Central Nervous System Germ Cell Tumors Research Articles

Central nervous system tumors in adolescents and young adults: A Society for Neuro-Oncology consensus review on diagnosis, management, and future directions.

Adolescents and young adults (AYAs; ages 15-39 years) are a vulnerable population facing challenges in oncological care, including access to specialized care, transition of care, unique tumor biology, and poor representation in clinical trials. Brain tumors are the second most common tumor type in AYA, with malignant brain tumors being the most common cause of cancer-related death. The 2021 WHO Classification for central nervous system (CNS) Tumors highlights the importance of integrated molecular characterization with histologic diagnosis in several tumors relevant to the AYA population. In this position paper from the Society for Neuro-Oncology (SNO), the diagnosis and management of CNS tumors in AYA is reviewed, focusing on the most common tumor types in this population, namely glioma, medulloblastoma, ependymoma, and CNS germ cell tumor. Current challenges and future directions specific to AYA are also highlighted. Finally, possible solutions to address barriers in the care of AYA patients are discussed, emphasizing the need for multidisciplinary and collaborative approaches that span the pediatric and adult paradigms of care, and incorporating advanced molecular testing, targeted therapy, and AYA-centered care.

GCT-15. CLINICAL AND MOLECULAR CHARACTERIZATION OF INFANTILE CENTRAL NERVOUS SYSTEM GERM CELL TUMORS

Abstract BACKGROUND The management of infantile central nervous system germ cell tumors (CNS-GCTs) presents unique challenges, including variable clinical presentations such as tumor size and propensity for hemorrhage. Moreover, data on the clinical and molecular features remain limited. METHODS We conducted a clinical and molecular analysis of CNS-GCTs in children aged 6 years or younger, registered with the Japan Children’s Cancer Group and the iGCT consortium. DNA methylation analysis was performed using the Illumina Methylation EPIC array to identify potential molecular prognostic indicators. RESULTS The cohort comprised 43 patients, with a median age at onset of 6.5 months (0–68 months). Notably, 23 patients (54%) were diagnosed before 1 year of age. The male-female ratio was 27:15. Most common tumor location was cerebellum (13 cases). The median AFP level was 538 ng/ml (0–206460). Pathologically, the tumors were predominantly diagnosed as teratomas and yolk sac tumors. Teratomas were more common in patients diagnosed before 1 year of age, while mixed GCTs were more frequent in those diagnosed after 3 years. Molecular analysis identified four cases as embryonal tumors, including three AT/RTs and one DICER1-mutant intracranial sarcoma. The 3-year overall survival rates varied significantly by diagnosis: mixed GCTs at 100%, teratomas at 90.6%, yolk sac tumors at 30.0%, and embryonal tumors at 0%. Notably, two patients with teratomas developed metachronous tumors more than 10 years post-diagnosis, with both secondary tumors exhibiting mutations in the MAPK pathway absent in the primary tumors. CONCLUSION Infantile CNS-GCTs exhibit distinct clinical and molecular profiles compared to those in older children and adults. Not all tumors classified as GCTs based on molecular characterization were GCTs; some were embryonal tumors, potentially impacting treatment strategy. The genetic analysis suggests that some metachronous GCTs may represent second primary tumors rather than recurrences.

GCT-01. CENTRAL NERVOUS SYSTEM GERM CELL TUMORS – GENERATING A CONSENSUS IN THEIR DIAGNOSIS AND MANAGEMENT

Abstract BACKGROUND Despite the excellent outcomes of central nervous system (CNS) germ cell tumors (GCTs), there still exists significant differences in how GCTs are diagnosed and managed in different parts of the world. Additionally, the long-term toxicities and morbidities of the current therapies, and their substantial negative impact on the social wellbeing of our patients should clearly indicate that the current achievements are not enough. Further, important molecular data have emerged over the past decade that we have not witnessed their translation into any of the ongoing clinical trials. METHODS A comprehensive review of all major CNS GCT clinical trials will be discussed, in addition to a detailed review of the several issues of debate. Moreover, the latest developments in molecular landscape of GCTs will be provided in order to identify the hurdles that affect their incorporation in GCT clinical trials. RESULTS Tumor marker cut-offs that differentiate between germinoma and non-germinomatous germ cell tumors are clearly different between the various groups around the world. Additionally, differences exist in the chemotherapy backbones, radiation therapy field and dose, and the appropriate regimens to treat some of the rarer GCTs. Furthermore, there is no clear guideline on how to treat patients who do not achieve complete response after chemotherapy. CONCLUSIONS Discussing the clear differences that exist in the diagnosis and management of CNS GCTs is a critical first step in generating a clear consensus between the North American, European, Asian, and Latin American groups, which will certainly guide future clinical trials, improve the outcomes as well as the long-term treatment effects for this group of patients.

GCT-10. OUTCOME OF CHILDREN AND ADOLESCENTS DIAGNOSED WITH GERMINOMA WITH HCGΒ VALUES BETWEEN 100-200 MUI/ML TREATED ACCORDING TO THE BRAZILIAN CNS GCT PROTOCOL

Abstract BACKGROUND Primary central nervous system (CNS) germ cell tumors (GCT) are rare tumors, classified according to histological components and tumor markers (TM) as Germinomas and Non-Germinomatous Germ Cell Tumors (NGGCT). The aim of this study is to assess the outcome of patients with Germinoma and HCGβ levels between 100-200mIU/ml treated according to the Brazilian CNS GCT Consortium Protocol. METHODS From 2013 to 2021, forty-three patients presented with histological and/or TM (serum and CSF) consistent with the diagnosis of germinoma, five of them with HCGβ levels between 100-200mIU/ml. The treatment plan performed was four cycles of carboplatin/etoposide followed by whole ventricular field irradiation (WVFI) of 18Gy with a boost to primary site(s) up to 30Gy and 24Gy craniospinal irradiation (CSI) for disseminated disease. RESULTS Average age 13.7 years (6.3-20.3 years), four males and one female. Diagnosis was made by TM (n=2), and biopsy +TM (n=3). The primary tumor location was pineal (n=2), suprasellar (n=1), and bifocal (n=2) with 1 case presenting ventricular spread at diagnosis. Three patients achieved complete response (CR) after two cycles of chemotherapy and one after four cycles. One patient showed partial radiological response (PR) with negative TM after four cycles and was submitted to a second-look surgery, with pathological report of residual scar tissue. Radiotherapy was performed as described in all patients with four patients receiving WVFI (18Gy+30Gy) and one CSI (24Gy+30Gy). In a mean follow-up of 64 months, overall and event-free survival was 100%. CONCLUSION Despite the small sample, the present study shows effectivity with excellent results and a possibility of increasing the cutoff and therefore reducing treatment for patients with HCGβ at levels up to 200mlU/ml currently treated in some protocols as NGGCT cases.

GCT-16. LONG-TERM OUTCOMES AND COMPLICATION MANAGEMENT IN CNS GERM CELL TUMORS: INSIGHTS FROM A PHASE II HISTOPATHOLOGY-STRATIFIED TREATMENT TRIAL

Abstract BACKGROUND This detailed examination merges outcomes from a Phase II clinical trial targeting central nervous system (CNS) germ cell tumors (GCTs) conducted between 1995 and 2003. It evaluates the impact of histopathologically driven treatment modalities on survival, recurrence, and post-treatment life and social outcomes, aiming to delineate the long-term effects of such stratified treatment approaches. METHODS The cohort comprised 228 patients, stratified into three groups based on histology: germinoma (n=161), intermediate prognosis (n=38), and poor prognosis (n=28), each receiving customized chemotherapy and radiation treatments. With a median follow-up duration of 222 months, this longitudinal study scrutinized survival rates, recurrence patterns, and a spectrum of socio-economic and health-related outcomes. RESULTS For the germinoma group, the 10- and 20-year event-free survival (EFS) rates stood impressively at 82% and 73%, respectively, with overall survival (OS) rates reaching 97% and 92%. The intermediate prognosis group witnessed 10- and 20-year EFS rates of 76% and 66%, and OS rates of 87% and 70%. The poor prognosis group recorded EFS rates of 49% at both intervals, with OS diminishing to 61% and 53%. Notably, germinomas localized in the basal ganglia exhibited high relapse rates absent initial whole-brain radiation, yet were effectively managed upon subsequent interventions. The comprehensive follow-up illuminated striking disparities in socio-economic achievements: higher educational attainments, more stable employment, and improved health outcomes were predominantly observed among patients without recurrence. Non-recurrent germinoma patients, in particular, showcased enhanced educational and employment status, vividly illustrating the profound impact of disease progression and treatment on life quality. CONCLUSIONS The findings highlight the critical importance of customized initial treatments for improving survival and life quality in CNS GCT patients, stressing the need for detailed long-term follow-up to address relapses and complications effectively. The study advocates for personalized care that balances treatment intensity to optimize long-term outcomes, enhancing post-treatment care.

Prognostic implications of distinctive imaging characteristics in primary intracranial germ cell tumors: A retrospective analysis

PurposePrimary central nervous system (CNS) germ cell tumors (GCTs) are rare brain tumors that encompass two subtypes: germinomas and non-germinomatous germ cell tumors (NGGCTs), NGGCTs have less favorable outcome and require multi-modality treatment. Biopsy is recommended for disease diagnosis, the specimen may not adequately reflect the entire tumor. This study aimed to assess distinct imaging characteristics to differentiate between GCT subgroups and to identify possible initial image and subgroup features that influence survival. MethodThis retrospective study, conducted from January 2006 to March 2023, analyzed patient data and MRI findings of primary CNS GCTs. It evaluated tumor characteristics including cysts, seeding, multifocality, and hemorrhage. Tumor volumes and apparent diffusion coefficient (ADC) values of both tumoral and normal-appearing contralateral white matter were measured. These factors were correlated with overall and 5-year survival rates. ResultsThis study included 51 participants with CGTs, comprising 19 germinoma and 32 NGGCTs cases. GCTs with hemorrhage had worse overall (P = 0.03) and 5-year (P = 0.01) survival rates. No survival difference between germinoma and non-hemorrhagic NGGCT. NGGCTs were more likely to bleed (P < 0.001) than germ cell tumor, especially those with choriocarcinoma or yolk sac tumor components (P = 0.001). The ADC ratios of germinomas were significantly lower than those of NGGCTs (P = 0.03 for whole tumor; P < 0.01 or solid part), The ADC ratios of choriocarcinoma were also lower than mixed tumor (P = 0.01; P = 0.02). ConclusionHemorrhage indicates worse prognosis. Intratumoral hemorrhage and ADC ratios differentiate germinoma from NGGCTs. Larger cohorts and advanced MR techniques are needed for future study.

Primary Co-Occurrence of Gonadal and Extragonadal Central Nervous System (CNS) Germ Cell Tumors (GCTs): Case Report and Review of the Literature

Background: The primary co-occurrence of gonadal and extragonadal central nervous system (CNS) germ cell tumors (GCTs) has rarely been reported in the literature, and a common opinion on the underlying etiopathogenetic mechanism is lacking. Objective: We aim to investigate the pathophysiological mechanisms and genetic pathways underlying the primary co-occurrence of gonadal and CNS GCTs. Methods: We reviewed data from 29 consecutive patients with a diagnosis of CNS GCT, evaluated in our Hospital over the past 23 years, and searched for those who had at least a primary gonadal co-occurrence of GCT. A systematic review of the literature according to the PRISMA guidelines was also conducted. For a comprehensive and detailed search, PubMed, Ovid MEDLINE, and Ovid EMBASE databases have been consulted. Boolean operators and MeSH terms were used to find studies. Only articles published between 2000 and 2023 were considered. Results: Including our Institutional case report, a total of 7 patients with both testicular NGGCTs and CNS GCTs were identified (5 patients with metachronous tumors and patients with synchronous presentation). The average age at tumor diagnosis was 17 years. The cerebral histotypes reported were mixed GCTs (3 cases; 43%), pure germinomas (3 cases, 43%), and one yolk sac tumor (14%). Two out of seven cases (29%) were syndromic, one suffering from Down Syndrome and the other from Testicular Dysgenesis Syndrome. Regarding the etiology and molecular mechanism of GCT development, several gene mutations have been reported in the literature. Particularly, genetic alterations in the MAPK and/or PI3K/AKT/mTOR pathway, together with mutations of the KIT gene, have been shown to guarantee survival and transformation of mismigrated totipotent primordial germ cells, while suppressor genes allow their resistance against apoptotic death. Aberrant chromosomes have also been reported to be responsible for oncogenic transformation. It is also known that CNS and testicular GCTs share some genetic/epigenetic profiles. Conclusions: The primary co-occurrence of testicular NGGCT and extragonadal CNS GCTs is extremely rare. Genetic factors seem to play a paramount role in their etiopathogenesis. Additional research is needed to elucidate molecular mechanisms of oncogenesis in such patients.

Clinicopathological spectrum of central nervous system germ cell tumors: A single-institution retrospective study.

Central nervous system germ cell tumors (CNSGCTs) though rare is the second most common extragonadal site for GCTs. To determine the clinicopathological features of CNSGCTs diagnosed at our center. A retrospective study of all histologically diagnosed CNSGCTs, during 2006-2019. The patients' data were retrieved from the hospital information systems and analyzed. Data on categorical variables were analyzed as percentages, and data on continuous variables calculated as mean. Chi-square test or Fisher's exact test was used to study association between variables. Of the total 34 cases with CNSGCT, age ranged from 1 to 27 years, majority in the second decade (19/34; 56%). Male: female (M: F) ratio was 1.6:1. Single site involvement was seen in 27 cases (27/34; 79%), whereas seven (7/34; 21%) showed bi/multifocal involvement. Among the unifocal cases, common sites involved were suprasellar (12/27; 44.4%), closely followed by the pineal (10/27; 37%). All multifocal tumors affected suprasellar compartment, being bifocal with pineal in four cases. A male gender predilection was noted among pineal region (9/10;90%) and multifocal tumors (5/7;71%). Germinoma was the commonest subtype (21/34; 61.8%) with male gender predilection (17/21; 81%) (M: F =4.3:1), with female predilection seen among mixed GCTs (MGCTs) (8/10; 80%) (M: F =1:4) and suprasellar location (M: F =1:2). Serum tumor markers (25 cases) and CSF markers (7 cases) were concordant with histology in all, except two cases. Though histology and immunohistochemistry were diagnostic, correlation between serum and/or CSF marker was essential to rule out GCT component(s) that may be missed on biopsy due to sampling error.

FRI317 Simultaneous Occurrence Of A Pineal Germ Cell Tumor And Pituitary Macroprolactinoma In A Young Male

Abstract Disclosure: E.P. Monsour: None. S. Badour: None. J.M. Munoz Pena: None. W.T. Donahoo: None. Background: Germ Cell Tumors (GCTs) are a group of heterogeneous tumors that derive from pluripotent germ cells and originate in the yolk sac of the embryo in early gestation. They account for 10% of all central nervous system (CNS) GCTs, primarily occurring in the pediatric and adolescent populations. The co-existence of macroprolactinoma and a mixed CNS GCT is extremely rare, with an unknown worldwide prevalence. Here we report a case of a pituitary macroprolactinoma occurring with a separate primary CNS mixed GCT. Clinical Case: A 19-year-old male presented with a 2-month history of headaches associated with nausea and vomiting. Relevant physical exam findings included decreased visual acuity, absent facial and axillary hair, and prominence of the left testis. Brain MRI demonstrated a pituitary adenoma measuring 3.5 x 2.3 x 3.2 cm extending into the cavernous sinus and an enhancing necrotic lesion in the third ventricle measuring 5.0 x 3.7 x 4.9 cm. Testicular ultrasound revealed two sub-centimeter ill-defined masses in the left testis. Pre-operative labs showed intact thyroid, adrenal, and growth hormone axis. He had a low total testosterone [14.2 ng/dl, reference range (RR): 230-800 ng/dL] with inappropriately normal gonadotrophins and markedly elevated prolactin (PRL) level (2,517 ng/mL, RR &amp;lt;14 ng/mL). Testicular tumor marker, alpha-fetoprotein, was elevated (15.3 ng/dL, RR &amp;lt;9 ng/dL). He was started on glucocorticoids for vasogenic edema and cabergoline twice weekly. He underwent left orchiectomy and subsequent pineal tumor resection. Testicular tumor pathology was consistent with teratoma and a well-differential neuroendocrine tumor with negative margins. Pineal tumor pathology was diagnostic of a mixed GCT. Despite optimal medical therapy, the patient ultimately opted to pursue transsphenoidal tumor resection. Pituitary mass pathology was compatible with a pituitary adenoma, immunoreactive for PRL. Post-operative PRL levels decreased to 6 ng/dL. He achieved a surgical cure without the need to restart dopamine agonist therapy. Conclusion: Simultaneous occurrence of primary brain tumors with different pathologies is estimated to be ∼0.9% of all brain tumors. To our knowledge, only one other case report described an adolescent with a craniopharyngioma and intracranial GCT. This is the first report in the literature of a pituitary macroprolactinoma synchronous with a mixed CNS GCT, and testicular well-differential neuroendocrine tumor with teratoma. Presentation: Friday, June 16, 2023

Unraveling the impact of upfront chemotherapy and proton beam therapy on treatment outcome and follow-up in central nervous system germ cell tumors: a single center experience.

Germ cell tumors (GCT) account for a minority of central nervous system (CNS) malignancies, highly prevalent in adolescents and young adults. Despite their aggressive biological behavior, prognosis is excellent in most cases with risk stratified treatment, consisting in a combination of chemotherapy and radiotherapy. Whole ventricular irradiation (WVI) and craniospinal irradiation, the treatment of choice for localized and metastatic disease, pose significant risk of collateral effects, therefore proton beam radiation (PBT) has been recently proposed for its steep dose fallout. We report our experience in a consecutive series of 17 patients treated for CNS GCT at our Institution from 2015 to 2021. Most frequent lesion location were sellar/suprasellar (35%) and bifocal germinoma (35%), followed by pineal (18%) and thalamic (12%). Two patients (12%), had evidence of disseminated disease at the time of diagnosis. At the latest follow-up all but one patient showed complete response to treatment. The only relapse was successfully rescued by additional chemotherapy and PBT. PBT was well tolerated in all cases. No visual, neurological or endocrinological worsening was documented during and after treatment. Neuropsychological evaluation demonstrated preservation of cognitive performance after PBT treatment. Our data, albeit preliminary, strongly support the favourable therapeutic profile of PBT for the treatment of CNS germ cell tumors.

Primary central nervous system germ cell tumors in children and young adults: A review of controversies in diagnostic and treatment approach

Primary central nervous system (CNS) germ cell tumors (GCT) are a rare heterogenous group of cancers, arising most commonly in the second decade of life. Through several clinical trials conducted around the world by various groups, the treatment approach for CNS GCT has advanced substantially with generally improved overall outcomes. In recent years, the goal of clinical trials has been focused on reduction of the radiotherapy burden and minimization of long-term toxicity. This review summarizes the current diagnostic and treatment regimens for CNS GCT, examines the controversies associated with these approaches, gaps in contemporary knowledge, and underscores the challenges we face. We also explore future directions in the management of CNS GCT with the ultimate overall aim of preserving curative outcomes, identifying novel biomarkers, and mitigating neurocognitive, endocrine, and psychological toxicity through prospective clinical studies.

PD-L1 and PD-1 expression in pediatric central nervous system germ cell tumors

Central nervous system (CNS) germ cell tumors (GCTs) represent 2–3% of all primary CNS tumors. The majority are germinomas, which are radiosensitive and have an excellent prognosis. Contrarily, CNS non-germinomatous GCTs (NGGCTs) have less favorable prognosis and require more aggressive treatment. The expression of checkpoint/immune markers in CNS GCTs, particularly NGGCTs, is unknown. We previously reported a case of a patient whose intracranial NGGCT (predominantly choriocarcinoma) responded to immune checkpoint inhibition therapy. This case led us to evaluate our archive of intracranial GCTs for expression of PD-L1 and PD-1. With IRB approval, we searched the pathology archives at our institution for CNS GCTs. Demographic, radiologic, clinical, and histologic information was extracted from the medical records. Immunohistochemistry for lymphocytic markers (CD4, CD8, CD20), PD-1, and PD-L1 was performed. PD-L1 was considered positive if greater than 1% of tumor cells were positive and PD-1 was reported as a percentage of positive inflammatory cells. Fifty cases were identified, including 28 germinomas (mean age at diagnosis: 15.5 years; 17 males, 11 females), and 22 NGGCTs (mean age at diagnosis: 12.0 years, 21 males, 1 female). Germinomas were mostly suprasellar (17/28) and NGGCTs were predominantly pineal (17/22). Twenty-two germinomas (79%) were positive for PD-L1 expression, and 13 NGGCTs (57%) were positive for PD-L1. Cases of choriocarcinoma showed the most diffuse PD-L1 expression. PD-1 expression was seen in lymphocytes among 27/28 of the germinomas and 20/23 of the NGGCTs (ranging from 1–40% of lymphocytes). As expected, larger quantities of inflammatory cells were present in cases of germinoma. We demonstrate immune activity in CNS GCTs, and our results suggest that immune checkpoint inhibitors may be efficacious in the treatment of intracranial GCTs. Among NGGCTs, cases of choriocarcinoma showed the highest expression of PD-L1 in tumor cells, suggesting that this subtype may have the greatest benefit from checkpoint blockade.

Intracranial germinoma in the lateral ventricle with polydipsia and polyuria: a case report and literature review.

Central nervous system germ cell tumors (CNSGCTs) are rare neoplasms which usually develop in the midline structures. They are occasionally involved in off-midline structures of the brain. Here, we report an extremely rare case of an intracranial germinoma in the lateral ventricle. The patient was a 10-year-old boy with a 1-year history of polydipsia and polyuria. Brain magnetic resonance imaging (MRI) showed a relatively homogeneously enhancing lesion in the lateral ventricle, and the posterior pituitary gland was not hyperintense on T1-weighted imaging. Subependymoma was suspected, and tumor removal operation was performed; however, because the intraoperative pathological investigation revealed germinoma, we could only perform partial removal of the tumor. Postoperative histology also confirmed germinoma. Then, the patient received chemotherapy, followed by radiation therapy. MRI showed no recurrence for 6years after treatment. Intracranial germinoma in the lateral ventricle is extremely rare. The diagnosis is occasionally challenging, especially when the tumors are located in atypical locations. This paper presents a literature review of previously described CNSGCTs of the lateral ventricle to improve awareness of CNSGCTs in atypical locations. We also consider the relationship between imaging findings and clinical manifestations.

LINC-22. Primary central nervous system (CNS) germ cell tumors (GCT) in Central America and the Caribbean region: an AHOPCA 20-year experience

BACKGROUND: Primary CNS GCT are rare neoplasms in pediatrics. Treatment depends on histological subtype and extent of disease. Overall survival (OS) is above 85% in high-income countries (HIC). OBJECTIVE: To describe the experience in treating CNS GCT in 4 of 8 countries, members of AHOPCA (Asociación de Hemato-Oncología Pediátrica de Centro América) and 5-year OS. DESIGN/METHODS: We conducted a retrospective chart review of patients treated for CNS GCT. Epidemiological, clinical characteristics, histology, treatment modalities and outcome were analyzed. RESULTS: From 2001 to 2021, 45 patients were included. Guatemala: 22, Nicaragua: 15, Dominican Republic: 3 and El Salvador: 5. Thirty (66.6%) were male, mean age at diagnosis was 8.6 years (range 12 months to 17 years). Presenting symptoms were headaches/vomiting (n=26, 57.7 %), visual disturbances (n=15, 33.3%), diabetes insipidus (n=7, 15.5%). Two patients (NGGCT) presented with precocious puberty. Upfront surgery was done in 33 cases (73.33%); 21 (63.6%) germinomas, 9 (27.2%) NGGCT and 3 (9%) CNS GCT. Eight patients were diagnosed and treated based on CSF tumor marker elevation; four germinomas (BHCG 11.32-29.41mUI/mL) and four NGGCT (BHCG 84.43-201.97mUI/mL or positive AFP>10 ng/mL). Tumor locations included suprasellar (n=15, 33.3%), pineal (n=14, 31.1%), thalamus/basal ganglia (n=5, 11%), other (n=6, 13.3%); and one bifocal. Four (8.8%) had metastatic disease, 6 with positive CSF, staging data was incomplete in 25 patients (55.5%). Patients were treated with varied chemotherapy and radiotherapy modalities. Nine patients had incomplete data regarding treatment. Five-year OS was 65% (61.5% for germinoma and 56% for NGGCT). Two patients with histologically confirmed germinoma relapsed. CONCLUSIONS: Germinoma was the most common histology and there was a male predominance. More than half patients had incomplete staging data and treatment was variable. OS is lower compared to HIC. Standardized treatment protocols will aid in adequate staging, treatment planning, prevent complications and improve survival.

GCT-18. Endoscopic third ventriculostomy (ETV) and tumor biopsy are not associated with relapse rate or patterns in primary central nervous system (CNS) germ cell tumor (GCT)

Abstract BACKGROUND: ETV and tumor biopsy are central to the surgical management of children with primary CNS GCT. An ETV creates a communication between the intraventricular compartment and the subarachnoid spaces and decompartmentalizes the ventricular system. “Tumor spill” or shedding may result from surgical interventions, such as biopsy. ETV with simultaneous biopsy may impart a greater tendency for dissemination and possible distant relapse. This is a concern in CNS GCT given the attempts of irradiation field and dose reduction following chemotherapy. METHODS: We performed a retrospective review of the prospective database for the Children’s Oncology Group (COG) ACNS1123 study. Possible associations were explored among ETV, endoscopic biopsy, and combined ETV+biopsy with relapse, distant relapse, progression free survival (PFS), and time to distant relapse. RESULTS: Among 244 eligible patients, 97 ETV+/-biopsies were performed, and 30 relapses occurred. There were no associations among ETV and/or biopsy with relapse (Cochran-Mantel-Haenszel [CMH] test, with histology (germinoma vs. nongerminomatous germ cell tumor (NGGCT)) as stratification variable: ETV: p=0.3167, biopsy: p=0.3375, combined: p=0.3066), distant relapse (CMH test, ETV: p=0.4631, ETV+biopsy: p=0.6795), PFS (log-rank test, ETV: NGGCT p=0.1632, germinoma p=0.9288; biopsy: NGGCT p=0.1682, germinoma p=0.9701; ETV+Biopsy: NGGCT p=0.1306, germinoma p=0.7758), or time to distant relapse with death/local relapse as competing risk (Gray’s test, ETV: NGGCT p=0.5694, germinoma p=0.2327; biopsy: NGGCT p=0.3505, germinoma p=0.5747; ETV+Biopsy: NGGCT p=0.3988, germinoma p=0.6839). CONCLUSIONS: Based on a secondary analysis of prospective data from the ACNS1123 trial, ETV and biopsy did not impart a greater likelihood of relapse in children with primary CNS GCT treated with combined chemotherapy and irradiation. However, three tract recurrences did occur (all germinoma), suggesting that they may affect pattern of relapse. Current and future prospective trials should continue to explore associations among these variables and relapse, including patterns of relapse.

SURG-12. Endoscopic evaluation of ventricular dissemination in primary central nervous system (CNS) germ cell tumors (GCTs)

Abstract INTRODUCTION: Endoscopic third ventriculostomy and endoscopic tumor biopsy have become integral to the surgical management of children with primary CNS GCTs. Observing ependymal tumor dissemination at the time of endoscopic surgery has been anecdotally reported. The incidence and impact of this finding in CNS GCT has not been reported. METHODS: Baseline neurosurgery data capture forms and operative reports from the Children’s Oncology Group (COG) ACNS1123 study were reviewed for ventriculoscopic findings of suspected tumor dissemination. The association between these findings and relapse was determined using Fisher’s exact test for each stratum and the Cochran-Mantel-Haenszel test for the entire cohort. Progression-free survival (PFS) was defined as time from enrollment to relapse, progression, death, or last follow-up; and survival probabilities were estimated using the Kaplan-Meier method with log-rank tests for outcome comparisons. RESULTS: 110/244 patients (45.1%) underwent endoscopic neurosurgery. Twelve patients (10.9%) had a documented observation suggestive of metastatic disease within the ventricular compartment. Ten were in the third ventricle and two were in the lateral ventricle. Nine of 12 were nongerminomatous germ cell tumors (NGGCTs) and three were germinoma. Ventriculoscopic findings of metastatic tumor were not significantly associated with relapse in NGGCT (p=0.4091), germinoma (p=0.1832), or overall (p=0.1540); odds ratio 2.57 (95%CI:0.66–10.11). PFS was not influenced in NGGCT (Log-rank test, p=0.1953) but was negatively impacted in germinoma (p=0.0250) when tumor dissemination was found during ventriculoscopy. CONCLUSIONS: Ventriculoscopic observation of tumor dissemination was reported in 10.9% of cases. This may negatively influence outcomes in children with germinoma, though due to the small number of relapses, more data is needed to verify these findings. Ventriculoscopic observation of tumor dissemination may contribute toward more accurate staging and influence future therapy, but a larger sample size is needed. Prospective studies should routinely integrate documentation of endoscopic observation in the study protocol.

GCT-02. Imaging response assessment for Central Nervous System Germ Cell Tumours: consensus recommendations from the European Society for Paediatric Oncology Brain Tumour Group (SIOPE-BTG) and North American Children’s Oncology Group (COG)

Abstract BACKGROUND: Central nervous system (CNS) germ cell tumours (GCT) comprise a heterogeneous and relatively rare group of neoplasms. Improving the ability to conduct international clinical trials for CNS GCT requires use of homogeneous, common objective disease assessments and standardised response criteria. Currently, different criteria are employed between European and North American protocols for assessing radiological disease response. METHODS: An international working group of the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group (BTG) and North American Children’s Oncology Group (COG) was therefore established to develop consensus recommendations for imaging response assessment for CNS GCT. The working group first reviewed existing literature and current practices and identified major challenges regarding imaging assessment. RESULTS: New clinical imaging standards were defined for the most common sites of intracranial GCT disease (suprasellar/pineal/bifocal), as well as for definition of loco-regional extension. In particular, clear standards were highlighted for definition of partial response (PR) and complete response (CR) to induction chemotherapy at different sites. Furthermore, growing teratoma syndrome (GTS) was clearly defined [apparent radiological increase in non-germinomatous GCT (NGGCT) size during induction chemotherapy despite normalising/normalised AFP/HCG markers – requiring surgery], to avoid such potential cases being classified as progressive disease (PD). CONCLUSION: This consensus will allow more consistent prospective neuroradiological evaluation of response to therapy for patients with CNS GCT and facilitate direct comparison of treatment outcomes across international studies. Ultimately, it may allow international trials to be developed and undertaken across a larger group of collaborating nations, which will be essential to answer many of the remaining questions for this rare but diverse group of tumours.

GCT-15. Multi-institutional analysis and literature review of central nervous system germ cell tumors in patients with Down syndrome

Abstract BACKGROUND: A standard-of-care has not been established for the management of patients with Down syndrome (DS) who develop primary central nervous system (CNS) germ cell tumors (GCTs) – the most common CNS neoplasm in DS – despite being more susceptible to treatment-related adverse events. METHODS: Data from large academic institutions were collected and a comprehensive review of the medical literature was conducted. RESULTS: Ten patients from six institutions (five USA, one Brazil) were reviewed. Additionally, thirty-one patients were identified in the literature from 1975-2021. Of the 41 total patients, mean age was ten years (range, birth to 35 years); males were predominant (61%). Basal ganglia were the most common tumor location (n=12; 29%), followed by posterior fossa (n=7; 17%). Sixteen patients had non-germinomatous germ cell tumors (NGGCTs) (39%), 14 had pure germinomas (34%), and eight had teratomas (20%); histology was unreported for two (5%). Nine patients (22%) experienced disease relapse, of which four died from tumor progression (one germinoma versus three teratoma). Fifteen patients (37%) experienced treatment-related complications - seven died (four germinoma versus three NGGCT). Of the germinoma patients, two died from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, and one from Moyamoya following radiation-therapy (RT) only. Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival (OS) was 66% for all histological types - 62% germinoma, 79% for NGGCT, and 53% for teratoma. Three-year OS for patients who received RT or chemotherapy was 71% and 75% respectively. Twenty-seven patients remain alive at latest follow-up (mean follow-up from diagnosis: 46.8 months). CONCLUSIONS: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered for this patient population to mitigate treatment-related complications and long-term neurocognitive sequelae.

GCT-17. Recurrence of CNS germ cell tumors (GCTs) along biopsy and ventriculostomy tracts

Abstract BACKGROUND: Central nervous system (CNS) germinoma relapses are rare. However, the latest Children’s Oncology Group (COG), ACNS1123 stratum 2, described three relapses along the biopsy tract out of eight total relapses; two along the biopsy and endoscopic third ventriculostomy (ETV) tract and one along the biopsy tract and external ventricular drain. Given these findings, we sought to describe other cases of GCT recurrence along surgical tracts. METHODS: We performed a literature review from 1980-2021 to identify cases of GCT recurrence along biopsy and ventriculostomy tracts. RESULTS: Three patients with pineal lesions were identified (13, 14, and 34-years old). All underwent ETV, cerebrospinal fluid (CSF) sampling, and tumor biopsy. Two patients had uncomplicated postoperative courses. One developed persistent hydrocephalus and underwent repeat ventriculostomy. Two were diagnosed with pure germinoma and treated with focal radiotherapy of 45 Gy alone or chemotherapy and radiation (50.4 Gy to the tumor volume and 36 Gy to adjacent high-risk area). The third was treated with methotrexate and corticosteroids. All three had recurrence on surveillance MRI (1-3 years after diagnosis). One had recurrence at the ventriculostomy bur hole site, and two had recurrence along the ventriculostomy tract. On biopsy, all three lesions were germinomas. One received pre-radiation chemotherapy and palliative radiation (36 Gy to surgical bed and 30.6 Gy to surrounding high-risk area). Another received chemotherapy and craniospinal radiation of 15 Gy. The third had a complicated post-biopsy course. He ultimately underwent chemotherapy and radiation (24 Gy). All were still alive at time of report. Two were disease free at 12 and 18 months, while one was still receiving chemotherapy. CONCLUSION: Recurrence along the biopsy or ventriculostomy tract is rarely reported in the literature. Future evaluation to determine the incidence could inform if biopsy and ventriculostomy tracts should be included in the radiation therapy field.

Central Nervous System Tumors in Children.

Central Nervous System Tumors in Children.