Implications of DNA Methylation Classification in Diagnosing Ependymoma.

BACKGROUND: Ependymoma is a central nervous system (CNS) tumor that arises from the ependymal cells of the brain's ventricles and spinal cord. The histopathology of ependymomas is indistinguishable regardless of the site of origin, and the prognosis varies. Recent studies have revealed that the development site and prognosis reflect the genetic background. In this study, we used genome-wide DNA methylation array analysis to investigate the epigenetic background of ependymomas from different locations treated at our hospital. METHODS: Four cases of posterior fossa ependymomas and 11 cases of spinal ependymomas were analyzed. RESULTS: DNA methylation profiling using the DKFZ methylation classifier showed that the methylation diagnoses of the 2 cases differed from the histopathological diagnoses, and 2 cases could not be classified. Tumor that spread from the brain to the spinal cord was molecularly distinguishable from other primary spinal tumors. CONCLUSIONS: Although adding DNA methylation classification to conventional diagnostic methods may be helpful, the diagnosis in some cases remains undetermined. This may affect decision-making regarding treatment strategies and follow-up. Further investigations are required to improve the diagnostic accuracy of these tumors.

Red flags alerting a posterior cranial fossa tumor from audiovestibular perspectives - a review.

BACKGROUND: There is no comprehensive and up-to-date overview of audiovestibular approach to the posterior fossa tumors in the literature. OBJECTIVE: This paper reviewed the literature relating to tumors at the posterior cranial fossa to find red flags alerting a posterior fossa lesion from audiovestibular perspectives. METHODS: This review was developed from articles published in those journals listed on the journal citation reports. Through the PubMed database, Embase, Google Scholar, and Cochrane library, 60 articles were finally obtained based on the PRISMA guidelines for reporting reviews. RESULTS: The presence of one red flag indicates a positive predictive value of 33% for detecting a posterior fossa lesion. Clinical features, namely, 1) mid-frequency sudden sensorineural hearing loss (SNHL), 2) bilateral sudden SNHL, and 3) rebound nystagmus may indicate a posterior fossa lesion, representing one, two, and three red flags, respectively. CONCLUSION: Those with 1) mid-frequency sudden SNHL, 2) bilateral sudden SNHL, and 3) rebound nystagmus trigger one, two, and three red flags, respectively, alerting clinicians the possibility of a posterior fossa lesion, which warrant MR imaging to exclude life-threatening or treatable conditions. SIGNIFICANCE: Patients with posterior fossa tumors may have potential life-threatening outcome.

Posterior fossa tumors in children: current insights.

While in adults most intracranial tumors develop around the cerebral hemispheres, 45 to 60% of pediatric lesions are found in the posterior fossa, although this anatomical region represents only 10% of the intracranial volume. The latest edition of the WHO classification for CNS tumors presented some fundamental paradigm shifts that particularly affected the classification of pediatric tumors, also influencing those that affect posterior fossa. Molecular biomarkers play an important role in the diagnosis, prognosis, and treatment of childhood posterior fossa tumors and can be used to predict patient outcomes and response to treatment and monitor its effectiveness. Although genetic studies have identified several posterior fossa tumor types, differing in terms of their location, cell of origin, genetic mechanisms, and clinical behavior, recent management strategies still depend on uniform approaches, mainly based on the extent of resection. However, significant progress has been made in guiding therapy decisions with biological or molecular stratification criteria and utilizing molecularly targeted treatments that address specific tumor biological characteristics. The primary focus of this review is on the latest advances in the diagnosis and treatment of common subtypes of posterior fossa tumors in children, as well as potential therapeutic approaches in the future.   Conclusion: Molecular biomarkers play a central role, not only in the diagnosis and prognosis of posterior fossa tumors in children but also in customizing treatment plans. They anticipate patient outcomes, measure treatment responses, and assess therapeutic effectiveness. Advances in neuroimaging and treatment have significantly enhanced outcomes for children with these tumors. What is Known: • Central nervous system tumors are the most common solid neoplasms in children and adolescents, with approximately 45 to 60% of them located in the posterior fossa. • Multimodal approaches that include neurosurgery, radiation therapy, and chemotherapy are typically used to manage childhood posterior fossa tumors What is New: • Notable progress has been achieved in the diagnosis, categorization and management of posterior fossa tumors in children, leading to improvement in survival and quality of life.

[Pediatric Posterior Fossa Tumors].

Posterior fossa tumors tend to entail obstructive hydrocephalus, and urges initiating prompt treatment. Prevalent pathologies include medulloblastoma, ependymoma, pilocytic astrocytoma, and atypical teratoid/rhabdoid tumor(AT/RT). In most cases, maximal safe resection is related to better prognosis. In some cases of ependymoma and AT/RT with high vascularity, second-look surgery with neoadjuvant chemotherapy is effective. The treatment strategy should be tailored according to each tumor.

Acute Myeloid Leukemia Presenting as a Posterior Fossa Tumor.

Extramedullary leukemia in pediatric acute myeloid leukemia can manifest as a myeloid sarcoma (MS), also known as granulocytic sarcoma or chloroma, in a variety of sites, or as leukemic blasts in the cerebrospinal fluid. Isolated MS of the central nervous system is rare. We report a case of acute myeloid leukemia with central nervous system-MS presenting as a posterior fossa mass mimicking a primary intracranial tumor.

A Diagnostic Algorithm for Posterior Fossa Tumors in Children: A Validation Study.

BACKGROUND AND PURPOSE: Primary posterior fossa tumors comprise a large group of neoplasias with variable aggressiveness and short and long-term outcomes. This study aimed to validate the clinical usefulness of a radiologic decision flow chart based on previously published neuroradiologic knowledge for the diagnosis of posterior fossa tumors in children. MATERIALS AND METHODS: A retrospective study was conducted (from January 2013 to October 2019) at 2 pediatric referral centers, Children's Hospital of Philadelphia, United States, and Great Ormond Street Hospital, United Kingdom. Inclusion criteria were younger than 18 years of age and histologically and molecularly confirmed posterior fossa tumors. Subjects with no available preoperative MR imaging and tumors located primarily in the brain stem were excluded. Imaging characteristics of the tumors were evaluated following a predesigned, step-by-step flow chart. Agreement between readers was tested with the Cohen κ, and each diagnosis was analyzed for accuracy. RESULTS: A total of 148 cases were included, with a median age of 3.4 years (interquartile range, 2.1-6.1 years), and a male/female ratio of 1.24. The predesigned flow chart facilitated identification of pilocytic astrocytoma, ependymoma, and medulloblastoma sonic hedgehog tumors with high sensitivity and specificity. On the basis of the results, the flow chart was adjusted so that it would also be able to better discriminate atypical teratoid/rhabdoid tumors and medulloblastoma groups 3 or 4 (sensitivity = 75%-79%; specificity = 92%-99%). Moreover, our adjusted flow chart was useful in ruling out ependymoma, pilocytic astrocytomas, and medulloblastoma sonic hedgehog tumors. CONCLUSIONS: The modified flow chart offers a structured tool to aid in the adjunct diagnosis of pediatric posterior fossa tumors. Our results also establish a useful starting point for prospective clinical studies and for the development of automated algorithms, which may provide precise and adequate diagnostic tools for these tumors in clinical practice.

Epithelioid Sarcoma Arising in a Long-Term Survivor of an Atypical Teratoid/Rhabdoid Tumor in a Patient With Rhabdoid Tumor Predisposition Syndrome.

Rhabdoid tumor predisposition syndrome (RTPS) is defined as the presence of a SMARCB1 or SMARCA4 genetic aberration in a patient with malignant rhabdoid tumor. Patients with RTPS are more likely to present with synchronous or metachronous rhabdoid tumors. Based on the current state of rhabdoid tumor taxonomy, these diagnoses are based largely on patient demographics, anatomic location of disease, and immunohistochemistry, despite their nearly identical histologic and immunohistochemical profiles. Thus, the true distinction between such tumors remains a diagnostic challenge. Central nervous system atypical teratoid/rhabdoid tumor (AT/RT) is a rare, aggressive, primarily pediatric malignancy with variable histologic features and a well documented association with loss of SMARCB1 expression. Epithelioid sarcoma (ES) is a rare soft tissue tumor arising in patients of all ages and characteristically staining for both mesenchymal and epithelial immunohistochemical markers while usually demonstrating loss of SMARCB1 expression. To our knowledge we herein present the first documented case of a patient with RTPS who presented with metachronous AT/RT and ES.

The role of external ventricular drainage for the management of posterior cranial fossa tumours: a systematic review.

Posterior cranial fossa tumours frequently develop hydrocephalus as first presentation in up to 80% of paediatric patients and 21.4% of adults, although it resolves after tumour removal in 70-90% and 96%, respectively. New onset hydrocephalus is reported in about 2.1% of adult and 10-40% of paediatric patients after posterior fossa surgery. There is no consensus concerning prophylactic external ventricular drainage (EVD) placement that is frequently used before posterior fossa lesion removal, as well in those cases without clear evidence of hydrocephalus. The aim of the study was to define the most correct management for patients who undergo posterior fossa tumour surgery, thus identifying cohorts of patients who are at risk of persistent hydrocephalus prior to surgery. A systematic review of literature has been performed, following PRISMA guidelines. Most of the studies reported CSF shunt only in the presence of hydrocephalus, whereas only a few authors suggested its prophylactic use in the absence of signs of ventricular dilatation. Predictive factors for postoperative hydrocephalus has been identified, including young age (< 3 years), severe symptomatic hydrocephalus at presentation, EVD placement before surgery, FOHR index > 0.46 and Evans index > 0.4, pseudomeningocele, CSF leak and infection. The use of pre-resection CSF shunt in case of signs and symptoms of hydrocephalus is mandatory, although it resolves in the majority of cases. As reported by several studies included in the present review, we suggest CSF shunt also in case of asymptomatic hydrocephalus, whereas it is not indicated without evidence of ventricular dilatation.

The impact of tracheostomy timing on clinical outcomes and adverse events in intubated patients with infratentorial lesions: early versus late tracheostomy.

We evaluated the association between the timing of tracheostomy and clinical outcomes in patients with infratentorial lesions. We performed a retrospective observational cohort study in a neurosurgical intensive care unit (ICU) at a tertiary academic medical center from January 2014 to December 2018. Consecutive adult patients admitted to the ICU who underwent resection of infratentorial lesions as well as tracheostomy were included for analysis. Early tracheostomy was defined as performed on postoperative days 1-10 and late tracheostomy on days 10-20 after operation. Univariate and multivariate analyses were used to compare the characteristics and outcomes between both cohorts. A total of 143 patients were identified, and 96 patients received early tracheostomy. Multivariable analysis identified early tracheostomy as an independent variable associated with lower occurrence of pneumonia (odds ratio, 0.25; 95% CI, 0.09-0.73; p = 0.011), shorter stays in ICUs (hazard ratio, 0.4; 95% CI, 0.3-0.6; p = 0.03), and earlier decannulation (hazard ratio, 0.5; 95% CI, 0.4-0.8; p = 0.003). However, no significant differences were observed between the early and late tracheostomy groups regarding hospital mortality (p > 0.999) and the modified Rankin scale after 6 months (p = 0.543). We also identified postoperative brainstem deficits, including cough, swallowing attempts, and extended tongue as well as GCS < 8 at ICU admission as the risk factors independently associated with patients underwent tracheostomy. There is a significant association between early tracheostomy and beneficial clinical outcomes or reduced adverse event occurrence in patients with infratentorial lesions.

A solitary hemangioblastoma of the posterior brain fossa: the role of radiotherapy.

We report here the case of a patient admitted for management of posterior fossa cerebral hemangioblastoma. A 16-year-old male patient with a history of intracranial hypertension syndrome consisting of progressively worsening headache, vomiting, especially morning and jet vomiting, and decreased visual acuity. The patient's symptomatology worsened a few days later with the appearance of a disturbance of balance with enlargement of the sustentation polygon. The patient initially benefited from a brain computed tomography (CT) scan that objectified a solidocystic process of the posterior brain fossa. The patient then underwent a surgical excision that was considered partial and the diagnosis of hemangioblastoma was made on the surgical specimen. Since the surgical removal was partial the patient was referred to our training where he received external radiotherapy on his hemangioblastoma of the posterior brain fossa. The patient was examined one month after the end of irradiation; he presented a spectacular improvement in his neurological symptomatology with a clear regression of balance disorders. The standard treatment for cerebellar hemangioblastoma is complete microsurgical removal, but our results show a high level of efficacy for fractional photon radiotherapy after partial surgery of this benign tumour.

Pediatric posterior fossa tumors outcomes: Experience in a tertiary care center in the Middle East.

BACKGROUND: Among all childhood cancers, brain tumors are second only to leukemia in incidence and are the most common solid pediatric tumors. More than 60 % of pediatric brain tumors are infra-tentorial. The first-line treatment for most infra-tentorial tumors in pediatric patients is surgical resection, with the goal of gross-total resection, relief of symptoms and hydrocephalus, and increased survival. The proximity to the fourth ventricle, and therefore, the cerebrospinal fluid (CSF) pathways, predisposes children with posterior fossa tumors to the development of obstructive hydrocephalus and multiple other co-morbidities pre and post-surgery. OBJECTIVES: This study aims to present our series of pediatric posterior fossa tumor surgeries in the Neurosurgical Department at the American University of Beirut Medical Center(AUBMC) and perform internal quality control for our single-institution consecutive series as one of the largest referral and tertiary care centers in the region. The second purpose of this retrospective study is to weigh the risks of surgery against the presumed advantages and to have specific knowledge about the complication rates, especially those related to the CSF pathway, comparing our results to those in the literature. METHODS: All pediatric patients (< 18 years of age), referred to our center from different regions in the middle east, and surgically treated for a posterior fossa tumor from June 2006 to June 2018 at the American University of Beirut Medical Center were included. A thorough review of all medical charts was performed to validate all the database records. RESULTS: The patient sample consisted of 64 patients having a mean age of 6.19 ±â€¯4.42 years and 59.37 % of whom were males. The most common tumor pathology was pilocytic astrocytoma (40.62 %) followed by medulloblastoma (35.93 %) and ependymoma. The most common type of tumor that was seen in patients that developed mutism postoperatively (n = 6, 9.37 %) was medulloblastoma (n = 4, 66.66 %). In this patient sample, 12.28 % (n = 7) of the patients developed hydrocephalus postoperatively.Midline tumors were more associated with the development of mutism(OR = 4.632, p = 0.306) and hydrocephalus (OR = 5.056, p = 0.135) postoperatively, albeit not statistically significantly.The presence of a preoperative shunt was shown to be protective against the development of CSF leak (OR = 0.636, p = 0.767), as none of the patients that came in with CSF diversion developed a CSF leak after their surgery. CONCLUSION: This study from a single center experience accompanied by a thorough literature review sheds light on the complications frequently encountered after posterior fossa tumor surgery in children. These included transient cerebellar mutism, CSF leak, and hydrocephalus as seen in some of our patients. Our findings highlight the need for prospective studies with well-defined protocols directed at assessing novel ways and approaches to minimize the risk of these complications.

Characterizing Posterior Fossa Syndrome: A Survey of Experts.

BACKGROUND: Despite recent efforts, disagreement remains among frontline clinicians regarding the operational definition of a syndrome commonly referred to as posterior fossa syndrome or cerebellar mutism syndrome. METHODS: We surveyed experts in the clinical care of children with posterior fossa tumors to identify trends and discrepancies in diagnosing posterior fossa syndrome. RESULTS: All surveyed professionals conceptualized posterior fossa syndrome as a spectrum diagnosis. The majority agreed that mutism is the most important symptom for diagnosis. However, results highlighted ongoing discrepancies related to important features of posterior fossa syndrome. CONCLUSIONS: Greater posterior fossa syndrome conceptual alignment among providers is needed to formulate specific diagnostic criteria that would further research and clinical care. The authors propose preliminary diagnostic criteria for posterior fossa syndrome that require refinement through careful clinical characterization and targeted empirical investigation.

Rosette-forming glioneuronal tumor: an update.

Rosette-forming glioneuronal tumor (RGNT) is a rare and distinct primary nervous system tumor. The literature on this novel neoplasm is sparse and limited to mostly case reports. Reviews on the characteristics of this tumor are fewer and far between with the latest up to a decade old. We thus provide a comprehensive review of recent literature to characterize presenting symptoms, radiological evidence, treatment options, and prognosis of this novel neoplasm. A Medline search for case reports detailing primary rosette-forming glioneuronal tumors was performed. RGNTs are a benign tumor of indolent course with mixed glial and neurocytic components. There is a slight female predominance with mean age of presentation at 23.57 years. Headaches, visual disturbances, and nausea and vomiting are the most common symptoms. Most RGNTs have solid and cystic components, arising most frequently in the fourth ventricle or cerebellum. Management is usually through surgery with gross total resection (GTR) providing better prognosis.

Neuropsychological Profile in Children with Posterior Fossa Tumors with or Without Postoperative Cerebellar Mutism Syndrome (CMS).

Cerebellar mutism syndrome (CMS) is a common surgical sequela in children following posterior fossa tumor (PFT) resection. Here, we analyze the neuropsychological features associated with PFT in children, focusing particularly on the differential profiles associated with the presence or absence of CMS after surgery. We further examine the effect of post-resection treatments, tumor type, and presence/absence of hydrocephalus on surgical outcome. Thirty-six patients diagnosed with PFT (19 with and 17 without CMS) and 34 age- and gender-matched healthy controls (HCs) were recruited. A comprehensive neuropsychological evaluation was conducted in all patients postoperatively and in HCs, including an assessment of general cognitive ability, motor skills, perception, language, memory, attention, executive functions, and academic competence. CMS was found to be a clinical marker of lower neuropsychological profile scores across all cognitive domains except auditory-verbal processing and visual memory tasks. PFT patients not presenting CMS exhibited milder impairment in intellectual functioning, motor tasks, reasoning, language, verbal learning and recall, attention, cognitive executive functions, and academic competence. High-grade tumors were associated with slower processing speed and verbal delayed recall as well as alterations in selective and sustained attention. Hydrocephalus was detrimental to motor functioning and nonverbal reasoning. Patients who had undergone surgery, chemotherapy, and radiotherapy presented impaired processing speed, verbal learning, and reading. In addition to the deleterious effects of PFT, post-resection PFT treatments have a negative cognitive impact. These undesired consequences and the associated tumor-related damage can be assessed using standardized, long-term neuropsychological evaluation when planning rehabilitation.

Utility of copy number variants in the classification of intracranial ependymoma.

Ependymomas are neuroepithelial tumors that differentiate along the ependymal cell lineage, a lining of the ventricles of the brain and the central canal of the spinal cord. They are rare in adults, but account for around 9% of brain tumors in children, where they usually have an aggressive course. Efficient stratification could lead to improved care but remains a challenge even in the genomic era. Recent studies proposed a multivariate classification system based on tumor location, age, and broad genomic findings like global patterns of methylation and copy number variants (CNVs). This system shows improved prognostic utility, but is relatively impractical in the routine clinical setting because it necessitates multiple diagnostic tests. We analyzed 13 intracranial grade II and III ependymoma specimens on a DNA microarray to identify discrete CNVs that could support the existing classification. The loss of chr22 and the gain of 5p15.31 were common throughout our cohort (6 and 11 cases, respectively). Other CNVs correlated well with the previously proposed classification system. For example, gains of chr20 were unique to PF-EPN-B tumors of the posterior fossa and may differentiate them from PF-EPN-A. Given the ease of detecting CNVs using multiple, clinically validated methods, these CNVs should be further studied to confirm their diagnostic and prognostic utility, for incorporation into clinical testing algorithms.

A Case of Infratentorial Meningioma Causing Spontaneous Downbeat Nystagmus: Case Report and Review of the Literature.

BACKGROUND: Spontaneous downbeat nystagmus is a finding that raises suspicions of a central nervous system disorder. Vermis and lower brainstem lesions are considered to be responsible, but the exact mechanism is still controversial. We observed a rare case of spontaneous downbeat nystagmus caused by an infratentorial meningioma. CASE DESCRIPTION: A 50-year-old woman was incidentally diagnosed with infratentorial tumor. Later, she suffered from oscillopsia and the symptom disturbed her daily life especially while driving. Magnetic resonance imaging showed a tumor of approximately 30 mm in diameter at the dorsal midline of the posterior fossa. The tumor was compressing the cerebellar vermis and was apparently responsible for the symptoms that affected her daily life; therefore, we decided to perform tumor removal. The postoperative course was uneventful, and the spontaneous downbeat nystagmus completely disappeared. CONCLUSIONS: Vertical nystagmus is a finding that raises suspicion of a central nervous system disorder, and requires detailed examination. In addition, in case of vertical nystagmus because of tumor compression of the vermis, removal of the tumor can be an effective treatment.

Tumors diagnosed as cerebellar glioblastoma comprise distinct molecular entities.

In this multi-institutional study we compiled a retrospective cohort of 86 posterior fossa tumors having received the diagnosis of cerebellar glioblastoma (cGBM). All tumors were reviewed histologically and subjected to array-based methylation analysis followed by algorithm-based classification into distinct methylation classes (MCs). The single MC containing the largest proportion of 25 tumors diagnosed as cGBM was MC anaplastic astrocytoma with piloid features representing a recently-described molecular tumor entity not yet included in the WHO Classification of Tumours of the Central Nervous System (WHO classification). Twenty-nine tumors molecularly corresponded to either of 6 methylation subclasses subsumed in the MC family GBM IDH wildtype. Further we identified 6 tumors belonging to the MC diffuse midline glioma H3 K27 M mutant and 6 tumors allotted to the MC IDH mutant glioma subclass astrocytoma. Two tumors were classified as MC pilocytic astrocytoma of the posterior fossa, one as MC CNS high grade neuroepithelial tumor with BCOR alteration and one as MC control tissue, inflammatory tumor microenvironment. The methylation profiles of 16 tumors could not clearly be assigned to one distinct MC. In comparison to supratentorial localization, the MC GBM IDH wildtype subclass midline was overrepresented, whereas the MCs GBM IDH wildtype subclass mesenchymal and subclass RTK II were underrepresented in the cerebellum. Based on the integration of molecular and histological findings all tumors received an integrated diagnosis in line with the WHO classification 2016. In conclusion, cGBM does not represent a molecularly uniform tumor entity, but rather comprises different brain tumor entities with diverse prognosis and therapeutic options. Distinction of these molecular tumor classes requires molecular analysis. More than 30% of tumors diagnosed as cGBM belong to the recently described molecular entity of anaplastic astrocytoma with piloid features.