Mediastinal seminomas are difficult to depict because of their rarity. In this study, we investigated a relatively large number of patients with primary mediastinal seminomas. Seminomas are different from other common thoracic malignancies [8,9] in that neither smoking nor alcohol use is a high-risk factor for the disease. Indeed, 81.5% of the patients in our study were nonsmokers and 96.3% reported no history of alcohol use.
Seminomas mostly occur in men, usually young patients. In our study, the median age was 28 years, which is consistent with that in previous reports (28-34 years) [3,10]. There have been only a few case reports on female patients [2,6,10]. Our study included a woman aged 44 years with pericardial invasion. She underwent R0 resection and postoperative chemoradiotherapy and survived until the last follow-up (8.9 months) with pleural metastasis. Although data showed inferior PFS and DMFS, it is difficult to appropriately determine the relationship between sex and survival rates.
Seminomas usually show slow growth and have an invasive course, although the disease is often asymptomatic at onset. The absence of symptoms leads to disease diagnosis at a more advanced stage because most patients do not seek medical attention until symptom manifestation. The most common symptoms in our study are consistent with those observed in previous studies, with chest pain (14.3-44%), cough (14.3-38%), and dyspnea (14.3%-38%) being the top three symptoms[3,10,11]. During diagnosis, only 11.1% of the patients in our study were asymptomatic, which is almost equivalent to that reported in previous studies (6-40%)[3-5,10].
Due to their slow growth, most seminomas are bulky when diagnosed. The median maximum diameter of the primary tumor (9.9 cm) is consistent with previous findings (8-12 cm) [3,10,11]. The tumor may extend to the mediastinum, leading to compression of adjacent structures and invasion, especially into the great vessels in the mediastinum, such as the SVC and aorta. In our study, 37% of patients were found to have SVCS, which is consistent with the findings of previous reports (10-57%) [3,4,10,11]. However, there was no mention of invasion into the aorta in these previous studies, which might cause difficulties in R0 resection.
In this study, the perivascular station was the most common invasion site (100%), followed by the para-aortic station (70.4%) and subaortic station (51.9%). These results are similar to those of previous studies, which found that mediastinal seminomas are usually located in the anterior mediastinum and in front of the aorta [11].The other common invasion sites were the bilateral lower paratracheal station (40.7%,40.7%) and bilateral upper paratracheal station (40.7%, 40.7%).
The results regarding the IHC characteristics of patients varied. The positivity rate for PLAP was 70.7% in a previous study [12]. In our study, all 18 patients who underwent the PLAP test were PLAP-positive. The positivity rates of OCT3/4, SALL4, and CD117 were also high. This suggests that PLAP could be the most remarkable marker for mediastinal seminoma.
Previous studies have reported elevated β-hCG levels in 0-85.7% of patients with primary mediastinal seminoma [3-5,10]. In our study, 51.8% of patients showed increased β-hCG levels, which is similar to the findings of a previous study [11]. Such elevated levels might be attributed to tumor enlargement. Meanwhile, serum LDH was not a typical marker of the disease, which is consistent with previous results [3,11].
There is no established staging system for mediastinal seminomas, and the testicular seminoma staging system cannot be used either. However, mediastinal seminomas seem to share some homogeneous characteristics with thymic neoplasms. Both are prevascular tumors and occur in the anterior mediastinum, both are with rare lymph node metastasis and both are associated with a good prognosis. On the basis of these common aspects, we adopted the Masaoka staging system, which is widely used for thymic neoplasms, to evaluate the status of mediastinal seminomas [6,11]. We found that 88.9% of patients were diagnosed as having Masaoka stage III-IV disease. Lymph node metastasis and distant metastasis, on the other hand, are not as common as great vessel invasion. A previous study found that lymph node metastasis occurred in 2.6-38% of patients [10]. Although these findings indicate no significant differences in the prognosis of patients with different Masaoka stages, we found a trend that patients with stage I-II disease exhibited higher DMFS and PFS.
In the univariate analysis, patients with SVCS demonstrated better PFS, which contradicted our current notion that tumor invasion into the great vessels is a worse prognostic factor. Possible reasons are: first, the occurrence of SVCS symptoms led the patient to seek medical consultation, resulting in an accurate diagnosis; second, even though great vessel invasion makes R0 resection difficult, the disease is sensitive to chemoradiotherapy.
Various treatments for mediastinal seminoma aim for complete cure rather than just symptom relief. Generally, most patients undergo chemotherapy and radiotherapy and receive BEP, as do patients with testicular seminoma. R0 resection is difficult to perform because of tumor invasion into adjacent mediastinal structures, with only 12.5% of patients undergoing such procedure in previous studies [10]. In our study, 33.3% of patients underwent R0 resection, showing good prognosis postoperatively. The postoperative disease control rate was reported as 90-100% in Chinese patients [12]. However, these findings indicate that R0 resection might not be associated with survival in mediastinal seminoma, unlike in testicular seminoma, probably because of a favorable prognosis and sensitivity to chemoradiotherapy.
Similar to testicular seminoma, mediastinal seminoma also demonstrates a high sensitivity to chemotherapy and radiotherapy. In this study, 92.6% and 59.3% of patients received chemotherapy and radiotherapy, with response rates of 85.0% and 100%, respectively, compared to those (100% and 90%, respectively) reported previously [12]. Furthermore, response rates for surgery alone, radiation alone, and chemotherapy alone were reported as 90.0%, 80.0%, and 83.3%, respectively [12]. Thus, the disease is sensitive to all three traditional treatments. The other response rates reported were: surgery+radiation, 91.7%; surgery+chemoradiotherapy, 90.0%; chemoradiotherapy, 100%; and surgery+chemotherapy, 100%.12 Our study also used different modes of combined therapies, and all of them achieved favorable results.
Unlike routine chemotherapy regimens, radiation is delivered in different doses (25.2-56 Gy). In one study, the patients received 2 Gy × 30 fractions [11]. Comparing this finding with our finding revealed no significant difference in either survival or response rate, which may be due to high chemoradiosensitivities. Furthermore, a dose of 45 Gy might be a reasonable choice when considering the patient’s quality of life as well as reducing the toxicities in long term.
In this study, the toxicities were tolerable. Hair loss was the most common toxicity probably because of the use of VP-16. Due to the special location of this disease and the delivery of bleomycin, we monitored for radiation-induced pneumonitis (RP). Only five patients were diagnosed with grade 1 RP, and no severe RP was observed because of both the reasonable radiation dose and the utilization of modern radiation techniques. Although there have been no cardiac-related adverse events documented, a long-term follow-up for cardiac toxicities is necessary because the heart is one of the adjacent organs.
In 2015, our institution carried out a retrospective study to investigate the clinical characteristics and outcomes of patients with primary malignant mediastinal non-seminomatous germ-cell tumor (MMNSGCT). Compared with that study, our study achieved better OS (100% vs. 49.2%) and PFS (100% vs. 32.8%) [13]. The result of the comparison is also consistent with that of previous reports [3,14,15]. A series of small combined studies also compared the OS of the two different types of mediastinal germ-cell carcinoma. The studies showed that patients with seminomas achieved a better 5-year OS than those with nonseminomas (87.0%-100% vs. 36.7%-83.0%), although not all the studies showed statistical significance due to limited sample size.
In previous small-scale studies and case reports, the 5- and 10-year OS of patients with primary mediastinal seminomas ranged from 87% to 100% and from 75% to 100%, respectively[2-4,10,11,15]. One study also showed a 5-year LRFS of 82.1%. These findings are consistent with our findings. None of the patients in our study died of seminoma at the last follow-up. Despite the cumulative 10-year risk of testicular malignancy of 10.3% after a diagnosis of extragonadal germ-cell tumor[16], no study patient showed testicular invasion or metastasis at the last follow-up. Thus, the prognosis of patients with primary mediastinal seminoma was generally good. Local relapse and distant metastasis were low after treatment.
To our knowledge, this is the largest study focusing on mediastinal seminomas. We found an association between PFS, DMFS, and Masaoka stage. Most of the patients in this study underwent modern radiation methods and could represent modern real-world data. Our findings could provide a basis for future treatment delivery in patients with primary mediastinal seminomas.
The study has a few limitations. First, different treatment regimens comprising various therapeutic agents were used with no definite guidelines. Second, certain components of the IHC test were not possible in some samples because of the long investigation period and deterioration in storage conditions. Finally, we did not have enough time to evaluate late toxicities due to the limited follow-up period.