extragonadal germ cell tumors ( egcts ) comprise 2.3%-8.2% of germ cell tumors ( gcts ) ( 12 ) . egcts usually occur in the midline of the body , including the mediastinum , retroperitoneum , and pineal gland . over 90% of egct occurs in young males between the ages of 20 and 35 yr ( 3 ) . the anterior mediastinum is the most common primary site , which accounts for 50%-70% of all egct ( 2 ) . patients with a primary mediastinal gct are usually asymptomatic , or present with cardiopulmonary symptoms due to the compressive effect of a large mass ( 4 ) . primary mediastinal gcts are separated into seminomas and non - seminomatous gcts . in the mediastinum , teratomas ( 40%-60% ) are the most common gct followed by mixed gcts ( 13%-25% ) and seminomas ( 15%-20% ) ( 56 ) . needle biopsy is performed for mediastinal masses prior to chemotherapy , as a diagnostic clue for gct or to exclude other diagnoses such as a seminoma , lymphoma or another thymic malignancy . diagnostic elements can be detected on needle biopsy , but non - diagnostic components such as totally necrotic tissue or fibrovascular tissue is also obtained , in the patient who is clinically suspected of mixed gct . however , when a patient with an anterior mediastinal mass presents with elevation of serum beta - human chorionic gonadotrophin ( bhcg ) and/or alpha - fetoprotein ( afp ) , the diagnosis of a mixed gct could be rendered and subsequent platinum - based chemotherapy is started . during chemotherapy , subsequent surgical resection follows in cases with a residual mass or a chemoresistant component . in most cases , the residual histology of the tumor after chemotherapy is comprised of a mature and/or immature teratoma . since the first - line treatment for a mixed gct is platinum - based chemotherapy , a detailed histologic component of the pre - existing mixed gct prior to chemotherapy has not been thoroughly investigated . we aimed to evaluate the histologic components of primary mediastinal mixed gcts by retrospectively reviewing cases of patients with mediastinal mixed gcts . clinical features and histology of the pre - treatment biopsy and post - treatment surgical resection were reviewed . retrospectively , 221 patients were diagnosed with a primary mediastinal gct at samsung medical center from march 1994 to august 2014 ( a 21-yr period ) . fourteen patients received subsequent surgical resection after chemotherapy , and among them , 8 patients were clinically and pathologically diagnosed with a mixed gct and finally included for further evaluation . clinicopathologic variables including gender , age , level of serum afp and bhcg , radiologic finding , and overall survival were collected . slides of the initial needle biopsy before chemotherapy , and those of the surgically resected specimens after chemotherapy were reviewed by two pathologists . available gross photos of resected specimens after chemotherapy were analyzed with image j program to assess the proportion of vasculoconnective tissue . this study protocol has been reviewed and exempted of review by the institutional review board ( irb ) of samsung medical center ( irb no . retrospectively , 221 patients were diagnosed with a primary mediastinal gct at samsung medical center from march 1994 to august 2014 ( a 21-yr period ) . fourteen patients received subsequent surgical resection after chemotherapy , and among them , 8 patients were clinically and pathologically diagnosed with a mixed gct and finally included for further evaluation . clinicopathologic variables including gender , age , level of serum afp and bhcg , radiologic finding , and overall survival were collected . slides of the initial needle biopsy before chemotherapy , and those of the surgically resected specimens after chemotherapy were reviewed by two pathologists . available gross photos of resected specimens after chemotherapy were analyzed with image j program to assess the proportion of vasculoconnective tissue . this study protocol has been reviewed and exempted of review by the institutional review board ( irb ) of samsung medical center ( irb no . among the 221 patients , pathologic diagnoses of the primary mediastinal gct were recorded as a mature teratoma in 172 ( 77.5% ) , seminoma in 12 ( 5.4% ) , yolk sac tumor in 12 ( 5.4% ) , mixed gct in 11 ( 6.3% ) , immature teratoma in 8 ( 3.6% ) , and mature teratoma associated with somatic carcinoma in 6 ( 2.7% ) patients . all of the female patients underwent surgical resection , and most of them were diagnosed with a mature teratoma , except for one patient who had a mature teratoma associated with somatic carcinoma . meanwhile , the male patients had variable types of gcts , though a mature teratoma was the most common diagnosis . the distribution of diagnoses according to specimen type and histological type is summarized in table 1 . 8 of these 14 patients were diagnosed with a mixed gct based on clinical and pathologic information and selected for further evaluation , as shown in table 2 . in these 8 patients , pathologic diagnoses on biopsy before chemotherapy were recorded as 1 yolk sac tumor , 4 mixed gcts , 2 non - diagnostic biopsies containing vasculoconnective tissue and 1 immature teratoma . the specimens surgically resected after chemotherapy were determined to be mostly mature teratomas ( 5/8 , 62.5% ) and mature teratomas with a focal immature teratoma ( 3/8 , 37.5% ) . all 8 patients were male , with a mean age of 23.9 yr ( range 13 - 45 yr ) , and the average follow - up period was 25.7 months ( range 4.7 - 70.1 months ) . the mean serum afp was 1,740.9 ng / ml ( range 326.2 - 5,760.0 ng / ml ) . six patients demonstrated an elevated serum bhcg along with afp , ranging from 25 - 2,471.2 miu / ml with an average of 619.4 miu / ml . three patients died of the disease , overall survival was 7 months on average ( range 6.5 - 7.6 months ) , and 5 patients are alive and well so far , for an average of 36.9 months ( ranged 4.7 - 70.1 months ) . two patients were diagnosed with non - diagnostic vasculoconnective tissue on the initial biopsy . since both patients had elevated serum afp ( 2,353.8 ng / ml and 930 ng / ml ) , and bhcg ( 2,471.2 miu / ml and 123.5 miu / ml ) , under a clinical diagnosis of mixed gct , they received 4 and 2 cycles of chemotherapy , respectively . the clinicopathologic profiles of these patients are summarized in table 3 . grossly , all patients exhibited large , well - circumscribed masses with multifocal hemorrhages and cystic changes in the cut surface ( fig . 1 ) . on microscopic examination , all 8 patients had obvious residual teratomatous components . when the pre - chemotherapy needle biopsies of 5 patients were reviewed retrospectively , a vasculoconnective component was observed in 4 of the 5 patients who had a vasculoconnective component in the resected specimen ( fig . 3a , e , g , and i ) . in 2 of the 5 resected specimens , vasculoconnective tissue intermingled with mature teratoma accounted for average 66.3% ( range 57.6%-71.5% ) of largest cut surface of the resected mediastinal mass . in the current study , we retrospectively reviewed paired needle biopsies and surgical resection specimens of primary mediastinal gcts before and after chemotherapy in 8 patients . interestingly , 5 of 8 patients showed predominant vasculoconnective components intermingled with mature teratoma in the resected specimens . interestingly , two cases in the present study showed frank cellular atypia in the vasculoconnective component , but it is different from previously described sarcomatous elements of gcts . according to malagon et al . ( 7 ) , sarcomatous component within a gct is characterized by expansile growth and infiltration into the peripheral surrounding tissue , and morphological and immunohistochemical features should demonstrate an obvious distinct type of sarcoma . in our two cases , furthermore , cellular atypia was not correlated with patient prognosis in the current study , in contrast to the poor prognosis of patients with a sarcomatous component in the study of malagon et al . although there has not been focused research on the vasculoconnective component of mediastinal gcts , several reports of mature and/or immature teratomas accompanied by hemangiomatous elements have been reported in ovarian gcts ( 8910 ) . since malignancies with neural components , such as glioblastomas and immature teratomas , have been association with vascular proliferation ( 11 ) , it has been suggested that the neural component of mature teratomas induces vascular proliferation ( 10 ) . however , in the current study , a neural component was not observed in the 5 resected specimens containing a vasculoconnective component . ironically , 3 of the 8 resected specimens without a vasculoconnective component had mature glial tissue in mature teratoma . this discordance could be due to the gender inequality between ovarian gct and mediastinal gct , and also may be resulted from limitation of the sample size of the current study . clinically , 8 patients in the current study had features of growing teratoma syndrome ( gts ) , which is characterized by the following features : tumor size might be not changed or may even increase during or after chemotherapy , though serum tumor markers are normalized , and surgically resected tumor exclusively shows a mature teratomatous component ( 12 ) . in such cases , surgical resection rather than chemotherapy is the treatment of choice , to avoid the cardiopulmonary deterioration of patients ( 1314 ) . in a prior study of primary mediastinal gts , all patients were young males , had variable prognosis , and demonstrated elevated serum afp ( 131516171819202122 ) . in a study by kesler et al . ( 21 ) , 5 out of 188 primary mediastinal nsgct patients had primary mediastinal gts . however , the angiosarcoma components have not been described clearly , and it is unclear whether it was a true discrete sarcomatous component or more similar to the vasculoconnective component in the present study . thus far , only two cases of vascular elements in mediastinal mixed gcts have been reported ( 2324 ) . ( 24 ) described a mediastinal mixed gct in a 14-yr - old boy , which was predominantly composed of vasculoconnective elements mimicking a hemangioma and a mature teratoma in the resected specimen after chemotherapy . however , nuti et al . ( 23 ) reported another case of a primary mediastinal mixed gct in a 37-yr - old male , and over 90% of the tumor was composed of vasculoconnective elements . in that study , the patient underwent surgical resection without prior chemotherapy , because the initial needle biopsy revealed only vasculoconnective tissue , which is suggestive of a hemangioma . even though there were no comments regarding the patient 's serum afp , it is suspected that the serum afp would have been elevated , because the resected specimen harbored a yolk sac tumor component together with a large amount of vasculoconnective tissue and a mature teratoma . recently , we encountered a mediastinal mixed gct in a 19-yr - old male , which is similar to the case of nuti et al . he was initially diagnosed with a hemangioma from needle biopsy of the anterior mediastinal mass , and underwent surgical resection without further work up or chemotherapy . the resected specimen was composed of a predominantly mature teratoma and hemangioma - like vasculoconnective tissue , with a focal yolk sac tumor , which was consistent with mixed gct ( fig . the serum afp level immediately after surgical resection was elevated up to 205.5 ng / ml . in the current study , we postulated that the vasculoconnective component in previous studies ( 2324 ) and the current study would be the intrinsic component of primary mediastinal mixed gct . these vasculoconnective components are different from sarcomatous components , because they are intermingled with residual teratoma , rather than forming a mass - like lesion or infiltrate into the surrounding tissue . furthermore , histology of the vasculoconnective component was insufficient for diagnosis of angiosarcoma , though a variable degree of cellular atypia was found in two patients . however , the atypia of the vasculoconnective component seemed to be unrelated to the patient 's prognosis and might be on the spectrum of chemotherapy - induced changes , though survival analysis was not feasible due to the small number of patients and short follow - up period of the current study . together with our recent case described above and previous studies ( 212324 ) , it is suspected that the vasculoconnective component may exist in mediastinal mixed gcts as an intrinsic component rather than a postchemotherapy - related change . when vasculoconnective tissue without a notable gct component is encountered in the biopsy of a mediastinal mass in a young male patient , it tends to be regarded as a mistargeted specimen , overlooked as a non - diagnostic element , or misdiagnosed as another lesion such as a vascular neoplasm . however , further work up including examination of serum afp and bhcg levels should be performed to exclude the possibility of an underlying mixed gct considering vasculoconnective tissue occupies over 50% of mediastinal mass in current study . also , the risk of development of gts should be considered when establishing a treatment plan in patients with mediastinal mixed gcts harboring a vasculoconnective component . extended prospective studies with larger cohorts are required to further evaluate the clinical implications of the vasculoconnective components of mediastinal mixed gcts .
we aimed to evaluate the histologic components of primary mediastinal mixed germ cell tumors . 
 a total of 221 patients diagnosed with a mediastinal germ cell tumor ( gct ) were retrospectively reviewed . among them , 14 patients underwent surgical resection after chemotherapy and 8 patients were diagnosed with mixed gct , who were then selected for further evaluation . 
 clinical chart review and histologic review of biopsy and surgical specimens of 8 patients were performed . 
 all 8 patients were young males and showed a mature teratoma or a mature teratoma with a focal immature teratoma in the resected specimens . 
 serum alpha - feto protein was variably elevated . 
 seven patients experienced an increase in tumor size after the chemotherapy . in 5 patients , a variable amount of vasculoconnective tissue 
 was found along with the mature teratoma occupying average 66.3% of resected mass , and 3 of them showed an identical vasculoconnective component on biopsy before chemotherapy . 
 we suggest that vasculoconnective tissue might be the intrinsic component of primary mediastinal mixed gct . 
 when vasculoconnective tissue is obtained on small biopsy of an anterior mediastinal mass of a young male , the possibility of underlying mixed gct should be considered and further clinical work up should be performed.graphical abstract