Pediatric Cerebellar Tumors Research Articles

QOL-16. IMPACT OF LESION LOCATION ON MOTOR AND COGNITIVE OUTCOMES IN PEDIATRIC CEREBELLAR TUMORS

Abstract BACKGROUND Children with cerebellar damage are at increased risk for various adverse outcomes, including higher rates of autism and long term neurocognitive challenges. Traditionally considered a motor structure, extensive evidence links the cerebellum to a range of behaviors and atypical cerebellar structure and function have been reported in multiple neurodevelopmental and psychiatric conditions. A key feature of cerebellar neuroanatomy are the functional subregions that support sensorimotor and non-motor functions, leading to the hypothesis that motor, cognitive and behavioral outcomes should be predicted by the cerebellar lesion location.We aimed to determine how lesion location relates to outcomes in pediatric cerebellar patients. We predicted that lesions of the anterior lobe would disrupt motor performance, posterolateral lesions would impact cognitive functions, and behavioral dysregulation would be associated with posterior midline damage. METHODS We conducted lesion-symptom mapping in 30 children with a history of cerebellar tumor resection (sex: 19 male, 11 female; age at diagnosis, mean 6.8 years [SD 4.2]). Clinical MRI scans and neuropsychological data were used to evaluate the impact of lesion location on motor (pegboard), cognitive (verbal comprehension, verbal fluency, working memory, processing speed) and behavioral control measures (BRIEF). We mapped individual lesions using T1-weighted MRIs and normalized the lesion maps into standard template space for group analyses. RESULTS Behavioral scores ranged from impaired to above average. Lesion overlap maps were used to assess the lesion patterns associated with performance. As predicted, anterior and medial lesions disrupted motor performance and processing speed; posterolateral lesions were associated with impaired cognitive scores. CONCLUSIONS These preliminary analyses indicate that long-term outcomes are associated with disruption of specific cerebellar subregions. This could aid in prognosis and management of pediatric cerebellar tumor patients. Future work will address age of surgery, longitudinal changes in performance, and the developmental impact of early cerebellar disruption on supratentorial structures.

The long-term impact of cerebellar tumor resection on executive functioning, anxiety, and fear of pain: A mixed methodology pilot study

This pilot study investigated the long-term impact of a surgery-only treatment (no exposure to other treatments, such as chemotherapy and radiation) for pediatric cerebellar low-grade gliomas on executive function, anxiety, and fear of pain (FOP) beliefs. Twelve patients who underwent surgical glioma resection during childhood (surgery age was 4–16 years, study visit age was 10–28 years), and 12 pain-free controls matched for age, sex, race, and handedness were tested. The spatial extent of resection was precisely mapped using magnetic resonance imaging (MRI). Executive function, anxiety, and FOP were assessed using validated self-report age-appropriate questionnaires for children and adults. Structured clinical interviews at a post-surgery follow-up visit were completed (average: 89 months, range: 20–99). No significant differences in FOP (FOPQ-C t[14 = 1.81, p = 0.09; FOPQ-III t[4] = 0.29, p = 0.79), executive function scores (BRIEF t[20] = 0.30, p = 0.28), or anxiety scores (MASC t[16] = 0.19, p = 0.85; MAQ t[4] = 1.80, p = 0.15) were found in pediatric or adult patients compared to pain-free controls. Clinical interviews mainly categorized pediatric patients as not anxious. One participant reported mild/subclinical anxiety, and one had moderate clinical anxiety. Neither psychologists nor patients endorsed impairments to executive functioning, anxiety, or FOP. Our pilot results suggest that pediatric cerebellar tumor survivors treated with surgery-only have favorable long-term functioning related to these themes. While these results are promising, they will need to be replicated in a larger patient sample.

White matter hyperintensities relate to executive dysfunction, apathy, but not disinhibition in long-term adult survivors of pediatric cerebellar tumor

White matter hyperintensities (WMHs) have been related to executive dysfunction, apathy and disinhibition in a wide range of neurological populations. However, this relationship has not been examined in survivors of pediatric brain tumor. The goal of this study was to investigate how executive dysfunction, apathy, and disinhibition relate to WMHs in 31 long-term survivors of pediatric cerebellar brain tumor and 58 controls, using informant-report data from the Frontal Systems Behavior Scale. Total WMH volume was quantified using the Lesion Growth Algorithm. Further, periventricular, and subcortical volumes were identified based on proximity to custom ventricle masks generated in FSL. A ratio of WMH volume to whole brain volume was used to obtain normalized WMH volumes. Additionally, a multivariate regression analysis was performed. On average, informant-report scores were within normal limits and only executive dysfunction was significantly higher in survivors compared to controls (t(47.9) = -2.4, p=.023). Informants reported clinically significant levels of apathy in 32.3% of survivors. Informants also reported clinically significant executive dysfunction in 19.4 % of survivors and clinically significant disinhibition in, again, 19.4 % of survivors. Increased volume of WMHs was positively correlated with executive dysfunction (r = 0.33, p = 0.02) and apathy (r = 0.23, p = .04). Similarly, multivariate regression demonstrated correlations with executive dysfunction (p=.05, FDR corrected) and apathy (p=.05, FDR corrected). Exploratory analysis demonstrated an interaction wherein the relationship between total WMHs and executive dysfunction and apathy depends on whether the participant was a survivor. The current findings indicate that increased WMH volumes are associated with higher ratings of apathy and executive dysfunction, and that these results are likely unique to cerebellar brain tumor survivors. WMH burden may serve as a useful marker to identify survivors at risk of executive dysfunction or increased apathy.

Mapping of long-term cognitive and motor deficits in pediatric cerebellar brain tumor survivors into a cerebellar white matter atlas

PurposeDiaschisis of cerebrocerebellar loops contributes to cognitive and motor deficits in pediatric cerebellar brain tumor survivors. We used a cerebellar white matter atlas and hypothesized that lesion symptom mapping may reveal the critical lesions of cerebellar tracts.MethodsWe examined 31 long-term survivors of pediatric posterior fossa tumors (13 pilocytic astrocytoma, 18 medulloblastoma). Patients underwent neuronal imaging, examination for ataxia, fine motor and cognitive function, planning abilities, and executive function. Individual consolidated cerebellar lesions were drawn manually onto patients’ individual MRI and normalized into Montreal Neurologic Institute (MNI) space for further analysis with voxel-based lesion symptom mapping.ResultsLesion symptom mapping linked deficits of motor function to the superior cerebellar peduncle (SCP), deep cerebellar nuclei (interposed nucleus (IN), fastigial nucleus (FN), ventromedial dentate nucleus (DN)), and inferior vermis (VIIIa, VIIIb, IX, X). Statistical maps of deficits of intelligence and executive function mapped with minor variations to the same cerebellar structures.ConclusionWe identified lesions to the SCP next to deep cerebellar nuclei as critical for limiting both motor and cognitive function in pediatric cerebellar tumor survivors. Future strategies safeguarding motor and cognitive function will have to identify patients preoperatively at risk for damage to these critical structures and adapt multimodal therapeutic options accordingly.

EPCT-22 SAFETY AND EFFICACY OF INTRAVENTRICULAR IMMUNOVIROTHERAPY WITH ONCOLYTIC HSV-1 G207 FOR TREATMENT OF LEPTOMENINGEAL DISEASE

Leptomeningeal metastatic disease (LMD) occurs in 30–50% of newly diagnosed and recurrent pediatric malignant cerebellar tumors and 20–45% of malignant supratentorial tumors. Radiation and chemotherapy often cause substantial long-term neurotoxicity and outcomes remain poor for patients with LMD. At recurrence, LMD is generally minimally responsive to conventional therapies. Immunovirotherapy with engineered oncolytic HSV-1 G207 has emerged as a promising treatment for children with high-grade brain tumors. G207 infects and kills tumor cells while sparing normal cells and stimulates a robust anti-tumor immune response. Intratumoral G207 inoculation demonstrated safety and preliminary efficacy in a pediatric Phase 1 trial in recurrent/progressive high-grade glioma (NCT02457845), and a Phase 2 trial (NCT04482933) is forthcoming. Additionally, a Phase 1 trial of intratumoral G207 in recurrent/progressive malignant pediatric cerebellar tumors is ongoing (NCT03911388). While intratumoral inoculation delivers G207 directly to a primary tumor, it requires neurosurgical procedures thereby limiting repeat doses. Thus, we sought to establish the safety and efficacy of intraventricular G207. Utilizing an immunocompetent, HSV-sensitive murine strain, we determined that a standard 1x107 plaque-forming units (PFU) dose of G207 resulted in damage to the ependymal lining. However, interferon induction with an intraventricular low-dose (1x104 PFU) of G207 or polyinosinic-polycytidylic acid (poly I:C), a toll-like receptor 3 agonist, three days prior to standard treatment dose protected the ependymal lining. This approach enabled safe delivery of multiple subsequent doses. Importantly, with these protective measures, G207 significantly prolonged survival in pediatric patient-derived xenograft models and an immunocompetent murine LMD model of group 3 medulloblastoma, the most aggressive and fatal subtype. Collectively, these data indicate that toxicity from intraventricular G207 can be safely mitigated prior to a therapeutic dose, and that intraventricular G207 effectively targets group 3 medulloblastoma including LMD. These findings provide support for clinical translation of intraventricular G207.

Pediatric postoperative cerebellar cognitive affective syndrome follows outflow pathway lesions.

To evaluate lesion location after pediatric cerebellar tumor resection in relation to the development of severe cognitive and affective disturbances, or cerebellar cognitive affective syndrome (CCAS). The postsurgical lesion location of 195 pediatric patients with cerebellar tumors was mapped onto a template brain. Individuals with CCAS were matched to 2 participants without CCAS by sex, age, and lesion volume. Lesion analyses included both a hypothesis-driven evaluation of the cerebellar outflow pathway (deep nuclei and superior cerebellar peduncles) and data-driven multivariate lesion symptom mapping. Lesion-associated networks were evaluated by comparing connectivity patterns between the lesion location of cases with and those without CCAS with resting-state functional connectivity MRI data from large normative adult and pediatric cohorts. CCAS was present in 48 of 195 participants (24.6%) and was strongly associated with cerebellar outflow tract lesions (p < 0.0001). Lesion symptom mapping also highlighted the cerebellar outflow pathway, with peak findings in the fastigial nuclei extending into the inferior vermis. Lesion network mapping revealed that the cerebellar region most associated with CCAS was functionally connected to the thalamic mediodorsal nucleus, among other sites, and that higher connectivity between lesion location and the mediodorsal nucleus predicts CCAS occurrence (p < 0.01). A secondary analysis of 27 participants with mutism revealed similar localization of lesions and lesion-associated networks. Lesions of the cerebellar outflow pathway and inferior vermis are associated with major cognitive and affective disturbances after pediatric cerebellar tumor resection, and disrupted communication between the cerebellum and the thalamic mediodorsal nucleus may be important.

P.095 Novel use of fluorescein sodium in the resection of a pediatric posterior fossa tumor

Background: Gross total resection of pediatric posterior fossa tumors is paramount towards improving progression-free survival.Fluorescein accumulates in tumoral tissue, where the blood-brain barrier is disrupted. It can therefore potentially aid in differentiating tumoral versus normal tissue. We aimed to evaluate the efficacy of fluorescent-guidance (using fluorescein) towards the resection of a pediatric cerebellar tumor, as the index case at our institution using this technique. Methods: 5 mg/kg of IV fluorescein sodium was injected upon induction of general anesthesia. During tumor resection, a yellow 560-nm filter (Kinevo microscope, Zeiss) was employed for fluorescent-guidance. The extent of resection was assessed via post-operative MRI. Results: There were no adverse side effects experienced by the patient. Tumoral material was clearly visualized under the yellow 560-nm filter, allowing for satisfactory gross total resection of the lesion (confirmed on post-operative MRI). Preliminary pathology was consistent with medulloblastoma. Conclusions: Fluorescent-guided resection of pediatric posterior fossa tumors appears to be a safe and useful adjunct for gross total resection of these lesions. To the best of our knowledge, this is the first reported case in Canada wherein IV fluorescein was used under a yellow 560-nm filter for resection of a posterior fossa medulloblastoma in a child.

DNA polymerase β deficiency in the p53 null cerebellum leads to medulloblastoma formation

Defects in DNA damage response or repair mechanisms during neurogenesis result in genomic instability, which is causative for several neural defects. These include brain tumors, particularly medulloblastoma, which occurs in the cerebellum with a high incidence in children. We generated an animal model with defective base excision repair during brain development through selective inactivation of DNA polymerase β (Polb) in neuroprogenitor cells. All of Polb conditional knockout mice developed medulloblastoma in a p53 null background, similar to the Xrcc1 and p53 double deficient animal model. XRCC1 is a scaffolding protein which is involved in DNA damage repair and binds to POLB. In both animal models, the histopathological characteristics of the medulloblastoma were similar to those of human classic medulloblastoma. Brain tumor development was slower in the Polb and p53 double null animals than in the Xrcc1 and p53 double knockout animals. Molecular marker analysis suggested that Polb- and Xrcc1-deficient medulloblastomas belonged to the SHHα subtype, underscoring the important role of genomic stability in preventing this devastating pediatric cerebellar tumor.

QOL-43. CEREBELLAR MUTISM, NEUROCOGNITIVE AND ACADEMIC OUTCOME IN A CONSECUTIVE SAMPLE OF PEDIATRIC CEREBELLAR TUMOR PATIENTS

The Cerebellar Mutism Syndrome (CMS) is a severe complication after resection of a pediatric cerebellar tumor. Incidence rates vary and sophisticated neurocognitive and academic outcome studies are still rare. CMS is characterized by entire absence of speech for a certain time period after surgery. However, during long-term follow-up other distinct neurocognitive deficits become apparent, which have the impact to severely influence everyday life and academic achievement. Hence, the aim of this study was to investigate the long-term impact of cerebellar tumor treatment with a special focus on CMS. Therefore we retrospectively analyzed a consecutive sample of n=105 pediatric cerebellar tumor patients, all treated at the Medical University of Vienna between 2001 and 2015. Most common histologies were pilocytic astrocytoma (45.7%), medulloblastoma (31.4%) and ependymoma (13.3%). Eight patients were diagnosed with CMS (incidence rate = 7.6%). All patients underwent a comprehensive standard-of-care neuropsychological test-battery. Median time between diagnosis and follow-up assessment was 4 years. All patients suffering from postoperative CMS needed a special form of academic/occupational support at the time of assessment, compared to only 33% in the total sample. Regarding neurocognitive functioning, CMS patients showed significantly lower results in certain cognitive domains (e.g. divided attention, information processing speed). In conclusion, patients with CMS turned out to be a high-risk-group regarding neurocognitive late-effects, which in turn affect academic achievement and the need for special support services. Moreover, the results indicate the need for deficit-specific neurocognitive therapy and counselling. for pediatric cerebellar tumor patients in order to overcome illness-related academic disadvantages.

Pediatric Cerebellar Tumors: Emerging Imaging Techniques and Advances in Understanding of Genetic Features.

Cerebellar tumors are the most common group of solid tumors in children. MR imaging provides an important role in characterization of these lesions, surgical planning, and postsurgical surveillance. Preoperative imaging can help predict the histologic subtype of tumors, which can provide guidance for surgical planning. Beyond histology, pediatric brain tumors are undergoing new classification schemes based on genetic features. Intraoperative MR imaging has emerged as an important tool in the surgical management of pediatric brain tumors. Effective understanding of the imaging features of pediatric cerebellar tumors can benefit communication with neurosurgeons and neuro-oncologists and can improve patient management.

Executive function deficits in pediatric cerebellar tumor survivors.

Besides motor function the cerebellum subserves frontal lobe functions. Thus, we investigated executive functions in pediatric posterior fossa tumor survivors. We tested information processing, aspects of attention, planning and intelligence in 42 pediatric posterior fossa tumor survivors (mean age 14.63yrs, SD 5.03). Seventeen low-grade tumor patients (LGCT) were treated with surgery only and 25 high-grade tumors patients (HGCT) received postsurgical adjuvant treatment. We evaluated simple reaction time, executive functioning, i.e. visuospatial memory, inhibition, and mental flexibility using the Amsterdam Neuropsychological Tasks program, whereas forward thinking was assessed with the Tower of London-test. Intelligence was determined using the Wechsler Intelligence Scale. Ataxia was assessed with the International Cooperative Ataxia Rating Scale. About one third of each patient group showed forward thinking scores below one standard deviation of the norm. Impaired forward thinking correlated significantly with degree of ataxia (r=-0.39, p=0.03) but not with fluid intelligence. Both patient groups exhibited executive function deficits in accuracy and reaction speed in more difficult tasks involving information speed and attention flexibility. Still, HGCT patients were significantly slower and committed more errors. Working memory was inferior in HGCT patients. Pediatric cerebellar tumor survivors with different disease and treatment related brain damage exhibit similar patterns of impairment in executive functioning, concerning forward thinking, inhibition and mental flexibility. The deficits are larger in high-grade tumor patients. The pattern of function loss seen in both groups is most probably due to comparable lesions to cerebro-cerebellar circuits that are known to modulate critical executive functions.

Imaging of pediatric cerebellar tumors

Imaging of pediatric cerebellar tumors

Morphological brain lesions of pediatric cerebellar tumor survivors correlate with inferior neurocognitive function but do not affect health-related quality of life.

We aimed to determine whether extent of morphological brain injury in pediatric cerebellar tumor survivors correlates with neurocognitive function and health-related quality of life (HrQoL). Seventeen cerebellar pilocytic astrocytoma (cPA) and 17 medulloblastoma (MB) survivors were examined for HrQoL, intelligence using the German version of the WISC-III, attention, working memory, and visual motor coordination. MRI scans were analyzed for extent of posterior fossa brain tissue loss. We found significant correlations between amount and extent morphological brain lesions of pediatric cerebellar tumor survivors and several cognitive impairments including intelligence and attention in both patient groups. These were in total more pronounced in MB patients when compared to cPA patients. Still, function loss and brain lesions detected on conventional MRI did not influence HrQoL. These findings support the notion that long-term neurocognitive deficits of pediatric posterior fossa tumor survivors significantly correlate with brain tissue damage. The cerebellum plays a role in regulating higher-order functions. On the contrary, the extent brain injury is not detected by HrQoL assessment.

Pediatric Cerebellar Tumors: Does ADC Analysis of Solid, Contrast-Enhancing Tumor Components Correlate Better with Tumor Grade than ADC Analysis of the Entire Tumor?

Apparent diffusion coefficient (ADC) values assist differentiating malignancy grades in pediatric cerebellar tumors. Previous studies reported the significance of ADC measurements within the solid, contrast-enhancing tumor component (SCT). These measurements take into account only a part of the tumor. In this study, we compared ADC measurements of the SCT versus entire tumor (ET). ADC values were measured in the SCT and ET. Absolute tumor ADC values and cerebellar and thalamic ratios were compared across tumor grades. Thirty-two children with 16 low-grade and 16 high-grade tumors were included. The median age at presurgical MRI was 7.66 years (range .08-17.38 years). In the SCT, absolute ADC values, cerebellar ratio, and thalamic ratio were higher in low- versus high-grade tumors (P < .001). In the ET, absolute ADC values, cerebellar ratio, and thalamic ratio were also higher in low- versus high-grade tumors (P < .005). Cut-off absolute ADC values of .9 × 10(-3) mm/s2 (sensitivity 94%, specificity 100%) and 1.5 × 10(-3) mm/s2 (sensitivity 88%, specificity 75%) were calculated for measurement in the SCT and ET, respectively, to differentiate between tumors grades. A rigorous ADC measurement of the SCT has a higher sensitivity and specificity in predicting tumor grade compared to ADC measurement of the ET.

Abstract B5: Identification of a role for REST in promoting preneoplastic events in a novel genetically engineered mouse model

Abstract Medulloblastoma is a pediatric cerebellar tumor that arises from undifferentiated neuronal stem/progenitor cells (NSCs). The Repressor Element-1 (RE1) Silencing Transcription Factor (REST) negatively regulates neurogenesis by repressing numerous genes involved in terminal neuronal differentiation. We previously showed that REST levels were abnormally elevated in medulloblastoma samples and that this was associated with poor prognosis for patients. Previous studies from two groups including ours showed that REST knockdown in human tumor cells blocked their tumorigenic potential in mouse orthotopic models, suggesting that REST was required for tumor maintenance. In addition, constitutively elevated expression of REST in neural progenitors in the context of Myc overexpression promoted tumorigenesis in the murine brain, implicating REST in tumor progression. However, a role for REST in tumor initiation has not been demonstrated. To examine if elevated REST expression in neuronal progenitors was sufficient to promote pre-neoplastic events such as proliferation, delayed differentiation and genetic instability, we generated a novel transgenic (Tg) mouse model in which human REST Tg expression could be conditionally elevated in the post-natal cerebellar progenitor cells. These studies revealed that cerebellar progenitors harvested from REST Tg mice, had sustained neurosphere formation and proliferation potential compared to progenitors from age-matched wild type littermates. Progenitors from REST Tg mice also exhibited substantially decreased expression of REST target neuronal differentiation genes such as Syn1 and SCG10 and displayed delayed onset of neurogenesis compared to wild type controls. Interestingly, progenitors with elevated REST expression had significantly perturbed telomere homeostasis associated with altered telomerase levels and increased genomic instability compared to wild type controls. The above findings were recapitulated in vivo where cerebella from REST Tg mice exhibited prolonged Ki-67 staining accompanied by lack of differentiation and accumulation of genetic instability. Furthermore, REST mediated genetic instability was associated with increased sensitivity to DNA damaging reagents such as etoposide compared to normal wild type progenitors. Thus, we provide the first demonstration of a role for elevated REST expression in neural progenitors in promoting tumor initiating events such as hyperproliferation, blockade of differentiation and telomere defects. We also show that the genetic instability contributes to the accelerated response of these cells to clinically relevant DNA damage-inducing agents. These observations may have therapeutic implications for high REST medulloblastomas. Citation Format: Tara Dobson, Ellen Busschers, Pete Taylor, Julianne Humphries, Sadhan Majumder, Vidya Gopalakrishnan. Identification of a role for REST in promoting preneoplastic events in a novel genetically engineered mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B5.

A gene signature based method for identifying subtypes and subtype-specific drivers in cancer with an application to medulloblastoma

BackgroundSubtypes are widely found in cancer. They are characterized with different behaviors in clinical and molecular profiles, such as survival rates, gene signature and copy number aberrations (CNAs). While cancer is generally believed to have been caused by genetic aberrations, the number of such events is tremendous in the cancer tissue and only a small subset of them may be tumorigenic. On the other hand, gene expression signature of a subtype represents residuals of the subtype-specific cancer mechanisms. Using high-throughput data to link these factors to define subtype boundaries and identify subtype-specific drivers, is a promising yet largely unexplored topic.ResultsWe report a systematic method to automate the identification of cancer subtypes and candidate drivers. Specifically, we propose an iterative algorithm that alternates between gene expression clustering and gene signature selection. We applied the method to datasets of the pediatric cerebellar tumor medulloblastoma (MB). The subtyping algorithm consistently converges on multiple datasets of medulloblastoma, and the converged signatures and copy number landscapes are also found to be highly reproducible across the datasets. Based on the identified subtypes, we developed a PCA-based approach for subtype-specific identification of cancer drivers. The top-ranked driver candidates are found to be enriched with known pathways in certain subtypes of MB. This might reveal new understandings for these subtypes.This article is an extended abstract of our ICCABS '12 paper (Chen et al. 2012), with revised methods in iterative subtyping, the use of canonical correlation analysis for driver-identification, and an extra dataset (Northcott90 dataset) for cross-validations. Discussions of the algorithm performance and of the slightly different gene lists identified are also added.ConclusionsOur study indicates that subtype-signature defines the subtype boundaries, characterizes the subtype-specific processes and can be used to prioritize signature-related drivers.

Apparent diffusion coefficient of pediatric cerebellar tumors: A biomarker of tumor grade?

The role of diffusion weighted imaging (DWI) to reliably differentiate tumor types and grades in pediatric cerebellar tumors is controversial. We aimed to clarify the discrepancy reported in previous articles. We retrospectively evaluated the apparent diffusion coefficient (ADC) values of the enhancing, solid parts of cerebellar tumors and correlated the absolute tumor ADC values and cerebellar and thalamic ratios with histology in a cohort of children with cerebellar tumors. Twenty-four children (12 females) were included in the study. The median age at pre-surgical MRI was 10 years (range 29 days-18.5 years). Absolute ADC values (mean 1.49, SD 0.25 vs. 0.63 ± 0.18), cerebellar (2.04 ± 0.33 vs. 0.83 ± 0.25), and thalamic ratio (1.98 ± 0.35 vs. 0.79 ± 0.23) were significantly higher in low- than in high-grade tumors (P < 0.0001). Absolute ADC values and cerebellar and thalamic ratios were significantly higher in low-grade astrocytomas than in MBs. Overlap was seen for WHO grade II and III ependymomas. One hundred percent specific cutoff ADC values of >1.2 × 10(3) and <0.8 × 10(-3) mm(2) /s were established for low- and high-grade tumors. ADC analysis of the solid, contrast enhancing components of pediatric cerebellar tumors may facilitate differentiation between various tumor histologies.

Diffusion MRI Improves the Accuracy of Preoperative Diagnosis of Common Pediatric Cerebellar Tumors among Reviewers with Different Experience Levels

Although utility of diffusion MR imaging in the preoperative diagnosis of common pediatric cerebellar tumors is generally recognized, its added value has not been systematically studied previously. The purpose of this study was to evaluate the impact of diffusion MR imaging on the accuracy of preoperative diagnosis of common pediatric cerebellar tumors among reviewers with different experience levels. Review of the neuro-oncology data base yielded 96 patients whose preoperative brain MR imaging included both diffusion MR imaging (b = 1000 s/mm(2)) and ADC maps. There were 38 pilocytic astrocytomas, 33 medulloblastomas, 17 ependymomas, and 8 atypical teratoid/rhabdoid tumors. Six reviewers (4 residents, 2 neuroradiologists) evaluated the examinations. Two sessions were conducted with each reviewer, without and with diffusion MR imaging data on 2 separate days. The impact of diffusion MR imaging on accuracy of diagnoses was assessed. In choosing the correct diagnosis of the 4 alternatives, performances of 5 of the 6 reviewers improved significantly with inclusion of the diffusion MR imaging data, from 63%-77% (P = .0003-.0233). The performance of 1 reviewer also improved, but the difference did not attain statistical significance (P = .1944). Inclusion of diffusion MR imaging data improved the likelihood of rendering a correct diagnosis (odds ratio = 3.16, 95% confidence interval = 2.07-4.00) over all tumor types. When embryonal tumors were regarded as a single group, the rate of correct diagnosis increased from 66%-83% with diffusion MR imaging data, and performances of all of the reviewers improved significantly (P = .0001-.05). The improvement in performances resulted from increased correct diagnoses of pilocytic astrocytomas, medulloblastomas, and atypical teratoid/rhabdoid tumors. There was no improvement in the correct diagnoses of ependymomas with inclusion of the diffusion MR imaging data. Diffusion MR imaging improves accuracy of preoperative diagnosis of common pediatric cerebellar tumors significantly among reviewers with differing experience levels.

Common Pediatric Cerebellar Tumors: Correlation between Cell Densities and Apparent Diffusion Coefficient Metrics

To test whether there is correlation between cell densities and apparent diffusion coefficient (ADC) metrics of common pediatric cerebellar tumors. This study was reviewed for issues of patient safety and confidentiality and was approved by the Institutional Review Board of the University of Texas Southwestern Medical Center and was compliant with HIPAA. The need for informed consent was waived. Ninety-five patients who had preoperative magnetic resonance imaging and surgical pathologic findings available between January 2003 and June 2011 were included. There were 37 pilocytic astrocytomas, 34 medulloblastomas (23 classic, eight desmoplastic-nodular, two large cell, one anaplastic), 17 ependymomas (13 World Health Organization [WHO] grade II, four WHO grade III), and seven atypical teratoid rhabdoid tumors. ADCs of solid tumor components and normal cerebellum were measured. Tumor-to-normal brain ADC ratios (hereafter, ADC ratio) were calculated. The medulloblastomas and ependymomas were subcategorized according to the latest WHO classification, and tumor cellularity was calculated. Correlation was sought between cell densities and mean tumor ADCs, minimum tumor ADCs, and ADC ratio. When all tumors were considered together, negative correlation was found between cellularity and mean tumor ADCs (ρ = -0.737, P < .05) and minimum tumor ADCs (ρ = -0.736, P < .05) of common pediatric cerebellar tumors. There was no correlation between cellularity and ADC ratio. Negative correlation was found between cellularity and minimum tumor ADC in atypical teratoid rhabdoid tumors (ρ = -0.786, P < .05). In atypical teratoid rhabdoid tumors, no correlation was found between cellularity and mean tumor ADC and ADC ratio. There was no correlation between the ADC metrics and cellularity of the pilocytic astrocytomas, medulloblastomas, and ependymomas. Negative correlation was found between cellularity and ADC metrics of common pediatric cerebellar tumors. Although ADC metrics are useful in the preoperative diagnosis of common pediatric cerebellar tumors and this utility is generally attributed to differences in cellularity of tumors, tumor cellularity may not be the sole determinant of the differences in diffusivity.

Utility of Apparent Diffusion Coefficient Ratios in Distinguishing Common Pediatric Cerebellar Tumors

The aim of this study was to identify clinically useful tumor/normal brain apparent diffusion coefficient (ADC) ratios for distinguishing common pediatric cerebellar tumors. Review of medical records revealed 79 patients with cerebellar tumors who underwent preoperative magnetic resonance imaging, including diffusion-weighted imaging sequences, and surgery. There were 31 pilocytic astrocytomas, 27 medulloblastomas, 14 ependymomas, and seven atypical teratoid/rhabdoid tumors. ADC values were measured by placing regions of interest on the solid tumor and normal brain parenchyma by two reviewers. Tumor/normal brain ADC ratios were calculated. Mean ADC values of the pilocytic astrocytomas were greater than those of ependymomas, whose mean ADC values were greater than those of medulloblastomas and atypical teratoid/rhabdoid tumors. Using a tumor/normal brain ADC ratio threshold of 1.70 to distinguish pilocytic astrocytomas from ependymomas, sensitivity of 92% and specificity of 79% were achieved. A tumor/normal brain ADC ratio threshold of 1.20 enabled the sorting of ependymomas from medulloblastomas with sensitivity of 93% and specificity of 88%. Tumor/normal brain ADC ratios allow the distinguishing of common pediatric cerebellar tumors.