Search

Medulloblastma (MB) is a highly malignant (WHO grade IV), primitive cerebellar tumor of neuroectodermal origin. Medulloblastomas have been classified, based on histopathological, biological, and clinical characteristics, into classic medulloblastoma (CMB), desmoplastic nodular medulloblastoma (DNMB), medulloblastoma with extensive nodularity and anaplastic/large cell medulloblastoma.Medulloblastoma shows heterogenous tumor features in each subtype. Based on these heterogeneity, magnetic resonance imaging (MRI) could differentiate pathological subtypes according to each imaging features. This study aimed to assess the relation between Magnetic Resonance imaging features of pediatric medulloblastoma and pathological subtypes to improve treatment outcomes of the disease.All patients were subjected to the following:o History taking.o Thorough clinical examination.o Conventional MRI study of the brain.o Susceptibility-weighted imaging of the brain with post processing phase image. The study was applied on a 1.5 Tesla Magnetom Avanto Siemens (left handed system) machine using conventional MRI sequences in addition to DWI. Imaging evaluation depended on tumor location, tumor enhancement and degree of tumor restriction on DWI. Histo-pathology remains the gold standard in differentiating subtypes, however we can use MRI in early prediction of the subtypes and early planning for their management, regardless MRI very important role in post-surgical assessment and follow up.

Objective Medulloblastoma is the most common malignant brain tumor in children younger than four years of age. Children diagnosed with desmoplastic nodular medulloblastoma (DNMB) have more favorable survival outcomes when compared to other subtypes of this disease and, to date, the demographics of DNMB have only been characterized by a few small clinical case series. Additionally, the current effort is being made at reducing radiotherapeutic modalities in this patient population to avoid the adverse effects associated with radiotherapy in children. Therefore, the goal of this study was to characterize the demographics, treatments, and survival outcomes of patients with DNMB using a large federal database. Methods The Surveillance, Epidemiology, and End Results database was queried to retrieve demographical, treatment, and survival data for patients diagnosed with DNMB. Statistical testing was performed with the R software stats package (R Foundation for Statistical Computing, Vienna, Austria). Student's t tests and analysis of variance tests were used to measure differences among survival rates. Results Data from 360 patients with DNMB were retrieved from 1975-2016. There was a higher prevalence of DNMB in children younger than four years of age (33% of all cases). Males had a higher prevalence than females (57%). There was a preponderance of diagnoses in white individuals (82% of all cases) and more diagnoses in the Pacific Coast region (49% of all cases). Distant metastases were present at initial diagnosis in 8.7%. Surgery was performed in almost all patients, and gross total resection was achieved in 77%. The overall rate of survival was 77.8% at five years; age, sex, race, and geographical region of diagnosis were not associated with differences in survival outcomes. Patients with no radiotherapy had a lower rate of survival compared to patients with postoperative radiotherapy (mean difference = 19.7%; [95% CI 1.4%-38.0%], p = 0.0314). However, radiotherapy did not improve survival outcomes in patients undergoing chemotherapeutic treatment to a degree with any statistical significance. There was no statistically significant improvement in survival for patients undergoing radiotherapy prior to procedure when compared to patients with no radiotherapy. Conclusions In patients undergoing chemotherapeutic treatment for the DNMB subtype of medulloblastoma specifically, additional radiotherapy may offer only minimal benefit to the survival outcome. It is essential continued clinical trials be performed for the purpose of devising alternate treatments to radiotherapy.

Individuals with Down syndrome (DS) have an increased risk of acute leukemia compared to a markedly decreased incidence of solid tumors. Medulloblastoma, the most common malignant brain tumor of childhood, is particularly rare in the DS population, with only one published case. As demonstrated in a mouse model, DS is associated with cerebellar hypoplasia and a decreased number of cerebellar granule neuron progenitor cells (CGNPs) in the external granule cell layer (EGL). Treatment of these mice with sonic hedgehog signaling pathway (Shh) agonists promote normalization of CGNPs and improved cognitive functioning. We describe a 21-month-old male with DS and concurrent desmoplastic/nodular medulloblastoma (DNMB)—a tumor derived from Shh dysregulation and over-activation of CGNPs. Molecular profiling further classified the tumor into the new consensus SHH molecular subgroup. Additional testing revealed a de novo heterozygous germ line mutation in the PTCH1 gene encoding a tumor suppressor protein in the Shh pathway. The developmental failure of CGNPs in DS patients offers a plausible explanation for the rarity of medulloblastoma in this population. Conversely, patients with PTCH1 germline mutations experience Shh overstimulation resulting in Gorlin (Nevoid Basal Cell Carcinoma) syndrome and an increased incidence of malignant transformation of CGNPs leading to medulloblastoma formation. This represents the first documented report of an individual with DS simultaneously carrying PTCH1 germline mutation. We have observed a highly unusual circumstance in which the PTCH1 mutation appears to “trump” the effects of DS in causation of Shh-activated medulloblastoma.

Smoothened (SMO) is a transmembrane protein which is regulated by SHH (Sonic hedgehog) protein binding to PTCH1. SMO activation controls GLI which then translocates into the nucleus and activates target genes. The SHH subtype of medulloblastoma has been extensively studied to have mutations within the SHH signaling pathway, often in PTCH1, SUFU, and SMO. We present a case of desmoplastic/nodular medulloblastoma with the mutation SMO c.1810G>A. The patient presented at 11 years old with a two-week history of headaches and morning vomiting. His neuroimaging revealed a T2 hyperintense, enhancing mass centered at the fourth ventricle. He underwent gross total resection and had no metastatic spread. There were no alterations in PTCH1, SUFU, Tp53, GLI2, MYC/MYCN, CTNNB1, or the WNT pathway. The SMO c.1810G>A alteration has not been previously identified as a somatic mutation in a CNS tumor. The functional effect of this mutation has not been studied. It is known that desmoplastic/nodular histology in medulloblastoma is associated with the SHH subtype and given the fact that SMO is regulated by SHH signaling, this patient was ultimately diagnosed with SHH subtype medulloblastoma. Findings of novel somatic mutations in patients raises the question of whether the mutation is in fact the driver of neoplasia.

Desmoplastic nodular medulloblastoma (DNMB) is among the most treatable pediatric brain tumors with overall survival often reported in the range of 80-90%. Recently, several attempts around the globe were initiated in order to scale back therapy with the hopes of reducing both the short and long term toxicities. Unfortunately, these efforts have not been successful to date, which is highlighted by the most recent early closure of the Children’s Oncology group trial, ACNS1221, due to increased incidence of progression. There is no consensus at this time regarding the best salvage regimen to use for patients who failed therapy on ACNS1221. Here we present two patients with DNMB who recurred after treatment on ACNS 1221 and were successfully salvaged with high dose chemotherapy and stem cell support at our institution. The first patient is a 3 years old male who recurred with metastatic disease within 3 months post-therapy. He was treated with a 5-drug regimen consisting of vincristine, cisplatin, etoposide, cyclophosphamide and high-dose methotrexate for 3 cycles with autologous tandem transplants and proton craniospinal irradiation therapy of 23.4Gy and a boost to the posterior fossa of 54 Gy and the spine to 45 Gy. The second patient is a 4 years old male with Gorlin Syndrome and Trisomy 21 who had local recurrence within 9 months from finishing therapy, and was salvaged with 3 cycles of carboplatin and thiotepa with autologous tandem stem cell support without the need for radiation therapy. Both patients are currently alive with no evidence of disease.

BACKGROUND: Children with desmoplastic nodular medulloblastoma (DNMB) have excellent survival, leading multiple groups globally to attempt reduction of treatment-related morbidity. In 2013, the Children’s Oncology Group began a clinical trial (ACNS1221) eliminating both radiation therapy (RT) and intraventricular methotrexate for children under 3 years of age with localized DNMB, aiming to build upon the excellent outcomes of the German (HIT) trials. ACNS1221 has recently closed due to increased incidence of recurrences noted at the 2-year interim analysis, raising important questions regarding optimal therapy for DNMB. METHODS: A review of major clinical trials that included children with DNMB was performed through July 2017. RESULTS: One hundred and eighty eight DNMB patients enrolled on 11 prospective clinical trials were identified. The use of marrow-ablative chemotherapy and autologous hematopoietic cell rescue (AuHCR), or treatment with intraventricular methotrexate has been associated with excellent outcomes. RT was usually required for patients with evidence of disease at the end of therapy. CONCLUSIONS: The minimal intensity and duration of chemotherapy required to maximally cure children with DNMB without need of RT, remains unknown. Further trials are required to better identify a subset of DNMB patients who can be cured without marrow-ablative chemotherapy or intraventricular methotrexate.

Desmoplastic medulloblastoma is a rare subtype of medulloblastoma in childhood and more rare in adults. Cerebrospinal fluid (CSF) occurrence is frequent and important for treatment and prognosis. We report the CSF cytologic features of recurrent desmoplastic/nodular medulloblastoma in a 30-aged male.

Background Children with desmoplastic nodular medulloblastoma (DNMB) have excellent survival, leading multiple groups globally to attempt reduction of treatment-related morbidity. In 2013, the Children's Oncology Group began a clinical trial (ACNS1221) eliminating both radiation therapy (RT) and intraventricular methotrexate for children under 3 years of age with localized DNMB, aiming to build upon the excellent outcomes of the German HIT trials. ACNS1221 has recently closed due to increased incidence of recurrences noted at the 2-year interim analysis, raising important questions regarding optimal therapy for DNMB. Methods A review of major clinical trials that included children with DNMB was performed through July 2017. Results One hundred and eighty-eight DNMB patients enrolled on 11 prospective clinical trials were identified. The use of marrow-ablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) or treatment with intraventricular methotrexate has been associated with excellent outcomes. RT was usually required for patients with evidence of disease at the end of therapy. Conclusions The minimal intensity and duration of chemotherapy required to maximally cure children with DNMB without need of RT remains unknown. Further trials are required to better identify a subset of DNMB patients who can be cured without marrow-ablative chemotherapy or intraventricular methotrexate.

The aim of this study was to better define the clinical and biopathological features of patients with desmoplastic/nodular medulloblastoma (DNMB) and to further characterize this subgroup. 17 children aged < 5 years, with initial DNMB treated according to the HIT-SKK protocol, were evaluated. A retrospective central radiological review, a pathological and immunohistochemical study, and array-CGH and sequencing of germline SUFU and PTCH1 genes were performed. 15 histologically reviewed cases were confirmed as DNMB including three cases of medulloblastoma with extensive nodularity. Median age at diagnosis was 26 months. Radiology showed five cases with a vermis location and one with T2 hyperintensity. All cases showed a SHH immuno-profile. A 9q deletion was found in 6 cases, a MYCN–MYCL amplification in 1 case, and a SUFU germline mutation in 1 case (/9). The presence of SUFU and PTCH1 germline mutations agreed with previous reports. At 3 years, progression-free survival and overall-survival rates were 72 ± 15% and 85 ± 10%, respectively. The rate of recurrence was relatively high (4 patients). This may have been because chemotherapy was delayed in two cases. Age > 3 years, and residual tumor may also have been an explanation for recurrence.

Purpose Germline mutations of the SUFU gene have been shown to be associated with genetic predisposition to medulloblastoma, mainly in families with multiple cases of medulloblastoma and/or in patients with symptoms similar to those of Gorlin syndrome. To evaluate the contribution of these mutations to the genesis of sporadic medulloblastomas, we screened a series of unselected patients with medulloblastoma for germline SUFU mutations. Patients and Methods A complete mutational analysis of the SUFU gene was performed on genomic DNA in all 131 consecutive patients treated for medulloblastoma in the pediatrics department of the Institut Gustave Roussy between 1972 and 2009 and for whom a blood sample was available. Results We identified eight germline mutations of the SUFU gene: one large genomic duplication and seven point mutations. Mutations were identified in three of three individuals with medulloblastoma with extensive nodularity, four of 20 with desmoplastic/nodular medulloblastomas, and one of 108 with other subtypes. All eight patients were younger than 3 years of age at diagnosis. The mutations were inherited from the healthy father in four of six patient cases in which the parents accepted genetic testing; de novo mutations accounted for the other two patient cases. Associated events were macrocrania in six patients, hypertelorism in three patients, and multiple basal cell carcinomas in the radiation field after age 18 years in one patient. Conclusion These data indicate that germline SUFU mutations were responsible for a high proportion of desmoplastic medulloblastoma in children younger than 3 years of age. Genetic testing should be offered to all children diagnosed with sonic hedgehog–driven medulloblastoma at a young age.

The mainstay of medulloblastoma treatment is high-quality interdisciplinary collaboration in diagnosis, treatment, and aftercare by all involved disciplines. The first step in treatment of medulloblastoma is a maximal safe surgery, followed by thorough staging. Surgery should only be performed in experienced neurosurgical centers, with age-appropriate postoperative care. As optimal risk stratification is based on histopathological and neuroradiological assessments, these should be performed or confirmed by experienced specialists. Central review of histopathological subtype, as well as review of staging evaluations is highly desirable. For young children with desmoplastic/nodular (DMB), or extensive nodular medulloblastoma, craniospinal or any radiotherapy should be avoided. For young children with classic medulloblastoma (CMB), large cell, or anaplastic medulloblastoma (LC/A MB) optimized strategies with high-dose chemotherapy and autologous stem cell rescue with or without local radiotherapy are under investigation. For older clinical standard risk patients (without metastases, without postoperative residual tumor1.5 cm(2)) with CMB or DMB, craniospinal radiotherapy with 23.4 Gy and boost to the posterior fossa to 54 Gy, followed by maintenance chemotherapy can be regarded as a standard therapy besides other currently applied regimen, such as the use of intensified chemotherapy after irradiation. Older children with LC/A MB, metastatic medulloblastoma, and/or large residual tumor can be regarded as high-risk patients and should receive intensified treatment: intensified chemotherapeutic regimen before or after radiotherapy with increased dose (36-Gy CSI normofractionated, or 40-Gy hyperfractionated) is used. For treatment to be effective, quality control of radiotherapy is of high relevance. Information on long-term sequelae is essential and appropriate multidisciplinary follow-up and support, including rehabilitation and help for reintegration, is necessary. Whenever possible, patients should be included in prospective studies, and tumor material should be sampled to facilitate further research on medulloblastoma biology, which will significantly influence the stratification criteria and the introduction of targeted therapies in standard treatment recommendations in the future.

Because individual histologic features in childhood medulloblastoma alter survival likelihood, the recent 4th edition of the World Health Organization (WHO) Classification of Brain Tumors recognizes desmoplastic/nodular medulloblastoma, medulloblastoma with extensive nodularity, large cell medulloblastoma, and anaplastic medulloblastoma, in addition to medulloblastoma with no other distinguishing features. To identify features affecting survival likelihood, we investigated 33 histologic features in 556 childhood tumors diagnosed as medulloblastoma in the Childhood Brain Tumor Consortium (CBTC) database; all features have CBTC verified read-reread reliability and those features important in the classification of medulloblastoma and its WHO variants regardless of their measured reliability. Nineteen features had no effect on survival likelihood, and 8 features were too prevalent or too rare to measure their effect on survival. Nodules, balls, high cell density, and fine fibrillary stroma improved survival likelihood; necrosis and prominent nucleoli worsened survival likelihood. Of note, the presence of desmoplasia, currently a defining feature (along with nodules) for desmoplastic/nodular medulloblastoma, had no effect on survival likelihood. We conclude that the presence of nodularity in medulloblastoma is important to improved survival likelihood, particularly when combined with balls and fine fibrillary stroma. Given the “overlap” of desmoplastic/nodular medulloblastoma and nodular medulloblastoma, we suggest they be combined into a diagnosis of nodular medulloblastoma, with nodules, balls, and fine fibrillary stroma as defining criteria. We also suggest that because of the considerable overlap of anaplastic medulloblastoma and large cell medulloblastoma they be combined into 1 diagnosis of anaplastic/large cell medulloblastoma, with necrosis and prominent nucleoli among the defining criteria.

BACKGROUND: Individuals with Trisomy 21 have a striking cancer distribution, with a 10- to 20- fold increased risk of acute leukemia compared to a markedly decreased incidence of solid tumors. Medulloblastoma, the most common malignant brain tumor of childhood, is particularly rare in the DS population, with only one published case. As demonstrated in a mouse model of DS, the supernumerary chromosome 21 is associated with cerebellar hypoplasia and a decreased number of external granule cell layer progenitor cells (EGLs). Treatment of these mice with sonic hedgehog (Shh) signaling pathway agonists promotes normalization of EGLs and improved cognitive functioning. PATIENT: We describe a 21 month-old male with DS with desmoplastic/nodular medulloblastoma (DNMB) - a tumor derived from Shh dysregulation and over-activation of EGLs. Immunohistochemistry revealed patchy cytoplasmic GAB-1 staining and patchy strong YAP-1 nuclear and cytoplasmic staining, further placing this DNMB into the new consensus molecular classification Shh subgroup. Additional testing revealed a de novo heterozygous germ line mutation in the PTCH1 gene encoding a tumor suppressor protein in the Shh pathway; both parents tested negative for this mutation. CONCLUSIONS: The reduced presence of EGLs in DS patients offers a plausible explanation for the disparity of medulloblastoma in this population. Conversely, patients with PTCH1 germ line mutations experience Shh pathway overstimulation resulting in Gorlin (Nevoid Basal Cell Carcinoma) Syndrome and an increased incidence of malignant transformation of EGLs leading to medulloblastoma formation. This represents the first documented report of an individual with DS (developmental failure of EGLs, decreased incidence of medulloblastoma) simultaneously carrying PTCH1 germ line mutation (overstimulated EGLs, increased incidence of medulloblastoma). Thus, we observe a highly unusual circumstance in which the PTCH1 mutation appears to ‘trump’ the effects of trisomy 21 in causation of Shh-activated medulloblastoma. Additional genomic studies are ongoing and will be presented.

While cavernous angioma (CVA) after cranial irradiation has been documented, its development after high-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) has not. We present a patient with desmoplastic/nodular medulloblastoma (DNMB) associated with anhidrotic ectodermal dysplasia (AED) who developed CVA 2 years after high-dose chemotherapy and PBSCT. A 1-year-old boy with ingravescent vomiting was admitted to our institute. He presented with a large head, a depressed nasal bridge, low-set ears, thick lips with peg-shaped teeth, hypohidrosis, sparse hair, thin atrophic skin, scaly dermatitis with frontal bossing, and a bulging anterior fontanel. Neuroradiological examination revealed multiple cerebellar masses with heterogeneous enhancement and speckled calcifications and severe obstructive hydrocephalus. The histological diagnosis of surgical specimens was DNMB, and he underwent postoperative multiple-drug chemotherapy with autologous PBSCT. The outcome was favorable and he did not undergo radiotherapy. After 2 years, intracranial hemorrhage was detected at his regular radiological check-up and he again underwent surgery. The histological diagnosis was CVA. To our knowledge, this is the first report of AED-associated DNMB and CVA.