Clinically aggressive pediatric spinal ependymoma with novel MYC amplification demonstrates molecular and histopathologic similarity to newly described MYCN-amplified spinal ependymomas

Primary spinal cord tumors contribute to ≤ 10% of central nervous system tumors in individuals of pediatric or adolescent age. Among intramedullary tumors, spinal ependymomas make up ~ 30% of this rare tumor population. A twelve-year-old male presented with an intradural, extramedullary mass occupying the dorsal spinal canal from C6 through T2. Gross total resection and histopathology revealed a World Health Organization (WHO) grade 2 ependymoma. He recurred eleven months later with extension from C2 through T1-T2. Subtotal resection was achieved followed by focal proton beam irradiation and chemotherapy. Histopathology was consistent with WHO grade 3 ependymoma. Molecular profiling of the primary and recurrent tumors revealed a novel amplification of the MYC (8q24) gene, which was confirmed by fluorescence in situ hybridization studies. Although MYC amplification in spinal ependymoma is exceedingly rare, a newly described classification of spinal ependymoma harboring MYCN (2p24) amplification (SP-MYCN) has been defined by DNA methylation-array based profiling. These individuals typically present with a malignant progression and dismal outcomes, contrary to the universally excellent survival outcomes seen in other spinal ependymomas. DNA methylation array-based classification confidently classified this tumor as SP-MYCN ependymoma. Notably, among the cohort of 52 tumors comprising the SP-MYCN methylation class, none harbor MYC amplification, highlighting the rarity of this genomic amplification in spinal ependymoma. A literature review comparing our individual to reported SP-MYCN tumors (n = 26) revealed similarities in clinical, histopathologic, and molecular features. Thus, we provide evidence from a single case to support the inclusion of MYC amplified spinal ependymoma within the molecular subgroup of SP-MYCN.

Interrogation of the microenvironmental landscape in spinal ependymomas reveals dual functions of tumor-associated macrophages

Spinal ependymomas are the most common spinal cord tumors in adults, but their intratumoral cellular heterogeneity has been less studied, and how spinal microglia are involved in tumor progression is still unknown. Here, our single-cell RNA-sequencing analyses of three spinal ependymoma subtypes dissect the microenvironmental landscape of spinal ependymomas and reveal tumor-associated macrophage (TAM) subsets with distinct functional phenotypes. CCL2+ TAMs are related to the immune response and exhibit a high capacity for apoptosis, while CD44+ TAMs are associated with tumor angiogenesis. By combining these results with those of single-cell ATAC-sequencing data analysis, we reveal that TEAD1 and EGR3 play roles in regulating the functional diversity of TAMs. We further identify diverse characteristics of both malignant cells and TAMs that might underlie the different malignant degrees of each subtype. Finally, assessment of cell-cell interactions reveal that stromal cells act as extracellular factors that mediate TAM diversity. Overall, our results reveal dual functions of TAMs in tumor progression, providing valuable insights for TAM-targeting immunotherapy.

EPCO-01. MOLECULAR PROFILING OF SPINAL CORD EPENDYMOMA

BACKGROUND Ependymomas are currently classified into 9 subgroups by DNA methylation profiles. Although spinal cord ependymoma (SP-EPN) is distinct from other tumors, diversity within SP-EPN is still unclear. Here, we used transcriptomic and epigenomic profiles to investigate the diversity among Japanese SP-EPN cases. MATERIALS AND METHODS We analyzed 57 SP-EPN patients (32 males and 25 females, aged from 18 to 78 years, median: 52), including two cases of neurofibromatosis type 2, five cases of grade 3 (WHO grade). We obtained transcriptome (RNA-seq) and DNA methylation (Infinium Methylation EPIC array) data from fresh frozen specimens of SP-EPN resected at the University of Tokyo Hospital and our collaborative groups. RESULTS Three cases had a previous intracranial ependymoma operation. Hierarchical clustering of the DNA methylation data showed that these three cases of intracranial origin as a different cluster from spinal origin. The 45 grade 2 spinal ependymoma showed a relatively homogenous methylation pattern. However, the methylation status of HOX gene cluster regions is compatible with the segment of origin, which reflects the cells of origins are derived after the determination of segment identity. RNA sequencing of 57 cases revealed two subgroups within grade 2. Gene ontology analysis of differentially expressed genes suggested the difference in metabolic state such as rRNA translation and mitochondrial respiration between the two expression subgroups. CONCLUSION Epigenetic analysis indicated the accurate body segment origin of SP-EPN. We observed that metabolic states could divide grade 2 spinal cord ependymoma into 2 subgroups and will present the relationship to clinicopathological information.

Cervical neuromyelitis optica with thoracic ependymoma

Background: The occurrence of cervical neuromyelitis optica (NMO) in a patient with a thoracic ependymoma is uncommon. Here, we present a patient with a spinal ependymoma who developed the new onset of NMO 2 months later. Case Description: A 66-year-old male presented with right lower limb weakness. The magnetic resonance (MR) revealed an intramedullary spinal cord tumor at the T2-T4 level. It was surgically excised and proved pathologically to be an ependymoma. 2 months later, the patient presented with an acute partial quadriparesis and a high signal intensity cord lesion at the C2-C3 level attributed to seropositive NMO (i.e. additional diagnostic studies confirmed this diagnosis). Conclusion: Patients with intramedullary thoracic ependymomas may also develop NMO resulting in recurrent/ new neurological deficits. Critical studies utilized to diagnose NMO include brain and spine MRs showing unique intramedullary brain/cord lesions, aquaporin-4 positive serology, and classical abnormal visual studies. If the diagnosis of NMO is established, multiple additional medical therapies are warranted.

C4-T3 Replacement Laminoplasty and Microsurgical Resection of Ependymoma: 2-Dimensional Operative Video

Spinal ependymomas are the most common intramedullary spinal cord tumors in adults.1-4 They are benign histologically, and maximum safe surgical resection should be pursued with the goal of maintaining neurological integrity.4 Spinal ependymoma resections have been described in the operative video literature, including those using techniques of laminoplasty to prevent postlaminectomy kyphosis.1-3,5 Defining the planes between tumor and normal spinal cord is critical to achieving safe maximum resection.3 This video will illustrate the microsurgical techniques used in the resection of a large spinal cord ependymoma in a patient who presented with progressive lower extremity paraparesis and incontinence and was found to have a large intradural, intramedullary C4-T3 lesion with a rostral glial tumor cyst. The patient consented to surgical intervention. The patient was placed prone in MAYFIELD 3-point pin fixation (Integra LifeSciences, Plainsboro Township, New Jersey). Intraoperative neurophysiological electrodes were placed for somatosensory evoked potentials, motor evoked potentials, and D-wave monitoring of corticospinal tracts.6,7 C3-T4 replacement laminoplasties were performed. A midline dural incision spanning C4-T4 was made. A midline myelotomy preserving the pial venous plexus was performed with a 69 Beaver blade.2 The attachments of the tumor to the normal white matter of the spinal cord were microsurgically defined, coagulated, and divided. Tumor debulking was performed with an ultrasonic aspirator. Once gross total resection was achieved, the pial edges of the spinal cord were reapproximated. The dura was closed in a watertight fashion. The patient recovered from surgery well with preservation of her motor function with a continued T7 sensory level.

Image-Guided Robotic Radiosurgery for the Management of Spinal Ependymomas

BackgroundEpendymomas are rare neoplasms of the central nervous system (CNS), usually localized intracranially and most commonly diagnosed in children. Spinal ependymomas are more frequent in young adults. They are either primary lesions or manifest as disseminated seeding of cranial tumors. Data on the management of spinal ependymoma lesions remain scarce, especially concerning stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT). The purpose of this study is to report the treatment outcomes of two institutions using robotic radiosurgery (RRS) for the treatment of spinal ependymomas.Materials and MethodsAll patients with a histopathologically confirmed diagnosis of an ependymoma WHO grade II or III who were treated with RRS for one or more spinal lesions were included in this analysis.ResultsTwelve patients underwent RRS for the treatment of 32 spinal ependymoma lesions between 2005 and 2020. Two patients were below the age of 18 when treated, whereas nine patients (75%) suffered from a primary spinal ependymoma. The median dose was 15 Gy prescribed to a median isodose of 70%, with 27 lesions (84%) receiving a single-session treatment. The local control (LC) after a median follow-up of 56.7 months was 84%. LC rates at 1, 3, and 5 years were 92, 85, and 77%, respectively. The Kaplan-Meier estimated overall survival after 1, 3, and 5 years were 75, 75, and 64%, respectively. Five patients died, all of them suffering from an anaplastic ependymoma, with widespread CNS tumor progression being the reason for death in four patients. The majority of patients (58%) showed a stable neurological status at the last available follow-up. Overall, the treatment was well tolerated.ConclusionRRS appears to be a safe and efficient treatment modality for managing primary and secondary spinal ependymal tumors in patients with multiple lesions and local recurrences.