Nervous System Germ Cell Tumors Research Articles

Detecting non-germinomatous germ cell tumor component by arterial spin labeling perfusion-weighted MR imaging in central nervous system germ cell tumor

PurposeDifferentiating between germinoma and non-germinomatous germ cell tumor (NGGCT) is important because sensitivity to chemotherapy and/or radiotherapy is quite different between these two subgroups. In this study, we evaluated whether the arterial spin labeling (ASL) based perfusion-weighted imaging (PWI) could provide additional information for the differential diagnosis between germinoma and NGGCT. MethodBetween 2011 and 2018, 20 patients with central nervous system (CNS) germ cell tumor (GCT) who underwent preoperative MR imaging including ASL-PWI were enrolled in this study. Relative tumor blood flow (rTBF) was evaluated on ASL-PWI by manually placing regions of interest at gadolinium enhanced part of the tumors and normal subcortical white matter. Presence of intratumoral T1 hyperintense foci and apparent diffusion coefficient (ADC) were also evaluated. The final diagnosis was made by the combination of tumor markers and the histological diagnosis. ResultsAmong 20 patients of CNS-GCT, 11 were diagnosed as germinoma and 9 were diagnosed as NGGCT. In the germinoma subgroup, the rTBF ranged from 0.90 to 1.71 (mean 1.21, median 1.09), while it ranged from 1.14 to 5.75 (mean 3.91, median 3.31) in NGGCT subgroup. The receiver operating characteristic (ROC) curve showed that calculating rTBF is useful for differentiating between germinoma and NGGCT (area under the curve (AUC) 0.929, P = 0.0012) compared to intratumoral T1 hyperintense foci (AUC 0.788, P = 0.0304) and ADC (AUC 0.919, P = 0.0016). ConclusionsHigh rTBF obtained by ASL-PWI implied the presence of NGGCT component. This information might help in deciding the chemotherapy/radiotherapy intensity.

GCT-46. MULTI-KINASE INHIBITORS AS NOVEL THERAPEUTIC AGENTS AGAINST INTRACRANIAL NON-GERMINOMATOUS GERM CELL TUMORS

Central nervous system germ cell tumors (CNS GCTs) are rare intracranial malignancies developing in adolescents and young adults which relatively frequently occur in East Asia region of the world including Japan. However, among CNS GCTs, non-germinomatous germ cell tumors (NGGCTs) are highly resistant to the current chemoradiotherapies, and the prognosis of CNS NGGCTs is still extremely poor. Therefore, development of novel therapeutic strategy against CNS NGGCTs is urgently needed. In this study, we screened small molecule inhibitors of kinases specifically targeting cell membrane receptors, such as receptor tyrosine kinases, and their related molecular signaling, which could effectively exert antitumor effects against NGGCT cells. As the NGGCT model cells, the Tcam2 cell, a mixed germ cell tumor cell line composed of germinoma and embryonal carcinoma components, and the YST1 cell, a novel yolk sac tumor cell line established in our institute, were used. As a result, effective induction of cell death in both cell lines was confirmed only by treatment with two multi-kinase inhibitors. Immunoblotting revealed these multi-kinase inhibitors suppressed activation of various kinases concurrently. Furthermore, these multi-kinase inhibitors also triggered cell death in the Tcam2 cell stably expressing mutant KIT, the most common oncogenic driver genes of CNS GCTs, suggesting that these inhibitors would be also effective against CNS GCTs harboring activated KIT mutants. In vivo studies of these multi-kinase inhibitors using CNS GCT xenografts are currently on going.

GCT-19. MODELING GERM CELL TUMORS WITH KIT MUTANT hiPSCs

Central Nervous System Germ Cell Tumor (CNS GCT) is the second most common pediatric brain tumor in Japan, and within CNS GCT, germinoma is the most common subtype, accounting for 62.3%. Recent reports of transcriptome and methylome analysis suggested that germinoma highly resemble the state of gonocytes, the germ cells at around 5th to 7th week of human embryo development. It is also identified that 60% of germinoma harbored somatic mutations in KIT/RAS pathway. As the protocol to derive gonocytes from human iPSCs have been reported, we aimed to recapitulate tumorigenesis by generating human iPSCs bearing common genetic mutations and derive gonocytes from them. We first introduced the most common mutation KITD816V to human iPSCs using CRISPR/Cas9, and confirmed in iPSCs that mutated KIT was phosphorylated in the absence of ligand stimulation, and also found that KIT activation contribute to the phosphorylation of AKT but not of ERK. Upon differentiation towards primordial germ cell -like cells (PGCLCs), KIT mutant lines were efficiently induced into PGCLCs, however, by comparing conditions with or without KIT ligand (SCF), mutant lines exhibited less dependency to SCF compared to wildtype cells. Mutant cells were further differentiated to gonocytes following published protocol and the cells were collected for transcriptome analysis. By comparing with the transcriptome of germinoma, we confirmed that germinoma samples express germ cell genes similar to gonocytes. We are attempting to identify the molecular mechanism of tumorigenesis in relation to KIT activation using this system.

GCT-22. PROTEIN DEUBIQUITINATION PATHWAY IS A NOVEL THERAPEUTIC TARGET AGAINST MALIGNANT NON-GERMINOMATOUS CNS GERM CELL TUMORS

Central nervous system germ cell tumors (CNSGCTs) are rare intracranial neoplasm usually developed in adolescents and young adults. However, in East Asia including Japan, incidence of CNSGCTs is considerably higher compare with other regions of the world. Whereas germinomas generally respond to chemo-radiotherapy well, malignant subtypes of non-germinomatous germ cell tumors (NGGCT) are refractory, and development of novel therapy against NGGCTs is urgently needed. To develop a new therapeutic strategy against aggressive NGGCTs, we have investigated novel molecular targets for NGGCT treatment. We screened a total of 120 CNSGCT tumor tissues (including 55 NGGCT), which were registered to the Intracranial Germ Cell Tumor Consortium (iGCT), and discovered multiple mutations of a molecule that regulates protein ubiquitination and degradation specifically in NGGCT cases (5 of 55 cases; 1 immature teratoma, 3 mixed gem cell tumors, and 1 embryonal carcinoma). An in vitro ubiquitination assay revealed the mutations of this molecule discovered in NGGCT cases were loss of function mutations. Reduced expression of this molecule by knockdown in an established human seminoma cell line Tcam2 or a human yolk sac tumor cell line YST1, which was recently established in our institute, resulted in enhanced proliferation as well as upregulation of MEK-ERK activation. Importantly, treatment of these two GCT cell lines with reduced expression of this molecule by MEK inhibitor trametinib suppressed augmented proliferation of these cells. Taken together, these results suggest that protein ubiquitination-related pathways as well as MEK-ERK cascade may serve as a novel therapeutic target against NGGCTs.

GCT-67. CENTRAL NERVOUS SYSTEM GERMINOMA IN TWO CAUCASIAN AMERICAN SIBLINGS WITH AUTISM SPECTRUM DISORDER

BACKGROUNDCentral nervous system germ cell tumors (CNS-GCT) account for approximately 5% of all pediatric brain tumors. These tumors are pathologically heterogeneous, but have recurrent somatic mutations in KIT and rare germline variants in a Japanese cohort. Chromosomal abnormalities, specifically Klinefelter Syndrome, are associated with increased tumor development and familial cases have been reported, but no germline tumor syndromes are known. We describe a pair of siblings, both with autism spectrum disorder (ASD) that developed CNS-GCT, which previously has not been described outside of Japan. CASES: We report two siblings with ASD who developed CNS germinomas within two months of each other. The older brother, with basal ganglia and hypothalamic tumors, underwent surgical resection followed by treatment per ACNS0232 with chemotherapy and whole-ventricular irradiation (WVI). The younger sibling, with a midbrain tumor, also received ACNS0232, but due to poor response required additional chemotherapy and WVI. Both siblings are without evidence of disease 7 years after end of therapy. Genetic testing, including chromosomal microarray, karyotyping, and whole genome sequencing did not elucidate any variant identified as causative at that time.CONCLUSIONSCNS-GCT are rare tumors, diverse in both histopathologic diagnosis and clinical outcomes. Currently there are known somatic alterations and germline chromosomal disorders associated with increased tumor development, but no known inheritable causes. Despite this, familial CNS-GCT have been reported in patients of Japanese descent. The description of two Caucasian American siblings with ASD and CNS-GCT is novel, refuting that familial CNS-GCT are limited to the Japanese population.

GCT-15. INTEGRATED CLINICAL, HISTOPATHOLOGICAL, AND MOLECULAR DATA ANALYSIS OF 190 CENTRAL NERVOUS SYSTEM GERM CELL TUMORS FROM THE IGCT CONSORTIUM

BACKGROUNDWe integrated clinical, histopathological, and molecular data of central nervous system germ cell tumors to provide insights into their management.METHODSData from the Intracranial Germ Cell Tumor Genome Analysis Consortium were reviewed. A total of 190 cases were classified as primary GCTs based on central pathological reviews.RESULTSAll but one of the cases that were bifocal (neurohypophysis and pineal glands) and cases with multiple lesions including neurohypophysis or pineal gland were germinomas (34 of 35). Age was significantly higher in patients with germinoma than other histologies. Comparison between tumor marker and histopathological diagnoses showed that 18.2% of histopathologically diagnosed germinomas were marker-positive and 6.1% of non-germinomatous GCTs were marker-negative, suggesting a limitation in the utility of markers or histopathology alone using small specimens for diagnosis. Comparison between local and central histopathological diagnoses revealed a discordance of 12.7%. Discordance was significantly less frequent in biopsy cases, implying difficulty in detecting all histopathological components of heterogeneous GCTs. Germinomas at the typical sites (neurohypophysis or pineal gland) showed a better PFS than those at atypical sites (p=0.03). A molecular-clinical association study revealed frequent MAPK pathway mutations in males (51.4 vs 14.3 %, p=0.007), and PI3K/mTOR pathway mutations in basal ganglia cases (p=0.004). Basal ganglia cases also had frequent chromosomal losses. Some chromosomal aberrations (2q, 8q gain, 5q, 9p/q, 13q, 15q loss) showed potential prognostic significance.CONCLUSIONSThese in-depth findings of this study regarding the clinical and molecular heterogeneity will increase our understanding of the pathogenesis of this enigmatic tumor.

GCT-36. TREATMENT RESULTS AND RADIATION-INDUCED TUMORS IN CASES OF CENTRAL NERVOUS SYSTEM GERM CELL TUMOR: A LONG-TERM FOLLOW-UP STUDY IN KUMAMOTO PREFECTURE

INTRODUCTIONCentral nervous system germ cell tumor (GCT) is one of the pediatric brain tumors. Although there have been epidemiological studies in the past, long-term prognosis and the late effects remained unclear. In this study, we examined GCT over the past 41 years in Kumamoto prefecture.METHODSEpidemiological features and complications with radiation-induced tumors were searched in patients diagnosed with GCT in the 41-year period from 1977 to 2018.RESULTSThere were 93 patients diagnosed with GCT. These cases were divided into 14-year periods before and after incorporation of chemotherapy into the treatment, and the results for germinomas were compared. An improvement in the 10-year survival rate from 12 of 23 cases (52.2%) between 1977 and 1991 to 19 of 28 cases (67.9%) between 1992 and 2006 was observed. The 10-year survival rate for germinoma cases that received medical treatment during a more recent 5-year period between 2004 and 2009 increased to over 90%. However, 10.3% of all long-term survivors of GCT developed radiation-induced glioblastoma. The examination results showed that regardless of the tumor type, patients who received a high dose of radiation during their initial treatment developed the complication of radiation-induced glioblastoma within 10 to 25 years after their initial treatment.CONCLUSIONThis study suggests that the long-term survival rates for GCT are improving but the rate of radiation-induced glioblastoma in these cases are too high to be ignored. Long-term follow-up of at least 10 years is essential to effectively evaluate the details of treatment for pediatric brain tumors.

GCT-62. DISSECTING INTRATUMORAL HETEROGENEITY OF CENTRAL NERVOUS SYSTEM GERM CELL TUMORS BY SINGLE-CELL RNA-SEQUENCING

BACKGROUNDCentral nervous system germ cell tumor (CNSGCT) is a rare pediatric brain tumor. However, they are found at a relatively high incidence in East Asia. Germinoma is sensitive toward radiotherapy and chemotherapy; however, non-germinoma GCTs (NGGCT) often show poor response. Some cases are a mixture of germinoma and NGGCT (mixed GCT), and they sometimes change histological subtypes at recurrence. Previous report demonstrated that a germinoma and NGGCT component within the same mixed GCT tissue shared the same gene mutation, whereas the genome-wide methylation profiles were distinct from each other. The methylation profiles of germinoma was similar to the primordial germ cells (PGC) at the migration phase, supporting a model that PGC is the cell of origin for CNSGCT. However, tumor heterogeneity hinder information of the mixed bulk RNA-sequence data, causing difficulty in elucidating the mechanism of tumor development. The purpose of this study was to investigate the tumor cells subpopulations at the resolution of individual cells by single-cell RNA-seq.RESULTSFresh surgical tumor tissue was immediately dissociated mechanically and enzymatically. Tumor cells are separated from CD45-labelled lymphocytes by FACS, and libraries were generated by Chromium Single cell 3’ Reagent Kit. Total of 11 tumor samples were collected and sequenced. Unsupervised Clustering showed individual clusters. One of the clusters had high expression of Oct-4, which is a marker of germinoma. The other clusters showed different subtypes of cells representing the heterogeneity of CNSGCT. Further analysis including a pseudo-time course analysis is underway to identify the lineage of tumor cell development.

GCT-71. SIOP STRATEGY TREATMENT FOR CENTRAL NERVOUS SYSTEM GERM CELL TUMORS IN A MIDDLE INCOME COUNTRY

BACKGROUND/OBJECTIVESCentral nervous system (CNS) germ cell tumors (GCTs) represent 3% of primary paediatric brain tumours in occident. They can be divided into major groups including germinomas and nongerminomatous GCTs (NGGCTs). The aim is to describe demographic characteristics, Event Free Survival (EFS) and Overall Survival (OS) in patients with GCTs treated at Oncology Unit of Garrahan Hospital (HG).DESIGN/METHODSRetrospective analysis of patients with GCTs admitted between September 1st,2000 to September 1st,2019. Variables analysed: age, localization, treatment, relapse and death. Patients were treated per SIOP-CNSGCTs protocol. For statically analysis SPSS (IBM), for EFS/OS Kaplan-Meyer, Long-rank for significance.RESULTSFifty-seven patients were included, comprising 38 Germinomas and 19 NGGCTS. Median age was 146 months (range 11–228). Primary site in localized Germinomas were pineal (16p), suprasellar (7p) and bifocal (7p). Five-year EFS and OS of 100% and 88.5%, respectively. Four patients presented metastatic disease, with an EFS and OS of 60.9% and 66.6%. Tumor site in localized NGGCT were pineal(8p) and suprasellar(5p). Five-year EFS was 81.8% and OS was 80.2%. No patients presented metastatic disease. All patients with high-risk tumor markers at diagnosis relapsed. No significative differences were found in OS neither EFS between groups (Germinomas OS5y 90% vs NGGCTs 74.6%p=0.19[CI95%0.0786–1.689]), (Germinomas EFS5y 78.9% vs NGGCTs5y 81.8%p=0.85[CI95%0.3046–4.230). Global OS and EFS5y was 83% and 72.9%.CONCLUSIONOS of our cohort is lower than what has been shown in current literature. This result may be related to the lack of resources and lower social economic status in our population.

GCT-56. ACUTE MYELOID LEUKEMIA FOLLOWING CHEMORADIOTHERAPY FOR INTRACRANIAL GERMINOMA: A CASE REPORT

INTRODUCTIONTherapy-related acute myeloid leukemia (t-AML) is known as possible complication of chemotherapy, especially topoisomerase Ⅱ inhibitor, alkylating agents, and platinum agents. Although there are many reports of therapy-related leukemia associated with gonadal germ cell tumor, few cases have been reported on central nervous system (CNS) germ cell tumor. CASE REPORT: A 35-year old gentleman presented with diplopia. CT and MR imaging showed enhancing nodules on his right hypothalamus and around fourth ventricle, and differential diagnoses included sarcoidosis and germinoma. Biopsy for fourth ventricle lesion was performed via transvermian approach, and histopathological diagnosis was germinoma. He was treated by 3 cycles of CARE chemotherapy (carboplatin and etoposide) followed by craniospinal irradiation (CSI, 24Gy). After completion of chemoradiotherapy, he was followed up every half year by MRI, and there had been no evidence of tumor recurrence. Two years after chemoradiotherapy, however, the patient presented with bleeding tendency, which led to the diagnosis of AML. Based on the history of chemoradiotherapy and the presence of t(16;21)(q24; q22), t-AML was diagnosed. Complete remission was successfully achieved by chemotherapy consisting of idarubicin and cytarabine.DISCUSSIONt-AML was diagnosed after chemoradiotherapy in a patient with CNS germinoma probably due to the administration of topoisomerase II inhibitor, etoposide. The prognosis of t-AML is known to be poorer as compared with de novo AML. Therefore, intensive therapy such as allogeneic stem cell transplantation should be considered in younger patients.CONCLUSIONA possibility of t-AML should be kept in mind following chemotherapy for CNS germ cell tumors.

GCT-58. BRAZILIAN CENTRAL NERVOUS SYSTEM GERM CELL TUMOR CONSORTIUM PROTOCOL

INTRODUCTIONPrimary central nervous system (CNS) germ cell tumors (GCT) account for 2–3% brain tumors children/adolescents in Western hemisphere. The report aim is to present the results of a Brazilian CNSGCT consortium protocol.METHODSSince 2013, 45 patients with histologic and/or tumor marker (TM) diagnosis of germinoma with/without HCGβ levels≤200mIU/ml (n=33), four between 100-200mIU/ml and NGGCT (n=12), received carboplatin/etoposide/cyclophosphamide (4–6 cycles), followed by 18Gy ventricular field irradiation and primary site(s) boost. Autologous bone marrow transplant (ABMT) was conducted for NGGCT low responders.RESULTSMean age 12.9 years (4.7-20y), 34 males. Diagnosis was made by TM (n=9), surgery (n=19), both (n=15). Two bifocal cases, (-)TM were treated as germinoma. Primary tumor location was pineal (n=20), suprasellar (n=13), bifocal (n=11) and basal ganglia/thalamus (n=1). Fourteen had ventricular/spinal spread. Second-look surgery occurred in 5 patients. For the germinoma group, 26 achieved complete response (CR) after chemotherapy, seven showed residual teratoma/scar. For the NGGCT after 2/4 cycles, four patients showed CR, 2 failure/progression and 6 partial response (4 (-)TM). Two were submitted to ABMT. Radiotherapy was performed as described, except in three. One recurrence to date. Two patients died (endocrinologic complications/progression). Toxicity was mostly grade ¾ neutropenia/thrombocytopenia during chemotherapy. At a median follow-up of 38 months, OS was 100% for Germinoma and 85% NGGCT.CONCLUSIONThe treatment is tolerable and VFI dose reduction to 18Gy seems to preserve efficacy. Further follow-up is warranted to assess the NG group and the slow-responder patients.

CBMS-11 PROTEIN DEUBIQUITINATION PATHWAY IS A NOVEL THERAPEUTIC TARGET AGAINST MALIGNANT CNS NON-GERMINOMATOUS GERM CELL TUMORS

Central nervous system germ cell tumors (CNSGCTs) are rare intracranial neoplasm usually developed in adolescents and young adults. However, in East Asia including Japan, incidence of CNSGCTs is considerably higher compare with other regions of the world. Whereas germinomas generally respond to chemo-radiotherapy well, malignant subtypes of non-germinomatous germ cell tumors (NGGCT) are refractory, and development of novel therapy against NGGCTs is urgently needed. To develop a new therapeutic strategy against aggressive NGGCTs, we have investigated novel molecular targets for NGGCT treatment. We screened a total of 120 CNSGCT tumor tissues (including 55 NGGCT), which were registered to the Intracranial Germ Cell Tumor Consortium (iGCT), and discovered multiple mutations of a molecule that regulates protein ubiquitination and degradation specifically in NGGCT cases (5 of 55 cases; 1 immature teratoma, 3 mixed gem cell tumors, and 1 embryonal carcinoma). An in vitro ubiquitination assay revealed the mutations of this molecule discovered in NGGCT cases were loss of function mutations. Reduced expression of this molecule by knockdown in an established human seminoma cell line Tcam2 or a human yolk sac tumor cell line YST1, which was recently established in our institute, resulted in enhanced proliferation as well as upregulation of MEK-ERK activation. Importantly, treatment of these two GCT cell lines with reduced expression of this molecule by MEK inhibitor trametinib suppressed augmented proliferation of these cells. Taken together, these results suggest that protein ubiquitination-related pathways as well as MEK-ERK cascade may serve as a novel therapeutic target against NGGCTs.

Treatment outcome and long-term follow-up of central nervous system germ cell tumor using upfront chemotherapy with subsequent photon or proton radiation therapy: a single tertiary center experience of 127 patients

BackgroundCentral nervous system germ cell tumors (CNS GCTs) are a heterogeneous group of brain tumors, which are more common in Asian countries. There have been different therapeutic strategies in treating germinoma and non-germinomatous germ cell tumors (NGGCT), depending on prognosis. Moreover, long-term follow up should be emphasized due to higher late complication rates. Here, we investigated long-term outcomes and complication profiles of 127 CNS GCT patients who received uniform upfront chemotherapy.MethodsWe retrospectively evaluated outcomes of CNS GCT patients treated in Seoul National University Children’s Hospital from August 2004 to April 2019. Patients were classified as low risk (LR) or high risk (HR) based on pathologic diagnosis and tumor markers. Most patients received upfront systemic chemotherapy with carboplatin, cyclophosphamide, etoposide, and/or bleomycin, followed by either proton or photon radiation therapy according to patients’ choice.ResultsThe median age at diagnosis was 11.9 (range, 3.8–25.1) years, and 54.3% of patients were LR. Photon and proton radiation therapy were administered to 73.2 and 25.2% of patients, respectively. In both LR and HR groups, there were no significant differences in survival between photon and proton radiation therapy. The 10-year relapse incidences were 9.3 and 5.6% in the LR and HR groups, respectively. All recurrences, except one, were local relapse. Six secondary malignancies occurred; the 10-year incidences of secondary malignancy were 2.2 and 7.6% in the LR and HR groups, respectively. The 10-year overall survival rates were 98.3 ± 1.7 and 91.8 ± 3.9% in the LR and HR groups, respectively. In a subgroup analysis of HR group, pathologically diagnosed NGGCT patients (n = 20) showed worse 10-year EFS (65.9 ± 11.9%, p < 0.001) and OS (77.9 ± 9.8%, p = 0.024) rates compared to other HR patients who were not pathologically diagnosed or were confirmed as germinoma with elevated tumor markers. All mortalities were related to disease progression or secondary malignancy.ConclusionThe strategy of treating CNS GCTs with upfront chemotherapy according to risk groups resulted in good clinical outcomes and acceptable relapse incidence. However, further modification in the definition of the HR group is needed to reduce long-term complications.

Endocrine manifestations of central nervous system germ cell tumors in children

IntroductionCentral nervous system germ cell tumors need to be adequately diagnosed because their treatment is usually effective and they do not always require surgery. The study objectives are to describe the endocrine manifestations of these tumors and to compare the time of their onset to that of the occurrence of neurological and visual changes. Patients and methodsThe medical histories of patients under 14 years of age seen at a pediatric endocrinology unit between 2000 and 2018 were reviewed. Wilcoxon and Fisher statistical tests were performed. ResultsWe found 12 patients (10 females) with an age at diagnosis of 9.4±1.7 years and a follow-up time of 5.5±3.0 years, 10 with tumors in the sellar region, and each one with a pineal gland and a bifocal tumor. Clinical changes leading to diagnosis were neurological and/or visual in nine patients and hormonal in three. Seven patients diagnosed on the basis of neurological or visual symptoms had previously reported hormonal changes, giving us a total of 10 children at diagnosis (the most common diagnosis was central diabetes insipidus, found in 8). Endocrine symptoms had been present before diagnosis for 25.0±26.2 months, considerably longer than neuro-ophthalmological complaints (2.0±2.1 months, p=0.012). ConclusionsAlmost all intracranial germ cell tumors have associated endocrine manifestations at diagnosis, with central diabetes insipidus the most common. Hormonal symptoms usually appear long before neuro-ophthalmological manifestations. Adequate clinical and endocrinological assessment may allow for an earlier diagnosis of these tumors.

Novel Diagnostic Methods and Posttreatment Clinical Phenotypes Among Intracranial Germ Cell Tumors.

Central nervous system (CNS) germ cell tumors (GCT) are rare and complex pediatric neoplasms, the optimal management of which remains an area of active investigation. To present an updated cohort study, with particular attention to novel diagnostic methods and posttreatment clinical phenotypes. A single-institution cohort study of 80 primary, neurosurgically managed, CNS GCTs was conducted at Mayo Clinic, 1988-2017. Postchemotherapy resection (eg, second-look surgery) was frequently required (27.0%), especially after adjuvant therapies for nongerminomatous GCTs (NGGCTs; 14 of 28 cases, excluding mature teratoma) and significantly associated with pineal lesions, as compared to neurohypophyseal or bifocal lesions (43.6%vs 5.9% vs 6.7%, P=.004), a finding that retained statistical significance after adjusting for index extent of resection and histology (P=.04). Essentially every NGGCT case underwent at least 1 craniotomy, either on presentation, as second-look surgery, or following local recurrence. Mature teratomatous tissue was highly incident in second-look specimens (84.2%), even among lesions initially diagnosed as germinomas. Pretreatment cerebrospinal fluid (CSF) cell fraction analysis demonstrated an association between single lesions and neutrophil predominance, whereas nongerminomatous GCTs were associated with increased monocyte fractions. CNS GCTs are clinically heterogeneous lesions, resulting in numerous opportunities for improved understanding and clinical management via novel diagnostic and therapeutic protocols. Samples from second-look surgeries for recurrent germinomas frequently demonstrate teratomatous tissue, suggesting possible underdiagnosis of mixed GCTs-particularly among pineal lesions. GCT subtypes demonstrate differential cell fraction distributions on CSF analysis, a novel and perhaps diagnostically helpful finding that requires validation in external cohorts.

Cerebrospinal fluid ctDNA and metabolites are informative biomarkers for the evaluation of CNS germ cell tumors

Serum and cerebrospinal fluid (CSF) levels of α-fetoprotein and β-subunit of human chorionic gonadotropin are used as biomarkers for the management of central nervous system (CNS) germ cell tumors (GCTs). However, additional discriminating biomarkers are required. Especially, biomarkers to differentiate non-germinomatous germ cell tumors (NGGCTs) from germinomas are critical, as these have a distinct prognosis. We investigated CSF samples from 12 patients with CNS-GCT patients (8 germinomas and 4 NGGCTs). We analyzed circulating tumor DNA (ctDNA) in CSF to detect mutated genes. We also used liquid chromatography-mass spectrometry to characterize metabolites in CSF. We detected KIT and/or NRAS mutation, known as frequently mutated genes in GCTs, in 3/12 (25%) patients. We also found significant differences in the abundance of 15 metabolites between control and GCT, with unsupervised hierarchical clustering analysis. Metabolites related to the TCA cycle were increased in GCTs. Urea, ornithine, and short-chain acylcarnitines were decreased in GCTs. Moreover, we also detected several metabolites (e.g., betaine, guanidine acetic acid, and 2-aminoheptanoic acid) that displayed significant differences in abundance in patients with germinomas and NGGCTs. Our results suggest that ctDNA and metabolites in CSF can serve as novel biomarkers for CNS-GCTs and can be useful to differentiate germinomas from NGGCTs.

Laser ablation-ICP-TOFMS imaging of germ cell tumors of patients undergoing platinum-based chemotherapy.

A low dispersion laser ablation setup in combination with inductively coupled plasma-time-of-flight mass spectrometry (LA-ICP-TOFMS) was applied to clinical samples of patients undergoing platinum-based chemotherapy. The platinum accumulation together with the distribution of elements with biological key functions (Mg, P, S, Ca, Fe, Cu and Zn) was studied in central nervous system germ cell tumor (CNS GCT) tissue, which is an aggressive tumor type located in the brain. Heterogeneous elemental distribution patterns were obtained with a pixel size of 10 μm and were correlated to histological analysis of serial sections using hematoxylin eosin staining. Highest platinum accumulation correlated with areas of necrosis, which exhibited high levels of magnesium, sulphur and calcium. Small traces of gadolinium were found in the tumor sections, which is a result of prior magnetic resonance imaging. Iron accumulated in regions, which were dense in blood vessels, whereas areas with fibrosis scar showed the lowest levels of all detected elements. This LA-ICP-TOFMS study demonstrates that the chemotherapeutic drug cisplatin accumulated in the germ cell tumor located in the brain, which is also reflected by the therapy response of the patients.

Manifestaciones endocrinas de los tumores germinales del sistema nervioso central en niños

IntroductionCentral nervous system germ cell tumors need to be adequately diagnosed because their treatment is usually effective and they do not always require surgery. The study objectives are to describe the endocrine manifestations of these tumors and to compare the time of their onset to that of the occurrence of neurological and visual changes. Patients and methodsThe medical histories of patients under 14 years of age seen at a pediatric endocrinology unit between 2000 and 2018 were reviewed. Wilcoxon and Fisher statistical tests were performed. ResultsWe found 12patients (10 females) with an age at diagnosis of 9.4±1.7 years and a follow-up time of 5.5±3.0 years, 10with tumors in the sellar region, and each one with a pineal gland and a bifocal tumor. Clinical changes leading to diagnosis were neurological and/or visual in 9patients and hormonal in three. Seven patients diagnosed on the basis of neurological or visual symptoms had previously reported hormonal changes, giving us a total of 10 children at diagnosis (the most common diagnosis was central diabetes insipidus, found in 8). Endocrine symptoms had been present before diagnosis for 25.0±26.2 months, considerably longer than neuro-ophthalmological complaints (2.0±2.1 months, p=0.012). ConclusionsAlmost all intracranial germ cell tumors have associated endocrine manifestations at diagnosis, with central diabetes insipidus the most common. Hormonal symptoms usually appear long before neuro-ophthalmological manifestations. Adequate clinical and endocrinological assessment may allow for an earlier diagnosis of these tumors.

Comparison on epidemiology, tumor location, histology, and prognosis of intracranial germ cell tumors between Mayo Clinic and Japanese consortium cohorts.

Central nervous system (CNS) germ cell tumors (GCTs) are rare malignant neoplasms that arise predominantly in adolescents and young adults. CNS GCTs demonstrate characteristic trends in national associations, with implications for both tumor incidence and genetics. Although the incidence of CNS GCTs is markedly higher in East Asia than Western countries, direct comparative analyses between these CNS GCT populations are limited. In Japan, to facilitate the genomic analyses of CNS GCTs, the Intracranial Germ Cell Tumor Genome Analysis Consortium was established in 2011, and more than 200 cases of GCTs are available for both tumor tissue and clinical data, which is organized by the National Cancer Center (NCC) Japan. At the Mayo Clinic, there have been 98 cases of intracranial GCTs treated by the Department of Neurologic Surgery since 1988. In this paper, the authors compared the epidemiology, clinical presentation including location and histology, and prognosis between cases treated in the US and Japan. There was no significant difference in age and sex distributions between the databases. However, there was a significant difference in the tumor locations; specifically, the frequency of basal ganglia was higher in the NCC database compared with the Mayo Clinic (8.4% vs 0%, p = 0.008), and bifocal location (neurohypophysis and pineal gland) was higher at the Mayo Clinic than at the NCC (18.8% vs 5.8%, p = 0.002). There was no difference in histological subdivisions between the databases. There was no difference in progression-free survival (PFS) and overall survival (OS) of germinoma cases and OS of nongerminomatous GCT (NGGCT) cases treated with chemotherapy and radiation therapy covering whole ventricles. However, PFS of NGGCTs differed significantly, and was better in the NCC cohorts (p = 0.04). There appears to be a differential distribution of GCTs by neuroanatomical location between major geographic and national groups. Further study is warranted to better characterize any underlying genomic, epigenetic, or environmental factors that may be driving the phenotypic differences.

Long-term outcome of and prognostic factors for the primary central nervous system germ cell tumors

Long-term outcome of and prognostic factors for the primary central nervous system germ cell tumors