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.

Differentiation of paediatric posterior fossa tumours by the multiregional and multiparametric MRI radiomics approach: a study on the selection of optimal multiple sequences and multiregions.

OBJECTIVE: To evaluate the diagnostic performance of a radiomics model based on multiregional and multiparametric MRI to classify paediatric posterior fossa tumours (PPFTs), explore the contribution of different MR sequences and tumour subregions in tumour classification, and examine whether contrast-enhanced T1 weighted (T1C) images have irreplaceable added value. METHODS: This retrospective study of 136 PPFTs extracted 11,958 multiregional (enhanced, non-enhanced, and total tumour) features from multiparametric MRI (T1- and T2 weighted, T1C, fluid-attenuated inversion recovery, and diffusion-weighted images). These features were subjected to fast correlation-based feature selection and classified by a support vector machine based on different tasks. Diagnostic performances of multiregional and multiparametric MRI features, different sequences, and different tumoral regions were evaluated using multiclass and one-vs-rest strategies. RESULTS: The established model achieved an overall area under the curve (AUC) of 0.977 in the validation cohort. The performance of PPFTs significantly improved after replacing T1C with apparent diffusion coefficient maps added into the plain scan sequences (AUC from 0.812 to 0.917). When oedema features were added to contrast-enhancing tumour volume, the performance did not significantly improve. CONCLUSION: The radiomics model built by multiregional and multiparametric MRI features allows for the excellent distinction of different PPFTs and provides valuable references for the rational adoption of MR sequences. ADVANCES IN KNOWLEDGE: This study emphasized that T1C has limited added value in predicting PPFTs and should be cautiously adopted. Selecting optimal MR sequences may help guide clinicians to better allocate acquisition sequences and reduce medical costs.

TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma.

Subependymomas are benign tumors characteristically encountered in the posterior fossa of adults that show distinct epigenetic profiles assigned to the molecular group "subependymoma, posterior fossa" (PFSE) of the recently established DNA methylation-based classification of central nervous system tumors. In contrast, most posterior fossa ependymomas exhibit a more aggressive biological behavior and are allocated to the molecular subgroups PFA or PFB. A subset of ependymomas shows epigenetic similarities with subependymomas, but the precise biology of these tumors and their potential relationships remain unknown. We therefore set out to characterize epigenetic traits, mutational profiles, and clinical outcomes of 50 posterior fossa ependymal tumors of the PFSE group. On histo-morphology, these tumors comprised 12 ependymomas, 14 subependymomas and 24 tumors with mixed ependymoma-subependymoma morphology. Mixed ependymoma-subependymoma tumors varied in their extent of ependymoma differentiation (2-95%) but consistently exhibited global epigenetic profiles of the PFSE group. Selective methylome analysis of microdissected tumor components revealed CpG signatures in mixed tumors that coalesce with their pure counterparts. Loss of chr6 (20/50 cases), as well as TERT mutations (21/50 cases), were frequent events enriched in tumors with pure ependymoma morphology (p < 0.001) and confined to areas with ependymoma differentiation in mixed tumors. Clinically, pure ependymoma phenotype, chr6 loss, and TERT mutations were associated with shorter progression-free survival (each p < 0.001). In conclusion, our results suggest that subependymomas may acquire genetic and epigenetic changes throughout tumor evolution giving rise to subclones with ependymoma morphology (resulting in mixed tumors) that eventually overpopulate the subependymoma component (pure PFSE ependymomas).

Solid Component Volume as a Proxy to Identify Distinct Hemangioblastoma Populations.

BACKGROUND: Posterior fossa hemangioblastomas usually consist of a small solid nodule with a large cyst, while more rarely they present as a large solid mass with a small or absent cyst, which can be surgically challenging. We sought to investigate the potential existence of multiple distinct hemangioblastoma populations using tumor volumetric data as an indicator. METHODS: We conducted a retrospective review of surgically treated hemangioblastomas between 2005 and 2019 in our unit, including clinical notes, preoperative magnetic resonance imaging volumetric analysis of the solid component of the tumor, and pathology. Finite Gaussian mixture modeling was applied on the solid component volume dataset to identify potential underlying Gaussian distributions with their associated characteristics. Nonparametric Mann-Whitney U tests were used to investigate significance of differences (P < 0.05) in solid component volume and different variables (Von Hippel-Lindau disease, extent of resection, outcome). RESULTS: A total of 68 consecutive patients were included. Solid component volumes followed a multimodal distribution (median = 1287 mm3, interquartile range of 3428 mm3). The best-fit finite Gaussian mixture modeling model identified 3 statistically significant different (P = 0.001) potential mixture components: X1 (219 ± 187 mm3), X2 (2686 ± 1299 mm3), and X3 (10,800 ± 5514 mm3). The second-best model detected 2 significantly different (P = 9.99e-08) mixture components Y1 (222 ± 189 mm3) and Y2 (5391 ± 5094 mm3). A significant difference in solid component volume was found between patients with favorable and unfavorable outcome (P = 0.002). CONCLUSIONS: This study has shown preliminary evidence that large solid hemangioblastomas may constitute a completely distinct population, rather than a variant of one large group of hemangioblastomas.

Deep Learning for Pediatric Posterior Fossa Tumor Detection and Classification: A Multi-Institutional Study.

BACKGROUND AND PURPOSE: Posterior fossa tumors are the most common pediatric brain tumors. MR imaging is key to tumor detection, diagnosis, and therapy guidance. We sought to develop an MR imaging-based deep learning model for posterior fossa tumor detection and tumor pathology classification. MATERIALS AND METHODS: The study cohort comprised 617 children (median age, 92 months; 56% males) from 5 pediatric institutions with posterior fossa tumors: diffuse midline glioma of the pons (n = 122), medulloblastoma (n = 272), pilocytic astrocytoma (n = 135), and ependymoma (n = 88). There were 199 controls. Tumor histology served as ground truth except for diffuse midline glioma of the pons, which was primarily diagnosed by MR imaging. A modified ResNeXt-50-32x4d architecture served as the backbone for a multitask classifier model, using T2-weighted MRIs as input to detect the presence of tumor and predict tumor class. Deep learning model performance was compared against that of 4 radiologists. RESULTS: Model tumor detection accuracy exceeded an AUROC of 0.99 and was similar to that of 4 radiologists. Model tumor classification accuracy was 92% with an F1 score of 0.80. The model was most accurate at predicting diffuse midline glioma of the pons, followed by pilocytic astrocytoma and medulloblastoma. Ependymoma prediction was the least accurate. Tumor type classification accuracy and F1 score were higher than those of 2 of the 4 radiologists. CONCLUSIONS: We present a multi-institutional deep learning model for pediatric posterior fossa tumor detection and classification with the potential to augment and improve the accuracy of radiologic diagnosis.

Automatic Machine Learning to Differentiate Pediatric Posterior Fossa Tumors on Routine MR Imaging.

BACKGROUND AND PURPOSE: Differentiating the types of pediatric posterior fossa tumors on routine imaging may help in preoperative evaluation and guide surgical resection planning. However, qualitative radiologic MR imaging review has limited performance. This study aimed to compare different machine learning approaches to classify pediatric posterior fossa tumors on routine MR imaging. MATERIALS AND METHODS: This retrospective study included preoperative MR imaging of 288 patients with pediatric posterior fossa tumors, including medulloblastoma (n = 111), ependymoma (n = 70), and pilocytic astrocytoma (n = 107). Radiomics features were extracted from T2-weighted images, contrast-enhanced T1-weighted images, and ADC maps. Models generated by standard manual optimization by a machine learning expert were compared with automatic machine learning via the Tree-Based Pipeline Optimization Tool for performance evaluation. RESULTS: For 3-way classification, the radiomics model by automatic machine learning with the Tree-Based Pipeline Optimization Tool achieved a test micro-averaged area under the curve of 0.91 with an accuracy of 0.83, while the most optimized model based on the feature-selection method χ2 score and the Generalized Linear Model classifier achieved a test micro-averaged area under the curve of 0.92 with an accuracy of 0.74. Tree-Based Pipeline Optimization Tool models achieved significantly higher accuracy than average qualitative expert MR imaging review (0.83 versus 0.54, P < .001). For binary classification, Tree-Based Pipeline Optimization Tool models achieved an area under the curve of 0.94 with an accuracy of 0.85 for medulloblastoma versus nonmedulloblastoma, an area under the curve of 0.84 with an accuracy of 0.80 for ependymoma versus nonependymoma, and an area under the curve of 0.94 with an accuracy of 0.88 for pilocytic astrocytoma versus non-pilocytic astrocytoma. CONCLUSIONS: Automatic machine learning based on routine MR imaging classified pediatric posterior fossa tumors with high accuracy compared with manual expert pipeline optimization and qualitative expert MR imaging review.

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.

Diagnostic challenges of posterior fossa hemangioblastomas: Refining current radiological classification scheme.

Hemangioblastomas (HBMs) are known to exhibit very typical radiological features and thus classified by well-established radiological classification scheme. We reviewed our series of posterior fossa HBMs in order not only to evaluate the relevance of current classification scheme, but also to possibly refine it. Also, we added descriptions on several cases with unusual radiological magnetic resonance imaging (MRI) findings in which differential diagnosis was challenging. We retrospectively reviewed preoperative MRI of 118 patients with pathologically diagnosed posterior fossa HBMs at our institution between 2002 and 2015. Total 128 tumors were included to this study and classified into four categories based on the presence and nature of cystic components: extratumoral cystic (Type Ce, classical cystic with a mural nodule), intratumoral cystic (Type Ci), mixed cystic (Type Cm), and solid (Type S). The association with von Hippel-Lindau (VHL) disease was also investigated. In 118 patients (65 male and 53 female), 79 (66.9%) had solitary HBMs and 39 (33.1%) were diagnosed with VHL disease. Type Ce with typical radiological findings was the most prevalent type of HBM (63.3%), followed by Type S (21.1%). HBMs with intratumoral cysts were uncommon (Type Ci, 11.7%) and mixed extratumoral and intratumoral cysts (Type Cm) accounted for only 3.9%. No intergroup differences were observed in the proportions of each subtype between the solitary and VHL disease-associated HBMs. The blood loss was much lower in Type Ce than in other subtypes. In Type Cm, radical resection was often challenging as the differentiation between intratumoral and extratumoral cysts was difficult resulting in incomplete resection. Refined radiological classification scheme is more practical because it does not only help surgeons determine whether the cystic wall should be removed or not, but also covers cases with atypical radiological presentations. For solid and extraparenchymal HBMs, differential diagnosis is more difficult as well as very critical as surgical removal is often very challenging.

Posterior fossa tumors in children: Radiological tips & tricks in the age of genomic tumor classification and advance MR technology.

Imaging plays a major role in the comprehensive assessment of posterior fossa tumor in children (PFTC). The objective is to propose a global method relying on the combined analysis of radiological, clinical and epidemiological criteria, (taking into account the child's age and the topography of the lesion) in order to improve our histological approach in imaging, helping the management and approach for surgeons in providing information to the patients' parents. Infratentorial tumors are the most frequent in children, representing mainly medulloblastoma, pilocytic astrocytoma and brainstem glioma. Pre-surgical identification of the tumor type and its aggressiveness could be improved by the combined analysis of key imaging features with epidemiologic data.

Immunohistochemical detection of ALK protein identifies APC mutated medulloblastoma and differentiates the WNT-activated medulloblastoma from other types of posterior fossa childhood tumors.

Expression of the ALK gene strongly correlates with the WNT-activated medulloblastomas, which are routinely identified by detection of CTNNB1 mutation. However, some tumors have mutations in other than CTNNB1 genes. Therefore, we investigated if ALK expression may identify WNT-activated tumors without CTNNB1 mutation. In addition, we examined if ALK expression may differentiate WNT-activated medulloblastoma from other malignant posterior fossa tumors. ALK expression was analyzed using immunohistochemistry (clone D5F3) in 70 patients with posterior fossa tumours. Among 55 medulloblastomas, 6 tumors showed ALK expression in > 50% of tumor cells. In one tumor, with ALK positive reaction, negative nuclear reaction against ß-catenin and the lack of CTNNB1 mutation, next generation sequencing revealed a presence of pathogenic variant c.3366_3369del in the APC gene, with homozygous deletion leading to inactivation of both copies in tumor cells. MLPA analysis displayed the presence of chromosome 6 monosomy, therefore, confirming the WNT type of this tumor. All analyzed 19 anaplastic ependymomas, 4 choroid plexus carcinomas and 2 atypical teratoid rhabdoid tumors were immunonegative for ALK expression. Therefore, we propose, that immunohistochemical detection of ALK protein should be highly recommended in routine investigation, in parallel to already established methods for identification and differentiation of WNT-activated medulloblastoma.

Heterogeneity within the PF-EPN-B ependymoma subgroup.

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.

Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.

Chromosome 1q gain and tenascin-C expression are candidate markers to define different risk groups in pediatric posterior fossa ependymoma.

Intracranial classic (WHO grade II) and anaplastic (WHO grade III) ependymomas are among the most common tumors in pediatric patients and have due to frequent recurrences and late relapses a relatively poor outcome. The impact of histopathological grading on patient outcome is controversial and therefore, molecular prognostic and predictive markers are needed to improve patient outcome. To date, the most promising candidate marker is chromosome 1q gain, which has been associated in independent studies with adverse outcome. Furthermore, gene expression and methylation profiles revealed distinct molecular subgroups in the supratentorial and posterior fossa (PF) compartment and Laminin alpha-2 (LAMA2) and Neural Epidermal Growth Factor Like-2 (NELL2) were suggested as surrogate markers for the two PF subgroups PF-EPN-A and PF-EPN-B. PF-EPN-A tumors were also characterized by tenascin-C (TNC) expression and tenascin-C has been suggested as candidate gene on 9q, involved in tumor progression. Therefore, we have analyzed the status of chromosome 1q, TNC, LAMA2, and NELL2 expression in a series of pediatric PF ependymomas in terms of their frequency, associations among themselves, and clinical parameters, as well as their prognostic impact. We confirm the negative prognostic impact of 1q gain and TNC expression and could classify PF ependymomas by these two markers into three molecular subgroups. Tumors with combined 1q gain and TNC expression had the poorest, tumors without 1q gain and TNC expression had a favorable and TNC positive 1q non-gained cases had an intermediate outcome. We found also differences in age and tumor grade in the three subgroups and thus, provide evidence that PF pediatric ependymomas can be divided by chromosome 1q status and TNC expression in three molecular subgroups with distinct clinico-pathological features. These analyses require only few amounts of tumor tissue, are broadly available in the routine clinical neuropathological setting and thus, could be used in further therapy trials to optimize treatment of ependymoma patients.

Posterior fossa and spinal gangliogliomas form two distinct clinicopathologic and molecular subgroups.

BACKGROUND: Gangliogliomas are low-grade glioneuronal tumors of the central nervous system and the commonest cause of chronic intractable epilepsy. Most gangliogliomas (>70%) arise in the temporal lobe, and infratentorial tumors account for less than 10%. Posterior fossa gangliogliomas can have the features of a classic supratentorial tumor or a pilocytic astrocytoma with focal gangliocytic differentiation, and this observation led to the hypothesis tested in this study - gangliogliomas of the posterior fossa and spinal cord consist of two morphologic types that can be distinguished by specific genetic alterations. RESULTS: Histological review of 27 pediatric gangliogliomas from the posterior fossa and spinal cord indicated that they could be readily placed into two groups: classic gangliogliomas (group I; n = 16) and tumors that appeared largely as a pilocytic astrocytoma, but with foci of gangliocytic differentiation (group II; n = 11). Detailed radiological review, which was blind to morphologic assignment, identified a triad of features, hemorrhage, midline location, and the presence of cysts or necrosis, that distinguished the two morphological groups with a sensitivity of 91% and specificity of 100%. Molecular genetic analysis revealed BRAF duplication and a KIAA1549-BRAF fusion gene in 82% of group II tumors, but in none of the group I tumors, and a BRAF:p.V600E mutation in 43% of group I tumors, but in none of the group II tumors. CONCLUSIONS: Our study provides support for a classification that would divide infratentorial gangliogliomas into two categories, (classic) gangliogliomas and pilocytic astrocytomas with gangliocytic differentiation, which have distinct morphological, radiological, and molecular characteristics.

Metrics and textural features of MRI diffusion to improve classification of pediatric posterior fossa tumors.

BACKGROUND AND PURPOSE: Qualitative radiologic MR imaging review affords limited differentiation among types of pediatric posterior fossa brain tumors and cannot detect histologic or molecular subtypes, which could help to stratify treatment. This study aimed to improve current posterior fossa discrimination of histologic tumor type by using support vector machine classifiers on quantitative MR imaging features. MATERIALS AND METHODS: This retrospective study included preoperative MRI in 40 children with posterior fossa tumors (17 medulloblastomas, 16 pilocytic astrocytomas, and 7 ependymomas). Shape, histogram, and textural features were computed from contrast-enhanced T2WI and T1WI and diffusivity (ADC) maps. Combinations of features were used to train tumor-type-specific classifiers for medulloblastoma, pilocytic astrocytoma, and ependymoma types in separation and as a joint posterior fossa classifier. A tumor-subtype classifier was also produced for classic medulloblastoma. The performance of different classifiers was assessed and compared by using randomly selected subsets of training and test data. RESULTS: ADC histogram features (25th and 75th percentiles and skewness) yielded the best classification of tumor type (on average >95.8% of medulloblastomas, >96.9% of pilocytic astrocytomas, and >94.3% of ependymomas by using 8 training samples). The resulting joint posterior fossa classifier correctly assigned >91.4% of the posterior fossa tumors. For subtype classification, 89.4% of classic medulloblastomas were correctly classified on the basis of ADC texture features extracted from the Gray-Level Co-Occurence Matrix. CONCLUSIONS: Support vector machine-based classifiers using ADC histogram features yielded very good discrimination among pediatric posterior fossa tumor types, and ADC textural features show promise for further subtype discrimination. These findings suggest an added diagnostic value of quantitative feature analysis of diffusion MR imaging in pediatric neuro-oncology.

Posterior fossa ependymomas: new radiological classification with surgical correlation.

PURPOSE: The key determinant of long-term outcome in infratentorial ependymomas remains the extent of surgical resection. We describe a new radiological classification system which is validated against surgical findings and correlated with risk of post-operative residual tumour. METHODS: Twenty-five consecutive patients (12 females, mean age 4.9 years, range 0.5-17 years) with infratentorial ependymomas were studied. Lesions were classified on pre-operative MRI according to the pattern of extension, brainstem displacement and involvement of the obex, as lateral-type or midfloor-type tumours. Twenty-one operative records were reviewed with respect to the microanatomical tumour origin by a paediatric neurosurgeon, blinded to MRI findings. Follow-up imaging studies were evaluated for residual tumour. RESULTS: There were 15 cases of midfloor-type tumour (anterior displacement of brainstem, infiltration of obex) and 10 cases of lateral-type tumour (lateral displacement of brainstem, obex free of tumour). Extension into prepontine or cerebellopontine cisterns was more common in lateral-type tumours. Agreement between the radiological classification and tumour origin, as defined by operative records, was seen in 18 out of 20 cases. Risk of residual tumour in lateral-type tumours was more than twice that of midfloor-type tumours (80% vs. 33%, p=0.04). Risk of tumour residual was also significantly higher when vessel encasement or prepontine extension was observed. CONCLUSIONS: Infratentorial ependymomas can be pre-operatively classified as lateral-type or midfloor-type tumours. This correlates well with operative findings. Lateral-type tumours have significantly increased risk of residual tumour compared to midfloor- type tumours and this may influence intensity of imaging surveillance.

Central nervous system atypical teratoid rhabdoid tumor: experience at the National Institute of Pediatrics, Mexico City.

OBJECTIVE: The purpose of this study is to present our experience with ten cases of Central nervous system atypical teratoid rhabdoid tumor (CNS/ATRT). PATIENTS AND METHODS: A series of ten patients with CNS/ATRT, were diagnosed and treated between 1990 and 2005, at the National Institute of Pediatrics, in Mexico City. The gender, age of presentation, clinical features, tumor localization, imaging studies, grade of tumor resection, complications, adjuvant therapy, and survival are presented. RESULTS: The mean age at diagnosis was 37.8 months, seven cases were male, and their average clinical course was 1.3 months. The more common clinical presentation was intracranial hypertension with cranial nerve deficits; location was infratentorial in four patients and supratentorial in six. Hydrocephalus was present as the most common complication (seven cases). In nine patients, the grade of resection was total or subtotal. In one case, it was only possible to perform a biopsy. There were two cases with longer survival (9 and 16 months), and their tumors were resected in total or subtotal manner and received adjuvant therapy (radiotherapy and chemotherapy). CONCLUSIONS: Preliminary results, show that in older children, we can improve their survival with the subtotal or total resection of the tumor and the addition of chemotherapy and radiotherapy.

Posterior petrous face meningiomas: an algorithm for surgical management.

OBJECTIVE: The objective of the present study was to report our surgical strategy in the management of 81 patients with posterior petrous face meningiomas. STUDY DESIGN: Retrospective study. SETTING: This study was conducted at a quaternary private otology and cranial base center. PATIENTS: Of 139 patients with posterior fossa meningioma, 81 occurred on the posterior petrous face of the temporal bone and were the object of this study. INTERVENTIONS: Thirty-one patients were approached by the enlarged translabyrinthine approach. The enlarged translabyrinthine approach with transapical extension Type II was performedin 29 patients. The combined retrosigmoid-retrolabyrinthine approach was chosen in 8 cases. The modified transcochlear approach Type A with permanent posterior transposition of the facial nerve (FN) was performed in 6 patients. Two patients underwent a retrolabyrinthine subtemporal transapical approach. One patient underwent a transpetrous middle cranial fossa approach. Four patients with intracanalicular meningiomas were operated on through the enlarged middle cranial fossa approach. RESULTS: Total removal of the tumor (Simpson Grades I and II) was achieved in most patients (92.5%). The FN was anatomically preserved in 79 of the 81 (97.5%) patients. Five patients had less than 1 year follow-up, and 2 patients were lost to follow-up and were excluded in evaluation of the final FN outcome. At 1-year follow-up, 46 patients (63%) had Grade I to II, 19 (26%) had Grade III, 4 (5.4%) had Grade IV, 1 (1.3%) had Grade V, and 3 (4.1%) had Grade VI. Hearing-preserving surgery was attempted in 15 patients (18.5%) with preoperative serviceable hearing. Of these 15 patients, 11 had their hearing preserved at the same preoperative level, and 4 experienced postoperative deafness. Postoperatively, a new deficit of 1 or more of the lower cranial nerves was recorded in 3 patients. One patient experienced subcutaneous cerebrospinal fluid collection that required surgical management. CONCLUSION: Total tumor removal (Simpson Grades I-II) remains our treatment of choice and takes priority over hearing preservation. Subtotal resection is indicated for older and debilitated patients with giant lesions to relieve the tumor compression on the cerebellum and brainstem. Subtotal removal is also preferred in the face of the absence of a plane of cleavage between the tumor and the brainstem, in the presence of encasement of vital neurovascular structures, in elderly patients with tumors adherent to preoperatively normal facial or lower cranial nerves.

Long-term neuromotor speech deficits in survivors of childhood posterior fossa tumors: effects of tumor type, radiation, age at diagnosis, and survival years.

The cerebellum is important for the coordination of fluent speech. The authors studied how childhood cerebellar tumors affect long-term neuromotor speech outcomes, including the relation between outcome and tumor type, radiation, age at diagnosis, and survival years. Videotaped speech samples of child and adult long-term survivors of childhood cerebellar astrocytoma (nonradiated) and medulloblastoma (radiated) tumors and healthy controls were analyzed by 2 speech pathologists for ataxic dysarthria, dysfluency, and speech rate. Ataxia varied with tumor type/radiation. Medulloblastoma survivors had significantly more ataxic dysarthric features than either survivors of astrocytomas or controls, who did not differ from each other. Dysfluency varied with a history of a posterior fossa tumor. Medulloblastoma and astrocytoma survivors were each significantly more dysfluent than controls but did not differ from each other. Speech rate varied with age and tumor type. Adult controls were significantly faster than child controls, although adult tumor survivors were comparable to their child counterparts. Adult controls had significantly faster speech rates than adult survivors of medulloblastoma tumors. Ataxic dysarthric speech characteristics are more frequent in radiated survivors of medulloblastoma tumors than nonradiated survivors of astrocytoma tumors. Dysfluent and slow speech occur in cerebellar tumor survivors, regardless of tumor type and radiation history. Cerebellar tumors in childhood limit speech rate in adulthood.

Analysis of chromosome 7 in adult and pediatric ependymomas using chromogenic in situ hybridization.

Few studies have yielded reliable data that distinguish between ependymal neoplasms based on molecular genetic attributes. The present study utilizes chromogenic in situ hybridization (CISH), a relatively recent hybridization technique, to retrospectively examine chromosome 7-copy number in pediatric and adult ependymomas. Of the 27 hybridizations, polysomy of chromosome 7 was detected in 10 out of 15 (66%) adult ependymomas, and in only three out of 12 (25%) pediatric lesions. All myxopapillary ependymomas showed polysomy. The remaining tumors were diploid. The authors conclude that (1) there are distinct genetic subsets of ependymoma, in particular, increases in copy number of chromosome 7 are almost exclusively found in myxopapillary ependymoma, and that (2) CISH is a rapid and sensitive method of stratifying morphological variants of ependymoma and potentially other central nervous system (CNS) tumors. These results encourage further investigations with CISH on a larger scale to determine its merit as an ancillary diagnostic and prognostic tool.