CNS Germ Cell Tumors Research Articles

NCOG-73. EFFECT OF TIME TO DIAGNOSIS IN CHILDREN WITH MALIGNANT CENTRAL NERVOUS SYSTEM TUMORS ON SURVIVAL OUTCOMES AND DISEASE-ASSOCIATED MORBIDITY: AN INSTITUTIONAL COHORT STUDY

Abstract OBJECTIVE To determine the impact of time to diagnosis on disease related morbidity and mortality. METHODS This is a retrospective review of all diagnoses of malignant CNS tumors in children presenting to BC Children’s Hospital (BCCH) from 2000-2019. Analyses were conducted to assess the relationship between time to diagnosis and overall survival as well as long-term morbidity; stratified by tumor type, age and presence of metastatic disease. RESULTS From 2000-2019, there were 116 children diagnosed with malignant CNS tumors at BCCH (mean age 9.5 years, 67% male). Tumors included medulloblastoma (27, 23.3%), ependymoma (14, 12.1%), high grade gliomas (19, 16.4%), CNS germ cell tumors (40, 34.4%), and other embryonal CNS tumors (16, 13.8%). Median time to diagnosis from first symptom onset was 63 days (IQR 26.5 – 237.5 days). 18% had metastatic disease. Within this cohort, 3-year EFS was 57%, and 5-year overall survival was 78.4%. 64% of patients were alive with no evidence of disease at median follow up from treatment completion of 4.31 years (IQR 1.77 – 6.15 years). Long-term morbidity included panhypopituitarism (20.7%), vision loss(22.4%), hearing loss(30.2%), learning disability(17.2%) and cognitive impairment (19.8%). In a cox proportional hazards model, overall survival was associated with time to diagnosis(estimate 0.0271;SE=1.6500;p=0.028), high grade glioma(estimate 8.3200; SE=0.6650; p=0.001), age at diagnosis(estimate 0.8590; SE=0.0532; p=0.004), relapse (estimate 4.9600; SE=0.6100; p=0.009) and metastatic disease (estimate 9.1700; SE=0.5660; p< 0.001). Vision loss was also significantly correlated with time to diagnosis (estimate 0.542; SE=0.2940; p=0.038). CONCLUSION Median time to diagnosis is associated with overall survival and long-term morbidity in pediatric patients treated for malignant CNS tumors. These data highlight that knowledge translation to the public, primary care and emergency room professionals should be a priority in order to promote early connection with medical care and mitigate morbidity and mortality in those with pediatric CNS 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.

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.

P14.47 Tissue immune markers for central nervous system germinoma

Abstract BACKGROUND Germinoma is the commonest CNS germ cell tumor. An important histological feature is prominent immune cell infiltrates. The composition of such immune cell infiltrates remains under-investigated in the literature. MATERIAL AND METHODS We collected a cohort of 40 cases of intra-cranial germinomas and examined the clinical and histopathological features. The tumor infiltrating immune cells were characterized by immunohistochemistry and image analysis. RESULTS Across the cohort, the mean positivity ± SE of CD3-positive T cell and CD20-positive B cells was 31.2% ± 3.1% and 15.2% ± 2.2%, respectively (p<0.001). The mean positivity of CD4-positive T helper cell and CD8-positive cytotoxic T cell was 19% ± 2.3% and 14.3% ± 1.7%, respectively (p<0.001). PD-L1 expression was detected in 50% of the cases and was observed exclusively in immune cells but not in neoplastic cells. Germinomas with positive PD-L1 expression had significantly more abundant CD3-positive T cells (p=0.001), CD4-positive T helper cells (p<0.001) and CD8-positive cytotoxic T cells (p=0.004) as compared with those lacking PD-L1 expression. Immunostain for HLA-A and HLA-B revealed loss of HLA class I expression occurring in 92.5% of the germinomas. Loss of HLA class I expression was associated with less abundant CD3-positive T cells (p=0.04). CONCLUSION Taken together, the predominant T cells infiltrate and PD-L1 expression suggest anti-PD-L1 therapeutic agents as potential novel treatment option for germinoma patients. The loss of HLA class I may represent one of the mechanisms for tumor immune escape in germinoma.

Eye Movement Abnormalities in CNS Germ Cell Tumors (P1.6-027)

Eye Movement Abnormalities in CNS Germ Cell Tumors (P1.6-027)

T2*-based MR imaging (gradient echo or susceptibility-weighted imaging) in midline and off-midline intracranial germ cell tumors: a pilot study.

The role of T2*-based MR imaging in intracranial germ cell tumors (GCTs) has not been fully elucidated. The aim of this study was to evaluate the susceptibility-weighted imaging (SWI) or T2* gradient echo (GRE) features of germinomas and non-germinomatous germ cell tumors (NGGCTs) in midline and off-midline locations. We retrospectively evaluated all consecutive pediatric patients referred to our institution between 2005 and 2016, for newly diagnosed, treatment-naïve intracranial GCT, who underwent MRI, including T2*-based MR imaging (T2* GRE sequences or SWI). Standard pre- and post-contrast T1- and T2-weighted imaging characteristics along with T2*-based MR imaging features of all lesions were evaluated. Diagnosis was performed in accordance with the SIOP CNS GCT protocol criteria. Twenty-four subjects met the inclusion criteria (17 males and 7 females). There were 17 patients with germinomas, including 5 basal ganglia primaries, and 7 patients with secreting NGGCT. All off-midline germinomas presented with SWI or GRE hypointensity; among midline GCT, all NGGCTs showed SWI or GRE hypointensity whereas all but one pure germinoma were isointense or hyperintense to normal parenchyma. A significant difference emerged on T2*-based MR imaging among midline germinomas, NGGCTs, and off-midline germinomas (p < 0.001). Assessment of the SWI or GRE characteristics of intracranial GCT may potentially assist in differentiating pure germinomas from NGGCT and in the characterization of basal ganglia involvement. T2*-based MR imaging is recommended in case of suspected intracranial GCT.

GERM-02. IMMUNOHISTOCHEMICAL EVALUATION FOR THE PATHOGENESIS OF INTRACRANIAL GERM CELL TUMORS: EXPRESSION OF PLURIPOTENCY AND CELL DIFFERENTIATION MARKERS

Abstract INTRODUCTION: Primary intracranial germ cell tumors (iGCT) are rare neoplasms that occur in children and adolescents. This study examined both the pathogenesis and the origin of these tumors, as it has been hypothesized that they originate from a totipotent primordial germ cell. MATERIALS AND METHODS: We applied recent knowledge from gonadal germ cell tumors and analyzed expression of a wide panel of stem cell-related proteins(C-KIT, OCT-3/4 (POU5F1), NANOG, SOX2, CD30 and PLAP). Expression shown by immunohistochemistry was analyzed in 12 children and young adults with iGCT, contributing to a careful description of these unusual tumors and adding to the understanding of pathogenesis. RESULTS: Immunohistochemistry showed 5/5 positive in Oct3/4, 5/5 in NANOG, 9/9 in C-KIT and 1/5 in SOX2. All cases that showed positive staining in Oct3/4 or NANOG indicated that the tumors contained germinoma or embryonal carcinoma component. Immunohistochemistry revealed that stem cell related proteins were highly expressed in iGCT, and many similarities were detected with their gonadal equivalents, including a close similarity with primordial germ cells. CONCLUSION: The expression of genes associated with embryonic stem cell pluripotency in CNS germ cell tumors strongly suggests that these tumors are derived from cells that retain, at least partially, an embryonic stem cell-like phenotype, which is a hallmark of primordial germ cells. In addition, these data can be applied to stratify iGCT for treatment strategy in order to provide good survival rate and good functional outcome.

Outcomes for pediatric patients with central nervous system germ cell tumors treated with proton therapy

PurposeWe assessed outcomes after proton therapy (PT) for central nervous system germinomas or non-germinomatous germ cell tumors (NGGCTs) in children. Patients and methodsWe identified children with germ cell tumors of the central nervous system who received proton therapy in 2006–2009 and extracted information on tumor response, treatment failures, and toxicity. ResultsOf the 20 identified patients (median age 12years [range 3–16]), 9 had germinoma and 11 NGGCTs; 19 patients received three-dimensional conformal PT and 1 scanning-beam PT. Fourteen patients had craniospinal irradiation (CSI), 4 had ventricular irradiation that excluded the 4th ventricle, and 2 had whole-ventricle irradiation. All received involved-field boosts. At a median follow-up interval of 5.6years (range, 0.3–8.2years), 1 patient with germinoma had an out-of-field failure in the 4th ventricle and 2 with NGGCT died from disease progression after CSI. Rates of local control, progression-free survival, and overall survival at 5years were 89%, 89%, and 100% for patients with germinoma; corresponding rates for NGGCTs were 82%, 82%, and 82%. The most common late toxicity (9 patients [45%]) was endocrinopathy. ConclusionsPT for CNS germ cell tumors is associated with acceptable disease control rates and toxicity profiles.

The High Prevalence of Functional Complement Defects Induced by Chemotherapy.

To date, oncology patients are more dependent on non-cellular host defense against pathogens due to intensive (chemo)therapy-related bone marrow suppression. Since data on complement functionality in oncology patients are limited, we aimed to investigate the innate complement function in relation to the type of malignancy and therapy in a longitudinal cohort of patients. A large single-center, prospective non-intervention study was conducted, in which blood samples were taken from patients before, during, and after treatment with chemotherapy and/or subsequent admittance for (febrile) neutropenia. Analysis of 48 patients showed a high percentage of defects in complement activity of the alternative pathway (19.1%), the classical pathway (4.3%), or both (42.6%). Post hoc analysis of six different treatment protocols with more than three patients each showed distinct effects of specific therapies. Whereas patients treated according to the Ewing, EpSSG-rhabdomyosarcoma, or SIOP CNS germ cell tumor protocol showed no defects, patients treated according to the ALL-11 (leukemia), the EURAMOS I (osteosarcoma), or the ACNS (medulloblastoma) protocols showed an almost universal reduction in complement function. Although we could not explain the reduced complement functionality under all conditions, a strong effect was observed following high-dose methotrexate or ifosfamide. Acquired complement defects were commonly observed in more than 50% of oncology patients, some of which associated with certain chemotherapeutic drugs. Additional studies are needed to determine the clinical and therapeutic context of complement defects and their possible effect on treatment outcome or the increased risk of infection.

CNS Germ Cell Tumors: A Clinical Review and Future Directions

CNS germ cell tumors (GCT) are rare tumors that arise in midline brain regions (mostly pineal or suprasellar). They are of two types, germinoma and nongerminomatous GCT (NGGCT) which include teratoma, choriocarcinoma, yolk sac, embyronal carcinoma and mixed GCT. Tissue is needed for diagnosis unless serum or cerebrospinal fluid markers, b-HCG or AFP, are elevated. Germinomas can be cured with radiation therapy (RT) alone (whole ventricle fields, if localized), but chemotherapy may permit RT dose-reduction. Best outcomes for NGGCT are with RT and chemotherapy. Craniospinal RT is needed for all disseminated tumors and best survival for localized NGGCT has included craniospinal RT. Recent genetic findings in CNS GCT may lead to therapies targeting their oncogenic pathways.

Psychiatric manifestations as initial presentation for pediatric CNS germ cell tumors, a case series

Psychiatric manifestations as initial presentation for pediatric CNS germ cell tumors, a case series

A New Microbeam Scanned Proton Therapy Option and Example CNS Germ Cell Tumor Treatment Planning Exercise With Improved Cognitive Sparing

A New Microbeam Scanned Proton Therapy Option and Example CNS Germ Cell Tumor Treatment Planning Exercise With Improved Cognitive Sparing

Abstracts From the 4th International CNS Germ Cell Tumor Symposium

Abstracts From the 4th International CNS Germ Cell Tumor Symposium

Neoadjuvant chemotherapy against newly diagnosed CNS germ-cell tumors: A case report

Intracranial germ cell tumors (GCTs) are rare brain tumors that typically arise in the pineal or suprasellar regions. A young man (22 years old) was presented with complaint of one year of headache, and recently vomiting, and in exam papilledema, lethargy, somnolence, diabetes insipidus. A Phase II trial with carboplatin based regimen was conducted in this newly diagnosed patient histologically and was confirmed radiologically evaluable CNS germinomas before they received radiotherapy. This patient was presented with a localized hypothalamic germinoma and had a CR after two courses of carboplatin based regimen (the CEB regimen). He received 30 Gy of involved field radiotherapy and now at end of treatment after three months is well being without any sign of relapse. Neoadjuvant chemotherapy carboplatin based regimen was highly active in treating newly diagnosed CNS germinomas. Further chemotherapy studies eventually may permit additional dose reductions and/or elimination of radiotherapy for patients with CNS germinomas.

PT-04 * PRELIMINARY RESULTS OF A PHASE I/II STUDY OF INTRA-ARTERIAL CHEMOTHERAPY WITH OSMOTIC BLOOD-BRAIN BARRIER DISRUPTION FOR PATIENTS WITH RECURRENT OR PROGRESSIVE CNS EMBRYONAL OR GERM CELL TUMORS

INTRODUCTION: Patients with refractory or recurrent CNS embryonal or germ cell tumors have poor prognosis and survivors suffer neuropsychological sequalae from radiotherapy and ototoxicity from chemotherapy. Prior retrospective studies suggest intra-arterial (IA) chemotherapy in conjunction with blood-brain barrier disruption (BBBD) may improve outcomes in patients with these challenging tumors. METHODS: In this prospective study, patients aged 1 to 30 with recurrent or refractory CNS embryonal or germ cell tumors were treated on 2 consecutive days, every 4 weeks, for up to a year with dose intensive IA carboplatin and IA melphalan with BBBD. The study objectives are to: determine the maximum tolerated dose of IA melphalan, estimate response rate, describe 2-year progression-free and overall survival, describe audiology and neuropsychological outcomes and describe overall toxicity. RESULTS: Nine patients were enrolled in the study (6 male) with a mean age was 14.75 years. There were three patients with medulloblastoma, two with atypical teratoid rhabdoid tumor, two with germ cell tumors, one with metastatic testicular teratoma, and one with PNET. The majority of patients thus far were treated at a melphalan dose of 6 mg/m2 for two days. Of the study participants two had stable disease, three had partial response, and three had disease progression. There were a total of 16 adverse events of grades three and higher with the majority being grade 3(63%). The most common adverse event was electrolyte disorder in 38% of patients, and bone marrow suppression in 25% of patients. CONCLUSIONS: This therapy is well tolerated and appears safe. The current melphalan dose is 6 mg/m2. Toxicity is predominantly related to electrolyte disturbances and bone marrow suppression. There appears to be a subgroup that responds to this therapy but further investigation is needed. The trial continues with further enrollment.

Childhood cancer incidence and survival 1985-2009, Khon Kaen, Thailand.

The Khon Kaen Cancer Registry (KKCR) was established in 1984. Previous population-based incidences and survivals of childhood cancer in Thailand were determined using a short cancer registration period. Data were retrieved of all children residing in Khon Kaen, between 0-15 years, diagnosed as having cancer and registered in the KKCR (1985-2009). The follow-up censored date was December 31, 2012. The childhood cancers were classified into 12 diagnostic groups, according to the International Classification of Childhood Cancer. The incidence was calculated by the standard method. Survival of childhood cancer was investigated using the KKCR population-based registration data and overall survival calculated using the Kaplan Meier method. In the study period, 912 newly diagnosed cases of childhood cancer were registered. The respective mean and median age was 6.4 (SD=4.6) and 6 (0-14) years. The age-peak for incidence was 0-4 years. The age-standardized rate (ASR) was 83 per million. Leukemia was the most common cancer (N=360, ASR 33.8) followed by neoplasms of the central nervous system (CNS, N=150, ASR 12.8) and lymphoma (N=79, ASR 7.0). The follow-up duration totaled 101,250 months. The death rate was 1.11 per 100 person-months (95%CI: 1.02 -1.20). The 5-year overall survival was 52% (95%CI: 53-56.9) for all cancers. The respective 5-year overall survival for (1) acute lymphoblastic leukemia (ALL), (2) acute non-lymphoblastic leukemia (ANLL), (3) lymphoma, (4) germ cell tumors, (5) renal tumors, (6) retinoblastoma, (7) soft tissue tumors, (8) CNS tumors, (9) bone tumors, (10) liver tumors, and (11) neuroblastoma was (1) 51%, (2) 37%, (3) 63%, (4) 74%, (5) 67%, (6) 55%, (7) 46%, (8) 44%, (9) 36%, (10) 34%, and (11) 25%. The incidence of childhood cancer is lower than those of western countries. Respective overall survival for ALL, lymphoma, renal tumors, liver tumors, retinoblastoma, soft tissue tumors is lower than that reported in developed countries while survival for CNS tumors, neuroblastoma and germ cell tumors is comparable.

Marker (+) CNS germ cell tumors in remission: Are surveillance MRI scans necessary?

Patients with marker (+) CNS germ cell tumors are usually followed with both surveillance MRI scans and serum tumor markers. We hypothesized that patients with elevated serum tumor markers at diagnosis who achieve a complete biochemical and radiological remission may not need surveillance MRI scans. We retrospectively identified 31 patients with CNS germ cell tumors who presented with an elevated serum tumor marker at the time of diagnosis. We reviewed the records of those patients who (1) achieved a complete biochemical and radiological remission and (2) later suffered tumor recurrence to determine whether the recurrence was detectable biochemically, radiologically, or via both modalities. Nine patients suffered tumor recurrence following initial remission. All 9 had elevated serum tumor markers at recurrence and 8 had MRI evidence of recurrence. The 1 patient with isolated biochemical evidence of recurrence developed MRI evidence of recurrence 15 months later without intervening treatment. One other patient (not one of the 9) had a secondary malignancy (anaplastic astrocytoma) identified by brain MRI scan. Patients with CNS germ cell tumors who present with elevated serum tumor markers at diagnosis and achieve a complete biochemical and radiological remission may not need surveillance MRI scans to monitor for recurrence, but MRI scans may be considered to monitor for secondary malignancy. If other series replicate these findings, surveillance via monitoring of serum tumor markers only could be done and omission or reduction of the frequency of surveillance MRI scans could save a significant amount of money.

Manifestations of CNS germ cell tumors

Sethi et al collected data retrospectively on symptoms, as well as time to and method of diagnosis, in 70 pediatric patients with an intracranial germ cell tumor (GCT) cared for at the Massachusetts General Hospital from 1998 to 2012. Forty patients had a pure germinoma (PG) and 30 had a nongerminomatous GCT. More than one-half of patients were evaluated by one or more pediatric subspecialists prior to diagnosis and more than one-half of patients had a delay of ≥6 months from onset of symptoms to the diagnostic magnetic resonance imaging study.

Primary CNS germ cell tumors in Japan and the United States: an analysis of 4 tumor registries

Intracranial germ cell tumors (GCTs) are relatively rare. Their incidence has been considered to be higher in East Asia than in the United States. This study estimates the incidence of CNS GCTs in Japan and the United States, investigates gender discrepancies in each country, and describes treatment outcomes. Data on primary CNS GCTs from 4 databases were utilized: population-based malignant incidence data from (1) the Japan Cancer Surveillance Research Group (2004-2006; 14 registries), malignant and nonmalignant incidence data from (2) the Surveillance, Epidemiology, and End ResultsProgram (2004-2008; 17 registries), and hospital-based observed survival data from (3) the Brain Tumor Registry of Japan (1984-2000) and (4) the US National Cancer Data Base (1990-2003). Incidence rates per 100 000 for malignant GCTs were not statistically significantly different between Japan (males = 0.143, females = 0.046) and the United States (males = 0.118, females = 0.030). The malignant incidence-rate ratio was higher for pineal GCTs versus nonpineal (ie, the rest of the brain) GCTs in Japan (11.5:1 vs 1.9:1, respectively) and the United States (16.0:1 vs 1.7:1, respectively). In general, 5-year survival estimates were high: over 75% for all GCTs, and over 81% for germinomas, regardless of the type of treatment in either Japan or the United States. The incidence of primary GCTs is similar between Japan and the United States and has the same gender-based patterns by location. High rates of survival were observed in both countries.

Insights revealed by high-throughput genomic arrays in nonglial primary brain tumors

Primary CNS tumors (PCNSTs) encompass a broad and heterogeneous group of tumors, including gliomas, meningiomas, embryonal tumors, primary CNS lymphomas, CNS germ cell tumors and sellar region tumors. In recent decades, research has focused on understanding the clinical and biological significance of molecular abnormalities detected in PCNSTs. The emergence of genomic arrays, including comparative genomic hybridization and SNP arrays, have helped in the discovery of novel critically important genes and novel genomic biomarkers involved in PCNST oncogenesis (e.g., BRAF duplication in pilocytic astrocytoma). Since a summary of data from genomic arrays using gliomas has been described in a previous review, in this article we will focus on the insights provided by genome-wide DNA arrays in the genetics and genomics of nonglial PCNSTs in adults. The high-throughput assessment of gene copy-number abnormalities has improved our knowledge of molecular pathogenesis in nonglial PCNSTs, allowing for the identification of new candidate genomic regions and genes involved in tumorigenesis. These chromosome imbalances provide a promising insight into potential targets for innovative drugs and new interesting diagnostic and prognostic biomarkers for clinical practice.