Outcomes following management of relapsed pediatric posterior fossa ependymoma in the molecular era.

PURPOSE: The overall survival and prognostic factors for children with multiply recurrent posterior fossa ependymoma are not well understood. We aimed to assess prognostic factors associated with survival for relapsed pediatric posterior fossa ependymoma. METHODS: An institutional database was queried for children with a primary diagnosis of posterior fossa ependymoma from 2000 to 2019. Kaplan-Meier survival analysis and Cox-proportional hazard regression were used to assess the relationship between treatment factors and overall survival. RESULTS: There were 60 patients identified; molecular subtype was available for 56, of which 49 (87.5%) were PF-A and 7 (12.5%) were PF-B. Relapse occurred in 29 patients (48%) at a mean time of 24 months following primary resection. Median 50% survival was 12.3 years for all patients and 3.3 years following diagnosis of first relapsed disease. GTR was associated with significantly improved survival following primary resection (HR 0.373, 95% CI 0.14-0.96). Presence of recurrent disease was significantly associated with worse survival (p < 0.0001). At recurrent disease diagnosis, disseminated disease was a negative prognostic factor (HR 11.0 95% CI 2.7-44) while GTR at first relapse was associated with improved survival HR 0.215 (95% CI: 0.048-0.96, p = 0.044). Beyond first relapse, the impact of GTR was not significant on survival, though surgery compared to no surgery was favorable with HR 0.155 (95% CI: 0.04-0.59). CONCLUSIONS: Disseminated disease at recurrence and extent of resection for first relapsed disease were important prognostic factors. Surgery compared to no surgery was associated with improved survival for the multiply recurrent ependymoma cohort.

"Soap bubble" sign as an imaging marker for posterior fossa ependymoma Group B.

PURPOSE: To investigate the predictive value of the "soap bubble" sign on molecular subtypes (Group A [PFA] and Group B [PFB]) of posterior fossa ependymomas (PF-EPNs). METHODS: MRI scans of 227 PF-EPNs (internal retrospective discovery set) were evaluated by two independent neuroradiologists to assess the "soap bubble" sign, which was defined as clusters of cysts of various sizes that look like "soap bubbles" on T2-weighted images. Two independent cohorts (external validation set [n = 31] and prospective validation set [n = 27]) were collected to validate the "soap bubble" sign. RESULTS: Across three datasets, the "soap bubble" sign was observed in 21 PFB cases (7.4% [21/285] of PF-EPNs and 12.9% [21/163] of PFB); none in PFA. Analysis of the internal retrospective discovery set demonstrated substantial interrater agreement (1st Rating: κ = 0.71 [0.53-0.90], 2nd Rating: κ = 0.83 [0.68-0.98]) and intrarater agreement (Rater 1: κ = 0.73 [0.55-0.91], Rater 2: κ = 0.74 [0.55-0.92]) for the "soap bubble" sign; all 13 cases positive for the "soap bubble" sign were PFB (p = 0.002; positive predictive value [PPV] = 100%, negative predictive value [NPV] = 44%, sensitivity = 10%, specificity = 100%). The findings from the external validation set and the prospective validation set were similar, all cases positive for the "soap bubble" sign were PFB (p < 0.001; PPV = 100%). CONCLUSION: The "soap bubble" sign represents a highly specific imaging marker for the PFB molecular subtype of PF-EPNs.

Combined telovelar posterolateral (far lateral) approach for the resection of a large posterior fossa ependymoma: how I do it.

BACKGROUND: Ependymomas are glial cell tumors whose recommended treatment, according to the recent European guidelines, is surgical. Patient outcomes, in terms of progression-free survival and overall survival, are strongly related to the extent of resection. However, in some cases, critical locations and/or large dimensions could make a gross total resection challenging. In this article, we describe the surgical anatomy and technique of a combined telovelar-posterolateral approach for the resection of a giant posterior fossa ependymoma. METHODS: A 24-year-old patient who presented to our institution complaining of a 3-month history of headache, vertigo, and imbalance. Preoperative MRI scans showed a large mass within the fourth ventricle, extending towards the left cerebellopontine angle and perimedullary space through the homolateral Luschka foramen. Surgical treatment was proposed with the aims of releasing the preoperative symptoms, obtaining the tumor's histopathological and molecular definition, and preventing any future neurological deterioration. The patient gave his written consent for surgery and consented to the publication of his images. A combined telovelar-posterolateral approach was then performed to maximize the tumor's exposure and resection. Surgical technique and anatomical exposure have been extensively described, and a 2-dimensional operative video has been included. RESULTS: The postoperative MRI scan demonstrated an almost complete resection of the lesion, with only a millimetric tumor remnant infiltrating the uppermost portion of the inferior medullary velum. Histo-molecular analysis revealed a grade 2 ependymoma. The patient was discharged home neurologically intact. CONCLUSIONS: The combined telovelar-posterolateral approach allowed to achieve a near total resection of a giant multicompartimental mass within the posterior fossa in a single surgical stage.

Posterior fossa ependymoma with preoperative cerebrospinal metastases: a case report with literature review.

BACKGROUND: Adult posterior fossa ependymomas (PF-EPN) with preoperative cerebrospinal metastases are extremely rare. Only 3 cases have been reported in previous literature. CASE PRESENTATION: A case of a 32-year-old male patient complained of headaches for three months. Pure tone audiometry showed a slight decrease in bilateral hearing. Auditory evoked potential indicated that the hearing on the left was slightly weaker than that on the right. Magnetic resonance imaging (MRI) revealed a primary tumor arising within the fourth ventricle and metastasizing to bilateral cerebellopontine angle (CPA), the third ventricle, the left lateral ventricle, T1, L1-2 and L5. A gross total resection (GTR) was performed on the lesion located in the left CPA. The histological examination showed a papillary ependymoma (WHO grade II). Immunohistochemical staining for H3K27me3 showed that nuclear positivity in more than 80% of cells. No NF2 mutation was observed. No progression was found during a 24-month follow-up. CONCLUSIONS: Our data indicate that preoperative multiple metastases in adult PF-EPN are extremely rare. This kind of disease usually has a low WHO grade and a favorable prognosis. GTR should be achieved when feasible and patients need a long-term follow-up with MRI.

Identification of key methylation differentially expressed genes in posterior fossa ependymoma based on epigenomic and transcriptome analysis.

BACKGROUND: Posterior fossa ependymoma (EPN-PF) can be classified into Group A posterior fossa ependymoma (EPN-PFA) and Group B posterior fossa ependymoma (EPN-PFB) according to DNA CpG island methylation profile status and gene expression. EPN-PFA usually occurs in children younger than 5 years and has a poor prognosis. METHODS: Using epigenome and transcriptome microarray data, a multi-component weighted gene co-expression network analysis (WGCNA) was used to systematically identify the hub genes of EPN-PF. We downloaded two microarray datasets (GSE66354 and GSE114523) from the Gene Expression Omnibus (GEO) database. The Limma R package was used to identify differentially expressed genes (DEGs), and ChAMP R was used to analyze the differential methylation genes (DMGs) between EPN-PFA and EPN-PFB. GO and KEGG enrichment analyses were performed using the Metascape database. RESULTS: GO analysis showed that enriched genes were significantly enriched in the extracellular matrix organization, adaptive immune response, membrane raft, focal adhesion, NF-kappa B pathway, and axon guidance, as suggested by KEGG analysis. Through WGCNA, we found that MEblue had a significant correlation with EPN-PF (R = 0.69, P = 1 × 10-08) and selected the 180 hub genes in the blue module. By comparing the DEGs, DMGs, and hub genes in the co-expression network, we identified five hypermethylated, lower expressed genes in EPN-PFA (ATP4B, CCDC151, DMKN, SCN4B, and TUBA4B), and three of them were confirmed by IHC. CONCLUSION: ssGSEA and GSVA analysis indicated that these five hub genes could lead to poor prognosis by inducing hypoxia, PI3K-Akt-mTOR, and TNFα-NFKB pathways. Further study of these dysmethylated hub genes in EPN-PF and the pathways they participate in may provides new ideas for EPN-PF treatment.

Complications following resection of primary and recurrent pediatric posterior fossa ependymoma.

OBJECTIVE: Extent of resection (EOR) is the most important modifiable prognostic variable for pediatric patients with posterior fossa ependymoma. An understanding of primary and recurrent ependymoma complications is essential to inform clinical decision-making for providers, patients, and families. In this study, the authors characterize postsurgical complications following resection of primary and recurrent pediatric posterior fossa ependymoma in a molecularly defined cohort. METHODS: The authors conducted a 20-year retrospective single-center review of pediatric patients undergoing resection of posterior fossa ependymoma at the Hospital for Sick Children in Toronto, Canada. Complications were dichotomized into major and minor groups; EOR was compared across complication categories. The association between complication occurrence with length of stay (LOS) and mortality was also assessed using multivariable regressions. RESULTS: There were 60 patients with primary resection included, 41 (68%) of whom were alive at the time of data collection. Gross-total resection was achieved in 33 (58%) of 57 patients at primary resection. There were no 30-day mortality events following primary and recurrent ependymoma resection. Following primary resection, 6 patients (10%) had posterior fossa syndrome (PFS) and 36 (60%) developed cranial neuropathies, 56% of which recovered within 1 year. One patient (1.7%) required a tracheostomy and 9 patients (15%) required gastrostomy tubes. There were 14 ventriculoperitoneal shunts (23%) inserted for postoperative hydrocephalus. Among recurrent cases, there were 48 recurrent resections performed in 24 patients. Complications included new cranial neuropathy in 10 patients (21%), of which 5 neuropathies resolved within 1 year. There were no cases of PFS following resection of recurrent ependymoma. Gastrostomy tube insertion was required in 3 patients (6.3%), and 1 patient (2.0%) required a tracheostomy. Given the differences in the location of tumor recurrence, a direct comparison between primary and recurrent resection complications was not feasible. Following multivariate analysis adjusting for sex, age, molecular status, and EOR, occurrence of major complications was found to be associated with prolonged LOS but not mortality. CONCLUSIONS: These results detail the spectrum of postsurgical morbidity following primary and recurrent posterior fossa ependymoma resection. The crude complication rate following resection of infratentorial recurrent ependymoma was lower than that of primary ependymoma, although a statistical comparison revealed no significant differences between the groups. These results should serve to inform providers of the morbidity profile following surgical management of posterior fossa ependymoma and inform perioperative counseling of patients and their families.

MRI-based texture analysis for differentiate between pediatric posterior fossa ependymoma type A and B.

PURPOSE: The aim of the study was to evaluate the feasibility of texture analysis in differentiating between posterior fossa ependymoma type A (PF-EPN-A) and type B (PF-EPN-B) among children. MATERIALS AND METHODS: Our retrospective study included 43 patients (37 PF-EPN-A and 6 PF-EPN-B) who were pathologically diagnosed with ependymomas in the posterior fossa. The texture features were extracted automatically from the volume of interests (VOIs), which were manually delineated on fluid-attenuated inversion recovery (FLAIR), contrast-enhanced T1-weighted (T1C), and diffusion-weighted imaging (DWI) MRI sequences. A receiver operating characteristic curve (ROC) was built to assess the diagnostic value of the texture parameters, and the prognostic value was evaluated by survival analysis. RESULTS: Texture parameter [Wavelet-LHH (H: High pass filter, L: Low pass. filter)_glcm (gray-level co-occurrence matrix)_Idn (Inverse difference normalized)] provides valuable information in distinguishing subgroups of ependymomas with higher specificity and positive predictive value (PPV). A total of 27 patients were divided into a high-risk group (IDN value＞0.916) and a low-risk group (IDN value＜0.916) with the most optimistic cut-off value (0.916). The Kaplan-Meier analysis of the survival curves showed significantly longer disease-free survival for low-risk groups compared to high-risk groups [hazard ratio (HR): 0.28, 95% confidence interval (CI): 0.11-0.69; p = 0.017]. CONCLUSION: Our results suggested that the texture parameters based on DWI images can be used to differentiate PF-EPN-A from PF-EPN-B. Texture analysis could be used as a noninvasive tool in distinguishing subgroup pediatric posterior fossa ependymomas and provide reliable prognostic information upon the verification of its reproducibility and feasibility by further studies.

Molecular subgrouping of ependymoma across three anatomic sites and their prognostic implications.

The 2021 WHO classification stratifies ependymoma (EPN) into nine molecular subgroups according to the anatomic locations which outperforms histological grading. We aimed at molecularly reclassifying 200 EPN using immunohistochemistry (IHC) and sequencing for ZFTA fusions in supratentorial (ST) EPN. Further, we assessed the utility of L1CAM, cyclinD1, and p65 markers in identifying ZFTA fusion. Demographic profiles, histologic features, molecular subgroups and clinical outcome were retrospectively analyzed. IHC for L1CAM, cyclinD1, p65, H3K27me3, and H3K27M and sequencing for ZFTA fusion were performed. ZFTA fusions were identified in 44.8% ST EPN. p65 displayed the highest specificity (93.8%), while L1CAM had the highest sensitivity (92.3%) in detecting ZFTA fusions. The negative predictive value approached 96.6% and sensitivity improved to 96.2% with combinatorial IHC (L1CAM, cyclinD1, p65). H3K27me3 loss (PF-A) was noted in 65% PF EPN. Our results provide evidence that a combination of two of three (L1CAM, p65, and cyclinD1) can be used as surrogate markers for predicting fusion. ZFTA fusion, and its surrogate markers in ST, and H3K27me3 and younger age (< 5 years) in PF showed significant correlation with PFS and OS on univariate and Kaplan-Meier analysis. On multivariate analysis, H3K27me3 loss and younger age group are associated with poor clinical outcome.

Adult outcome after treatment of pediatric posterior fossa ependymoma: long-term follow-up of a single consecutive institutional series of 22 patients with more than 5 years of survival.

OBJECTIVE: Ependymoma is the third most common posterior fossa tumor in children; however, there is a lack of long-term follow-up data on outcomes after surgical treatment of posterior fossa ependymoma (PFE) in pediatric patients. Therefore, the authors sought to investigate the long-term outcomes of children treated for PFE at their institution. METHODS: The authors performed a retrospective analysis of outcome data from children who underwent treatment for PFE and survived for at least 5 years. RESULTS: The authors identified 22 children (median age at the time of surgery 3 years, range 0-18 years) who underwent primary tumor resection of PFE during the period from 1945 to 2014 and who had at least 5 years of observed survival. None of these 22 patients were lost to follow-up, and they represent the long-term survivors (38%) from a total of 58 pediatric PFE patients treated. Nine (26%) of the 34 children treated during the pre-MRI era (1945-1986) were long-term survivors, while the observed 5-year survival rate in the children treated during the MRI era (1987-2014) was 13 (54%) of 24 patients. The majority of patients (n = 16) received adjuvant radiotherapy, and 4 of these received proton-beam irradiation. Six children had either no adjuvant treatment (n = 3) or only chemotherapy as adjuvant treatment (n = 3). Fourteen patients were alive at the time of this report. According to MRI findings, all of these patients were tumor free except 1 patient (age 78 years) with a known residual tumor after 65 years of event-free survival.Repeat resections for residual or recurrent tumor were performed in 9 patients, mostly for local residual disease with progressive clinical symptoms; 4 patients underwent only 1 repeated resection, whereas 5 patients each had 3 or more resections within 15 years after their initial surgery. At further follow-up, 5 of the patients who underwent a second surgery were found to be dead from the disease with or without undergoing additional resections, which were performed from 6 to 13 years after the second procedure. The other 4 patients, however, were tumor free on the latest follow-up MRI, performed from 6 to 27 years after the last resection. Hence, repeated surgery appears to increase the chance of tumor control in some patients, along with modern (proton-beam) radiotherapy. Six of 8 patients with more than 20 years of survival are in a good clinical condition, 5 of them in full-time work and 1 in part-time work. CONCLUSIONS: Pediatric PFE occurs mostly in young children, and there is marked risk for local recurrence among 5-year survivors even after gross-total resection and postoperative radiotherapy. Repeated resections are therefore an important part of treatment and may lead to persistent tumor control. Even though the majority of children with PFE die from their tumor disease, some patients survive for more than 50 years with excellent functional outcome and working capacity.

Radiation-induced Supratentorial Osteosarcoma Following Curative Treatment of Infratentorial Ependymoma in a Child.

The development of secondary neoplasms following therapeutic cranial irradiation is rare and quite often lethal. Meningiomas, sarcomas, and high-grade gliomas are the most common tumors that manifest as a result of radiation therapy. We report the case of an 11-year-old child who presented with symptoms of supratentorial space-occupying lesion 7 years after curative surgery and cranial irradiation for a posterior fossa ependymoma. Magnetic resonance imaging of the brain revealed a right-sided temporoparietal dural-based contrast-enhancing lesion with evidence of overlying bone and skin involvement. The histological report of ependymoma from the previous surgery led us to suspect that we were dealing with a recurrence until the histopathology of the second surgery revealed highly malignant osteosarcoma. The child recovered fully and underwent chemotherapy, but ultimately succumbed to the disease. We report this case to highlight the importance of recognizing these neoplasms and to review its management.

Radiology Profile as a Potential Instrument to Differentiate Between Posterior Fossa Ependymoma (PF-EPN) Group A and B.

OBJECTIVE: Posterior fossa ependymoma (PF-EPN) was categorized into PF-EPN-A and PF-EPN-B subgroups based on the DNA methylation profiling. PF-EPN-A was reported to have poorer prognosis compared with PF-EPN-B. In this study, we particularly evaluated preoperative imaging to distinguish PF-EPN-A from PF-EPN-B. METHODS: Sixteen cases of PF-EPN were treated in our institution from 1999 to 2018. The patients were divided into PF-EPN-A and PF-EPN-B groups based on H3K27me3 immunostaining positivity. We evaluated progression-free survival, overall survival, as well as preoperative magnetic resonance imaging and computed tomography scan images in both groups. Based on T1WI and Gd-T1WI magnetic resonance images, the tumor contrast rate was determined from dividing the volume of gadolinium enhanced tumor by the overall tumor volume. RESULTS: Nine cases (4 male, 5 female) were grouped as PF-EPN-A, and 7 (4 male, 3 female) as PF-EPN-B. The median age of PF-EPN-A and PF-EPN-B were 4 and 43 years old, respectively. In the PF-EPN-A group, the progression-free survival median value was 32.6 months, and the overall survival median was 96.9 months. In contrast, PFS in PF-EPN-B did not reach a median value (P < 0.05) and all the patients were alive (P < 0.05) at the end of the study. With imaging, tumor contrast rate in PF-EPN-B was more than 50% and significantly different from PF-EPN-A (P = 0.0294). Calcification was mainly observed in PF-EPN-A, whereas cystic formation was only seen in PF-EPN-B. CONCLUSIONS: Contrast rate less than 50%, based on the magnetic resonance images, was characteristic in the PF-EPN-A group. Comparatively, cystic component and absence of calcification were more characteristic in the PF-EPN-B group.

CN133, a Novel Brain-Penetrating Histone Deacetylase Inhibitor, Hampers Tumor Growth in Patient-Derived Pediatric Posterior Fossa Ependymoma Models.

Pediatric ependymoma (EPN) is a highly aggressive tumor of the central nervous system that remains incurable in 40% of cases. In children, the majority of cases develop in the posterior fossa and can be classified into two distinct molecular entities: EPN posterior fossa A (PF-EPN-A) and EPN posterior fossa B (PF-EPN-B). Patients with PF-EPN-A have poor outcome and are in demand of new therapies. In general, PF-EPN-A tumors show a balanced chromosome copy number profile and have no recurrent somatic nucleotide variants. However, these tumors present abundant epigenetic deregulations, thereby suggesting that epigenetic therapies could provide new opportunities for PF-EPN-A patients. In vitro epigenetic drug screening of 11 compounds showed that histone deacetylase inhibitors (HDACi) had the highest anti-proliferative activity in two PF-EPN-A patient-derived cell lines. Further screening of 5 new brain-penetrating HDACi showed that CN133 induced apoptosis in vitro, reduced tumor growth in vivo and significantly extended the survival of mice with orthotopically-implanted EPN tumors by modulation of the unfolded protein response, PI3K/Akt/mTOR signaling, and apoptotic pathways among others. In summary, our results provide solid preclinical evidence for the use of CN133 as a new therapeutic agent against PF-EPN-A tumors.

Four-Hand Suction-Irrigation Technique Leads to Gross Total Resection and Long-Term Progression-Free Survival in Fourth Ventricular Ependymoma.

BACKGROUND: Gross total resection is often avoided in posterior fossa ependymoma surgery because of the fear of permanent neurologic deficits after operation. However, the extent of resection is a major prognostic factor for progression-free and overall survival. This study evaluates the outcome of posterior fossa ependymoma gross total resection in adult patients using a 4-hand suction-irrigation technique at the floor of the fourth ventricle. METHODS: All surgical procedures for posterior fossa ependymomas performed since 2001 in the Department of Neurosurgery, University Medicine Greifswald were analyzed. RESULTS: Eight patients (2 women and 6 men; mean age, 41.9 years; range, 29-56 years) underwent surgery for posterior fossa ependymoma. All tumors were World Health Organization grade II. Tumor adherence was found to be in the caudal rhomboid fossa (between the obex and striae medullare, but below the facial colliculus) in all patients. The 4-hand suction-irrigation technique led to gross total resection in all patients (100%), without significant permanent neurologic deficits after surgery. None of the patients got further treatment (chemotherapy, radiation therapy, or second surgery). In none of these patients, tumor recurrence was seen on magnetic resonance imaging after a mean follow-up of 102 months (range, 14-181 months). CONCLUSIONS: Long-term progression-free survival in adult patients suffering from posterior fossa ependymoma is possible by gross total resection without adjuvant radio- or chemotherapy. By careful bimanual microsurgical dissection using the 4-hand suction-irrigation technique and avoidance of bipolar coagulation on the floor of the fourth ventricle, the risk for permanent neurologic deficits is low.

Treatment implications of posterior fossa ependymoma subgroups.

Posterior fossa ependymoma comprises two distinct molecular entities, ependymoma_posterior fossa A (EPN_PFA) and ependymoma_posterior fossa B (EPN_PFB), with differentiable gene expression profiles. As yet, the response of the two entities to treatment is unclear. To determine the relationship between the two molecular subgroups of posterior fossa ependymoma and treatment, we studied a cohort of 820 patients with molecularly profiled, clinically annotated posterior fossa ependymomas. We found that the strongest predictor of poor outcome in patients with posterior fossa ependymoma across the entire age spectrum was molecular subgroup EPN_PFA, which was recently reported in the paper entitled "Therapeutic impact of cytoreductive surgery and irradiation of posterior fossa ependymoma in the molecular era: a retrospective multicohort analysis" in the Journal of Clinical Oncology. Patients with incompletely resected EPN_PFA tumors had a very poor outcome despite receiving adjuvant radiation therapy, whereas a substantial proportion of patients with EPN_PFB tumors can be cured with surgery alone.