Abstract Spinal ependymoma (EPN) with MYCN-amplification (SP-EPN-MYCN) was recently recognized as a distinct tumor type within the 2021 WHO classification of CNS tumors. To date, information about the epidemiological, clinical, and biological features of SP-EPN-MYCN remain sparse. Using DNA-methylation profiling, we collected a cohort of n = 71 (54 primaries, 17 relapses) SP-EPN-MYCNs. Based on the Heidelberg Methylation Brain Tumor Classifier V12.5, 95.6% (68/71) reached a classifier score of ≥ 0.9. In 68/71 cases, focal amplifications of MYCN were detected by copy number variation (CNV) analysis. Two tumors of pediatric patients harbored MYC-amplifications. Other repeated CNVs amongst the primary cases included gains of chromosomes 5 (5/54) and 18 (5/54), loss of chromosome 10 (14/51), and combined 17p loss and 17q gain (5/54). FISH (n = 17) and immunohistochemistry (n = 19) provided positive results for the detection of the MYCN-amplification. Epidemiological data was available for 63% (34/54) of all patients, showing an even sex distribution (17 female patients). Twenty-four percent (8/34) were children and adolescents younger than 20 years. The rest of the cohort consisted of an AYA-population with an overall median age of 31.5 years. Primary lesions were predominantly located in the thoracic (72%) and/or cervical (55%) spinal cord. Two patients showed extra-CNS metastasis to the humerus and the paraspinal musculature, respectively. At the point of analysis, 38% (10/26) of all patients had died, and 10/16 alive patients had already developed disseminated disease. Of patients with available information, 90% (18/20) had relapsed, whereas 10% (2/20) showed stable disease with leptomeningeal spread. Median PFS (n = 17) and OS (n = 25) were 15,5 (12 – 34) and 85 (61 – NA) months. In summary, SP-EPN-MYCN is a disease with dismal prognosis that can disseminate outside of the CNS and affects mainly children and AYA. Currently, comprehensive multi-omics analyses are ongoing.
Abstract BACKGROUND The discovery of unique EP300:BCOR and CREBBP:BCORL1 fusions has extended the spectrum of BCOR altered CNS tumors previously associated with BCOR internal tandem duplication (ITD). Due to the rarity of CNS tumors with BCOR alterations, there is limited information on the clinical outcomes and the effective treatment strategies. METHODS Literature review and retrospective chart analysis RESULTS An 18-year-old male who presented with seizures was found to have a left temporal mass. Histologic diagnosis was low grade glioneural tumor harboring a pathogenic CREBBP:BCOR1 fusion, matching to CNS tumor with EP300:BCOR/BCORL1 fusion by methylation. A re-resection aimed at gross total resection was then performed. Histologic examination revealed residual glioma with focal high-grade transformation, Ki67 up to 35% and CDKN2A loss via FISH analysis. The patient was treated with focal radiation to 54Gy. He remains disease- and seizure-free 1 month post radiation therapy. This case displayed some similarities to previously reported cases, including oligodendroglial- or ependymoma-like features, positivity for Olig2 and/or GFAP, presence of calcifications, and branching capillary networks. However, this case had less frequent mitoses than previously reported cases. In a series of 21 patients with BCOR altered tumors, BCOR-fusion tumor patients had a more favorable PFS compared to BCOR-ITD tumors. In a reported case series of high grade BCOR altered CNS tumors, 5 out of 8 patients remained alive, all of whom received radiation therapy as a primary treatment or at relapse. There is one prior report of an EP300:BCOR tumor undergoing high-grade transformation; increased mitoses, cellularity, and necrosis were observed. This case was lacked necrosis. CONCLUSIONS The optimal treatment for BCOR altered tumors of the CNS is largely unknown given the limited reported cases. Radiation therapy in addition to gross total resection may be an effective treatment leading to more favorable PFS and OS.
Abstract BACKGROUND: Low-grade gliomas (LGG) are the most common solid tumor of childhood and can result in neurologic complications, including seizures, focal neurologic deficits, and learning difficulties. Molecularly targeted agents are increasingly being utilized to treat LGG, but the effect of these agents on accompanying neurologic complications are poorly understood. CASE: An 8-years old male with Neurofibromatosis Type 1 (NF1), medically refractory epilepsy and deep extensive glioma (extending from the optic pathway and involving the basal ganglia and corpus collosum) began selumetinib therapy due to radiographic and symptomatic tumor progression. Radiographic response (resolution of enhancement) was observed at 12 weeks of therapy, accompanied by improvement in seizure frequency, hemiparesis, and academic performance. Due to cardiotoxicity observed at that time (asymptomatic decreased ejection fraction and shortening fraction on echocardiogram), selumetinib was reduced to 50% dosing. On this reduced dose of selumetinib, seizures increased in frequency with subsequent worsening hemiparesis and recurrence of learning difficulties. One month later, dosing was escalated back to 100% due to interval resolution of cardiotoxicity, resulting in resolution of seizures and improvement in focal neurologic deficits and cognition. DISCUSSION: Dose-dependent response to MEK inhibition was observed without concurrent changes in anti-epileptic medications. The tumor was stable in size despite improved enhancement with treatment, suggesting that objective response by RANO criteria is not necessary for improved seizure control in LGG. Recent work has implicated the RAS/MEK/ERK pathway in neuronal precursor cells as a cause for epilepsy, suggesting that MEK inhibition of NF1-heterozygous neurons could be contributing to treatment response in this patient. Improvements in weakness and academic performance may have been due to improved seizure control or a direct effect of MEK inhibition on NF1-heterozygous neurons. CONCLUSION: MEK inhibition may have a clinically relevant anti-seizure effect for patients with pediatric LGG or NF1.
Abstract Fetoplacental neuroblastoma metastasis has been postulated as a mechanism accounting for concordant cases where one twin develops a primary tumour and the second twin manifests the disease without an identifiable primary site. These tumours may originate and spread concomitantly due to the same genetic background shared by monozygotic twins. This study investigated the molecular profile of stage MS neuroblastoma presenting concomitantly in monozygotic twins. Comparative genomic hybridisation (aCGH) was done for each of the twin liver tumour and peripheral blood samples at diagnosis. Comparison of copy-number variation (CNV) regions revealed a set of CNVs that were common to both tumour specimens and not apparent in the blood. The CNV signature in both twins’ tumours was highly similar, suggesting a common clonal origin. Additional findings included large deletion of chromosome 10 and amplification of chromosome 17. Notably, both liver samples had amplification of a short region involving DEIN (chromosome 4q34.1). Similar CNVs strongly support a common clonal origin and metastatic spread from one twin to the other. DEIN is a long-coding RNA (IncRNA) that has been found highly expressed in stage MS neuroblastoma and is likely involved in biological processes such as cell migration and metastasis.
Abstract INTRODUCTION: Medulloblastoma is the most common malignant brain tumor in children, with 5-year overall survival (OS) ranging from 60%-95% depending on subgroup and risk status. The POG 8631/CCG 923 trial (accrual 1986-1990) found a 63% 5 year OS for patients with local disease after gross total resection treated with radiation at a dose of 23.4 Gy craniospinal radiation and posterior fossa boost to 54 Gy, vs. 80.5% 5-year OS for patients treated as per full ACNS0331 therapy including maintenance chemotherapy. Herein, we describe a long-term survival with standard-risk medulloblastoma who only received surgical resection and radiation therapy. CASE: A 17-year-old male presented with acute onset of hypertension, bradycardia, headache, and blurry vision and was found to have a heterogeneously enhancing posterior fossa mass with mass effect on the fourth ventricle and hydrocephalus on brain MRI. He underwent gross total resection of the tumor and histopathology revealed medulloblastoma with classic and large cell features. Fluorescence in situ hybridization (FISH) was negative for MYC, MYCN amplification, or HER2 gain. Cerebrospinal fluid cytology was negative for neoplastic cells, and spinal MRI did not reveal any drop metastases. The patient initiated therapy per ACNS0331 with craniospinal irradiation posterior fossa boost. He also received weekly vincristine. After completion of radiation therapy, the family declined further chemotherapy despite medical advice. He had no evidence of relapse most recently at 51 months from completion of therapy. Next generation sequencing and methylation testing are currently pending. CONCLUSION: Current efforts aim at optimizing therapy based on molecular subgrouping, to minimize long-term adverse events associated with current therapies. We report a unique case of an adolescent male with an standard-risk medulloblastoma, who achieved remission with only radiotherapy. Further molecular tumor analysis may elucidate the response of the tumor.
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).
Abstract BACKGROUND: Primary intracranial germ cell tumors (GCTs) are rare heterogeneous tumors, with germinoma accounting for two-thirds of cases. Neoadjuvant chemotherapy with response-based reduced radiotherapy dose and field has become the standard management of localized CNS germinomas, however, treatment of primary metastatic disease has remained controversial. Furthermore, there is limited published research on the use of neoadjuvant chemotherapy in primary metastatic germinoma. METHODS: We performed a retrospective multi-institutional data collection and analysis of patients diagnosed with metastatic germinoma since 2000 to assess the overall survival (OS) and event-free survival (EFS) of the different treatment modalities administered. RESULTS: We identified 78 patients with germinoma, in two tertiary care centers, of which nine patients (11.5%; eight males) had metastatic disease. The median age at presentation was 13.3 years. All patients had a biopsy at presentation confirming the diagnosis. Three patients had positive CSF cytology (M1). Six patients received craniospinal irradiation (CSI) with boost to primary and metastatic sites, of which five patients received total CSI dose of 24 Gy, while the dose was unknown for one patient. One patient required one cycle of chemotherapy prior to CSI due to worsening visual changes, which subsequently resolved. One patient received two cycles followed by whole ventricular irradiation (WVI) of 23.4 Gy with a boost to the primary bed. One patient received WVI without neoadjuvant chemotherapy. One patient developed anoxic brain injury and only received chemotherapy. He died of recurrent progressive disease 15 months post-diagnosis. The median follow-up time was 77.5 months (range 15-130.5 months), with an OS of 88.9%. Further multi-institutional data collection and analysis is underway and will be presented at the meeting. CONCLUSION: We anticipate our results may elucidate the role of neoadjuvant chemotherapy in the treatment of metastatic germinoma, and whether when combined with lower CSI doses did not compromise EFS/OS.
Abstract Retinoblastoma is a childhood cancer of the retina involving germline or somatic alterations of the RB Transcriptional Corepressor 1 gene, RB1 . Rare cases of sellar-suprasellar region retinoblastoma without evidence of ocular or pineal tumors have been described. A nine-month-old male presented with a sellar-suprasellar region mass. Histopathology showed an embryonal tumor with focal Flexner-Wintersteiner-like rosettes and loss of retinoblastoma protein (RB1) expression by immunohistochemistry. DNA array-based methylation profiling confidently classified the tumor as pineoblastoma group A/intracranial retinoblastoma. The patient was subsequently enrolled on an institutional translational cancer research protocol and underwent comprehensive molecular profiling, including paired tumor/normal exome and genome sequencing and RNA-sequencing of the tumor. Additionally, Pacific Biosciences (PacBio) Single Molecule Real Time (SMRT) sequencing was performed from comparator normal and disease-involved tissue to resolve complex structural variations. RNA-sequencing revealed multiple fusions clustered within 13q14.1-q21.3, including a novel in-frame fusion of RB1-SIAH3 predicted to prematurely truncate the RB1 protein. SMRT sequencing revealed a complex structural rearrangement spanning 13q14.11-q31.3, including two somatic structural variants within intron 17 of RB1 . These events corresponded to the RB1-SIAH3 fusion and a novel RB1 rearrangement expected to correlate with the complete absence of RB1 protein expression. Comprehensive molecular analysis, including DNA array-based methylation profiling and sequencing-based methodologies, were critical for classification and understanding the complex mechanism of RB1 inactivation in this diagnostically challenging tumor.
Diffuse Intrinsic Pontine Glioma (DIPG) is an extensively invasive tumor of brainstem. Tumor biopsy was rarely performed until recently, because of the possible complications associated with the procedure, therefore, the data on the DIPG histology is relatively limited. We identified 29 consecutive cases of DIPG diagnosed from 2002 to 2017 at Children’s Hospital of Michigan, and tumor biopsy was performed in 22 cases. The histology was consistent with low grade glioma (LGG) in 4 of the 22 cases (18%). We retrospectively reviewed these 4 cases, including the histology, MRI findings, H3 mutation and BRAF alteration status, treatment and survival. There was one Grade I astrocytoma, one Grade I ganglioglioma, and two grade II astrocytomas. Radiologically, 3 were consistent with typical DIPG, one with atypical DIPG. The testing for H3 mutation and BRAF alteration was performed in two recent cases. One case had H3F3A K27 mutation, but no BRAF alteration was identified in either case. All patients received involved-field external beam radiation as part of their initial treatment. Three patients succumbed to their disease with overall survival of 9–17 months, and one patient is alive with no clinical or radiological sign of disease at 6 months following diagnosis. In summary, histology was consistent with LGG in 4 out of 22(18%) of our biopsied DIPG series. One patient with ganglioglioma was found to have histone H3 mutation, a rare finding in LGG but common in midline high grade glioma, who progressed at 11 months, and died at 17 months following initial diagnosis.
