Intracranial Germinoma in Two Caucasian American Siblings With Autism Spectrum Disorder.

Intracranial germ cell tumors (IGCTs) comprise 3% to 5% of all pediatric brain tumors in the West, with a significantly higher prevalence in Asia. Although these tumors are histologically diverse, repeated somatic variants have been demonstrated. Chromosomal aneuploidies, such as Klinefelter and Down syndromes, are associated with IGCTs, but no familial germline tumor syndromes are currently known. Here, we report the novel case of 2 American siblings with underlying autism spectrum disorder who developed intracranial germinoma within months of each other, in the absence of external risk factors. Extensive genetic testing was performed, including karyotyping, chromosomal microarray, and whole exome and whole genome sequencing, and did not identify any variants accounting for the phenotypes. Despite the absence of overlapping variants, a recent retrospective review demonstrated a threefold greater prevalence of autism spectrum disorder in patients with intracranial germinoma compared with national prevalence. This report highlights the complexity of tumor development, as well as the need for further research regarding IGCTs in a neurodivergent population.

Time to dismiss boost? Outcomes of children with localized and metastatic germinoma.

PURPOSE: To determine long-term outcomes of a cohort of children with germinoma treated with chemotherapy and radiation therapy without primary tumor boost even in the absence of complete response to chemotherapy METHODS: This retrospective study analyzed the outcome of patients with germinoma consecutively diagnosed and treated at a tertiary care center from January 2000 to December 2021. MRIs were reviewed by two radiologists, blinded to patient data. Tumor location at diagnosis, tumor response to chemotherapy and at completion of radiation therapy and site of relapse were assessed. Tumor response was assessed radiologically by determining the tumor size and response on diffusion-weighted imaging, in addition to biochemical, cytological parameters and neurological status. RESULTS: Of 46 pediatric germinoma patients, 29 children (14 male; median age 12.8 years) received no primary tumor boost. Median follow-up was 63 months (range 9-187 months). Twenty-five children had localized disease and tumor location was suprasellar (n = 11), pineal (n = 10), bifocal (n = 3) and basal ganglia (n = 1) while 4 children had metastatic disease at presentation. All patients completed multi-agent chemotherapy followed by either ventricular irradiation (VI) (23.4 Gy) (n = 23), whole brain (WBI) (23.4 Gy) (n = 5) or craniospinal radiation (CSI) (23.4 Gy) (n = 1). Two children, who had localized disease at presentation and received VI after chemotherapy, relapsed 9 months and 32 months after completion of treatment respectively. No patient had a local relapse. Location of relapse was distant, outside (n = 1) and out- and inside (n = 1) the irradiation field. Five-year progression free survival (PFS) was 91% and overall survival (OS) was 100%. CONCLUSIONS: In this case series, excellent 5-year PFS and OS rates were achieved with chemotherapy followed by radiation therapy of 23.4 Gy delivered without primary tumor boost. No local relapse was observed despite omitting primary tumor boost in patients with localized and metastatic germinoma.

Treatment outcomes for response-based radiotherapy in children and adolescents with central nervous system germinoma: a prospective study.

PURPOSE: The optimal dose and range of radiotherapy for central nervous system (CNS) germinoma have not yet been established. This study aimed to investigate the effects of individualized radiotherapy on the prognosis of patients with germinoma. METHODS: Based on imaging examination, tumor markers, and pathologic results, patients with germinoma received different radiotherapy strategies, including R1 (24 Gy whole ventricular irradiation + tumor-bed boost to 40 Gy), R2 (24-30 Gy craniospinal irradiation + tumor-bed boost to 54 Gy), R3 (24 Gy craniospinal irradiation + tumor-bed boost to 40 Gy), and R4 (30 Gy craniospinal irradiation + tumor-bed boost to 54 Gy with 45 Gy to spinal metastasis). RESULTS: A total of 77 patients were enrolled in this study between January 2015 and March 2021. The 3-year event-free survival (EFS) and overall survival (OS) of the whole cohort were 94.7% ± 2.6% and 96.0% ± 2.3%, respectively. The 3-year EFS for patients with localized and metastatic disease were 96.6% ± 2.4% and 89.2% ± 7.2%, respectively. The 3-year EFS of patients receiving R1, R2, R3, and R4 radiotherapy were 100%, 94.1% ± 5.7%, 100%, and 86.2% ± 9.1%, respectively. CONCLUSION: Good prognosis was still achieved after reducing dose and extent of radiation for the patients who achieved complete response (CR) after induction chemotherapy or pathological CR after second-look surgery.

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.

The role of neoadjuvant chemotherapy in the management of metastatic central nervous system germinoma: A meta-analysis.

BACKGROUND: The role of neoadjuvant chemotherapy in treating patients with metastatic central nervous system (CNS) germinoma is controversial. METHODS: We compared the relapse-free survival (RFS) of different treatment modalities by performing a meta-analysis using published data. We summarized all data using standard descriptive statistics. We used the Kaplan-Meier method to estimate RFS and their corresponding 95% confidence intervals (CIs). We used the log-rank test for the comparison of survival functions. RESULTS: We identified 97 patients with a median age at presentation of 15 years (range: 7-38). Sites of metastasis were cerebrospinal fluid (CSF) disease only (n = 12), brain parenchyma (n = 18), spinal cord (n = 9), ventricular and CSF (n = 10), ventricular only (n = 31), and other (n = 17). The 3-year RFS among patients who received any form of radiotherapy was 89% (95% CI: 83-96) compared with 0% for patients who received a chemotherapy-only regimen (p = .001). Five-year RFS among patients who received craniospinal irradiation (CSI) was 92% (95% CI: 84-100) compared with 76.4% (95% CI: 63-90) in the non-CSI group (with or without neoadjuvant chemotherapy) (p = .014). Five-year RFS of patients who received CSI less than 24 Gy with neoadjuvant chemotherapy was 100% compared with 92% (95% CI: 83-100) CSI dose greater than or equal to 24 Gy alone (p = .3). CONCLUSIONS: Our analysis does not support avoiding spinal irradiation among patients with radiographic metastatic CNS germinoma. Future studies are needed to confirm whether neoadjuvant chemotherapy will allow a reduction of irradiation dose without compromising survival.

Intracranial Germinomas: Diagnosis, Pathogenesis, Clinical Presentation, and Management.

PURPOSE OF REVIEW: Intracranial germinomas constitute a rare brain tumor entity of unknown etiology, characterized by unique histopathology and molecular biology. In this manuscript, we review the literature focusing on the epidemiology, histopathology with molecular biology, clinical presentation with emphasis on tumor location, diagnostic workup, and current treatment strategies with related clinical outcomes of intracranial germinomas. RECENT FINDINGS: Although the optimal treatment strategy remains a matter of debate, intracranial germinomas respond well to radiotherapy, chemotherapy, or a combination of both and are characterized by very high cure and survival rates. It is well-known that early discrimination of germinomas from other intracranial neoplasms facilitates the timely initiation of appropriate treatment, thereby contributing to the reduction of morbidity as well as mortality. Ongoing research will need to be directed towards discovering and refining reliable parameters for early diagnosis and evaluation of prognosis in patients with intracranial germinomas.

Clinical significance and pitfalls of human chorionic gonadotropin-related tumor markers for intracranial germinomas.

PURPOSE: Measuring serum and cerebrospinal fluid human chorionic gonadotropin (hCG) is essential for the diagnosis of intracranial germ cell tumors. There are three types of hCG-related markers in clinical use: hCGß, intact hCG, and total hCG. The best marker for the diagnosis of intracranial germ cell tumors, especially germinoma, is currently unknown. This study aimed to evaluate the usefulness of these hCG-related markers. METHODS: We investigated 19 serum samples obtained from 6 patients with histologically diagnosed germinoma treated in our institute. Serum hCGß, intact hCG, and total hCG values were measured before, during, and after treatment. Samples with hCG values above the lower limits were considered positive. RESULTS: The positivity rates of serum hCGß, intact hCG, and total hCG were 6% (1/17), 47% (7/15), and 42% (8/19), respectively, with the latter two having significantly higher positivity rates than hCGß (p = 0.041). Both intact and total hCGs showed similar values. The median values of hCGß, intact hCG, and total hCG before treatment were 0.1 ng/mL, 4.6 mIU/mL, and 4.5 mIU/mL, respectively. CONCLUSION: Serum intact and total hCGs have higher detection rates than hCGß in patients with germinoma using available commercial measurement tools.

Histogenesis of intracranial germ cell tumors: primordial germ cell vs. embryonic stem cell.

INTRODUCTION: Intracranial germ cell tumor (iGCT) is a rare disorder and often occurs during childhood and adolescence. iGCTs are frequently localized in pineal region and hypothalamic-neurohypophyseal axis (HNA). In spite of well-established clinical and pathological entity, histogenesis of iGCTs remains unsettled. Current theories of histogenesis of iGCTs include germ cell theory (from primordial germ cells (PGCs) of aberrant migration) and stem cell theory (transformed embryonic stem (ES) cells). In order to comprehend the histogenesis, we revisit the origin, migration, and fate of the human PGCs, and their transformation processes to iGCT. DISCUSSION: In "germ cell theory," transformation of ectopic PGCs to iGCT is complex and involves multiple transcription factors. Germinoma is derived from ectopic PGCs and is considered a prototype of all GCTs. Non-germinomatous germ cell tumors (NGGCTs) develop from more differentiated counterparts of embryonic and extra-embryonic tissues. However, there is a distinct genomic/epigenomic landscape between germinoma and NGGCT. ES cells transformed from ectopic PGCs through molecular dysregulation or de-differentiation may become the source of iGCT. "Stem cell theory" is transformation of endogenous ES cells or primitive neural stem cell to iGCTs. It supports histological diversity of NGGCTs because of ES cell's pluripotency. However, neural stem cells are abundantly present along the subependymal zone; therefore, it does not explain why iGCTs almost exclusively occur in pineal and HNA locations. Also, the vast difference of methylation status between germinoma and NGGCT makes it difficult to theorize all iGCTs derive from the common cellular linage. CONCLUSION: Transformation of PGCs to ES cells is the most logical mechanism for histogenesis of iGCT. However, its detail remains an enigma and needs further investigations.

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 6 years 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.

Multiple ectopic germinomas presenting as focal dystonia of fingers: a case report and literature review.

BACKGROUND: Intracranial primary germinomas predominantly develop on or near the midline structure in children and young adults and are diagnosed by brain imaging and biopsy. However, if brain imaging and pathology show unusual findings, it becomes difficult to make an accurate diagnosis. CASE REPORT: Herein, we report the case of a 14-year-old boy who presented with focal dystonia of the fingers as an initial symptom. Magnetic resonance imaging of the brain showed multifocal heterogeneous lesions with solid and cystic components involving the right frontal lobe, corpus callosum, left basal ganglia, and left corona radiata. A stereotactic biopsy of the right frontal lesion revealed several granulomatous areas with abundant inflammatory cells. After immunohistochemical staining, the patient was diagnosed with germinoma and treated with chemoradiotherapy according to the Korean Society for Pediatric Neuro-Oncology protocol. The patient has been in complete remission for five years. CONCLUSION: Germinomas can develop in intracranial off-midline structures, with unusual clinical, radiological, and pathological presentations. It is important to include intracranial germinomas in the differential diagnosis of infiltrative parenchymal tumors, especially in children.

Pediatric pineal region masses: a single-center experience over 25 years.

PURPOSE: Pineal region tumors (PRT) represent less than 1% of brain neoplasms. The rare and heterogeneous nature of these tumors is reflected in the variety of treatment modalities employed. METHODS: A single-center retrospective review of all pediatric patients with pineal region tumors between November 1996 and June 2021 was performed. Fifty-six cases of pineal tumors were reviewed for age and symptoms upon presentation, diagnostic methods, imaging characteristics, histological classification, treatment modalities, recurrence, and mortality rates. RESULTS: The average age at diagnosis was 11.3 years. The majority of patients were male (82.1%) and Caucasian (73.2%). The most common presenting symptoms were headache (n = 38, 67.9%) and visual problems (n = 34, 60.7%). Hydrocephalus was present in 49 patients (87.5%). Germinoma (n = 20, 35.7%) and non-germinomatous germ cell tumor (NGGCT) (n = 17, 30.4%) were the most common tumors. Chemotherapy was employed for 54 patients (96.4%), radiation for 49 (87.5%), and surgical resection for 14 (25.0%). The average duration of treatment was 5.9 months. Progression-free survival was 74.4% at 5 years and 72.0% at 10 years. Overall survival was 85.7% at 5 years and 77.1% at 10 years. CONCLUSION: Treatment of pineal region tumors must be targeted to each patient based on presentation, subtype, presence of hydrocephalus, and extent of disease. Upfront surgical resection is usually not indicated. As advances in oncological care proceed, treatment modalities may continue to improve in efficacy.

Brain and Spinal Tumors Originating from the Germ Line Cells.

Primary central nervous system germ cell tumors (CNS GCTs) are part of the GCTs in children and adults. This tumor entity presents with geographic variation, age, and sex predilection. There are two age peaks of incidence distribution at the first few months of life and in adolescence. CNS GCTs are heterogeneous in histopathological subtypes, locations, and tumor marker (AFP, ß-hCG) secretions. In the WHO CNS tumor classification, GCTS are classified as germinoma and nongerminomatous GCT (NGGCT) with different subtypes (including teratoma). Excluding mature teratoma, the remaining NGGCTs are malignant (NGMGCT). In teratoma, growing teratoma syndrome and teratoma with somatic-type malignancy should be highlighted. The common intracranial locations are pineal region, neurohypophysis (NH), bifocal pineal-NH, basal ganglia, and cerebral ventricle. Above 50% of intracranial GCTs (IGCTs) present obstructive hydrocephalus. Spinal tumors are rare. Age, locations, hydrocephalus, and serum/CSF titer of ß-hCG correlate with clinical manifestations. Delayed diagnosis is common in tumors arising in neurohypophysis, bifocal, and basal ganglia resulting in the increasing of physical dysfunction and hormonal deficits. Staging work-up includes CSF cytology for tumor cells and contrast-enhanced MRI of brain and spine for macroscopic metastasis before treatment commences. The therapeutic approach of CNS GCTs integrates locations, histopathology, staging, tumor marker level, and therapeutic classification. Treatment strategies include surgical biopsy/excision, chemotherapy, radiotherapy (single or combination). Secreting tumors with consistent imaging may not require histopathological diagnosis. Primary germinomas are highly radiosensitive and the therapeutic aim is to maintain high survival rate using optimal radiotherapy regimen with/without chemotherapy combination. Primary NGNGCTs are less radiosensitive. The therapeutic aim is to increase survival utilizing more intensive chemotherapy and radiotherapy. The negative prognostic factors are residue disease at the end of treatment and serum or CSF AFP level >1000 ng/mL at diagnosis. In refractory or recurrent NMGGCTs, besides high-dose chemotherapy, new therapy is necessary. Molecular profiling and analysis help for translational research. Survivors of pediatric brain tumors frequently experience cancer-related cognitive dysfunction, physical disability, pituitary hormone deficiency, and other CNS complications after cranial radiotherapy. Continuous surveillance and assessment may lead to improvements in treatment protocols, transdisciplinary interventions, after-treatment rehabilitation, and quality of life.

[Molecular Characteristics and Clinical Significance of Germ Cell Tumors].

Germ cell tumors(GCT), which predominantly emerge in the early to middle teenage years among males, affect the pineal gland, followed by the neurohypophysis, often presenting with site-specific symptoms. Diagnosis hinges on imaging, tumor markers(HCG and AFP), and pathological evaluation. The radiation dose/coverage and chemotherapy intensity are tailored to the distinction between the germinoma and non-germinoma types. Surgical resection is reserved for residual non-germinomas. Biological investigations have revealed frequent mutations in the RAS, MAPK, and PI3K pathways, with no obvious structural variations. These mutations are more prevalent in germinomas than in non-germinomas. Germinomas exhibit a strikingly low methylation status across the genome, mirroring the state of primordial germ cells(PGC), deemed as the cells of origin. Mitosis/meiosis-related genes are highly expressed in germinoma, which is another supporting evidence of PGCs as cells of origin. In contrast, non-germinomas display transcriptomic features that differentiate them into tissue formation and organogenesis. Frequent copy number alterations are another hallmark of GCTs. Among these, 12p gain has been identified as a negative prognostic factor in non-germinomas. Pathologically confirmed tumor cell content serves as a poor prognostic indicator in germinomas and requires external validation as a reliable marker. Given the significant long-term sequelae stemming from treatment burdens in vulnerable young patients, a need for targeted therapy has arisen. Ongoing genomic studies are exploring the pathogenesis and uncovering potential leads for the establishment of precision medicine.

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.

Outcomes of intracranial non-germinomatous germ cell tumors: a retrospective Asian multinational study on treatment strategies and prognostic factors.

PURPOSE: Non-germinomatous germ cell tumors (NGGCTs) are rare pediatric conditions. This multicenter study using Asian multinational patient data investigated treatment outcomes and prognostic factors for NGGCTs. METHODS: Medical records of 251 patients with NGGCTs treated from 1995 to 2015 were retrospectively analyzed from participating centers in Asian countries (Korea, Taiwan, Singapore, and Japan). RESULTS: The median follow up was 8.5 years (95% CI 7.8-9.9). In the total cohort, 5-year event-free survival (EFS) and overall survival (OS) rates were 78.2% and 85.4%, respectively. In 17.9% of the patients, diagnosis was determined by tumor markers alone (alpha-fetoprotein ≥ 10 ng/mL (Korea) or > 25 ng/mL (Taiwan and Singapore), and/or ß-human chorionic gonadotropin (ß-hCG) ≥ 50 mIU/mL). Patients with immature teratomas and mature teratomas comprised 12.0% and 8.4%, respectively. The 5-year EFS rate was higher in patients with histologically confirmed germinoma with elevated ß-hCG (n = 28) than those in patients with malignant NGGCTs (n = 127). Among malignant NGGCTs, patients with choriocarcinoma showed the highest 5-year OS of 87.6%, while yolk sac tumors showed the lowest OS (68.8%). For malignant NGGCT subgroups, an increase in serum ß-hCG levels by 100 mIU/mL was identified as a significant prognostic factor associated with the EFS and OS. CONCLUSION: Our result shows excellent survival outcomes of overall CNS NGGCT. However, treatment outcome varied widely across the histopathologic subgroup of NGGCT. Hence, this study suggests the necessity for accurate diagnosis by surgical biopsy and further optimization of diagnosis and treatment according to the histopathology of NGGCTs. Future clinical trials should be designed for individualized treatments for different NGGCTs subsets.

Epidemiology, Management, and Long-Term Survival Outcomes of Intracranial Typical Site Germinomas: An Analysis of the Surveillance, Epidemiology, and End-Results (SEER) Database.

BACKGROUND: The correlations of epidemiological characteristics and clinical outcomes with different tumor sites in patients with intracranial typical site germinomas (ICTSGs) have not yet been well established. We analyzed ICTSGs using a multicenter database, focusing on its demographic, management patterns, and long-term survival outcomes. METHODS: Patients diagnosed with ICTSGs were selected from the Surveillance, Epidemiology, and End-Results (SEER) database. Demographic information and management patterns of ICTSGs were extracted for data analysis stratified by different tumor sites. Kaplan-Meier curves were used to evaluate the survival outcome stratified by treatment, tumor site and tumor size. RESULTS: Among the 327 patients enrolled in the study, 16.21% had tumors located in the suprasellar region and 83.79% in the pineal region. The proportion of males was significantly higher among pineal germinomas (94.16 vs 66.04%; P < .001). Smaller tumors (<24 mm) were more common in the suprasellar region (37.74 vs 18.87%; P < .001). A higher percentage of patients with suprasellar germinomas underwent surgery. Radiotherapy (RT) and chemotherapy (CT) was, respectively, administered to 82.97 and 60.61% of patients during the treatment period, with no significant difference between suprasellar and pineal germinomas. CT plus RT was the most common treatment modality for both pituitary (30.19%) and pineal (33.94%) germinomas. Both RT and CT were associated with improved long-term survival. No survival difference was observed between suprasellar and pineal germinomas. CONCLUSIONS: Despite significant differences in epidemiology and management, pineal and suprasellar germinomas had a similar long-term clinical outcome.

Vinblastine monotherapy induction prior to radiotherapy for patients with intracranial germinoma during the COVID-19 pandemic.

BACKGROUND: Patients with localized intracranial germinoma have excellent survival. Reducing treatment burden and long-term sequelae is a priority. Intensive inpatient chemotherapy (e.g., carboPEI = carboplatin/etoposide/ifosfamide) has been effectively employed to reduce radiotherapy treatment volume/dose. Outpatient-based carboplatin monotherapy is associated with excellent outcomes in metastatic testicular seminoma (an identical pathology), and successful vinblastine monotherapy induction (with 77% tumor volume reduction after just two weekly vinblastine doses) has recently been reported in an intracranial germinoma patient. METHODS: Adapted UK guidelines for germ cell tumor management were distributed during the COVID-19 pandemic, including nonstandard treatment options to reduce hospital visits and/or admissions. This included vinblastine monotherapy for intracranial germinoma (6 mg/m2 intravenously, or 4 mg/m2 for moderate count suppression, delivered weekly). We describe two such patients treated using this approach. RESULTS: A 30-year-old male with a localized pineal tumor received 12-week vinblastine induction, with >60% volume reduction, prior to definitive radiotherapy. A 12-year-old female with a metastatic suprasellar tumor and progression at all sites of disease whilst awaiting proton radiotherapy received two vinblastine doses with good early response, including 36% primary tumor volume reduction. The patients tolerated vinblastine well. CONCLUSION: Patients with intracranial germinoma have excellent outcomes, and reduction of late effects remains a priority. The description of vinblastine monotherapy in these intracranial germinoma patients warrants further exploration.

Multi-institutional analysis of central nervous system germ cell tumors in patients with Down syndrome.

PURPOSE: Primary germ cell tumors (GCTs) are the most common central nervous system (CNS) neoplasm in patients with Down syndrome (DS). However, a standard of care has not been established due to paucity of data. METHODS: A retrospective multi-institutional analysis was conducted, in addition to a comprehensive review of the literature. RESULTS: Ten patients from six institutions (five USA, one Brazil) were identified, in addition to 31 patients in the literature from 1975 to 2021. Of the 41 total patients (mean age 9.9 years; 61% male), 16 (39%) had non-germinomatous germ cell tumors (NGGCTs), 16 (39%) had pure germinomas, and eight (19.5%) had teratomas. Basal ganglia was the most common tumor location (n = 13; 31.7%), followed by posterior fossa (n = 7; 17%). Nine patients (22%) experienced disease relapse or progression, of which four died from tumor progression (one germinoma, three teratomas). Sixteen patients (39%) experienced treatment-related complications, of which eight (50%) died (five germinomas, three NGGCTs). Of the germinoma patients, two died from chemotherapy-related sepsis, one from postsurgery cardiopulmonary failure, one from pneumonia, and one from moyamoya following radiation therapy (RT). Of the NGGCT patients, one died from chemotherapy-related sepsis, one from postsurgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival was 66% for all histological types: 62% germinomas, 79% for NGGCTs, and 53% for teratomas. CONCLUSION: 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 to mitigate treatment-related complications and long-term neurocognitive sequelae.

Feasibility of treating pediatric intracranial germ cell tumors in a middle-income country: The Jordanian experience.

BACKGROUND: Pediatric intracranial germ cell tumors (iGCT) are rare, with limited data available from Arabic countries. METHODS: We retrospectively reviewed the medical charts of children <18 years diagnosed with iGCT at King Hussein Cancer Center/Jordan (January 2003 to December 2020) for clinical characteristics, treatment, and morbidities. RESULTS: Sixteen patients had germinoma; median age was 6.9 years and median symptoms duration 8 months. Nine tumors were suprasellar, five pineal, and two bifocal. Four were metastatic. Eight patients had slightly elevated beta subunit human chorionic gonadotropin and 11 patients had resection/biopsy. Fifteen patients received chemotherapy; mostly carboplatin (450 mg/m2 )/etoposide, which had low toxicity. All patients received radiotherapy (different doses and fields). At median follow-up of 7.7 years, one tumor recurred (progression-free survival: 91% ± 8%). Twelve patients who continued follow-up had stable visual and endocrine deficits to their initial presentation. Five finished or are finishing diploma and seven had poor school performance (four left school). Six patients were diagnosed with nongerminomatous germ cell tumor; median symptom duration was 1 month. Three tumors were pineal, two suprasellar, and one at quadrigeminal plate. Three were metastatic. Five tested patients had high tumor markers and four had resection/biopsy. All patients received chemotherapy, and then five received craniospinal radiation. Two patients are alive, two died with tumor progression, one died in remission with electrolyte imbalance, and one developed leukemia and died with septic shock. CONCLUSIONS: We achieved excellent survival in treating germinoma using a feasible protocol for low middle-income countries. However, patients encountered significant morbidities exacerbated by delayed diagnosis and unnecessary surgical interventions despite abnormal tumor markers. Raising awareness on iGCT symptomatology and diagnosis may help limit these morbidities.

Advances in Molecular Profiling and Developing Clinical Trials of CNS Germ Cell Tumors: Present and Future Directions.

PURPOSE OF REVIEW: The last decade has seen significant improvements in the management and understanding of the pathogenesis of CNS germ cell tumors (GCTs) by studies on genomic and epigenomic analyses, and published results of clinical trials. This review highlights the new findings to stay up-to-date on the knowledge and better inform the future directions. RECENT FINDINGS: CNS GCTs are characterized by either MAPK or PI3K pathway mutations. Germinoma has a striking global hypo-methylation, analogous to its hypothesized cell-of-origin; primordial germ cell. Micro RNA cluster mir-371-373 and mir-302/367 are characteristic of GCTs, which have potential for liquid biopsy. Clinical trials have revealed whole-ventricular irradiation for germinoma and local radiotherapy for localized non-germinomatous GCTs seem to be sufficient for tumor control. Advancements in basic, translational, and clinical studies are improving our understanding of this rare disease. Further studies are needed, especially in the field of radiomics, liquid biopsy, genomic structural variants, and treatment stratification, to better structure the future management scheme.