A coordinated approach for the assessment of molecular subgroups in pediatric ependymomas using low-cost methods.

Although ependymoma (EPN) molecular subgroups have been well established by integrated high-throughput platforms, low- and middle-income countries still need low-cost techniques to promptly classify these molecular subtypes. Here, we applied low-cost methods to classify EPNs from a Brazilian cohort with 60 pediatric EPN patients. Fusion transcripts (C11orf95-RELA, YAP1-MAMLD1, and YAP1-FAM118B) were investigated in supratentorial EPN (ST-EPNs) samples through RT-PCR/Sanger sequencing and immunohistochemistry (IHC) for p65/L1CAM. qRT-PCR and IHC were used to evaluate expression profiling of CXorf67, LAMA2, NELL2, and H3K27me3 in posterior fossa EPN (PF-EPNs) samples. In silico analysis was performed using public microarray data to validate the molecular assignment PF-EPNs with LAMA2/NELL2 markers. RELA cases and YAP1-MAMLD1 fusions were identified in nine and four ST-EPNs, respectively. An additional RELA case was identified by IHC. Of note, LAMA2 and NELL2 gene expression and immunoprofiling were less accurate for classifying PF-EPNs, which were confirmed by in silico analysis. Yet, H3K27me3 staining was sufficient to classify PF-EPN subgroups. Our results emphasize the feasibility of a simplified strategy to molecularly classify EPNs in the vast majority of cases (49/60; 81.7%). A coordinated combination of simple methods can be effective to screen pediatric EPN with the available laboratory resources at most low-/mid-income countries, giving support for clinical practice in pediatric EPN. KEY MESSAGES: Low- and middle-income countries need effective low-cost approaches to promptly distinguish between EPN molecular subgroups. RT-PCR plus Sanger sequencing is able to recognize the most common types of RELA and YAP1 fusion transcripts in ST-EPNs. Genetic and protein expressions of LAMA2 and NELL2 are of limited value to accurately stratify PF-EPNs. Immunohistochemical staining for H3K27me3 may be used as a robust method to accurately diagnose PF-EPNs subgroups. A coordinated flow diagram based on these validated low-cost methods is proposed to help clinical-decision making and to reduce costs with NGS assessment outside research protocols.

Caracterización de los pacientes con ependimoma intracraneal en el hospital pediátrico Juan Manuel Márquez. 2012-2017 / Characterization of patients with intracranial ependymoma in the pediatric hospital Juan Manuel Márquez. 2012-2017

RESUMEN Introducción: los ependimomas constituyen aproximadamente del 3-5 % de los tumores intracraneales y del 5-10 % de los tumores cerebrales, en la edad pediátrica. Objetivo: caracterizar los pacientes con ependimomas intracraneales intervenidos quirúrgicamente, en el Hospital Pediátrico ¨Juan Manuel Márquez. ¨ Materiales y método: estudio descriptivo, retrospectivo, a pacientes en edad pediátrica con diagnóstico histológico de ependimoma de localización intracraneal. En el período de enero 2012 a diciembre 2017. El universo quedó conformado por todos los pacientes en edad pediátrica operados con diagnóstico histológico de ependimoma intracraneal en el lugar y período antes mencionado (N=22). Resultados: la edad media fue 2,75 años con límites entre 1 y 17 y una desviación estándar de 3,65. Los pacientes del sexo masculino representaron el 63,64 %, la relación con el sexo femenino en los primeros 4 años fue de 1:1. En cuanto al cuadro clínico, se observó predominio de la hidrocefalia en el 72,73 % de los pacientes. Los ependimomas intracraneales de localización infratentorial, (63,64 %) predominaron. El 45,45 % de las lesiones estudiadas se correspondían con el subtipo histológico de ependimoma anaplásico. Conclusiones: la combinación de cirugía, radioterapia y quimioterapia se empleó en la mayoría de los casos. Predominó el abordaje directo de la lesión a través de craneotomía y exéresis adecuada a la localización del ependimoma, sin embargo, en la mayoría solo se logró resección entre el 50 y 90 %. En la mayoría de los pacientes la evolución luego del diagnóstico, evidenció una tendencia hacia la estabilidad (AU).

ABSTRACT Introduction: ependymoma are almost 3-5 % of the intracranial tumors and 5-10 % of the brain tumors in pediatric age. Objective: to characterize the patients with intracranial ependymoma who underwent surgery in the Pediatric Hospital ¨Juan Manuel Márquez.¨ Materials and method: retrospective, descriptive study of patients in pediatric age with histological diagnosis of ependymoma of intracranial location in the period January 2012-December 2017. The universe was formed by all patients of pediatric age who underwent surgery with histological diagnosis of intracranial ependymoma in the before-mentioned place and period (N=22). Results: the average age was 2.75 years with limits between 1 and 17 years old. Male patients represented 63.64 %; the relation with female sex during the first 4 years was 1:1. Regarding the clinical characteristics, hydrocephaly predominated in 72.73 % of patients. Intracranial ependymoma of infratentorial location (63.64 %) predominated. 45.45 % of the studied lesions corresponded to the histological subtype of anaplastic ependymoma. Conclusions: the combination of surgery, radiotherapy and chemotherapy was used in most of the cases. The direct approach of the lesion through craniotomy and a removal adequate to ependymoma location predominated. However, in most of them just the resection of 50-90 % was achieved. The evolution of most of patients after the diagnosis evidenced a tendency to the stability (AU).

Ependymoma with Intraorbital Extracerebral Recurrence: Case Report

Ependymomas are rare neuroepithelial tumors that originate from a type of glial cell called ependymal cell. In general, they correspond to 1.2 to 7.8% of all intracranial neoplasms, and to2 to 6%of all gliomas. Although it corresponds only to2 to 3%of all primary brain tumors, ependymoma is the fourthmost common cerebral neoplasmin children, especially in children younger than 3 years of age.1,2 In patients younger than 20 years of age, the majority (90%) of ependymomas are infratentorial,more precisely from the IV ventricle. In spite of this, in adults, medullary ependymomas are more frequent (60%). In this context, supratentorial and extraventricular ependymomas, as in the case reported in the present article, are infrequent in both adults and children.1,2 Both sexes are equally affected.3 Recurrence of intracranial ependymomas occurs in almost 50% of the cases, and the followup outcome is not favorable.4 In another perspective, the recurrence of extracerebral ependymomas is extremely rare, and even more unusual in the intraorbital site, as it occurred in the case in question.

Pediatric ependymoma: current treatment and newer therapeutic insights.

Advances in genomic, transcriptomic and epigenomic profiling now identifies pediatric ependymoma as a defined biological entity. Molecular interrogation has segregated these tumors into distinct biological subtypes based on anatomical location, age and clinical outcome, which now defines the need to tailor therapy even for histologically similar tumors. These findings now provide reasons for a paradigm shift in therapy, which should profile future clinical trials focused on targeted therapeutic strategies and risk-based treatment. The need to diagnose and differentiate the aggressive variants, which include the posterior fossa group A and the supratentorial RELA fusion subtypes, is imperative to escalate therapy and improve survival.

Recent Advances in the Classification and Treatment of Ependymomas.

OPINION STATEMENT: Ependymomas are a subgroup of ependymal glia-derived neoplasms that affect children as well as adults. Arising within any CNS compartment, symptoms at presentation can range from acute onset due to increased intracranial pressure to insidious myelopathy. The overall survival (OS) outcomes in adult patients across the subgroups is heterogeneous with subependymoma having an excellent prognosis often even in the absence of any treatment, whereas supratentorial ependymomas tend to be higher grade in nature and may have an OS of 5 years despite gross total resection and adjuvant radiation. The rarity of ependymal tumors, together still only representing 1.8% of all primary CNS tumors, has been a long-standing challenge in defining optimal treatment guidelines via prospective randomized trials. Retrospective studies have supported maximal safe resection, ideally gross total resection, as the optimal treatment with adjuvant radiation therapy proffering additional tumor control. The evidence for efficacy of chemotherapy and targeted agents in adult ependymomas is minimal. Recent investigations of the molecular, genetic, and DNA methylation profiles of ependymal tumors across all age groups and CNS compartments have identified distinct oncogenic gene products as well as nine molecular subgroups correlating with similar outcomes. The 2016 World Health Organization of Tumors of the Central Nervous System update addresses some of these findings, although their clinical significance has not yet been fully validated. There are inconsistent survival outcomes in retrospective studies for ependymomas graded as II versus III, bringing into question the validity of histologic grading which is subject to high interobserver variability in part due to inconsistent application of mitotic count parameters.

Intracranial papillary endothelial hyperplasia (Masson's tumour) following gamma knife radiosurgery for temporal lobe epilepsy.

We present a rare case of intracranial papillary endothelial hyperplasia, or 'Masson's tumour,' following gamma knife radiosurgery for epilepsy. A 59-year-old woman presented with a 4-month history of escalating headaches and progressive neurological deficit. MR scan of brain showed enlargement of an enhancing right temporal lobe lesion, midline shift and obstructive hydrocephalus. She had previously undergone non-curative gamma knife radiosurgery at the age of 44 years for medically refractory complex partial seizures. Postprocedure imaging had shown signal change and enhancement within the right temporal lobe consistent with radiation necrosis, which remained stable over the next decade. Now, 15 years following radiosurgery, we suspected an intrinsic high-grade neoplasm, but surgical excision instead found a benign pseudoneoplasm. Papillary endothelial hyperplasia should be considered in the differential diagnosis for mass lesions following gamma knife radiosurgery, particularly as resection can be curative. Remarkably, she has become seizure free.

MR imaging features that distinguish spinal cavernous angioma from hemorrhagic ependymoma and serial MRI changes in cavernous angioma.

Cavernous angiomas of the spinal cord exhibit imaging characteristics that may overlap with those of hemorrhagic ependymoma. In the present study, we aimed to identify specific magnetic resonance imaging (MRI) findings that could be used to differentiate cavernous angioma from hemorrhagic ependymoma, and to evaluate serial MRI changes in cases of cavernous angioma. We retrospectively evaluated MR images of spinal cord tumors collected at our hospital from 2007 to 2015. From this cohort of images, 11 pathologically confirmed cavernous angiomas and 14 pathologically confirmed hemorrhagic ependymomas were compared with respect to the size of the tumor, longitudinal location, axial location, enhancement pattern, syrinx, edema, tumor margin, signal intensity of T2WI, signal intensity of T1WI, and longitudinal spreading of the hemorrhage. Serial MR images of seven spinal cavernous angiomas were reviewed. Small size, eccentric axial location, minimal enhancement, and absence of edema were more frequently observed on images of cavernous angioma compared to those of hemorrhagic ependymoma (p < 0.01). Serial MRI changes in cases of cavernous angioma included increased longitudinal spreading of the hemorrhage (6/7, 86 %) and emergence of high signal intensity on T1WI (1/7, 14 %). Small size, eccentric axial location, minimal enhancement, and absence of edema are significant MRI findings that may be used to distinguish Type I and Type II spinal cavernous angiomas from hemorrhagic ependymomas. Furthermore, longitudinal spreading of the hemorrhage may be observed on follow-up MRIs of cavernous angiomas.

Spinal ependymoma in a patient with Kabuki syndrome: a case report.

BACKGROUND: Kabuki syndrome is a rare disorder characterized by the association of mental retardation and postnatal growth deficiency with distinctive facial appearance, skeletal anomalies, cardiac and renal malformation. Two causative genes have been identified in patients with Kabuki syndrome. Mutation of KMT2D (MLL2) was identified in 55-80% of patients, while 9-14% of KMT2D negative patients have mutation in KDM6A gene. So far, few tumors have been reported in patients with Kabuki syndrome. We describe the first case of a patient with spinal ependymoma and Kabuki syndrome. CASE PRESENTATION: A 23 years old girl followed at our Center for KMT2D mutated Kabuki syndrome since she was 4 years old presented with acute lumbar pain and intermittent tactile hyposthenia of the feet. Spine magnetic resonance revealed a lumbar endocanalar mass. She underwent surgical resection of the lesion and histologic examination showed a tanycytic ependymoma (WHO grade II). CONCLUSION: Kabuki syndrome is not considered a cancer predisposition syndrome. Nonetheless, a number of tumors have been reported in patients with Kabuki syndrome. Spinal ependymoma is a rare disease in the pediatric and young adult population. Whereas NF2 mutations are frequently associated to ependymoma such an association has never been described in Kabuki syndrome. To our knowledge this is the first case of ependymoma in a KMT2D mutated Kabuki syndrome patient. Despite KMT2D role in cancer has previously been described, no genetic data are available for previously reported Kabuki syndrome patients with tumors. Nonetheless, the association of two rare diseases raises the suspicion for a common determinant.

Gamma knife surgery-induced ependymoma after the treatment of meningioma - a case report.

Gamma knife surgery is widely used for a number of neurological disorders. However, little is known about its long-term complications such as carcinogenic risks. Here, we present a case of a radiosurgery-induced ependymoma by gamma knife surgery for the treatment of a spinal meningioma in a 7-year-old patient. In light of reviewing the previous reports, we advocate high caution in making young patients receive this treatment.

Developmental origins of brain tumors.

Brain tumors are devastating owing to the high fatality rate and the devastating impact on life qualities of patients. Recent advancement of comparative transcriptome profiling tools and mouse genetic models has greatly deepened our understanding of the developmental origins of these tumors, which could lead to effective therapeutic strategies. We review recent progresses in three types of brain tumors: ependymoma, medulloblastoma, and malignant glioma. The conceptual framework established by these studies converged on three important aspects. First, subtypes in each tumor group originate from distinct cell types. Second, each cell-of-origin is uniquely susceptible to some but not other genetic mutations. Lastly, mutant stem cells may not transform until they differentiate into more restricted progenitor cell type. Overall, these findings indicate the existence of intricate interactions between gene mutations and developmental program for the formation of brain tumors.

[Stem cells: implications in the development of brain tumors]. / Células madre: implicaciones en el desarrollo de tumores cerebrales.

Stem cells are characterized by their capacity for self-renewal, for giving rise to new cells in specific tissues, and for maintaining this capacity throughout the entire life of their host. Stem cells are pluripotent and maintain continuous production of neurons, astrocytes, and oligodendrocytes. Stem cells in brain tumors also proliferate, undergo self-renewal, and give rise to other poorly differentiated cells. Unlike non-tumor stem cells, tumor stem cells lack the normal mechanisms that regulate proliferation and differentiation, resulting in uncontrolled production and incomplete differentiation of tumor cells. Discovering the role of tumor stem cells in the brain has given us a new perspective about the molecular pathways involved in signaling and about oncogenesis in the central nervous system; it can also help us explain the high rate of recurrence of some tumors and the diffuse nature of glioblastomas. Ideally, this perspective can be expected to lead to better treatments. This article reviews the characteristics of non-tumor and tumor stem cells, emphasizing the importance of brain tumor stem cells in the pathogenesis of common brain tumors.

Neurofibromatosis-2 and spinal cord ependymomas: Report of two cases and review of the literature.

OBJECT: The incidence of ependymoma in patients with neurofibromatosis-2 (NF-2) is low and information regarding treatment and prognosis is lacking. We present two cases of cervicomedullary tumors in patients with NF-2 from our institution, and we provide a review of the literature in order to summarize the known clinical information about this rare occurrence. PATIENTS AND METHODS: Patient #1 had histological confirmation of ependymoma and was treated with subtotal resection followed by observation and has had no evidence of progression for 11 months. Patient #2 has been observed for 4 1/2 years without treatment for a cervicomedullary tumor, which appears to be an ependymoma by imaging. Although it has increased in size very slowly, there have been no clinical symptoms. Among the additional 21 cases of NF-2 and ependymoma from the literature, the most common location is the cervical spine (70%), and the median age at diagnosis is 15 years. Surgical resection was performed in 85% of the cases and subtotal resection in 64% of cases. Fifteen patients (75%) were reported alive at the time of the published reports, with survival ranging from 0.1 to 10 years, and the 8-year survival estimated as 51%. Survival was related to the location of the tumor. CONCLUSIONS: We conclude from our two cases and review of the existing literature that NF-2 associated spinal ependymomas have an indolent course and typically can be observed or treated by surgical excision alone.

Spinal cord tanycytic ependymoma associated with neurofibromatosis type 2.

Tanycytic ependymoma is a rare subtype of ependymoma. Reports of this tumor in neurofibromatosis type 2 (NF-2) are rare. A 16-year-old girl presented with gait disturbance and a palpable neck mass, which had been present for 2 years. MRI revealed an intramedullary lesion within the upper cervical spinal cord, which was removed surgically. Pathological investigation revealed an uncommon form of tanycytic ependymoma associated with NF-2. This rare morphology of tanycytic ependymoma could be misinterpreted as pilocytic astrocytoma or other tumor types that exhibit elongated cells. Increased awareness of this transitional form of intramedullary ependymoma among neurosurgeons and pathologists might avoid incorrect surgical approaches and postoperative treatments.

Spinal myxopapillary ependymoma with Down syndrome: exploring an unusual association.

SUMMARY: In patients with Down syndrome, cancers like leukemia and testicular tumors are frequent, but association with central nervous system tumors is rare. Only 1 case of ependymoma has been observed as an incidental autopsy finding in a 19-week-old female fetus. We herein report the second case of ependymoma and the fifth case of spinal tumor occurring in association with Down syndrome. We have also attempted to elucidate the various mechanisms of tumorigenesis implicated in this multiple malformation syndrome. A 13-year-old girl with Down syndrome presented with progressively increasing paraparesis and neurogenic bladder. Magnetic resonance imaging of dorsolumbar spine revealed an intramedullary mass (L1 to L5 level). The patient underwent near total excision of tumor with postoperative histopathology showing myxopapillary ependymoma. Karyotyping showed classic Down syndrome with trisomy 21. Postoperative irradiation (45 Gy in 25 fractions over 5 wk followed by boost up to 55 Gy) was subsequently delivered. One year after the completion of the tumor-directed therapy, the patient is in radiologic complete remission, with improved power in both lower limbs. Association of ependymoma with Down syndrome is a rarity, which at best, can be explained as a chance phenomenon.

Birth weight and subsequent risk of childhood primary brain tumors: a meta-analysis.

The etiology of primary brain tumors is largely unknown. Since a peak of incidence occurs during childhood, factors operating very early in life might play a key role. Previous studies have suggested that high birth weight is associated with an increased brain tumor risk. The authors conducted a meta-analysis on the association between birth weight and risk of specific histologic types of primary brain tumors. They included published studies (1966-2007) that reported odds ratios and 95% confidence intervals for brain tumors associated with birth weight. The authors identified eight studies involving 1,748,964 children, of whom 4,162 suffered from brain tumors of three histologic types (astrocytoma, medulloblastoma, and ependymoma). For astrocytoma, high birth weight (>4,000 g) was associated with increased risk (odds ratio = 1.38, 95% confidence interval (CI): 1.07, 1.79), with each 1,000-g increase in birth weight being associated with a 19% (95% CI: 4, 36) increase in risk. For medulloblastoma, high birth weight was also positively associated with increased risk (odds ratio = 1.27, 95% CI: 1.02, 1.60). No association was found for ependymoma. These findings indicate that birth weight is related to the development of childhood brain tumors, with high birth weight being a risk factor for the two most common types of brain tumors.

Combination of myxopapillary ependymoma and fatty filum in a child with tethered cord syndrome. Case report.

The authors present a case of a child with a tethered spinal cord associated with a myxopapillary ependymoma. This 16-month-old boy presented to the authors' institution with developmental delays in standing and walking. Magnetic resonance (MR) imaging demonstrated a fatty terminal filum and tethered cord. The child underwent surgical exploration of the spine with resection of the fatty filum tissue and release of the cord. Histological analysis of the fatty filum suggested the presence of a coexisting myxopapillary ependymoma. The child made a good recovery with no evidence of tumor recurrence after 4-years of follow-up with serial MR imaging. This unusual combination has not previously been reported in children, and to the authors' knowledge there is only one reported case in an adult. The likelihood of a common pathophysiological process in these conditions is also discussed.

Intradural extramedullary ependymoma: is there constantly a hormonal relationship?

BACKGROUND: Ependymoma is a glial tumor that occurs in the central nervous system. The intradural extramedullary location of this neoplasm is very rare. The authors report a case of spinal intradural extramedullary ependymoma in a male and discuss its pathogenesis as well as its clinical, radiological, and therapeutical features. CASE DESCRIPTION: A 31-year-old man was admitted at the author's institution. The patient has had 1-year history of cervical pain, progressive quadriplegia, and bladder disturbances. Magnetic resonance imaging revealed an enhanced cervical intradural extramedullary tumor extending from the bulbomedullary junction to the C3 level, with severe spinal cord compression. Emergency surgical resection was performed, and a total removal of the lesion was accomplished. One year and half later, a local recurrence associated to a small cerebellar lesion was noticed justifying a second spinal intervention. Both surgical interventions demonstrated an intradural extramedullary ependymoma without attachment to the spinal cord or to the dura mater. Adjuvant craniospinal radiotherapy was recommended to the patient. CONCLUSION: The insufficiency of hormonal theory to explain solely the pathogenesis of this tumor might reveal other potential factors that have not been discussed in earlier literature.