic carcinomas separately. Granting its rare incidence, clinical studies of true thymic carcinomas are very few. Therefore, we retrospectively reviewed the clinical and pathologic data of patients with thymic carcinomas to evaluate treatment outcomes and to find prognostic factors for survivals.

Between May 1988 and May 2009, 41 patients were diagnosed as thymic carcinoma with tissue confirmation in Seoul National University Hospital, Seoul, Korea. Of these, 40 patients were the subject of the present study excluding one patient with immediate follow-up loss after treatment. The present study was approved by Institutional Review Board.

The stage of thymic carcinoma was classified based on the Masaoka staging system for thymomas and histologic subtypes were determined by findings from microscopy and immunohistochemical staining according to 2004 WHO histologic classification. We only included patients with true thymic carcinoma (type C), excluding well-differentiated thymic carcinoma (type B3), small cell carcinoma, or carcinoid tumors.

All patients were followed up for at least 12 months or until the time of their death. The median follow-up of patients was 51.0 months ranging from 6.7 to 187.5 months. After completing treatment, treatment responses were evaluated through computed tomography (CT) scan and/or positron emission tomography scan with some intervals. Disappearance of all measurable lesions was defined as complete remission (CR) and tumor size decrease less than 30% of initial long diameter as partial remission (PR). Tumor size increase larger than 20% of initial long diameter or new lesions on imaging scans was defined as progressive disease (PD), and other condition that does not meet both PR and PD as stable disease (SD).

The radiotherapy-related toxicities were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) ver. 3.0.

Patient characteristics and histologic subtypes according to the stage are summarized in Table 1. The mean age of all patients was 58.3 years ranging from 19.8 to 80.8 years and male to female ratio was 23 to 17. Only 2 patients with routine check-up abnormality in chest CT scan had Eastern Cooperative Group performance status (ECOG PS) 0 and the other patients had ECOG PS 1 or 2. In the stage distribution, patients having stage III or IV were three-fourths of all patients. These patients were younger than those with stage I or II, but there was no statistical difference between each stages (p = 0.875). Squamous cell carcinoma (65.0%) was the most common histologic subtype followed by undifferentiated carcinoma (22.5%), lymphoepithelioma-like carcinoma (7.5%), and basaloid carcinoma (5.0%). Treatment strategies of patients are displayed in Table 2.

The status of resection is one of the widely accepted prognostic factors for survival [4-9]. Blumberg at al. [5] demonstrated that when surgical resection was incomplete, main pattern of failure was local recurrence. Huang et al. [4], in a similar context, reported in their study, in which 21 of 23 patients with thymic carcinoma underwent PORT, that incomplete resection was associated with local relapse and early distant metastasis. Patterns of failure in the present study is similar to the study of Huang et al. [4] in that local or regional recurrence had developed infrequently, but failure at distant sites exceeded three-fourths of all failures. In the present study, R0 resection was associated with DMFS (p = 0.040) but not LRC (p = 0.289). These results may be explained by the small number of event regarding locoregional failure that statistical power to detect the difference cannot be achieved.

Although surgical resection remains the mainstay in the treatment of thymic carcinoma, it is unclear which combination of treatment modalities is best for improving the survival of patients with advanced disease. Moreover, the role of PORT in thymic carcinomas is still controversial. In patients with R1 or R2 resection margin, PORT serves additional local control [10,11]. However, the high failure rate at distant sites raises a question regarding actual survival benefit of PORT in thymic carcinoma. In the largest retrospective study performed by Kondo and Monden [7], there was no difference of survival between surgery only and surgery plus PORT in patients with stage III and IV thymic carcinoma. Conversely, some authors argued routine use of PORT as a part of standard treatment for thymic carcinoma [12,13]. In the present study, the role of PORT cannot be assessed because most of the patients underwent PORT. However, it is of note that excellent locoregional control rate over 90% was achieved by PORT without acute grade 3 or 4 toxicities. The role of PORT, not only in patients with incomplete resection but also in complete resection, should further be investigated.

The IOGVs by thymic carcinomas is a poor prognostic factor for survival, often indicating unresectable disease. Blumberg et al. [5] showed that survival of patients was dependent on innominate vessel invasion, and Tseng et al. [3] also reported that invasion of the SVC, pulmonary vessels, or aorta was a significant predictor for poor prognosis. In the present study, DMFS and PFS were affected by IOGVs by thymic carcinomas as well: in 8 patients with IOGVs in this study, 6 had eventually developed distant metastases. However, in some selected patients with IOGVs by thymic carcinomas, surgical resection should be carefully considered as a part of treatment. Tseng et al. [3] suggested that if the tumor invading the SVC could be en-bloc resected, one could achieve long-term survival. In the present study, among 7 patients who underwent en-bloc resection of the SVC or innominate vein, early distant metastases within 4 months after surgery were found in 2 patients. Among the others, 3 patients had experienced distant metastasis at 12, 20, and 25 months of follow-up and 2 were disease-free at the last follow-up.

The prognosis of patients with locally advanced disease is dismal that to improve therapeutic outcomes, several studies addressed the potential role of neoadjuvant chemotherapy. In the present study, 6 patients underwent neoadjuvant chemotherapy and obtained clinical response of 33.3% which is similar to other studies [5,14]. However, Lucchi et al. [15] reported excellent response rate of thymic carcinoma to neoadjuvant chemotherapy based on cisplatin regimen. Moreover, a prospective phase II study enrolling patients with Masaoka stage III/IV thymic epithelial tumors adopted neoadjuvant doublet chemotherapy consisted of docetaxel and cisplatin. A promising result of PR 63% and SD 37% was shown, leading to complete resection of disease in 55.6% of patients [16]. In this regard, clinical trials evaluating the role of neoadjuvant chemotherapy in locally advanced thymic carcinomas should be conducted in a multi-institutional setting, considering the rarity of this disease.

The staging system of thymic carcinoma is a point of dispute. Although Masaoka staging system is being widely used, the prognostic value of this system has not been proved. Some authors [7] have insisted the usefulness of Masaoka staging system, but others [5,9] have not become convinced of its value. In the present study, the Masaoka stage was not a significant predictor for PFS in multivariate analysis (p = 0.322), but instead IOGVs or atrial invasion was more powerful factor predicting PFS. Especially, PFS of patients with unfavorable factors such as IOGVs and/or atrial invasion by thymic carcinomas did not show distinct difference from that of patients with stage IV. Given that IOGVs or atrial invasion by thymic carcinomas is associated with unresectability and early distant metastasis, it might be reasonable to regard such patients with unfavorable factors as stage IV. When those factors were regarded as stage IVA, the predictive value of modified Masaoka staging system was much improved compared with original system (p = 0.052 vs. p = 0.006 in univariate analysis; p = 0.697 vs. p = 0.046 in multivariate analysis). Furthermore, in the modified Masakoka system, a marginal OS difference was shown between stage I-III and IV (84.8% vs 53.0% at 5 years, p = 0.055).

There are some limitations of the present study. Besides of its retrospective nature, the heterogeneity of chemotherapeutic agents and schedules made it difficult to evaluate the appropriate efficacy of chemotherapy. Small number of patients, which may result in a few events, is another critical limitation of the present study.

In conclusion, complete resection followed by PORT provided remarkable local control without severe toxicity in stage II and favorable stage III thymic carcinoma. IOGVs and/or atrial invasion by thymic carcinomas were significant negative predictive factors for PFS. In patients with IOGVs and/or atrial invasion, multidisciplinary approach such as neoadjvuant chemotherapy followed by local treatment, surgery and/or radiotherapy, should be considered, given the high incidence of distant failure.