Nongerminomatous Germ Cell Tumors Research Articles

Complex Treatment of A Rare Non-Germinomatous Germ Cell Optic-Chiasmal Brain Tumor In An Adolescent Child-A Clinical Case With Literature Review

Non-germ cell tumours (NGCTs) are rare intracranial neoplasms occurring in adolescents and young adults. A multidisciplinary team including a neurosurgeon, oncologist, radiologist, pathohistologist, ophthalmologist, pediatric oncohematologist, neurologist and endocrinologist is required for diagnosis and treatment. We present a rarely diagnosed optic-chiasmal non-germinomatous germ cell tumour (NGGCT) in a 16-year-old boy, accompanied by pituitary insufficiency (diabetes insipidus and central hypothyroidism) and severely impaired vision bilaterally. The immunohistochemistry (IHC) of the tumor biopsy, as well as the level of tumor markers (human chorionic gonadotropin and alpha-fetoprotein) in the serum and cerebrospinal fluid are significant factors for determining the diagnosis-cranial GCT or cranial NGCT. Because the tumor was inoperable, we performed 3 courses of neoadjuvant chemotherapy followed by definitive radiotherapy to a total tumor dose of 55 Gy. In such rare childhood brain tumors, complex treatment achieves long-term local tumor control, requiring long-term monitoring by an ophthalmologist and endocrinologist.

Off-label prescribing of immune checkpoint inhibitor therapy at a single pediatric cancer center.

Immune checkpoint inhibitors (ICI) have improved outcomes in a variety of adult cancers and are prescribed with increasing frequency across oncology. However, patterns of off-label use of ICI in pediatrics remain unclear. This is a single-institution, retrospective cohort study evaluating off-label ICI use in pediatric and young adult patients with cancer treated at our institution from 2014 to 2022. Response was based on clinician assessment derived from clinical records. Immune-related adverse events (iRAEs) were classified according to CTCAE v5.0. We identified 50 unique patients treated with off-label ICI (28 with solid tumors, 20 with central nervous system (CNS) tumors, 2 with hematologic malignancies). At time of ICI initiation, only five patients (10%) had localized disease, and all but one patient was treated in the relapsed/refractory setting. All patients were treated with the FDA-approved weight-based dosing recommendations. Overall, there was disease control in 21 patients (42%), with best response including one complete response (melanoma), two partial responses (high-grade glioma, CNS nongerminomatous germ cell tumor), and 18 patients with stable disease. Forty-four patients (88%) eventually experienced disease progression. Among 22 patients (44%) experiencing iRAEs, 10 (20%) had a grade ≥3 irAE, 12 (24%) required corticosteroids, and 14 (28%) required ICI discontinuation. irAE occurrence was associated with significantly improved progression-free survival (HR 0.35; 95% CI: 0.18 to 0.68; p = 0.002) and overall survival (HR 0.33; 95% CI: 0.17 to 0.66; p = 0.002). At our institution, ICI was most commonly prescribed in the relapsed/refractory setting to patients with metastatic disease. The treatment was generally well-tolerated in the pediatric population. The overall response rate was low, and the majority of patients eventually experienced disease progression. A few patients, however, had durable treatment responses. Further studies are needed to identify which pediatric patients are most likely to benefit from ICI.

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 tumors expand therapeutic opportunities.

Intracranial germ cell tumors (IGCTs) are a rare group of malignancies that are clinically classified as germinomas and nongerminomatous germ cell tumors (NGGCTs). Previous studies have found that somatic mutations involving the mitogen-activated protein kinase/mTOR signaling 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 signaling 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 tumors 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.

Consensus guidelines for the management of pineal region tumours for low- and middle-income countries.

Pineal region tumours are rare and mainly arise at a younger age. They can be categorized into various types: germ cell tumours (GCT), pineal parenchymal tumours (PPT), meningiomas, gliomas, pineoblastoma, pineal parenchymal tumours of intermediate differentiation, papillary tumours of the pineal region, and SMARCB1- mutant desmoplastic myxoid tumour. Within GCT, germinomas are the most prevalent, comprising the majority of tumours in this region, while nongerminomatous GCTs are also present. In rare instances, metastases from other sites may manifest. These tumours often lead to obstructive hydrocephalus and commonly exhibit symptoms related to mass effect, including headache, nausea, vomiting, and impaired gait stability. Different subtypes of pineal region tumours exhibit distinct radiological characteristics, thus imaging remains the primary diagnostic tool. Histologic diagnosis necessitates biopsy, unless in cases of germ cell tumours, particularly germinomas, which can be identified through elevated levels of tumour markers like alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) in both cerebrospinal fluid (CSF) and serum. While benign tumours might be effectively treated with radical resection alone, malignant tumours demand additional chemotherapy and radiotherapy following surgical removal.

Primary central nervous system germ cell tumors in Central America and the Caribbean Region: an AHOPCA 20-year experience.

Primary central nervous system germ cell tumors (GCT) are rare neoplasms in pediatrics. Treatment depends on the histological subtype and extent of the disease. Overall survival (OS) is above 90% for germinomas and 70%-80% for nongerminomatous GCT (NGGCT) in high-income countries (HIC) while data are usually lacking for patients in Low-Middle Income country (LMIC). This study aims to describe the experience of treating patients with CNS GCT in four of eight countries, members of the Asociación de Hemato-Oncología Pediátrica de Centro América (AHOPCA), and determine their 5-year OS. We conducted a retrospective chart review of patients treated for CNS GCT. Epidemiological and clinical characteristics, histology, treatment modalities, and outcomes were analyzed. From 2001 to 2021, 48 patients were included: 22 from Guatemala, 18 from Nicaragua, three from the Dominican Republic, and five from El Salvador. Thirty-one (64.6%) were boys; the median age at diagnosis was 10.2 years (range: 1 to 17 years). Presenting symptoms were headaches (n = 24, 50%), visual disturbances (n = 17, 35.4%), vomiting (n = 12, 25%), nausea (n = 8, 16.7%), and diabetes insipidus (n = 7, 14.6%). Two patients with NGGCT presented with precocious puberty. Biopsy or tumor resection was performed in 38 cases (79.2%): 23 (88.4%) germinomas, 11 (78.6%) NGGCT, and four (50%) CNS GCT. Eight patients were diagnosed and treated based on CSF tumor marker elevation; four germinomas (BHCG 11.32-29.41 mUI/mL) and four NGGCT (BHCG 84.43-201.97 mUI/mL or positive AFP > 10 UI/mL). Tumor locations included suprasellar (n = 17, 35.4%), pineal (n = 13, 27.1%), thalamus/basal ganglia (n = 5, 10.4%), other (n = 12, 25%), and one bifocal. Four (8.3%) had metastatic disease, and six had positive CSF; staging data were incomplete in 25 patients (52%). Patients were treated with varied chemotherapy and radiotherapy modalities. Nine patients had incomplete data regarding treatment. Five-year OS was 65% (68% for germinoma, 50.6% for NGGCT, and 85.7% for unclassified GCT). Germinoma was the most common histology, and there was a male predominance. More than half of patients had incomplete staging data and treatment was variable across the region. OS is lower compared to HIC. Standardized treatment protocols will aid in adequate staging and treatment planning, prevent complications, and improve survival.

10121-BT-8 CLINICOPATHOLOGICAL ANALYSIS OF CENTRAL NERVOUS SYSTEM GERM CELL TUMORS -387CASES IN THE JCCG COHORT AND THE IGCT CONSORTIUM COHORT

Abstract BACKGROUND Central nervous system germ cell tumors (CNS GCTs) are rare primary tumors that tend to occur in East Asian boys. In Japan, the Japan Children's Cancer Group (JCCG) and the CNS GCT Genome Analysis Consortium (iGCT Consortium) have been accumulating clinical and pathological data on CNS-GCT cases. METHODS Statistical analyses were performed on 178 cases in the JCCG's Solid Tumor Observational Study (2016-2022) and 209 cases in the iGCT Consortium (2011-2021) for age, gender, site of origin, and pathological diagnosis. RESULTS There were 306 primary cases and 44 recurrent cases, 296 (77%) males and 90 (23%) females, with a median age of 13 years, 11 years for JCCG and 16 years for iGCT Consortium, with differences between these two cohorts. The most common pathological diagnosis was germinoma in 200 cases (52%). Non-germinomatous germ cell tumors (NGGCTs) in 167 cases (43%), of which 69 cases (18%) were mixed GCT with germinoma, 34 cases were immature teratoma, mature teratoma in 32 cases (8%), yolk sac tumor in 20 cases (5%), mixed GCT without germinoma in 5 cases (1%), choriocarcinoma in 5 cases (1%), embryonal carcinoma in 2 cases (0.5%). The median age of patients with germinoma was 15 years, while with other histological types was 12 years. The pineal gland was the most common site (208 cases, 56%) and 114 cases (31%) occurred in the neurohypophysis. 38 cases of them were bifocal. Tumor development in the basal ganglia occurred in 40 cases (11%), and multiple lesions were seen in 37 cases (10%). In the neurohypophysis, the male-to-female ratio was 1:1, while in the pineal region was 11:1. In the neurohypophysis, 67% had germinoma and 9% had teratoma, whereas, in the pineal regions, 50% had germinoma and 19% had teratoma. CONCLUSIONS CNS GCT is closely correlated with age, sex, site of origin, and histology.

Treatment Outcome of Response-Based Radiation Therapy in Children and Adolescents With Central Nervous System Nongerminomatous Germ Cell Tumors: Results of a Prospective Study

The optimal dose and range of radiation therapy for central nervous system nongerminomatous germ cell tumors (NGGCTs) have not been uniformly established. Therefore, this study aimed to investigate the effect of individualized radiation therapy, based on the response to induction chemotherapy combined with surgery, on the prognosis of patients with NGGCTs. Based on the imaging examination and tumor markers after induction chemotherapy and pathologic results of second-look surgery, patients with NGGCT received different radiation therapy strategies, including 30.6 Gy whole ventricular irradiation+tumor-bed boost to 54 Gy, 30.6 Gy craniospinal irradiation+tumor-bed boost to 54 Gy, 36 Gy craniospinal irradiation+tumor-bed boost to 54 Gy, and 36 Gy craniospinal irradiation+54 Gy tumor-bed boost with 45 Gy to metastatic spinal lesions. A total of 51 patients were enrolled between January 2015 and March 2021, with a median age of 10.3 years. The 3-year event-free survival and overall survival (OS) of the entire cohort were 70.2% ± 6.9% and 77.5% ± 6.0%, respectively. The 3-year OS of patients achieving partial response after induction chemotherapy was higher than that of patients with stable disease (P=.03) or progressive disease (P=.002). The 3-year event-free survival and OS of the 18 patients receiving 30.6 Gy whole ventricular irradiation and 54 Gy tumor-bed boost were 88.9% ± 7.4% and 94.4% ± 5.4%, respectively. The results suggest that an individualized radiation therapy strategy based on response to induction chemotherapy and surgery is a feasible and promising means of achieving reduction in dose and extent of radiation in patients while still providing good response.

NIMG-79. DIFFERENTIATION OF SUBTYPES IN AFULLY AUTOMATED DEEP LEARN TUMORS USING PREOPERATIVEM RIMAGES ING APPROACH FOR ACCURATE PRIMARY INTRACRANIAL

Abstract BACKGROUND Intracranial germ cell tumors (iGCTs) are divided into germinomas (GEs) and nongerminomatous germ cell tumors (NGGCTs), each having distinct treatments and prognoses. However, predictive biomarkers for differentiation are limited. Here, we aim to develop a deep learning (DL) model that can automatically differentiate GEs from NGGCTs using preoperative magnetic resonance (MR) images and analyzing how our model improved clinical decision making among five physicians. METHODS: This multicenter study included patients with pathology-confirmed iGCTs for the developed set (total n = 280), which was split into training (n = 200) and testing datasets (n= 80), and three independent validation datasets (n = 64), respectively. We developed a DL model based on 3D nnU-Net and preoperative MR images to differentiate GEs from NGGCTs. To evaluate the clinical value of the DL model, five physicians' accuracy and level of consistency in identifying tumor types were compared in the testing and three validation datasets, with and without referring to the DL model’s output. RESULTS The DL model achieved AUCs of 0.950, 0.921, 0.869, and 0.905 in the testing and three validation datasets, respectively, which is superior to using conventional information including MR features and clinical information (AUC=0.768, P=0.009). The physicians’ diagnostic performance improved from an average AUC of 0.695 without reference to the DL output to 0.842 using the DL output in the testing and independent validation datasets (21.2% improvement, P=0.014). CONCLUSIONS We developed and validated a DL model using a large dataset to accurately differentiate GEs from NGGCTs using preoperative MR images.

PAEDIATRIC-07 IMAGING OF PINEAL REGION TUMOURS IN CHILDREN

Abstract Pineal tumors comprise between 3% and 8% of all pediatric brain tumors. Pineal region tumors can be divided into four categories: Germ cell tumors, pineal cysts, pineal parenchymal tumors, and tumors of the supporting tissues of the pineal gland or adjacent structures (such as pineal gliomas, dermoids, and epidermoids). The most common pineal region tumors are germ cell tumors, most are pure germinomas. Other variants such as nongerminomatous germ cell tumors, mixed germ cell tumors, teratomas, embryonal cell carcinoma, yolk sac tumor, and choriocarcinoma constitute the remainder. Germinomas are hyperdense on CT and enhance homogenously. The typical appearance on CT is a calcified pineal gland surrounded by noncalcified tumor. On MRI, these lesions have homogenous signal isointense to gray matter on all sequences with intense contrast enhancement. These tumors may infiltrate the thalami and midbrain. Spinal dissemination is seen in up to 36% of cases. Pineocytomas are well-differentiated tumors that retain morphologic features of the pineal parenchymal cells. They are slow-growing, circumscribed, but noncapsulated tumors. They are more commonly solid tumors, although cystic variants have been described. Solid tumors are either hypointense or isointense to gray matter and T2-hyperintense. Enhancement is homogenous and calcification is common. Cystic variants are often indistinguishable from pineal cysts. Pineoblastomas are malignant, unencapsulated tumors that resemble embryonal tumors NOS, but are distinct from such tumors in other locations due to their photosensory differentiation. On MRI, these lesions are hypointense to isointense on T1-weighted images and variable low, high, or mixed signal on T2-weighted images. They have lobulated contours and enhance homogenously. They calcify less often than pineocytomas. The “exploded pattern” of calcification with peripheral displacement of pineal gland calcification is considered more typical of pineal parenchymal tumors, differentiating them from germ cell tumors.

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.

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.

Prospective Feasibility Trial of Vertebral Body Sparing Pencil Beam Scanning Proton Craniospinal Irradiation in Growing Children

Advanced proton therapy techniques now allow for delivery of craniospinal irradiation (CSI) to the entire brain and thecal sac while sparing many of the anterior vertebral bodies from doses expected to inhibit growth, though this technique has not been prospectively studied. The purpose of this trial is to test the feasibility and robustness of vertebral body sparing (VBS) CSI in children with standard image guidance, to assess the dosimetric and toxicity benefits of this approach, and to report early clinical outcomes. Children 3-18 years old requiring CSI treatment were eligible for this IRB approved prospective clinical trial. The CSI clinical target volume (CTV) included the brain, entire thecal sac and neural foramina with no expansion. Select anterior vertebral bodies (AVB) could be included at the physician's discretion. The spinal portion of the CTV was treated with PA beam(s) with robust optimization (+/-3.5% range, 5mm positional uncertainty). Daily image guidance included kV/kV imaging. Cone beam CT (CBCT) was acquired weekly after final positioning and a virtual CT (vCT) was created for quality assurance (QA) analysis. Acute toxicity was prospectively assessed weekly during treatment and 1 month after per CTCAE v5.0. Ten children with a median patient age and CSI dose of 9 years (range 3-16) and 36 Gy (RBE) (range 15-36 Gy (RBE)) were enrolled. Common diagnoses were medulloblastoma (n = 4) and non-germinomatous germ cell tumor (n = 3). Seven patients received prior chemotherapy; 2 patients were treated with palliative intent. Dose statistics for the anterior vertebral body varied according to age, CSI dose and portion of the spine, with the greatest sparing in the lower thoracic and lumbar vertebrae for all patients. Nine patients completed all QA CTs; one patient required a replan due to weight gain. For all remaining patients the treatment was highly robust: CTV V95 reduction at the C-spine, T-spine, and L-spine was 0.0±0.1%, 0.6±1.3%, and 0.8±1.1%, respectively. The highest grade non-hematologic acute toxicity was grade 2 alopecia (n = 9) and grade 2 nausea/vomiting (n = 5). One patient reported transient grade 1 esophagitis during treatment. Hematologic toxicity included >/ = grade 3 lymphopenia in 7 patients, >/ = grade 3 leukopenia in 1 patient, >/ = grade 2 anemia in 6 patients, and >/ = grade 1 thrombocytopenia in 3 patients. Median follow-up is 16.6 months (range 10-36 months). Three patients experience intracranial disease progression: 2 local and 1 distant intracranial failure. There were no failures within the spine. Proton vertebral body sparing CSI targeting the thecal sac only is a highly robust treatment technique and is well tolerated. Weekly CBCT to assess changes in soft tissue posterior to the spine is recommended. Further follow-up is required to assess long-term growth outcomes.

Distinct patterns of copy number alterations may predict poor outcome in central nervous system germ cell tumors

We have previously reported that 12p gain may predict the presence of malignant components and poor prognosis for CNS germ cell tumor (GCT). Recently, 3p25.3 gain was identified as an independent predictor of poor prognosis for testicular GCT. Eighty-one CNS GCTs were analyzed. Copy number was calculated using methylation arrays. Five cases (6.2%) showed 3p25.3 gain, but only among the 40 non-germinomatous GCTs (NGGCTs) (5/40, 12.5%; p = 0.03). Among NGGCTs, those with a yolk sac tumor component showed a significantly higher frequency of 3p25.3 gain (18.2%) than those without (1.5%; p = 0.048). NGGCTs with gain showed significantly shorter progression-free survival (PFS) than those without (p = 0.047). The 3p25.3 gain and 12p gain were independent from each other. The combination of 3p25.3 gain and/or 12p gain was more frequent among NGGCTs with malignant components (69%) than among those without (29%; p = 0.02). Germinomas containing a higher number of copy number alterations showed shorter PFS than those with fewer (p = 0.03). Taken together, a finding of 3p25.3 gain may be a copy number alteration specific to NGGCTs and in combination with 12p gain could serve as a marker of negative prognosis or treatment resistance. Germinoma with frequent chromosomal instability may constitute an unfavorable subgroup.

​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.

Characterizing Lymphovascular Invasion in Pediatric and Adolescent Malignant Ovarian Nongerminomatous Germ Cell Tumors: A Report from the Children's Oncology Group

BackgroundLymphovascular invasion (LVI) has been identified as a poor prognostic factor for a variety of tumors; however, its significance in malignant ovarian germ cell tumors (MOGCT) in pediatric and adolescent patients is not well described. We aim to clarify the significance of LVI in the subset of patients with nongerminomatous MOGCT. MethodsRecords of patients 0–20 years of age with MOGCT enrolled on Children's Oncology Group study AGCT0132 were reviewed. Patients with documented presence or absence of LVI in either institutional or central review pathology reports were included. ResultsOf 130 patients with MOGCTs, 83 patients had of the presence or absence of LVI documented in their pathology report. 42/83 patients (50.6%) were found to have LVI present. The estimated odds of having LVI was higher in patients with stage II and III disease, 11 years and older and with the presence of choriocarcinoma. Event-free survival (EFS) and overall survival (OS) remained high in patients with LVI. Approximately 50% of patients with a documented LVI status in either institutional pathology report or central review were found to have LVI. ConclusionsThe presence of LVI was higher in tumors with adverse risk factors including higher stage and age greater than 11 years. While LVI was not associated with EFS or OS in the intermediate risk group, further work is necessary to determine the effect of LVI on long-term disease-free survival. We, therefore, recommend routinely incorporating LVI status into institutional pathology reports for pediatric and adolescent patients with MOGCT. Level of EvidenceIII.

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.

RARE-07. BONE MARROW ABLATIVE CHEMOTHERAPY ASSOCIATED WITH IMPROVED OUTCOMES AMONG PATIENTS WITH RELAPSED CENTRAL NERVOUS SYSTEM NON-GERMINOMATOUS GERM CELL TUMORS

Abstract PURPOSE Patients with relapsed/refractory central nervous system (CNS) non-germinomatous germ cell tumors (NGGCTs) have poor outcomes. There is no universal agreement on managing these patients secondary to the rarity of the disease and lack of prospective trials. We aim to explore prognostic factors that may help guide the management of patients with relapsed/refractory CNS NGGCTs. METHODS We performed a multinational retrospective study of relapsed/refractory CNS NGGCTs. We summarized all data using standard descriptive statistics. Overall survival (OS) was evaluated using Kaplan-Meier and Fisher’s exact test to estimate odds ratios (OR) and 95% confidence intervals (CI) using SPSS software. RESULTS We identified 28 patients from 7 centers. Twenty-three patients (82%) were males. The median age at initial diagnosis was 11 years (range: 8-15). Twelve patients (43%) suffered from relapse, and 16 patients (57%) had an initial refractory disease. The median time to first relapse/progression was 29 months (range: 5-26). Eight patients (29%) received bone marrow ablative chemotherapy (HDCx) at relapse/progression. Sixteen patients (57%) received re-irradiation at relapse/progression. Six patients (21%) achieved complete remission (CR) at relapse. Only eight patients (29%) were alive at the last follow-up. The median follow-up time since relapse/progression was 16 months (range: 1 -153 months). HDCx (OR=25, 95%CI: 2.9-2223) – not re-irradiation (OR=7.8 95%CI: 0.795-76.1) – was associated with being alive at the last follow-up. All patients who achieved CR at the end of relapse treatment survived. Only one patient with the refractory disease was alive at the last follow-up. CONCLUSIONS Patients with refractory CNS NGGCTs have dismal outcomes. HDCx and achieving CR at the end of relapse therapy are associated with improved survival. A multinational registry is needed to collate standardized data to inform future prospective clinical trials and improve the outcomes of patients with relapsed/refractory CNS NGCCTs.

Prognostic factors of pediatric pineal region tumors at a single institution.

This study aimed to identify factors of a worse prognosis among different histological types of pineal region tumors in pediatric patients treat at a single institution in a 30-year period. Pediatric patients (151; < 18years of age) treated between 1991 and 2020 were analyzed. Kaplan-Meyer survival curves were created, and the log-rank test was used to compare the main prognostic factors in the different histological types. Germinoma was found in 33.1%, with an overall 60-month survival rate of 88%; the female sex was the only factor of a worse prognosis. Non-germinomatous germ cell tumors were found in 27.1%, with an overall 60-month survival rate of 67.2%; metastasis upon diagnosis, residual tumor, and the absence of radiotherapy were associated with a worse diagnosis. Pineoblastoma was found in 22.5%, with an overall 60-month survival rate of 40.7%; the male sex was the only factor of a worse prognosis; a tendency toward a worse outcome was found in patients < 3years of age and those with metastasis upon diagnosis. Glioma was identified in 12.5%, with an overall 60-month survival rate of 72.6%; high-grade gliomas were associated with a worse prognosis. Atypical teratoid rhabdoid tumors was found in 3.3%, and all patients died within a 19-month period. Pineal region tumors are characterized by the heterogeneity of histological types, which exert an influence on the outcome. Knowledge of the prognostic factors for each histological types is of extreme importance to the determination of guided multidisciplinary treatment.

Update on MRI in pediatric intracranial germ cell tumors-The clinical and radiological features.

Intracranial germ cell tumors (iGCTs) are uncommon brain tumors that mainly occur in children. Differing in histology, location, and gender of the patients, iGCTs are often divided into germinomas and non-germinomatous germ cell tumors (NGGCTs). Early diagnosis and timely treatment are crucial to iGCTs, the subtypes of which have substantial variations. This review summarized the clinical and radiological features of iGCTs at different sites, and reviewed the recent advances in neuroimaging of iGCTs, which can help predict tumor subtypes early and guide clinical decision-making.