The authors analyzed 153 cases of histologically verified intracranial germ cell tumors. The histological diagnosis was germinoma in 63 patients (41.2%), teratoma in 30 (19.6%), and other types of tumors in 60 patients (39.2%). The patients were treated by a consistent policy of surgical removal with histological verification followed by radiation therapy with or without chemotherapy. The 10- and 20-year survival rates of patients with pure germinoma were 92.7% and 80.6%, respectively. The 10-year survival rates of patients with mature teratoma and malignant teratoma were 92.9% and 70.7%, respectively. Patients with pure malignant germ cell tumors (embryonal carcinoma, yolk sac tumor, or choriocarcinoma) had a 3-year survival rate of 27.3%. The mixed tumors were divided into three subgroups: 1) mixed germinoma and teratoma; 2) mixed tumors whose predominant characteristics were germinoma or teratoma combined with some elements of pure malignant tumors; and 3) mixed tumors with predominantly pure malignant elements. The 3-year survival rates were 94.1% for the first group, 70% for the second group, and 9.3% for the third group, and the differences were statistically significant. Twenty-six patients with malignant tumors received chemotherapy that consisted of cisplatin and carboplatin combinations with or without radiation therapy. However, chemotherapy was not significantly more effective than radiation therapy alone. From these treatment results, the authors classified tumors into three groups with different prognoses and proposed a treatment guideline appropriate for the subgroups.

The management of intracranial germ-cell tumours is complex because of varied clinical presentations, tumour sites, treatments and outcomes, and the need for multidisciplinary input. Participants of the 2013 Third International CNS Germ Cell Tumour Symposium (Cambridge, UK) agreed to undertake a multidisciplinary Delphi process to identify consensus in the clinical management of intracranial germ-cell tumours. 77 delegates from the symposium were selected as suitable experts in the field and were invited to participate in the Delphi survey, of which 64 (83%) responded to the invitation. Invited participants represented multiple disciplines from Asia, Australasia, Europe, and the Americas. 38 consensus statements encompassing aspects of intracranial germ-cell tumour work-up, staging, treatment, and follow-up were prepared. To achieve consensus, statements required at least 70% agreement from at least 60% of respondents. Overall, 34 (89%) of 38 statements met consensus criteria. This international Delphi approach has defined key areas of consensus that will help guide and streamline clinical management of patients with intracranial germ-cell tumours. Additionally, the Delphi approach identified areas of different understanding and clinical practice internationally in the management of these tumours, areas which should be the focus of future collaborative studies. Such efforts should translate into improved patient outcomes.

Podoplanin (aggrus) is a mucin-like transmembrane sialoglycoprotein that is expressed on lymphatic endothelial cells. Podoplanin is putatively involved in cancer cell migration, invasion, metastasis, and malignant progression and may be involved in platelet aggregation. Previously, we showed upregulated expression of podoplanin in central nervous system (CNS) germinomas, but not in non-germinomatous germ cell tumors, except for parts of immature teratomas in limited numbers. However, little information exists about its role in CNS astrocytic tumors. In this study, 188 astrocytic tumors (30 diffuse astrocytomas, 43 anaplastic astrocytomas, and 115 glioblastomas) were investigated using immunohistochemistry with an anti-podoplanin antibody, YM-1. In 11 of 43 anaplastic astrocytomas (25.6%) and in 54 of 115 glioblastomas (47.0%), podoplanin was expressed on the surface of anaplastic astrocytoma cells and glioblastoma cells, especially around necrotic areas and proliferating endothelial cells. However, the surrounding brain parenchyma was not stained by YM-1. On the other hand, podoplanin expression was not observed in diffuse astrocytoma (0/30: 0%). Furthermore, we investigated the expression of podoplanin using quantitative real-time PCR and Western blot analysis in 54 frozen astrocytic tumors (6 diffuse astrocytomas, 14 anaplastic astrocytomas, and 34 glioblastomas). Podoplanin mRNA and protein expression were markedly higher in glioblastomas than in anaplastic astrocytomas. These data suggest that podoplanin expression might be associated with malignancy of astrocytic tumors.

We analyzed our treatment results in 153 patients with histologically verified intracranial germ cell tumors and proposed classifying them into three therapeutic groups with good prognosis, intermediate prognosis, and poor prognosis. In this work, we selected patients treated with chemotherapy (cisplatin or carboplatin combinations) in each subgroup, and we discuss the role of chemotherapy in their treatment. Our combination chemotherapy regimens are: cisplatin-vinblastine-bleomycin, cisplatin-etoposide, and carboplatin-etoposide. We delivered these chemotherapies to the last 33 patients and compared their treatment results with those obtained in the previous 31 patients, who were treated with conventional radiation therapy alone. A combination with chemotherapy and a reduced dose of irradiation with local field was given to 7 patients with germinoma to increase the cure rate and reduce radiation-induced side effects, including anterior pituitary dysfunction. We obtained an excellent initial response to chemotherapy. The chemotherapy we delivered had significantly better effects in the group with intermediate prognosis, but not in the group with poor prognosis. More aggressive chemotherapy and radiation therapy should be given as the initial treatment.

Germ cell tumors constitute a heterogeneous group that displays a broad spectrum of morphology. They often arise in testes; however, extragonadal occurrence, in particular brain, is not uncommon, and whether they share a common pathogenesis is unknown. We performed whole exome sequencing in 41 pairs of central nervous system germ cell tumors (CNS GCTs) of various histology and their matched normal tissues. We then performed targeted sequencing of 41 selected genes in a total of 124 CNS GCTs, 65 testicular germ cell tumors (tGCTs) and 8 metastatic GCTs to the CNS. The results showed that mutually exclusive mutations of genes involved in the MAPK pathway were most common (48.4 %), typically in KIT (27.4 %), followed by those in the PI3K pathway (12.9 %), particularly in MTOR (6.5 %), among the 124 CNS GCTs. Pure germinomas and non-germinomatous germ cell tumors (NGGCTs), as well as CNS and testicular GCTs, showed similar mutational profiles, suggesting that GCTs share a common molecular pathogenesis. Mutated MTOR identified in CNS GCTs upregulated phosphorylation of the AKT pathway proteins including AKT and 4EBP1 in nutrient-deprived conditions and enhanced soft-agar colony formation; both events were suppressed in a dose-dependent manner by addition of the MTOR inhibitor pp242. Our findings indicate that the dominant genetic drivers of GCTs regardless of the site of origin are activation of the MAPK and/or PI3K pathways by somatic point mutations. Mutated MTOR represents a potential target for novel targeted therapies for refractory GCTs.