Intracranial Germ Cell Tumors Research Articles

Intracranial non-germinomatous germ cell tumors in children and adolescents: how can the experience from an uppermiddle-income country contribute to the worldwide effort to improve outcomes?

Non-germinomatous germ cell tumors (NGGCT) accounts for one third of intracranial GCT. While the germinoma group have an excellent overall survival, the standard of practice for children with NGGCT is still under evaluation. Describe the results of the of the Brazilian consortium protocol. Since 2013, 15 patients with a diagnosis of NGGCT by histopathology and/or serum/cerebrospinal fluid (CSF) tumor markers, βHCG >200mlU/ml and/or positive alpha-fetoprotein were treated with neoadjuvant chemotherapy with carboplatin, cyclophosphamide and etoposide followed by ventricular radiotherapy (RTV) of 18Gy with boost (32Gy) to the primary site. Metastatic patients underwent craniospinal irradiation (CSI) and "slow responders" to the four initial cycles of CT, to autologous stem cell transplantation (ASCT) followed by CSI. Mean age, 13.1 years. Thirteen males. Primary sites: pineal (n=12), suprasellar (n=2) and bifocal (n=1). Four patients were metastatic at diagnosis. Eight patients had CSF and/or serum alpha-fetoprotein levels > 1,000ng/ml. Tumor responses after chemotherapy demonstrated complete in six cases and partial in seven, with "second-look" surgery being performed in five cases, and two patients presenting viable lesions being referred to ASCT. The main toxicity observed was hematological grades 3/4. Two patients with metastatic disease, one with Down Syndrome and AFP > 1,000ng/ml and the other with choriocarcinoma and pulmonary metastases, developed progressive disease resulting in death, as well as two other patients without evidence of disease, due to endocrinological disorders. Event-free and overall survival at 2 and 5 years were 80% and 72.7%, respectively, with a mean follow-up of 48 months (range, 7-107). Despite the small number of patients, in our series, treatment with six cycles of chemotherapy and RTV with focal boost for localized disease (n=11) and ACST for identified slow responders (n=2) seem to be effective strategies contributing to the overall effort to improve outcomes of this group of patients.

Novel molecular subtypes of intracranial germ cell tumours expand therapeutic opportunities.

Intracranial germ cell tumours (IGCTs) are a rare group of malignancies that are clinically classified as germinomas and nongerminomatous germ cell tumours (NGGCTs). Previous studies have found that somatic mutations involving the MAPK/mTOR signalling pathway are common early events. However, a comprehensive genomic understanding of IGCTs is still lacking. We established a cohort including over 100 IGCTs and conducted genomic and transcriptomic sequencing. We identified novel recurrent driver genomic aberrations, including USP28 truncation mutations and high-level copy number amplification of KRAS and CRKL caused by replication of extrachromosomal DNA. Three distinct subtypes associated with unique genomic and clinical profiles were identified with transcriptome analysis: immune-hot, MYC/E2F and SHH. Both immune-hot and MYC/E2F were predominantly identified in germinomas and shared similar mutations involving the RAS/MAPK signalling pathway. However, the immune-hot group showed an older disease onset age and a significant immune response. MYC/E2F was characterized by a younger disease onset age and increased genomic instability, with a higher proportion of tumours showing whole-genome doubling. Additionally, the SHH subtype was mostly identified in NGGCTs. Novel genomic aberrations and molecular subtypes were identified in IGCTs. These findings provide molecular basis for the potential introduction of new treatment strategies in this setting.

Primary central nervous system tumors survival in children in ten Colombian cities: a VIGICANCER report.

Primary central nervous system (CNS) tumors are the second most common cancer in children and adolescents, leading to premature death and disability. Population-based survival estimates aid decision-making in cancer control, however data on survival for primary CNS tumors in Latin America is lacking. We describe survival rates for children with primary CNS tumors treated in ten Colombian cities. We analyzed data from children and adolescents newly diagnosed with cancer between 2012 and 2021, participating in the Childhood Cancer Clinical Outcomes Surveillance System (VIGICANCER) in ten cities in Colombia. VIGICANCER collects information on clinical outcomes from twenty-seven pediatric oncology units and conducts active follow-up every three months. VIGICANCER does not register craniopharyngiomas; we excluded intracranial germ cell tumors for this report. We used the Kaplan-Meier method to estimate the overall survival probability, stratified by sociodemographic variables, topography, WHO grading, receipt of radiation therapy, and type of surgical resection. We analyzed the prognostic capacity of variables using multivariate proportional Cox's regression, stratified by city and year of diagnosis. During the study period, VIGICANCER included 989 primary CNS tumors in 879 children and 110 adolescents. The cohort median age was 9 years; 53% of patients were males, and 8% were Afro-descendants. Most common tumors were supratentorial astrocytomas (47%), astrocytic tumors (35%), medulloblastomas (20%), ependymomas (11%), and mixed and unspecified gliomas (10%). Five-year overall survival of the entire cohort was 54% (95% CI, 51-58); for supratentorial gliomas, WHO grade I was 77%, II was 62%, III-IV was 27%, respectively, and for medulloblastoma was 61%. The adjusted hazard rate ratio for patients with WHO grade III and IV, for those with subtotal resection, for brainstem location, and for those not receiving radiation therapy was 7.4 (95% CI, 4.7-11.8), 6.4 (95% CI, 4.2-9.8), 2.8 (95% 2.1-3.8), 2.0 (95% CI, 1.3-2.8) and 2.3 (95% CI, 1.7-3.0), respectively. We found that half of Colombia's children and adolescents with primary CNS tumors survive five years, compared to 70% to 80% in high-income countries. In addition to tumor biology and location, gross total resection was crucial for improved survival in this cohort. Systematic monitoring of survival and its determinants provides empirical data for guiding cancer control policies.

Whole-exome sequencing has revealed novel genetic characteristics in intracranial germ cell tumours in the Chinese.

Intracranial germ cell tumour (IGCT) is a type of rare central nervous system tumour that mainly occurs in children and adolescents, with great variation in its incidence rate and molecular characteristics in patients from different populations. The genetic alterations of IGCT in the Chinese population are still unknown. In this study, 47 patients were enrolled and their tumour specimens were analysed by whole-exome sequencing (WES). We found that KIT was the most significantly mutated gene (15/47, 32%), which mainly occurred in the germinoma group (13/20, 65%), and less frequently in NGGCT (2/27, 7%). Copy number variations (CNVs) of FGF6 and TFE3 only appeared in NGGCT patients (P = 0.003 and 0.032, respectively), while CNVs of CXCR4, RAC2, PDGFA, and FEV only appeared in germinoma patients (P = 0.004 of CXCR4 and P = 0.027 for the last three genes). Compared with a previous Japanese cohort, the somatic mutation rates of RELN and SYNE1 were higher in the Chinese. Prognostic analysis showed that the NF1 mutation was associated with shorter overall survival and progression-free survival in IGCT patients. Clonal evolution analysis revealed an early branched evolutionary pattern in two IGCT patients who underwent changes in the histological subtype or degree of differentiation during disease surveillance. This study indicated that Chinese IGCT patients may have distinct genetic characteristics and identified several possible genetic alterations that have the potential to become prognostic biomarkers of NGGCT patients.

Overview of current European practice for the management of patients with intracranial germ cell tumours

Central nervous system germ cell tumours (CNS GCT) form a diverse group of tumour entities, including germinoma, yolk sac tumour, embryonal carcinoma, choriocarcinoma, teratoma, and mixed tumours. Incidence peaks in the second decade, predominantly in males. Incidence rates vary globally, higher in Asia, suggesting genetic factors are important. CNS GCTs split into pure germinomas and non-germinomatous GCTs (NGGCT), influencing prognosis/treatment. Serum and CSF markers (alpha-fetoprotein, human chorionic gonadotropin) aid diagnosis, potentially avoiding neurosurgical biopsy. Histological features are distinguished by immunohistochemical staining. Studies have identified specific microRNAs in serum/CSF at diagnosis as promising biomarkers. Mutated pathways have been identified, but targeted therapies have shown limited success to date. Diagnosis involves recognising symptoms like raised intracranial pressure, endocrinological, and ophthalmological disturbances. MRI imaging is crucial for diagnosis and guiding treatment decisions. Treatment strategies vary, as pure germinomas respond well to chemotherapy and radiotherapy, or craniospinal radiotherapy alone, with excellent outcomes; in contrast NGGCTs demand aggressive combined chemo-radiotherapy, yielding generally inferior outcomes. Teratomas are typically chemo-/radio-resistant, requiring surgical intervention. Relapses need re-staging and (re-)biopsy consideration. Relapsed germinomas, though rare, may be cured with standard-dose chemotherapy and re-irradiation, or high-dose chemotherapy with stem-cell-transplantation, with/without further radiation. The more commonly observed NGGCT relapses have poor prognosis, even with thiotepa-based high-dose chemotherapy and stem-cell-transplantation delivered with curative intent. In summary, CNS GCT management integrates clinical, radiological, and histological findings, along with serum and CSF markers, for tailored treatment. Ongoing research aims to incorporate microRNA markers and molecular pathology for improved diagnosis, prognostication, and therapeutic intervention.

Treatment outcomes and risk factors of patients with intracranial germ cell tumour with choriocarcinoma element or β-HCG level higher than 500IU/L.

In previous studies, patients with intracranial germ cell tumour (iGCT) with pure choriocarcinoma or mixed germ cell tumours with choriocarcinoma element showed similar dismal prognoses, with median overall survival (OS) of 22months and 1-year survival rate of approximately 60%. However, these conclusions need to be updated because radiotherapy, which is the mainstay for this disease, was not applied in a number of patients. Additionally, prognostic factors need to be explored in this population. Clinical data of patients with iGCTs with histologically confirmed choriocarcinoma element or beta-human chorionic gonadotropin (β-HCG) > 500IU/L were collected from the archives of our institution and retrospectively studied. A total of 76 patients were eligible for this study. Except for two early deaths, all patients received radiotherapy (craniospinal irradiation [CSI], n = 23; non-CSI, n = 51). The median follow-up duration for the entire series was 63months (range, 6-188months). The 5-year event-free survival (EFS) and OS rates were 81.5% and 84.1%, respectively. Among patients who did not have early death or progressive disease after induction chemotherapy, multivariate analysis revealed that chemotherapy cycles (> 4 vs. ≤ 4) (hazard ratio [HR] for EFS 0.144, p = 0.020; HR for OS 0.111, p = 0.028) and β-HCG levels (> 3000IU/L vs. ≤ 3000IU/L) (HR for EFS 4.342, p = 0.059; HR for OS 6.614, p = 0.033) were independent factors for survival. Patients with iGCTs with choriocarcinoma element or β-HCG > 500IU/L showed improved survival with radiotherapy-based treatments. Additional chemotherapy cycles could result in additional survival benefits. Patients with β-HCG level > 3000IU/L had poorer prognosis.

Intracranial Germ Cell Tumors.

Intracranial germ cell tumors are rare tumors occurring in adolescents and young adults, which include germinomas and non-germinomatous type germ cell tumors (NGGCT). In the past few decades, cooperative trial groups in Europe and North America have developed successful strategies to improve survival outcomes and decrease treatment-related toxicities. New approaches to establishing diagnosis have deferred the need for radical surgery. The 5-year event-free survival (EFS) is above 90% and even patients who present with metastatic germinoma can still be cured with chemotherapy and craniospinal irradiation. The combination of surgery, chemotherapy, and radiation therapy is tailored to patients based on grouping and staging. For NGGCT, neoadjuvant chemotherapy followed by delayed surgery for residual disease and radiotherapy can yield a 5-year EFS of 70%. Further strategies should focus on reducing long-term complications while preserving high cure rates.

A Segmentation Framework with Unsupervised Learning-Based Label Mapper for the Ventricular Target of Intracranial Germ Cell Tumor.

Intracranial germ cell tumors are rare tumors that mainly affect children and adolescents. Radiotherapy is the cornerstone of interdisciplinary treatment methods. Radiation of the whole ventricle system and the local tumor can reduce the complications in the late stage of radiotherapy while ensuring the curative effect. However, manually delineating the ventricular system is labor-intensive and time-consuming for physicians. The diverse ventricle shape and the hydrocephalus-induced ventricle dilation increase the difficulty of automatic segmentation algorithms. Therefore, this study proposed a fully automatic segmentation framework. Firstly, we designed a novel unsupervised learning-based label mapper, which is used to handle the ventricle shape variations and obtain the preliminary segmentation result. Then, to boost the segmentation performance of the framework, we improved the region growth algorithm and combined the fully connected conditional random field to optimize the preliminary results from both regional and voxel scales. In the case of only one set of annotated data is required, the average time cost is 153.01s, and the average target segmentation accuracy can reach 84.69%. Furthermore, we verified the algorithm in practical clinical applications. The results demonstrate that our proposed method is beneficial for physicians to delineate radiotherapy targets, which is feasible and clinically practical, and may fill the gap of automatic delineation methods for the ventricular target of intracranial germ celltumors.

Intracranial germ cell tumors: a view of the endocrinologist.

Intracranial germ cell tumors (iGCTs) are rare malignant neoplasms that mainly affect children and adolescents. The incidence, clinical presentation, and prognosis of iGCTs exhibit high heterogeneity. Previous studies have primarily focused on eliminating tumors, reducing tumor recurrence, and improving survival rates, while neglecting the impact of the tumors and their treatment on neuroendocrine function. Throughout the entire course of the disease, neuroendocrine dysfunction may occur and is frequently overlooked by oncologists, neurosurgeons, and radiologists. Endocrinologists, however, are more interested in this issue and have varying priorities at different stages of the disease. From onset to the diagnostic phase, most patients with iGCTs may present with symptoms related to impaired neuroendocrine function, or even experience these symptoms as their first indication of the condition. Particularly, a minority of patients with sellar/suprasellar lesions may exhibit typical imaging features and elevated tumor markers long after the onset of initial symptoms. This can further complicate the diagnosis process. During the peritumor treatment phase, the neuroendocrine function shows dynamic changes and needs to be evaluated dynamically. Once diabetes insipidus and dysfunction of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-thyroid axes occur, hormone replacement therapy should be administered promptly to ensure successful tumor treatment for the patient. Subsequently, during the long-term management phase after the completion of tumor treatment, the evaluation of growth and development as well as corresponding hormone replacement therapy are the most concerning and complex issues. Thus, this paper reviews the interest of endocrinologists in iGCTs at different stages.

Treatment Course and Outcomes of Intracranial Teratomas in Pediatric Patients: A Retrospective 15-Year Case Series Study

Introduction: There is no standard treatment paradigm for intracranial teratomas, a rare subset of primary intracranial non-germinomatous germ cell tumors (NGGCT), which comprise less than 1% of pediatric brain tumors. This case series retrospectively analyzes treatment and outcomes of pediatric intracranial teratomas from a single institution. Methods: Authors reviewed a comprehensive pathology database at Stanford’s Lucile Packard Children’s Hospital for intracranial teratomas in pediatric patients treated from 2006 to 2021; their demographics, treatment, and clinical course were analyzed. Results: Among 14 patients, median follow-up time was 4.6 years and mean age at diagnosis was 10.5 years. Ten had elevated tumor markers and underwent chemotherapy as initial treatment for NGGCT. Ultimately, these patients all required surgery for progressive or residual disease. Two patients did not undergo radiation. After biopsy or resection, 8 patients had pure mature teratoma, five had mixed germ cell tumor with teratoma component, and one had immature teratoma. The patient with immature teratoma died during chemotherapy from septic shock. No patients experienced recurrence. Common sequelae were endocrine (42.8%) and eye movement (50.0%) abnormalities. Discussion/Conclusion: We highlight the variable treatment course and outcome for pediatric patients with intracranial teratomas. Elevated tumor markers at presentation, along with imaging findings, favor chemotherapy initiation for presumed NGGCT. Resection of residual tumor is recommended even if tumor markers return to normal. Prognosis remains excellent; no patients had recurrence with a median follow-up of 4.6 years.

Clinical, imaging, and molecular features of radiation-induced glioblastomas developing more than 20 years after radiation therapy for intracranial germinomatous germ cell tumor: illustrative cases.

Germinomatous germ cell tumor is highly sensitive to chemoradiotherapy; patients are expected to survive for decades. Many radiation-induced malignant gliomas (RIMGs) occur >10 years after radiotherapy. Standard therapy for RIMGs has not been established because of the lesion's rarity, the patient's shorter survival period, and the risk of radiation necrosis by repeat radiation. Two patients, a 32-year-old man and a 50-year-old man, developed glioblastomas more than 20 years after radiation monotherapy for germinoma with or without mature teratoma. The first patient showed a tumor in the left frontotemporal region with disseminated lesions and died 2 months after partial resection of the tumor without responding to the chemotherapy with temozolomide and bevacizumab. Methylation classifier analysis classified the pathology as closest to diffuse pediatric-type high-grade glioma, Rtk1 subtype. The second patient showed a tumor mass in the brainstem and left cerebellar peduncle, which worsened progressively during chemotherapy with temozolomide and bevacizumab. The tumor transiently responded to stereotactic radiotherapy with the CyberKnife. However, the patient died of RIMG recurrence-related aspiration pneumonia 11 months after the biopsy. Methylation classifier analysis classified the pathology as closest to infratentorial pilocytic astrocytoma. Chemoradiotherapy may improve the survival of patients with RIMGs. Furthermore, molecular features may influence the clinical, locoregional, and pathological features of RIMG.

Final report of the phase II NEXT/CNS-GCT-4 trial: GemPOx followed by marrow-ablative chemotherapy for recurrent intracranial germ cell tumors.

Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx). A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR. Treatment response was determined based on radiographic tumor assessments and tumor markers. A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease. GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy.

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 <14 ng/mL). Testicular tumor marker, alpha-fetoprotein, was elevated (15.3 ng/dL, RR <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

​Occult extracranial malignancy after complete remission of pineal mixed germ cell tumors: a rare case report and literature review

Background​Extracranial metastasis can occur in intracranial germ cell tumors (GCTs), but it is very rare. Recurrence or metastasis of non-germinomatous germ cell tumors (NGGCTs) is often accompanied by elevated tumor markers. ​Occult extracranial metastases or recurrences with negative markers are often difficult to detect in time, resulting in a very poor prognosis.Case presentationA 12-year-old boy was admitted to our institution with dizziness, headache, vomiting, and sleepiness. Magnetic resonance imaging (MRI) showed a pineal mass, accompanied by a significant increase in serum alpha-fetoprotein (AFP). The patient subsequently underwent total removal of the tumor. Pathology revealed that the tumor was a mixed GCT, consisting of mature teratoma, germinoma, and yolk sac tumor. Intracranial GCT achieved complete remission after intensive adjuvant chemotherapy and radiotherapy. Regular follow-up MRI revealed no recurrence of the intracranial tumor and continued monitoring of tumor markers revealed no abnormalities. ​Eight months later, the patient was readmitted due to progressive abdominal pain. Imaging and physical examination revealed abdominal occupation and lymphatic mass in the neck. He received salvage chemotherapy, anti-PD-1 immunotherapy, and palliative chemotherapy, but still developed multiple organ dysfunction syndromes (MODS) due to tumor progression and eventually died after one month.Conclusions​This profound case suggests that intracranial NGGCTs may develop occult extracranial malignancy, which can be very severe at the time of clinical symptoms and has an extremely poor prognosis. Therefore, in addition to tumor marker monitoring, regular follow-up with extracranial imaging may be warranted to detect extracranial tumors as early as possible, although perhaps not as frequently as with neuroimaging.

Non-invasive differential diagnosis of teratomas from other intracranial germ cell tumours using MRI-based fractal and radiomic analyses.

The histologic subtype of intracranial germ cell tumours (IGCTs) is an important factor in deciding the treatment strategy, especially for teratomas. In this study, we aimed to non-invasively diagnose teratomas based on fractal and radiomic features. This retrospective study included 330 IGCT patients, including a discovery set (n = 296) and an independent validation set (n = 34). Fractal and radiomic features were extracted from T1-weighted, T2-weighted, and post-contrast T1-weighted images. Five classifiers, including logistic regression, random forests, support vector machines, K-nearest neighbours, and XGBoost, were compared for our task. Based on the optimal classifier, we compared the performance of clinical, fractal, and radiomic models and the model combining these features in predicting teratomas. Among the diagnostic models, the fractal and radiomic models performed better than the clinical model. The final model that combined all the features showed the best performance, with an area under the curve, precision, sensitivity, and specificity of 0.946 [95% confidence interval (CI): 0.882-0.994], 95.65% (95% CI: 88.64-100%), 88.00% (95% CI: 77.78-96.36%), and 91.67% (95% CI: 78.26-100%), respectively, in the test set of the discovery set, and 0.944 (95% CI: 0.855-1.000), 85.71% (95% CI: 68.18-100%), 94.74% (95% CI: 83.33-100%), and 80.00% (95% CI: 58.33-100%), respectively, in the independent validation set. SHapley Additive exPlanations indicated that two fractal features, two radiomic features, and age were the top five features highly associated with the presence of teratomas. The predictive model including image and clinical features could help guide treatment strategies for IGCTs. Our machine learning model including image and clinical features can non-invasively predict teratoma components, which could help guide treatment strategies for intracranial germ cell tumours (IGCT). • Fractals and radiomics can quantitatively evaluate imaging characteristics of intracranial germ cell tumours. • Model combing imaging and clinical features had the best predictive performance. • The diagnostic model could guide treatment strategies for intracranial germ cell tumours.

Deep learning based on preoperative MR to differentiate germinomas from nongerminomatous cell tumors.

19 Background: Intracranial germ cell tumors (iGCTs) are highly malignant brain tumors that predominantly occur in children. Two types of iGCTs exist: germinomas (GEs) and non-germinomatous germ cell tumors (NGGCTs), each having different treatments and prognoses. However, predictive biomarkers for differentiation are limited. Methods: This multicenter Development-validation set study included patients with iGCTs with pathology-confirmed for the developed dataset (n = 280), which was split into training (n = 200) and testing sets (n= 80), and three independent validation sets (n = 64), respectively. Patients were included between January 2010 and December 2021. We developed a DL model based on 3D nnU-Net and preoperative T2-weighted images to differentiate GE from NGGCT, and we compared the model performance with the diagnoses made by five physicians of different majors and experiences with and without referring to the DL model’s output. Data analysis was performed from February 2021 to May 2022.We calculated the diagnostic performances of the model and physicians using the area under the curve (AUC), accuracy, sensitivity, and specificity. Results: The DL pipeline showed an average AUC of 0.837 in the testing set and three independent validation sets, superior to that using conventional information alone (combine with MR features and clinical information, AUC=0.768, p=0.009). The physicians’ diagnoses showed an average AUC of 0.695 without reference to the DL output and 0.842 concerning the DL output in the testing and prospective internal validation sets, with a 21.15% improvement (p=0.014). Conclusions: We developed and validated a DL model using a large dataset to accurately differentiate GE from NGGCT using preoperative T2-weighted images, which is relatively easily incorporated into the workflow of clinical diagnosis at minimal additional cost, and may enhance precision therapy.

Comparison of different predominant lesions in intracranial bifocal germ cell tumors to predict neuroendocrine outcomes.

Intracranial germ cell tumors frequently arise from the midline of the brain, occasionally presenting as bifocal diseases. The predominant lesion might affect clinical characteristics and neuroendocrine outcomes. A retrospective cohort study involving 38 patients with intracranial bifocal germ cell tumors was performed. Twenty-one patients were assigned to the sellar-predominant group, while the other 17 patients were assigned to the non-sellar-predominant group. Differences in gender ratio, age, manifestation, the incidence of metastasis, the incidence of elevated tumor markers, human chorionic gonadotropin levels in serum and in cerebrospinal fluid, diagnostic method, and tumor type were not significant between the sellar-predominant group and the non-sellar-predominant group. Before treatment, the sellar-predominant group had a higher incidence of adenohypophysis hormone deficiencies and central diabetes insipidus than those of the non-sellar-predominant group, without significant differences. After multidisciplinary therapy, the sellar-predominant group also had a higher incidence of adenohypophysis hormone deficiencies and central diabetes insipidus than those of the non-sellar-predominant group. The differences in the hypothalamic-pituitary-adrenal (HPA) axis impairment (P = 0.008), hypothalamic-pituitary-thyroid (HPT) axis impairment (P = 0.048), and hypothalamic-pituitary-gonad (HPG) axis impairment (P = 0.029) were significant between sellar-predominant group and non-sellar-predominant group, while the others were not. At median 6 (3, 43) months of follow-up visit, sellar-predominant group had a higher incidence of adenohypophysis hormone deficiencies than those of non-sellar-predominant group. The differences in the HPA impairment (P = 0.002), HPT impairment (P = 0.024), and HPG impairment (P < 0.000) were significant, while the others were not. Further comparison of the neuroendocrine function between different subtypes of sellar-predominant patients indicated that the differences in adenohypophysis hormone deficiencies and central diabetes insipidus were not significant between the two subtype groups. Bifocal patients with different predominant lesions present similar manifestations and neuroendocrine disorders before treatment. Non-sellar-predominant patients would have better neuroendocrine outcomes after tumor treatment. The distinction of the predominant lesion in patients with bifocal intracranial germ cell tumor plays a valuable role in predicting neuroendocrine outcomes, as well as in optimizing long-term neuroendocrine management during survival time.

OCT3/4 is a potential immunohistochemical biomarker for diagnosis and prognosis of primary intracranial germ cell tumors: a systematic review and meta-analysis.

Intracranial germ cell tumors (iGCTs), comprising of germinoma (GE) and non-germinomatous GCT (NGGCT), are a group of heterogenous brain tumors. Immunohistochemical markers, such as placental-like alkaline phosphatase (PLAP), are commonly used in diagnosis but show moderate sensitivity. Organic cation transporter 3/4 (OCT3/4) has been proposed as a novel biomarker for diagnosis and prognosis of iGCTs. This paper aimed to compare OCT3/4 with PLAP as potential immunohistochemical biomarkers in iGCTs diagnosis and clarify the relationship between OCT3/4 and prognosis of patients with iGCTs. Meta-analyses were performed to estimate pooled percentage point differences in positive rates between OCT3/4 and PLAP, their sensitivities, and correlation between OCT3/4 and prognosis in iGCTs. Nine articles were included representing of 241 patients. A fixed-effects model meta-analysis revealed that OCT3/4s positive rate was 8.6% higher (95% CI, 0.7% lower to 17.9% higher) than that of PLAP. Using fixed-effects models, sensitivities of OCT3/4 as a potential immunohistochemical biomarker in CNS GE and NGGCT were 85% (95% CI, 79% to 89%) and 56% (95% CI, 39% to 71%), respectively. In comparison, PLAP had lower sensitivities in both GE (73%; 95% CI, 64% to 91%) and NGGCT (43%; 95% CI, 27% to 61%). Moreover, OCT3/4 was significantly negatively correlated with 5-year progression free survival in patients with CNS GE (HR = 2.56, 95 % CI 1.47 to 4.44; p = 0.0008). Sensitivity analyses showed similar results. This study provides the first comprehensive assessment of the efficacies of OCT3/4 and PLAP in iGCTs detection and prognosis prediction, indicating OCT3/4 seems to be a more sensitive and reliable immunohistochemical marker in iGCT diagnosis.

Mutational landscape of intracranial germ cell tumors.

e14060 Background: Intracranial germ cell tumours (GCTs) are relatively rare tumours of the central nervous system, which account for 1% to 3% of cases. The pathogenesis of intracranial GCTs is unknown, molecular diagnostic methods currently play only a minor role in the diagnosis of CNS germ cell tumours, which generally rest on histopathological and secretory features. The objective of this study was to explore the molecular profile associated with Chinese intracranial GCT patients. Methods: This study retrospectively analyzed the genomic features of 24 intracranial GCT patients. Next-generation sequencing (NGS) of 551-gene panel was performed to detect gene mutations in tumor and blood samples of the patients. Results: The tumors originated most frequently in the pineal region (41.6%, 10/24), followed by the sellar tumor (16.6%, 4/24). The average age of the patients was 14 years (range, 4-55years), There is a male preponderance of 2:1. The most common mutation genes were KIT (4.23%, n=6), KRAS (2.82%, n=4) and PTEN (2.11%, n=3). KIT mutations are mainly missense mutations concentrated in exon 17, exon 11 and exon 13. Exon 2 and exon 3 of KRAS gene were the main mutation hotspots, mainly G12X(2.08%) missense mutation. The co-mutation of KIT and KRAS was only in one patient. Unexpectedly, four patients (16.6%) carried germline deleterious mutations, in FANCA(n=1), FANCD2(n=1), FANCE(n=1), SDHA(n=1). Two of the patients with germline mutations co-mutated with KIT and KRAS, respectively. Conclusions: 16.6% of the intracranial GCT patients carry germline deleterious mutations, and 12.5% in Fanconi anemia (FA) gene. Overall, these findings indicate that the Fanconi anemia (FA) pathway and the PI3K/AKT pathway play a significant role in intracranial GCTs tumorigenesis.

RARE-04. DEVELOPMENT OF A PLATFORM TO PROFILE MICRORNA IN CEREBROSPINAL FLUID FROM PATIENTS WITH INTRACRANIAL GERM CELL TUMORS

Abstract BACKGROUND Current diagnosis of intracranial germ cell tumors (iGCTs) utilizes alpha fetoprotein (AFP) and chorionic gonadotropin (β-HCG) as biomarkers in the blood or cerebrospinal fluid (CSF). Two thirds of iGCTs are marker negative and AFP/HCG are not specific to iGCTs. Thus, there is a need to develop other biomarkers to improve the diagnosis of iGCT. Two microRNA (miRNA) clusters, miR-371-373 and miR-302/367 have previously been identified as biomarkers for extracranial GCTs and preliminary data from our lab and others confirmed their potential utility in iGCTs. However, the optimal way to profile miRNAs in CSF is not fully established. Two commonly used methods are real-time polymerase chain reaction (qPCR) or droplet digital polymerase chain reaction (ddPCR). METHODS CSF samples were obtained from biorepositories at Connecticut Children’s and through the Children’s Brain Tumor Network. Cell culture media from an embryonal carcinoma cell line was used as positive control. MicroRNA was extracted from 50uL of CSF, reverse transcribed into cDNA and pre-amplified. Samples were then diluted 1:5 for qPCR and 1:10 or 1:50 for ddPCR. RESULTS We profiled the CSF from 6 germinomas and 4 non-germinomatous, including two mature teratomas. Additionally, we profiled CSF from two non-iGCT brain tumors and two leukemia patients, as non-iGCT controls. For qPCR, raw CT values were evaluated with CT &amp;lt;35 considered detectable. Both platforms, qPCR and ddPCR were able to detect miR-371-373 and miR-302/367 in malignant iGCTs, including marker negative germinomas. miR-302/367 cluster showed varying expression in non-iGCT samples. CONCLUSIONS We were able to use low input (50uL) of CSF to identify markers of malignant iGCT, the microRNA clusters miR-371-373 and miR-302/367. Both platforms were able to identify the microRNAs. More samples will need to be profiled to evaluate which platform ddPCR or qPCR is best to move forward towards a clinically validated platform.