Application of the Rotterdam postoperative cerebellar mutism syndrome prediction model in patients undergoing surgery for medulloblastoma in a single institution.

OBJECTIVE: Postoperative cerebellar mutism syndrome (CMS) develops in up to 40% of children with medulloblastoma. The Rotterdam model (RM) has been reported to predict a 66% risk of CMS in patients with a score of ≥ 100. The aim of this study was to retrospectively apply the RM to an independent cohort of patients with newly diagnosed medulloblastoma and study the applicability of the RM in predicting postoperative CMS. METHODS: Participants had to have their first tumor resection at the authors' institution and be enrolled in the SJMB12 protocol (NCT01878617). All participants underwent structured serial neurological evaluations before and then periodically after completing radiation therapy. Imaging was reviewed by the study neurologist who was blinded to CMS status when reviewing the scans and retrospectively applied RM score to each participant. RESULTS: Forty participants were included (14 females and 26 males). Four (10%) patients had CMS. The median age at tumor resection was 11.7 years (range 3.5-17.8 years). Tumor location was midline in 30 (75%), right lateral in 6 (15%), and left lateral in 4 (10%). The median Evans index was 0.3 (range 0.2-0.4), and 34 (85%) patients had an Evans index ≥ 0.3. Five participants required a ventricular shunt. The median tumor volume was 51.97 cm3 (range 20.13-180.58 cm3). Gross-total resection was achieved in 35 (87.5%) patients, near-total resection in 4 (10%), and subtotal in 1. The median RM score was 90 (range 25-145). Eighteen participants had an RM score of ≥ 100, and of these 16.7% (n = 3) had CMS. Of the 22 patients with an RM score < 100, 1 child developed CMS (4.5%, CI 0.1%-22.8%); 3 of the 18 patients with an RM score ≥ 100 developed CMS (16.7%, CI 3.6%-41.4%). The observed rate of CMS in the cohort of children with an RM score ≥ 100 was significantly lower than the observed rate in the original RM cohort (66.7%, CI 51%-80.0%, p < 0.001). A greater risk of CMS in patients with an RM score ≥ 100 could not be confirmed (p = 0.31). CONCLUSIONS: At the authors' institution, the incidence of CMS in patients who had an RM ≥ 100 was significantly lower than the RM cohort. These findings raise questions regarding generalizability of RM; however, fewer cases of CMS and a relatively small cohort limit this conclusion.

Incidence and Risk Factors for Necessitating Cerebrospinal Fluid Diversion Following Medulloblastoma Surgery in Children.

BACKGROUND: There are insufficient data on pediatric patients with medulloblastoma who require cerebrospinal fluid (CSF) diversion following resection. Therefore, this study aimed to determine the incidence and the characteristics associated with it in this subset of patients. METHODS: We conducted a single-center, retrospective, observational cohort study of patients aged 18 years or less who underwent medulloblastoma resection at our department between 2010 and 2021. The primary outcome was the incidence of CSF diversion surgery required after resection. Participant demographics, tumor biology, and interventions were analyzed using univariate- and multivariate-adjusted models. RESULTS: Of the 183 patients admitted to our department, 131 (71.6%) participated in this study. The incidence of permanent CSF diversion was 26.0% (95% confidence interval [CI]: 18.7 to 34.3). Factors independently associated with requirement of permanent CSF diversion were medulloblastoma volume >46.4 cm3 (odds ratio [OR]: 2.919, 95% CI: 1.191 to 7.156) and CSF channel invasion (OR: 2.849, 95% CI: 1.142 to 7.102). The duration of manifestation may be a covariate of tumor volume with increased risk of requirement for permanent CSF diversion (OR: 1.006, 95% CI: 1.000 to 1.013), and tumor volume may be a predictor in patients who underwent subtotal resection (OR: 4.900, 95% CI: 0.992 to 24.208, P = 0.05). Finally, patients who required permanent CSF diversion were divided according to medulloblastoma molecular subgroups, and no significant differences were found. CONCLUSION: We report major predictive factors for permanent CSF diversion surgery in patients with medulloblastoma. Our study suggests that the presence of postresection hydrocephalus is not high enough to warrant permanent, prophylactic CSF diversion in all patients.

Male Predisposition in Cerebellar Mutism Syndrome: a Cohort Study.

The aim of this study was to explore the association between sex and cerebellar mutism syndrome and to examine other potential risk factors. This ambispective cohort study examined 218 pediatric patients (132 boys) with a posterior fossa tumor who underwent tumor resection from July 2013 to March 2021. The patients' demographics and tumor characteristics were examined and statistically analyzed to explore the associations among the variables. Multivariable and subgroup analyses were conducted to validate the independent risk factors for cerebellar mutism syndrome (CMS). The male and female patients did not differ significantly in terms of age, tumor size, tumor location, tumor consistency, VP shunt placement before resection, extent of resection, or surgeon, as well as with respect to the presence of hydrocephalus or paraventricular edema. The overall incidence of CMS was 32.6%. The incidence of CMS was significantly higher in male patients than that in female patients (41.7% vs. 18.6%; P = 0.001). In the multivariable analysis, male sex (adjusted odds ratio [OR], 3.27; P = 0.001), solid tumor consistency (adjusted OR, 5.61; P = 0.001), midline location (adjusted OR, 3.78; P = 0.004), and hydrocephalus (adjusted OR, 2.56; P = 0.047) were independent risk factors for the CMS. Chi-square analysis revealed that solid tumor consistency and midline location were associated with medulloblastoma (P < 0.001). Male patients had a higher risk of developing CMS after a posterior fossa tumor resection. Midline location, solid tumor consistency, and hydrocephalus were independent risk factors for CMS.

A case of postoperative cerebellar mutism with hyperphagia in a child following gross total resection of medulloblastoma occupying the cerebellar vermis.

INTRODUCTION: Cerebellar mutism syndrome is a well-known complication following posterior fossa tumor resection. Its incidence is markedly increased among patients with medulloblastoma. Patients typically present with an inability to communicate verbally due to disruption of the dentato-thalamocortical pathway. CASE DESCRIPTION: We present a unique case of cerebellar mutism in a three-year-old girl who underwent gross total resection of medulloblastoma occupying the cerebellar vermis. In addition to mutism, the patient developed hyperphagia. DISCUSSION: This case report aims to contribute to current understanding of the role of cerebello-hypothalamic connections in cerebellar mutism and their clinical significance.

Global variation in young adult central nervous system tumor incidence by region, age, and sex from 1988 to 2012.

BACKGROUND: Central nervous system (CNS) tumors result in tremendous morbidity and mortality. Incidence of CNS tumors in young adults is less studied. It is unknown how young adult CNS tumor incidence has changed globally in recent decades. METHODS: We used Cancer Incidence in Five Continents (CI5) data (1988-2012) to estimate incidence rates (IR), average annual percent change in incidence (AAPC; 95% confidence intervals [95% CI]), and male-to-female incidence rate ratios (IRR; 95% CI) by six histologies and age at diagnosis (20-29years, 30-39years). Tumors were classified as astrocytic, medulloblastoma, ependymal, oligodendroglial, meninges, and other embryonal. Geographic regions were defined using the United Nations Statistics Division geoscheme. RESULTS: There were 78,240 CNS tumor cases included. 20-29-year-old (yo) rates were lower than 30-39 yo in most regions for astrocytic, oligodendroglial and ependymal tumors. Globally, astrocytic tumor incidence decreased (20-29 yo AAPC: - 0.70; 95% CI: - 1.32, - 0.08) while incidence increased for oligodendroglial (20-29 yo AAPC: 3.03; 95% CI: 1.57-4.51; 30-39 yo AAPC: 2.67; 95% CI: 0.79-4.58), ependymal (20-29 yo AAPC: 1.16; 95% CI: 0.31-2.03; 30-39 yo AAPC: 2.29; 95% CI: 1.14-3.46), medulloblastoma (30-39 yo AAPC: 0.6; 95% CI: 0.04-1.24) and tumors of the meninges (20-29 yo AAPC: 1.55; 95% CI: 0.04-3.07). There was a 20-40% male incidence excess in all histologies except for meninge tumors (30-39 yo IRR: 0.71; 95% CI: 0.61, 0.84). CONCLUSIONS: Incidence of oligodendroglial and ependymal tumors increased globally in 20-39 yo suggesting better diagnoses or changes in risk factors. Males had a higher incidence of CNS tumors for most tumors studied and in most regions.

Epidemiological characteristics and survival outcomes of children with medulloblastoma treated at the National Cancer Institute (INCA) in Rio de Janeiro, Brazil.

BACKGROUND: Medulloblastoma (MB),the most common malignant brain tumor of childhood has survival outcomes exceeding 80% for standard-risk and 60% for high-risk patients in high-income countries (HICs). These results have not been replicated in low- and middle-income countries (LMICs), where 80% of children with cancer live. METHODS: This is a retrospective review of 114 children aged 3-18 years diagnosed with MB from 1997 to 2016 at National Cancer Institute (INCA). Sociodemographic, clinical, and treatment data were extracted from the medical records and summarized descriptively. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. RESULTS: The male-to-female ratio was 1.32 and the median age at diagnosis was 8.2 years. Headache (83%) and nausea/vomiting (78%) were the most common presenting symptoms. Five-year OS was 59.1% and PFS was 58.4%. The OS for standard-risk and high-risk patients was 69% and 53%, respectively. The median time to diagnosis interval was 50.5 days and the median time from surgery to radiation therapy initiation was 50.4 days. Patients who lived >40 km from INCA fared better (OS = 68.2% vs. 51.1%, p = .032). Almost 20% of families lived below the Brazilian minimum wage. Forty-five patients (35%) had metastatic disease at admission. Gross total resection was achieved in 57% of the patitents. CONCLUSIONS: Although there are considerable barriers to deliver effective MB treatment in countries like Brazil, the OS seen in the present study demonstrates that good outcomes are not only feasible but can and should be increased with appropriate interventions.

Medulloblastoma outcomes in tertiary care set-up in India using contemporary treatment protocols - A retrospective study.

Background: Medulloblastoma is the commonest embryonal brain tumor in children. It has shown improved outcomes with combined modality treatment. We aimed to study patient characteristics and survival outcomes of patients with this disease across two tertiary care centers in India. Methods: We analyzed data of patients with histological diagnosis of medulloblastoma treated from January 2010 to January 2016. Patient characteristics and follow-up data were retrieved from hospital records. Descriptive statistics were used to describe clinical and pathological characteristics. Overall survival (OS) was calculated from date of diagnosis to death due to any cause. Relapse-free survival (RFS) was calculated from date of diagnosis to occurrence of relapse or death. Result: Out of 26 patients treated, 24 were children and 2 were adults. Median age was 10 years (range = 0.8-22 years). Twenty (76.9%) patients were male. Fifteen (57.7%) patients were stratified as high-risk (HR), rest 11 (42.3%) were categorized as average risk (AR). Histopathology showed classical variety in majority of patients except for 4 (15%) cases, 3 with desmoplastic and 1 with anaplastic subtype. Median follow-up was 49.7 months (range= 4.2-102.5 months). Overall, eight (30.8%) patients relapsed and six (23%) deaths occurred. Five (33.3%) patients in HR category and 3 (27.3%) patients in AR group showed relapse. Median RFS and OS were not yet reached. Five-year RFS was 69.2% whereas five-year OS was 76.9%. Conclusion: This study highlighted patient characteristics and treatment outcomes in Indian patients. With adherence to standard treatment, high remission rates and improvement in mortality rates were achieved.

Immunosuppression in Medulloblastoma: Insights into Cancer Immunity and Immunotherapy.

OPINION STATEMENT: Medulloblastoma (MB) is the most common pediatric brain malignancy, with a 5-year overall survival (OS) rate of around 65%. The conventional MB treatment, comprising surgical resection followed by irradiation and adjuvant chemotherapy, often leads to impairment in normal body functions and poor quality of life, especially with the increased risk of recurrence and subsequent development of secondary malignancies. The development and progression of MB are facilitated by a variety of immune-evading mechanisms such as the secretion of immunosuppressive molecules, activation of immunosuppressive cells, inhibition of immune checkpoint molecules, impairment of adhesive molecules, downregulation of the major histocompatibility complex (MHC) molecules, protection against apoptosis, and activation of immunosuppressive pathways. Understanding the tumor-immune relationship in MB is crucial for effective development of immune-based therapeutic strategies. In this comprehensive review, we discuss the immunological aspect of the brain, focusing on the current knowledge tackling the mechanisms of MB immune suppression and evasion. We also highlight several key immunotherapeutic approaches developed to date for the treatment of MB.

Comparison of Clinical and Molecular Wnt and SHH Subgroups in Medulloblastoma Tumor Cases.

AIM: To determine the Wnt and SHH subtypes at the molecular level, and to compare them clinically by examining the changes in CTNNB1, AXIN, PTCH1, SMO, SUFU, and GLI1 mRNA expression in the medulloblastoma of a Turkish population determined according to patient selection criteria. In this context, the clinical distinction between Wnt and SHH groups are realized by considering the age, gender, survival time, location of the lesion, and radiological features of the patients. MATERIAL AND METHODS: Molecular separation was performed by RT-PCR analysis of CTNNB1, AXIN, PTCH1, SMO, SUFU, and GLI1 mRNA expression changes. RESULTS: About 17.8% and 22.2% of the cases were included in the Wnt and the SHH group, respectively. When comparing group differences based on clinical and molecular data, 72.7% and 66.6% of matches were observed in the Wnt and the SHH group, respectively. CONCLUSION: It has been revealed that molecular analysis and grouping of patients with medulloblastoma can provide support for clinically determined subgroups.

Observed-to-expected incidence ratios of second malignant neoplasms after radiation therapy for medulloblastoma: A Surveillance, Epidemiology, and End Results analysis.

BACKGROUND: The authors analyzed the incidence and types of second malignant neoplasms (SMNs) in patients treated for medulloblastoma. METHODS: The authors compared the incidence of SMNs after radiotherapy (RT) for medulloblastoma in patients treated in 1973-2014 with the incidence in the general population with the multiple primary-standardized incidence ratio function of Surveillance, Epidemiology, and End Results 9. Observed-to-expected incidence (O/E) ratios and 95% confidence intervals (CIs) were reported for the entire cohort and by disease site according to age at diagnosis, treatment era, and receipt of chemotherapy. P values < .05 were considered statistically significant. RESULTS: Of the 1294 patients with medulloblastoma who received RT, 68 developed 75 SMNs. The O/E ratio for SMNs among all patients was 4.49 (95% CI, 3.53-5.62; P < .05). The site at highest risk was the central nervous system (CNS; O/E, 40.62; 95% CI, 25.46-61.51), which was followed by the endocrine system (O/E, 15.95; 95% CI, 9.12-25.91), bone (O/E, 14.45; 95% CI, 1.75-52.21), soft tissues (O/E, 9.01; 95% CI, 1.09-32.56), the digestive system (O/E, 5.03; 95% CI, 2.51-9.00), and the lymphatic/hematopoietic system (O/E, 3.37; 95% CI, 1.35-6.94). The O/E ratio was higher for patients given chemotherapy and RT (O/E, 5.52; 95% CI, 3.75-7.83) than for those given RT only (O/E, 3.96; 95% CI, 2.88-5.32). CONCLUSIONS: Patients with medulloblastoma are at elevated risk for SMNs in comparison with the general population. Variations in O/E for SMNs by organ systems were found for treatment modality, age at diagnosis, and time of diagnosis. The most common site, the CNS, was involved more often in younger patients and those given chemotherapy with RT.

Medulloblastoma and familial adenomatous polyposis: Good prognosis and good quality of life in the long-term?

INTRODUCTION: Mutations of the APC (adenomatous polyposis coli) gene correlate mainly with familial adenomatous polyposis (FAP), but can occasionally be pathogenic for medulloblastoma (MBL) wingless-related integration site (WNT) subtype, the course of which has only recently been described. METHODS: We retrieved all patients with documented germline APC mutations and a diagnosis of MBL to examine their outcome, late effects of treatment, and further oncological events. RESULTS: Between 2007 and 2016, we treated six patients, all with a pathogenic APC variant mutation and all with MBL, classic histotype. None had metastatic disease. All patients were in complete remission a median 65 months after treatment with craniospinal irradiation at 23.4 Gy, plus a boost on the posterior fossa/tumor bed up to 54 Gy, followed by cisplatin/carboplatin, lomustine, and vincristine for a maximum of eight courses. Five of six diagnostic revised MRI were suggestive of the WNT molecular subgroup typical aspects. Methylation profile score (in two cases) and copy number variation analysis (chromosome 6 deletion in two cases) performed on four of six retrieved samples confirmed WNT molecular subgroup. Four out of six patients had a positive family history of FAP, while gastrointestinal symptoms prompted its identification in the other two cases. Four patients developed other tumors (desmoid, MELTUMP, melanoma, pancreatoblastoma, thyroid Tir3) from 5 to 7 years after MBL. DISCUSSION: Our data confirm a good prognosis for patients with MBL associated with FAP. Patients' secondary tumors may or may not be related to their syndrome or treatment, but warrant adequate attention when planning shared guidelines for these patients.

Surgical management of posterior fossa medulloblastoma in children: The Lyon experience.

INTRODUCTION: Modern approach for the treatment of posterior fossa medulloblastomas remains a challenge for pediatric neurosurgeons and pediatric oncologists and requires a multidisciplinary approach to optimize survival and clinical results. MATERIAL AND METHODS: We report the surgical principles of the treatment of posterior fossa medulloblastomas in children and how to avoid technical mistakes especially in very young patients. We also report our experience in a series of 64 patients operated from a medulloblastoma between 2000 and 2018 in Lyon. RESULTS: All patients had a craniospinal MRI. Eighty-one percent of the patients (n=50) had strictly midline tumor while 19% (n=14) had lateralized one. Eleven percent (n=7) had metastasis at diagnosis on the initial MRI. Forty-one percent (n=29) had an emergency ETV to treat hydrocephaly and the intracranial hypertension. All patient underwent a direct approach and a complete removal was achieved in 78% (n=58) of the cases on the postoperative MRI realized within 48h postsurgery. Histological findings revealed classical medulloblastoma in 73% (n=46), desmoplastic medulloblastoma in 17% (n=11) and anaplastic/large cell medulloblastoma in 10% (n=7). Patients were classified as low risk in 7 cases, standard risk in 30 cases and high risk in 27 cases. Ninety-six percent (n=61) of the patient received radiotherapy. Seventy-six percent (n=48) received pre-irradiation or adjuvant chemotherapy. At last follow-up in December 2018, 65% (n=41) of the patient were in complete remission, 12% (n=8) were in relapse and 27% (n=15) had died from their disease. The overall survival at five , ten and fifteen years for all the series was of 76%, 73% and 65.7% respectively. CONCLUSIONS: Medulloblastomas remain a chimiosensible and radiosensible disease and the complete surgical removal represents a favorable prognostic factor. The extension of surgery has also to be weighted in consideration of the new biomolecular and genetic knowledge that have to be integrated by surgeons to improve quality of life of patients.

Medulloblastoma of the adult: results from a multicenter retrospective study by AINO (Italian Association of Neuro-Oncology) and SIN (Italian Society of Neurology).

INTRODUCTION: Medulloblastoma (MB) is the most common primary malignant intracranial tumor in childhood, but it is very rare in adults, and for this reason, the optimal treatment has not yet been defined. We designed a multicentric study in order to define relevant outcome measures for future prospective studies. MATERIALS AND METHODS: The project involved 10 Italian centers. The database shared among the centers contains epidemiological, diagnostic (radiological and histological/molecular), therapeutic, recurrence information, and survival data. RESULTS: A total of 152 patients (102 males and 50 females, median age 32) were included in the study. Twenty-three of 152 patients had a diagnosis of classic medulloblastoma, 52/152 had desmoplastic/extensive nodularity, 2/152 had large-cell anaplastic medulloblastoma, and the remaining had diagnoses not otherwise specified. Almost all patients underwent craniospinal irradiation after surgery; in 85.5% of patients, adjuvant chemotherapy, mainly platinum- and etoposide-based chemotherapy, was performed immediately after RT. Upon recurrence, most patients were retreated with various chemotherapy regimens, including intrathecal chemotherapy in patients with leptomeningeal dissemination. The overall survival (OS) rate at 5 years was 73.3% (95% CI, 65.0-80.0%). The median OS for the whole group of patients was 112 months. CONCLUSIONS: The data collected were mainly consistent with the literature. A limitation of this study was the large number of patients lost to follow-up and the lack of molecular data for most patients diagnosed until 2010. An important challenge for the future will be MB biologic characterization in adults, with the identification of specific genetic patterns. It will be important to have more national and international collaborations to provide evidence-based management strategies that attempt to obtain a standard of care.

Long-term outcome of posterior fossa medulloblastoma in patients surviving more than 20 years following primary treatment in childhood.

The aim of the study was to analyze the long-term outcome (>20 years) after treatment of posterior fossa medulloblastoma (MB) in childhood. We analyzed data from patients treated for posterior fossa MB between 1974 (introduction of the first international treatment protocol in Norway) and 1987 (when use of radiotherapy was abandoned in children under 4 years of age). Out of 47 children, 24 survived >20 years. At the time of analysis, 16 patients (median age 41 years, range 32-52) were alive (median follow-up 34 years, range 30-42), while 8 patients died 22-41 years (median 31 years) after primary treatment: one late death (after 22 years) was due to tumor recurrence whilst other 7 deaths (after 23 to 41 years) were related to the detrimental effects of the treatment (secondary tumors, stroke, severe epilepsy and depression). Observed 20- and 30-year survival rates were 51% and 44%, respectively. Despite successful treatment of MB in childhood and satisfactory tumor control during the first 20 years following primary treatment, our data indicates that even long-term survivors may die from tumor recurrence. However, the main factors causing late mortality and morbidity in long-term survivors seem to be the complications related to radiotherapy given in childhood.

Expression of GNAS, TP53, and PTEN Improves the Patient Prognostication in Sonic Hedgehog (SHH) Medulloblastoma Subgroup.

Medulloblastoma (MB) is the most common malignant brain tumor in children. It is currently classified in four main molecular subgroups with different clinical outcomes: sonic hedgehog, wingless, group 3, and group 4 (MBSHH, MBWNT, MBGRP3, or MBGRP4). Presently, a 22-gene expression panel has been efficiently applied for molecular subgrouping using nCounter technology. In this study, formalin-fixed, paraffin-embedded samples from 164 Brazilian medulloblastomas were evaluated, applying the 22-gene panel, and subclassified into the low and high expression of nine key medulloblastoma-related genes. In addition, TP53 mutation status was assessed using TruSight Tumor 15 Panel, and its correlation with expression and prognostic impact was evaluated. Samples from 149 of 164 patients (90%) were classified into MBSHH (47.7%), MBWNT (16.1%), MBGRP3 (15.4%), and MBGRP4 (20.8%). GNAS presented the highest expression levels, with higher expression in MBSHH. TP53, MYCN, SOX2, and MET were also up-regulated in MBSHH, whereas PTEN was up-regulated in MBGRP4. GNAS, TP53, and PTEN low expression was associated with the unfavorable patient outcome only for MBSHH (P = 0.04, P = 0.01, and P = 0.02, respectively). TP53 mutations were detected in 28.57% of MBSHH cases and exhibited association with lower expression and worse clinical outcome, although not statistically significant. The 22-gene panel for molecular classification of medulloblastoma associated with the expression of GNAS, TP53, and PTEN improves the patient prognostication in MBSHH subgroup and can be easily incorporated in the 22-gene panel without any additional costs.

Medulloblastoma in the age of molecular subgroups: a review.

Medulloblastoma is the most common pediatric malignant brain tumor. Advances in molecular profiling have uncovered significant heterogeneity among medulloblastomas and led to the identification of four distinct subgroups (wingless [WNT], sonic hedgehog [SHH], group 3, and group 4) that represent distinct disease entities in both underlying biology and clinical characteristics. The rapidly expanding repertoire of tools to study developmental and cancer biology is providing a wealth of knowledge about these embryonal tumors and is continuously refining the understanding of this complex cancer. In this review, the history of discovery in medulloblastoma is discussed, setting a foundation to outline the current state of understanding of the molecular underpinnings of this disease, with a focus on genomic events that define the aforementioned subgroups and evolving areas of focus, such as the cell of origin of medulloblastoma and medulloblastoma subtypes. With these recent discoveries in mind, the current state of medulloblastoma treatment and clinical trials is reviewed, including a novel risk stratification system that accounts for the molecular biomarkers of patients with a high risk for refractory disease. Lastly, critical areas of focus for future basic science and clinical research on this disease are discussed, such as the complexities of medulloblastoma metastases and recurrence as well as the priorities and strategies to implement in future clinical trials.

Association of Aggresomes with Survival Outcomes in Pediatric Medulloblastoma.

Aggresomes are inclusion bodies for misfolded/aggregated proteins. Despite the role of misfolded/aggregated proteins in neurological disorders, their role in cancer pathogenesis is poorly defined. In the current study we aimed to investigate whether aggresomes-positivity could be used to improve the disease subclassification and prognosis prediction of pediatric medulloblastoma. Ninety three pediatric medulloblastoma tumor samples were retrospectively stratified into three molecular subgroups; WNT, SHH and non-WNT/non-SHH, using immunohistochemistry and Multiplex Ligation Probe Amplification. Formation of aggresomes were detected using immunohistochemistry. Overall survival (OS) and event-free survival (EFS) were determined according to risk stratification criteria. Multivariate Cox regression analyses were carried out to exclude confounders. Aggresomes formation was detected in 63.4% (n = 59/93) of samples. Aggresomes were non-randomly distributed among different molecular subgroups (P = 0.00002). Multivariate Cox model identified aggresomes' percentage at ≥20% to be significantly correlated with patient outcome in both OS (HR = 3.419; 95% CI, 1.30-8.93; P = 0.01) and EFS (HR = 3; 95% CI, 1.19-7.53; P = 0.02). The presence of aggresomes in ≥20% of the tumor identified poor responders in standard risk patients; OS (P = 0.02) and EFS (P = 0.06), and significantly correlated with poor outcome in non-WNT/non-SHH molecular subgroup; OS (P = 0.0002) and EFS (P = 0.0004).