Thymic epithelial tumors (TETs, or thymic malignancies) which comprise thymoma and thymic carcinoma, are rare cancers according to the definition of the RARECARE project, which is supported by the European Commission. Their annual incidence is approximately 0.15 cases in the United States [1] and 0.32 cases in the Netherlands [2] per 100,000 person-years. Thymic malignancies are extremely heterogeneous, with an exceedingly broad spectrum of morphological appearances and immunological abnormalities. Because thymomas are bioactive and have organotypic features that lead to autoimmune manifestations, whereas thymic carcinomas are not immunologically active and lack organotypic features, patients with thymic carcinoma usually have symptoms associated with tumor extension or metastasis.

Because of their rarity, the clinical characteristics and prognostic indicators in patients with thymic malignancies have not been well characterized [3]. Therefore, the International Thymic Malignancy Interest Group (ITMIG) was organized. Despite the paucity of evidence, this group has reached consensus agreements in support of some treatment modalities, having conducted some single-arm phase II studies and a few retrospective studies of small groups of treated patients with diverse backgrounds [4]. However, the optimal therapeutic strategy remains controversial. In previous studies, patients with thymoma and thymic carcinoma have basically received the same treatment. However, it has recently been suggested that the two types of tumors should be considered separate entities [5]. In addition, the ITMIG has proposed using the Masaoka–Koga staging system [6] and the 2004 World Health Organization (WHO) histological classification; both proposals have been accepted [7]. Thus, we believe it is necessary to review and clarify the nature and characteristics of these clinical entities in light of the proposed criteria. Furthermore, the National Comprehensive Cancer Network has updated its guidelines for the clinical management and treatment of thymic malignancies, despite their rarity [8].

The objective of the present study was to retrospectively clarify the clinical characteristics, prognosis, and prognostic indicators of patients with thymoma and thymic carcinoma according to the 2004 WHO classification [7] who had attended our institution over a 30-year period.

The present retrospective analysis examined the clinical outcomes of 187 patients with thymic malignancies. The clinical characteristics and outcomes in these unselected subjects were similar to those previously reported from large, multi-institutional series.

The present study is based on a relatively large database including all treated cases from the department of surgery, medical oncology, and radiation oncology. Additionally, we found that thymomas and thymic carcinomas exhibited a variety of clinical behaviors as reported in the past study. We believe that our single-institution data are reliable in that all cases were diagnosed by a pathologist who authored the thymic carcinoma section of the WHO classification book [7]. The lack of correlation between survival and WHO classification in thymomas may be attributable to the small numbers of patients studied, immunological abnormalities, or too few events because of the characteristically long survival. In our study, patients with thymomas had a similar prognosis to that previously reported, whereas both indolent and aggressive clinical courses occurred in patients with thymic carcinomas, including thymic squamous cell carcinoma. In neuroendocrine thymic tumors (or carcinomas) (NETT), the present small cohort of well-differentiated and poorly differentiated NETT showed similar clinical behavior to that reported in previous studies [21]. In the present study, no patients with NETT developed multiple endocrine neoplastic syndrome. As previously reported for NETT, the prognosis in this subgroup was poor [22]. The clinical entity of NETT is gradually becoming better known: the European Society of Medical Oncology has already published guidelines for NETT [23].

The key limitation of the present study was the small numbers of patients in each stage of thymoma or thymic carcinoma, resulting in a paucity of data compared with that obtained in randomized trials. However, this is a common limitation of studies of rare cancers. Second, we were unable to follow patients up, particularly young patients with thymoma or early stages of carcinoma whose tumors had been resected and who had no immunological abnormalities. Thus, there were more censored patients in the thymoma cohort than in the carcinoma cohort.

Large-scale databases are being established in Japan, the USA, and Europe as a first step toward conquering thymic malignancies. This approach appears to be a role model for studying rare diseases. Because these databases are drawn from surgical cases, they will provide little data on the clinical entities of thymic malignancies. Therefore, single-institution databases, such as that used in this study, are still meaningful because of the consistency of treatment and pathological evaluation; the latter would result in more reliable and reproducible diagnoses of thymic malignancies. Nevertheless unified, multi-institutional databases centered on the ITMIG are indispensable. Studies using such databases will clarify the clinical entities of and evolve treatment strategies for rare cancers such as thymic malignancies, which tend to fall behind in treatment development compared with common cancers. To minimize the biases from limited data concerning the reliability of diagnosis or treatment, every strategy must be carried out to overcome obstacles owing to the rarity of the cancer.

Plans are being made for prospective clinical trials on this rare cancer. However, the inevitably small sample size of future phase II studies will likely mean they have insufficient power to establish that findings are significant. In addition, as Weksler et al. have pointed out, a fundamental problem still remains in that the diagnosis of thymic malignancies, especially thymic carcinomas, is difficult [24]. In fact, in the WJTOG 4207L trial [25], 25% of patients diagnosed with thymic carcinoma by local hospitals were found to have incorrect diagnoses when centrally reviewed. Thus, central review of diagnoses is essential and the results of such studies must be interpreted with care. Investigators who plan clinical trials of thymic malignancies should incorporate central review by reliable pathologists who have experience with thymic malignancies. The importance of central review in clinical trials on rare cancers was demonstrated in the multi-institutional clinical trial of imatinib for c-Kit or platelet-derived growth factor receptor (PDGFR) positive sarcoma. In this trial, the concordance rate between the trial sites and central review for immunohistochemical staining was only 63.3% [26]. Also, the guidelines for gastrointestinal stromal tumors (GISTs) recommend taking care with the diagnosis of c-Kit-negative GIST, which requires consulting a specialist in GISTs who has experience in additional antibody staining or c-Kit or PDGFR gene analysis [27, 28].

In summary, the further clinical management of thymoma and thymic carcinoma should be investigated separately because of the clinical differences between thymoma and thymic carcinoma. Moreover, a detailed population-based series that highlights the many challenges clinicians face when treating thymic malignancies, for which little evidence-based data concerning therapy is available. Also, the advantages and disadvantages of a single-institutional database, especially on rare cancers, such as that used in this study, have been discussed. Although there have been advances in surgical techniques, radiation planning, systemic therapy, and supportive care for patients with thymic malignancies, more research and collaborative efforts are needed to produce evidence-based guidelines. International database projects and multidisciplinary meetings supported by the ITMIG will undoubtedly help fulfill this need.