primary intracranial germ cell tumor ( gct ) is a rare subset of intracranial tumors . they are known to occur primarily in the 2nd and 3rd decades of life and arise from the midline structure , especially the pineal gland or suprasellar region due to aberrant migration during embryogenesis . although intracranial gct is known to show a high cure rate because of its sensitivity to radiation and chemotherapy , there are several points to be considered , especially in unusual cases . here , we report two unusual cases of intracranial germinoma ( 1 germinoma and 1 chriocarcinoma ) . induction chemotherapy with 4 cycles of ifosfamide , carboplatin and etoposide combination chemotherapy showed a remarkable response without complications in both patients . a 16-year - old male without a past medical history presented to our hospital due to headache and diplopia . an initial brain magnetic resonance image ( mri ) revealed a well - enhanced 3.8  2.7 cm sized multicystic mass in the pineal gland with hydrocephalus ( fig . laboratory findings revealed that serum -human chorionic gonadotropin ( hcg ) was increased to 19,920 miu / ml , and the -fetoprotein level was 3.6 ng / ml . craniotomy was performed for tumor removal , as well as external ventricular drainage . given the risk of bleeding , a minimal tissue biopsy with ventricular drainage was performed . a whole - body positron emission tomography / computed tomography ( pet - ct ) scan did not reveal any lesions , including the mediastinum and gonad . concerning hemorrhagic complication , ifosfamide ( 900 mg / m on days 15 ) , cisplatin ( 20 mg / m on days 15 ) and etoposide ( 50 mg / m on days 15 ) combination chemotherapy was administered . after 2 cycles of chemotherapy , complete regression of the intracranial mass was identified without complication ( fig . after an additional 2 cycles of chemotherapy , radiation therapy covering the entire ventricular system and the spine was performed for consolidation purpose . a 17-year - old male without a previous medical history presented with headache , vomiting , polydipsia and polyuria . initial brain mri revealed two well - enhanced t1 and t2 isointense masses in the suprasellar region and pineal gland ( fig . laboratory findings showed serum -fetoprotein ( 1.1 ng / ml ) and -hcg ( 1.56 miu / ml ) levels within the normal range . despite increased serum osmolality , the prolactin level was increased up to 77.65 ng / ml ( range 1.113.0 ) . during navigation - guided craniotomy with tumor biopsy , which was performed on the suprasellar mass , sequential spine mri and spinal tapping did not reveal any concomitant lesions on the entire spine . to reduce the radiation dose and field , upfront chemotherapy was decided on . ifosfamide ( 1,800 mg / m on days 15 ) and etoposide ( 100 mg / m on days 13 ) combination chemotherapy was administered alternatively with etoposide ( 100 mg / m on days 13 ) and carboplatin ( 600 mg / m on day 1 ) . he completed 4 cycles of neoadjuvant chemotherapy without specific treatment - related complications ; however , grade 4 hematologic toxicity was identified . after 4 cycles of chemotherapy , complete regression of all masses on both lesions was identified ( fig . consolidative radiation therapy was performed on the whole ventricular system ( 24 gy ) , and a boost dose of 16 gy was irradiated to the tumor bed . a 16-year - old male without a past medical history presented to our hospital due to headache and diplopia . an initial brain magnetic resonance image ( mri ) revealed a well - enhanced 3.8  2.7 cm sized multicystic mass in the pineal gland with hydrocephalus ( fig . laboratory findings revealed that serum -human chorionic gonadotropin ( hcg ) was increased to 19,920 miu / ml , and the -fetoprotein level was 3.6 ng / ml . craniotomy was performed for tumor removal , as well as external ventricular drainage . given the risk of bleeding , a minimal tissue biopsy with ventricular drainage was performed . a whole - body positron emission tomography / computed tomography ( pet - ct ) scan did not reveal any lesions , including the mediastinum and gonad . concerning hemorrhagic complication , ifosfamide ( 900 mg / m on days 15 ) , cisplatin ( 20 mg / m on days 15 ) and etoposide ( 50 mg / m on days 15 ) combination chemotherapy was administered . after 2 cycles of chemotherapy , complete regression of the intracranial mass was identified without complication ( fig . after an additional 2 cycles of chemotherapy , radiation therapy covering the entire ventricular system and the spine was performed for consolidation purpose . a 17-year - old male without a previous medical history presented with headache , vomiting , polydipsia and polyuria . initial brain mri revealed two well - enhanced t1 and t2 isointense masses in the suprasellar region and pineal gland ( fig . laboratory findings showed serum -fetoprotein ( 1.1 ng / ml ) and -hcg ( 1.56 miu / ml ) levels within the normal range . despite increased serum osmolality , the prolactin level was increased up to 77.65 ng / ml ( range 1.113.0 ) . during navigation - guided craniotomy with tumor biopsy , which was performed on the suprasellar mass , sequential spine mri and spinal tapping did not reveal any concomitant lesions on the entire spine . to reduce the radiation dose and field , ifosfamide ( 1,800 mg / m on days 15 ) and etoposide ( 100 mg / m on days 13 ) combination chemotherapy was administered alternatively with etoposide ( 100 mg / m on days 13 ) and carboplatin ( 600 mg / m on day 1 ) . he completed 4 cycles of neoadjuvant chemotherapy without specific treatment - related complications ; however , grade 4 hematologic toxicity was identified . after 4 cycles of chemotherapy , complete regression of all masses on both lesions was identified ( fig . consolidative radiation therapy was performed on the whole ventricular system ( 24 gy ) , and a boost dose of 16 gy was irradiated to the tumor bed . when planning the initial treatment strategy against intracranial gct , pathological subtype and disease extent ( especially spinal metastasis ) are the most important factors . in general , germinoma shows high radiosensitivity and excellent prognosis . although the treatment strategy against germinoma , which is a major component of intracranial gct , is relatively well established , in the case of a rare pathologic subtype other than germinoma or uncommon clinical presentation , such as bifocal disease , optimal treatment has not yet been settled . moreover , although craniospinal irradiation ( csr ) has traditionally been considered as the gold standard of treatment against intracranial germinoma , concern about late neurologic detrimental effects of csr , especially in young patients , led physicians to omit spinal irradiation and try to reduce the radiation field as much as possible in limited disease . as a result , multimodality therapy including preirradiation chemotherapy was attempted . firstly , a few prospective studies of the sfop ( french pediatric oncology society ) , cog ( children 's oncology group ) and siop ( international society of pediatric oncology ) showed the feasibility of upfront chemotherapy in intracranial germinoma . however , the facts that chemotherapy alone can not replace radiotherapy and that the radiation volume should include at least the whole ventricular system remain unchanged . to reduce complications of radiation treatment and improve treatment outcome in intracranial germinoma , the appropriate role of chemotherapy should be further studied . in the case of nongerminomatous gct ( nggct ) , nggct is known to have a poor prognosis and a high recurrence rate compared with the germinoma - like gonadal counterpart tumor . in practice , many retrospective studies demonstrated that treatment with radiation alone in nggct showed high relapse rates and shorter recurrence - free survival . in addition , the superiority of combined modality therapy over treatment with radiation alone in nggct has been proposed by several landmark studies such as the siop - cns - gct 96 trial and the japanese cooperative study [ 3 , 4 ] . although the importance of chemotherapy in the treatment of intracranial gct was recognized , there is no standardized chemotherapeutic protocol , which includes the fine details about pathologic subtype , dosage , treatment duration and temporal sequence with radiation therapy . the chemotherapeutic agents were selected primarily based on the experience in gonadal gct treatment . based on previous reports about chemotherapy against intracranial gct , methotrexate , acnu , vinblastine , vincristine , bleomycin , ifosfamide , etoposide and carboplatin / cisplatin have been used as main chemotherapeutic agents . recently , many institutions have preferentially used etoposide , ifosfamide and cisplatin , but the administration schedule is inconsistent . on some occasions , etoposide and ifosfamide were used alternatively with a platinum agent and , in other cases , all 3 agents were used at once . in a few case reports , therefore , we performed a pubmed search for induction chemotherapy of intracranial gct to organize chemotherapeutic regimens systematically . in addition , we searched the literature for treatment strategies performed in unusual cases , such as bifocal intracranial germinoma and primary intracranial choriocarcinoma ( piccc ) . based on one international cns gct study , which intended to demonstrate the efficacy of a chemotherapy only strategy , chemotherapy intensity was shown to be quite strong . in low - risk patients , carboplatin ( 1,200 mg / m)/etoposide ( 450 mg / m ) and cyclophosphamide ( 4 g / m)/etoposide ( 450 mg / m ) were administered alternatively , and response evaluation was performed every 2 cycles . if patients achieved complete response , radiation therapy was not performed , and if patients did not achieve complete response after 4 cycles of chemotherapy , surgical resection with pathologic evaluation to exclude teratoma or high - dose myeloablative chemotherapy with autologous hematopoietic cell rescue was considered . in high - risk patients , including those with nggct , the 3-drug regimen consisting of carboplatin , cyclophosphamide and etoposide was administered at once . however , according to these regimens , grade iii and iv hematologic toxicity occurred in > 90% of patients . the 6-year event - free survival was 27.3% in the low - risk and 50% in the high - risk group . consequently , this study demonstrated the toxicity of high - dose chemotherapy ; nevertheless , the effect of the 3-drug regimen in the high - risk group including nggct was favorable and worth considering a neoadjuvant chemotherapy regimen . in the study of kochi et al . , the intensity of the chemotherapy was attenuated . in the low - risk group , cisplatin ( 20 mg / m ) and etoposide ( 60 mg / m ) were administered , and in the group with a poor prognosis , ifosfamide ( 900 mg / m ) , cisplatin ( 20 mg / m ) and etoposide ( 60 mg / m ) were administered for 5 consecutive days . usually , 3 cycles were performed before radiation therapy . although enrolled patients were small in number , the outcome was encouraging . although many other regimens have been reported , there was no report which compared various neoadjuvant chemotherapy regimens in terms of efficacy and toxicity due to the paucity of intracranial gct . therefore , we also used this regimen for our two cases . whereas most patients who have been diagnosed with intracranial gct present with a single mass , about 525% of the patients present with synchronous lesions in both the pineal gland and neurohypophyseal region , and these patients have been described as until now , many authors have put more weight on synchronous lesions rather than on metastasis . many previous studies have supported this theory by showing a favorable outcome of bifocal intracranial gct to limited field irradiation . however , some authors insist that these patients also impose a risk of dissemination , proposing results that bifocal gct showed a significantly shorter event - free and overall survival than germinoma from a single site of origin . moreover , because bifocal lesions are not an exclusive sign of germinoma and performing a biopsy from both sites is not feasible , the possible presence of a nongerminomatous component can not totally be excluded . therefore , in bifocal gct , a multimodal treatment strategy including neoadjuvant chemotherapy , even in the case of germinoma which has been pathologically confirmed on either site , would be reasonable . however , if the tumor marker , such as -hcg , does not strongly imply nggct , an intensive regimen will not be suitable . in conclusion , neoadjuvant chemotherapy with an alternating chemotherapy regimen consisting of two drugs followed by reduced field irradiation is thought to be reasonable , like in our case . piccc is a very rare but most malignant subtype of intracranial gct , with a few unique features which make treatment complicated . based on a clinical study on 66 piccc cases ( including mixed gct ) , the median survival time was just 22 months , and fatal complications such as tumor hemorrhage and cerebrospinal fluid metastasis were more frequent than in other types of intracranial gct . especially , tumor hemorrhage occurred in 22 of 66 cases , and some of them were associated with catastrophic consequences . furthermore , 5 cases with hemorrhages were caused by radiation therapy whereas no case of hemorrhage was identified during chemotherapy . due to the hemorrhagic tendency of choriocarcinoma , upfront surgical resection is difficult and , sometimes , even biopsy confirmation is omitted in practice . many oncologists have been interested in the incidence of hemorrhagic complications and how to reduce them , and the opinion that radiation therapy can provoke tumor hemorrhage has been proposed . although there were 2 reports which treated piccc with concurrent chemoradiation therapy [ 9 , 10 ] , considering the potential hemorrhagic complications by radiation and treatment - related bone marrow toxicity , a more careful approach , a platinum - containing regimen has been used with favorable outcomes , like in other subtypes of nggct . the previous two studies also used a combination chemotherapy consisting of ifosfamide , cisplatin and etoposide as one of the mainstay of treatment . in conclusion , neoadjuvant chemotherapy consisting of 3 drugs followed by csr or reduced field radiation therapy
primary intracranial germ cell tumor ( gct ) is a rare tumor that generally occurs due to developmental anomaly . 
 although intracranial gct is sensitive to treatment , a high recurrence rate , treatment - related long - term complications and the heterogeneity of this tumor group make treatment complicated . 
 moreover , because of its location , hydrocephalus and visual field defect , functional disturbance of the pituitary gland can occur and require attention . 
 treatment primarily relies on chemotherapy and radiation therapy but the management of intracranial gct remains unsettled , especially in the case of unusual circumstances such as multifocal tumor or nongerminomatous gct . here , 
 we present two unusual cases of intracranial gct : one case with a bifocal intracranial germinoma , and the other with an intracranial choriocarcinoma . 
 both cases were treated with neoadjuvant chemotherapy followed by reduced - field radiation therapy without significant treatment - related complication . 
 further , we performed a pubmed search to investigate the appropriate treatment strategy for this unusual subtype of intracranial gct .