Epidemiology of brainstem high-grade gliomas in children and adolescents in the United States, 2000-2017.

BACKGROUND: Limited population-based data exist for the brainstem gliomas for children ages ≤19 years, which includes high-grade aggressively growing tumors such as diffuse intrinsic pontine glioma (DIPG). We examined the overall incidence and survival patterns in children with brainstem high-grade glioma (HGG) by age, sex, and race and ethnicity. METHODS: We used data from Central Brain Tumor Registry of the United States (CBTRUS), obtained through data use agreements with the Centers for Disease Control (CDC) and the National Cancer Institute (NCI) from 2000 to 2017, and survival data from the CDCs National Program of Cancer Registries (NPCR), from 2001 to 2016 for malignant brainstem HGG for ages ≤19 years (per WHO ICD-O-3 codes). HGG was determined by established histologic and/or imaging criteria. Age-adjusted incidence rates and survival data were used to assess differences overall and by age, sex race, and ethnicity. RESULTS: The incidence of brainstem HGG was higher among the female and Non-Hispanic population. Majority (69.8%) of these tumors were diagnosed radiographically. Incidence was higher in children aged 1-9 years compared to older children. Whites had a higher incidence compared to Blacks. However, the risk of death was higher among Blacks and Other race compared to Whites. There was no difference in survival by sex. CONCLUSIONS: We report the most comprehensive incidence and survival data on these lethal brainstem HGGs. Incidence and survival among patients with brainstem HGGs differed significantly by race, ethnicity, age-groups, and grade.

Pontine gliomas a 10-year population-based study: a report from The Canadian Paediatric Brain Tumour Consortium (CPBTC).

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) are midline gliomas that arise from the pons and the majority are lethal within a few months after diagnosis. Due to the lack of histological diagnosis the epidemiology of DIPG is not completely understood. The aim of this report is to provide population-based data to characterize the descriptive epidemiology of this condition in Canadian children. PATIENTS AND METHODS: A national retrospective study of children and adolescents diagnosed with DIPG between 2000 and 2010 was undertaken. All cases underwent central review to determine clinical and radiological diagnostic characteristics. Crude incidence figures were calculated using age-adjusted (0-17 year) population data from Statistics Canada. Survival analyses were performed using the Kaplan-Meier method. RESULTS: A total of 163 patients with pontine lesions were identified. Central review determined one-hundred and forty-three patients who met clinical, radiological and/or histological criteria for diagnosis. We estimate an incidence rate of 1.9 DIPG/1,000,000 children/year in the Canadian population over a 10 years period. Median age at diagnosis was 6.8 years and 50.3% of patients were female. Most patients presented with cranial nerve palsies (76%) and ataxia (66%). Despite typical clinical and radiological characteristics, histological confirmation reported three lesions to be low-grade gliomas and three were diagnosed as CNS embryonal tumor not otherwise specified (NOS). CONCLUSIONS: Our study highlights the challenges associated with epidemiology studies on DIPG and the importance of central review for incidence rate estimations. It emphasizes that tissue biopsies are required for accurate histological and molecular diagnosis in patients presenting with pontine lesions and reinforces the limitations of radiological and clinical diagnosis in DIPG. Likewise, it underscores the urgent need to increase the availability and accessibility to clinical trials.

Response assessment in diffuse intrinsic pontine glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Optimising the conduct of clinical trials for diffuse intrinsic pontine glioma involves use of consistent, objective disease assessments and standardised response criteria. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. A working group was formed specifically to address response assessment in children and young adults with diffuse intrinsic pontine glioma and to develop a consensus on recommendations for response assessment. Response should be assessed using MRI of brain and spine, neurological examination, and anti-inflammatory or antiangiogenic drugs. Clinical imaging standards are defined. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.

Pediatric diffuse intrinsic pontine glioma: where do we stand?

Pediatric diffuse intrinsic pontine glioma (DIPG) represents approximately 20% of all pediatric CNS tumors. However, disease outcomes are dismal with a median survival of less than 1 year and a 2-year overall survival rate of less than 10%. Despite extensive efforts to improve survival outcomes, progress towards clinical improvement has been largely stagnant throughout the last 4 decades. Focal radiotherapy remains the standard of care with no promising single-agent alternatives and no evidence for improvement with the addition of a long list of systemic therapies. A better understanding of the biology of DIPG, though not easy due to obstacles in obtaining pathological material to study, is promising for the development of specific individualized treatment for this fatal disease. Recent studies have found epigenetic mutations to be successful predictors and prognostic factors for developing future management policies. The aim of this review is to give a global overview about the epidemiology, diagnosis, and treatment of DIPG. We further examine the controversial biopsy and autopsy issue that is unique to DIPG and assess the subsequent impact this issue has on the research efforts and clinical management of DIPG.

The incidence of brainstem primitive neuroectodermal tumors of childhood based on SEER data.

PURPOSE: Incidence of BS primitive neuroectodermal tumors (BS-PNET) in children is not reported to date. Our main objectives were to estimate the incidence and report the outcome of BS-PNET in children. METHODS: Data were collected using the Surveillance Epidemiology and End Results cancer registry. RESULTS: From 1973 to 2013, we identified 83 pediatric patients (aged 0-21 years). Patients were divided into two age groups (0-3 years and 4-21 years). Median overall survival was 53 months. Patients in the older age group had a significant survival advantage (P < 0.001), as did those who received three modalities of therapy (surgery, chemotherapy, and radiation therapy) (P < 0.001) and patients with gross or subtotal tumor resection (P < 0.001). CONCLUSIONS: This study presents the first estimate of incidence and the largest cohort of pediatric BS-PNETs to date. A high index of suspicion of BS-PNET in similar cases is crucial for diagnosis, treatment, and outcome.

Survival rates and prognostic predictors of high grade brain stem gliomas in childhood: a systematic review and meta-analysis.

Diagnosis of a pediatric high grade brain stem glioma is devastating with dismal outcomes. This systematic review and meta-analysis was undertaken to determine the survival rates and assess potential prognostic factors including selected interventions. Studies included involved pediatric participants with high grade brain stem gliomas diagnosed by magnetic resonance imaging or biopsy reporting overall survival rates. Meta-analysis was undertaken using a binomial random effects model. Sixty-five studies (2336 participants) were included. Meta-analysis showed 1 year overall survival (OS) of 41% (95% confidence interval (CI) 38-44%, I-sq 52%, 2083 participants), 2 year OS of 15.3% (95% confidence interval 12-20%, I-sq 73.1%, 1329 participants) and 3 year OS of 7.3% (95% confidence interval 5.2-10%, I-sq 26%, 584 participants). Meta-analyses of median overall survival results was not possible due to the lack of reported measures of variance. Subgroup analysis comparing date of study, classification of tumor, use of temozolomide, non-standard interventions or phase 1/2 versus other studies demonstrated no difference in survival outcomes. There was insufficient data to undertake subgroup meta-analysis of patient age, duration of symptoms, K27M histone mutations and AVCR1 mutations. Survival outcomes of high grade brain stem gliomas have remained very poor, and do not clearly vary according to classification, phase of study or use of different therapeutic interventions. Future studies should harmonize outcome and prognostic variable reporting to enable accurate meta-analysis and better exploration of prognosis.

A multi-institutional study of brainstem gliomas in children with neurofibromatosis type 1.

OBJECTIVE: To define the clinical and radiologic features of brainstem gliomas (BSGs) in children with neurofibromatosis type 1 (NF1). METHODS: We performed a retrospective cross-sectional study of 133 children with NF1 and concurrent BSGs cared for at 4 NF1 referral centers. BSG was determined using radiographic criteria. Age at diagnosis, tumor location and appearance, clinical symptoms, treatment, and presence of a concurrent optic pathway glioma were assessed. RESULTS: The average age at BSG diagnosis was 7.2 years, and tumors occurred most often in the midbrain and medulla (66%). The majority of children with NF1-BSGs were asymptomatic (54%) and were not treated (88%). Only 9 of the 72 asymptomatic children received treatment because of progressive tumor enlargement. In contrast, 61 children presented with clinical signs/symptoms attributable to their BSG; these individuals were older and more often had focal lesions. Thirty-one patients underwent treatment for their tumor, and 14 received CSF diversion only. Progression-free survival was ∼3 years shorter for children receiving tumor-directed therapy relative to those who had either no treatment or CSF diversion only. Overall survival was 85% for the tumor-directed therapy group, whereas no deaths were reported in the untreated or CSF diversion groups. CONCLUSIONS: Unlike children with sporadically occurring BSGs, most children with NF1-BSGs were asymptomatic, and few individuals died from complications of their tumor. Those requiring tumor-directed treatment tended to be older children with focal lesions, and had clinically more aggressive disease relative to those who were not treated or underwent CSF diversion only.

Risk of subsequent cancer among pediatric, adult and elderly patients following a primary diagnosis of glioblastoma multiforme: a population-based study of the SEER database.

Purpose/aim of the study: Our objective was to determine the risk of a subsequent malignancy in patients with glioblastoma multiforme (GBM). MATERIALS AND METHODS: Data of patients with a primary diagnosis of GBM were extracted from the Surveillance, Epidemiology, and End Results database. Patients were divided into three age groups: pediatric, ≤19 years of age; adult, 20-59 years; elderly, ≥60 years. Outcomes were overall survival and incidence of second cancer. RESULTS: A total of 24 348 patients with primary GBM were identified during the period from 2004 to 2013: 349 pediatric, 9841 adults and 14 518 elderly. There were significant differences in terms of sex, race, registry site, tumor histological type, tumor size and extension among the groups. The median survival time for pediatric, adult and elderly patients was 15, 15 and 5 months, respectively. Of the study population, 1.8% developed a second malignancy and the rates of the three groups were statistically different. Secondary tumors of the cranial nerves and other nervous system were the most common occurrence in the adults and elderly. Female, registry site, giant cell glioblastoma, undergoing surgery or radiation therapy were associated with developing a second malignancy. CONCLUSIONS: The risk of a second malignancy in GBM patients is 1.8%, and associated with certain patient and treatment factors.

The international diffuse intrinsic pontine glioma registry: an infrastructure to accelerate collaborative research for an orphan disease.

Diffuse intrinsic pontine glioma (DIPG), a rare, often fatal childhood brain tumor, remains a major therapeutic challenge. In 2012, investigators, funded by the DIPG Collaborative (a philanthropic partnership among 29 private foundations), launched the International DIPG Registry (IDIPGR) to advance understanding of DIPG. Comprised of comprehensive deidentified but linked clinical, imaging, histopathological, and genomic repositories, the IDIPGR uses standardized case report forms for uniform data collection; serial imaging and histopathology are centrally reviewed by IDIPGR neuro-radiologists and neuro-pathologists, respectively. Tissue and genomic data, and cell cultures derived from autopsies coordinated by the IDIPGR are available to investigators for studies approved by the Scientific Advisory Committee. From April 2012 to December 2016, 670 patients diagnosed with DIPG have been enrolled from 55 participating institutions in the US, Canada, Australia and New Zealand. The radiology repository contains 3558 studies from 448 patients. The pathology repository contains tissue on 81 patients with another 98 samples available for submission. Fresh DIPG tissue from seven autopsies has been sent to investigators to develop primary cell cultures. The bioinformatics repository contains next-generation sequencing data on 66 tumors. Nine projects using data/tissue from the IDIPGR by 13 principle investigators from around the world are now underway. The IDIPGR, a successful alliance among philanthropic agencies and investigators, has developed and maintained a highly collaborative, hypothesis-driven research infrastructure for interdisciplinary and translational projects in DIPG to improve diagnosis, response assessment, treatment and outcome for patients.

Diffuse Intrinsic Pontine Glioma: New Pathophysiological Insights and Emerging Therapeutic Targets.

BACKGROUND: Diffuse Intrinsic Pontine Glioma (DIPG) is the leading cause of brain tumor-related death in children, with median survival of less than one year. Despite decades of clinical trials, there has been no improvement in prognosis since the introduction of radiotherapy over thirty years ago. OBJECTIVE: To review the clinical features and current treatment challenges of DIPG, and discuss emerging insights into the unique genomic and epigenomic mechanisms driving DIPG pathogenesis that present new opportunities for the identification of therapeutic targets. CONCLUSION: In recent years, an increased availability of biopsy and rapid autopsy tissue samples for preclinical investigation has combined with the advent of new genomic and epigenomic profiling tools to yield remarkable advancements in our understanding of DIPG disease mechanisms. As well, a deeper understanding of the developmental context of DIPG is shedding light on therapeutic targets in the microenvironment of the childhood brain.

Adult Brainstem Gliomas: Retrospective Analysis of 51 Patients.

AIM: Brainstem gliomas (BSG) constitute less than 2% of brain tumors in adults. Therapeutic options are limited and BSG are associated with a high morbidity and mortality. MATERIAL AND METHODS: We reviewed the records of 51 patients with BSG treated at the Institute of Neurosurgery, Clinical Center of Serbia in Belgrade between 1998 and 2012. We recorded demographic and clinical variables as well as radiological findings and survival. RESULTS: Of the 51 patients, 62.7% were male and 37.3% were female. The mean age was 30.6±19.3 years. High grade glioma (Astrocytoma grade III and IV) was most common at the age of 38.2±17.9 years (t=.481, p=0.017) while low grade glioma (Astrocytoma grade I and II) was common in younger age as 25.4±17.4 years (X2=4.013; p=0.045), with localization in the pons (X2=5.299; p=0.021) and exophytic presentation (X2=3.862; p=0.049). Ataxia, as initial symptom, was a predictor of poor outcome (HR:5.546, p=0.012). CONCLUSION: Due to its specific localization, BSG present a major challenge for neurosurgery, because of the necessity of safe approach for radical resection. Histological verification of BSG determines the need for additional therapeutic procedures such as radiotherapy and chemotherapy. Benefit from correct diagnosis is reflected in the avoidance of potentially adverse effects of treatment.

Diffuse Intrinsic Pontine Glioma: Time for Cautious Optimism.

Diffuse intrinsic pontine glioma is a lethal brain cancer that arises in the pons of children. The median survival for children with diffuse intrinsic pontine glioma is less than 1 year from diagnosis, and no improvement in survival has been realized in more than 30 years. Currently, the standard of care for diffuse intrinsic pontine glioma is focal radiation therapy, which provides only temporary relief. Recent genomic analysis of tumors from biopsies and autopsies, have resulted in the discovery of K27M H3.3/H3.1 mutations in 80% and ACVR1 mutations in 25% of diffuse intrinsic pontine gliomas, providing renewed hope for future success in identifying effective therapies. In addition, as stereotactic tumor biopsies at diagnosis at specialized centers have been demonstrated to be safe, biopsies have now been incorporated into several prospective clinical trials. This article summarizes the epidemiology, clinical presentation, diagnosis, prognosis, molecular genetics, current treatment, and future therapeutic directions for diffuse intrinsic pontine glioma.

Risk of seizures in children with tectal gliomas.

The objective of this study was to determine the prevalence of seizures in children with tectal gliomas and to determine if there are common clinical, electroencephalography (EEG), or radiologic findings that predict risk of seizures in these patients. We conducted a retrospective review of all patients with tectal gliomas over a 22-year period at a single institution. Data extraction included sex, age at presentation of tectal glioma and age of presentation with seizures, magnetic resonance imaging (MRI) findings, seizure frequency and semiology, and EEG findings. We identified 79 patients, 66 of whom had adequate imaging and clinical data for further analysis. Eight patients (12.1%) had a history of seizures. Three patients had a clear symptomatic cause of seizures. Three patients were diagnosed with a tectal glioma as an incidental finding after a first seizure. One patient had a history of febrile convulsions. One patient had a generalized seizure 5 years after presenting with macrocephaly. Although the risk of seizure in children with known tectal glioma was relatively high, we did not identify specific clinical, radiologic, EEG, or MRI features that are predictive of increased risk. Thus, in children with tectal gliomas who have seizures, alternative causes for the seizures must be sought.

Cervicomedullary tumors in children.

OBJECT: Cervicomedullary tumors (CMTs) represent a heterogeneous group of intrinsic neoplasms that are typically low grade and generally carry a good prognosis. This single-institution study was undertaken to document the outcomes and current treatment philosophy for these challenging neoplasms. METHODS: The charts of all pediatric patients with CMTs who received treatment at St. Jude Children's Research Hospital between January 1988 and May 2013 were retrospectively reviewed. Demographic, surgical, clinical, radiological, pathological, and survival data were collected. Treatment-free survival and overall survival were estimated, and predictors of recurrence were analyzed. RESULTS: Thirty-one children (16 boys, 15 girls) with at least 12 months of follow-up data were identified. The median age at diagnosis was 6 years (range 7 months-17 years) and the median follow-up was 4.3 years. Low-grade tumors (Grade I or II) were present in 26 (84%) patients. Thirty patients underwent either a biopsy alone or resection, with the majority of patients undergoing biopsy only (n = 12, 39%) or subtotal resection (n = 14, 45%). Only 4 patients were treated solely with resection; 21 patients received radiotherapy alone or in combination with other treatments. Recurrent tumor developed in 14 children (45%) and 4 died as a result of their malignancy. A high-grade pathological type was the only independent variable that predicted recurrence. The 5- and 10-year treatment-free survival estimates are 64.7% and 45.3%, respectively. The 5- and 10-year overall survival estimate is 86.7%. CONCLUSIONS: Children with CMTs typically have low-grade neoplasms and consequently long-term survival, but high risk of recurrence. Therapy should be directed at achieving local tumor control while preserving and even restoring neurological function.

Histologically proven, low-grade brainstem gliomas in children: 30-year experience with long-term follow-up at Mayo Clinic.

INTRODUCTION: To evaluate long-term overall survival (OS), progression-free survival (PFS), and outcomes in pathologically proven brainstem low-grade gliomas (BS-LGG) in children. METHODS: The Mayo Clinic tumor registry identified 48 consecutive children (≤20 y, 52% female) with biopsy-proven BS-LGG treated at Mayo Clinic between January 1971 and December 2004. Medical records were retrospectively reviewed. For analysis, patients were censored at the time of recurrence, death, or last follow-up. RESULTS: The median age at diagnosis was 12 years with a median follow-up of 6.0 years. The majority of tumors were grade I (69%) and pathology was consistent with an astrocytoma in the majority of patients (98%). Gross total resection was obtained in 4, subtotal in 17, and 27 patients were biopsied only. Postoperative radiotherapy (RT) was used in 29 patients. Median OS for the entire group was 14.8 years with a 1-, 5-, and 10-year OS of 85%, 67% and 59%, respectively. Median PFS for the entire group was 7.3 years. Improved survival was associated with undergoing resection versus biopsy-only with 5-year OS rates of 85% and 50% (P=0.002), respectively. A high proportion of patients (42%) had diffuse tumors and 13 patients (27%) had diffuse pontine gliomas (DPGs). DPGs had an OS of 1.8 years with a worse median PFS than non-DPGs (1.8 vs. 11.1 y; P=0.009). RT was used preferentially in patients with poor prognosis such as those who had a biopsy-only procedure (19/27) and DPGs (9/13). CONCLUSIONS: OS in this single institution retrospective study in pathologically proven BS-LGG with extensive follow-up displayed favorable long-term outcomes. Improved outcomes were associated with nondiffuse classification.

Feasibility, safety, and indications for surgical biopsy of intrinsic brainstem tumors in children.

PURPOSE: Diffuse intrinsic pontine gliomas (DIPGs) are rapidly progressive and aggressive tumors that usually arise in children. Their anatomic location makes gross total surgical resection impossible, and fewer than 10% of patients survive more than 2 years after diagnosis. Often, these lesions are treated based on imaging characteristics alone. However, despite aggressive chemotherapy and radiation treatments available, prognosis remains poor. There is therefore a need for new therapies directed by biologic profiling. This necessitates a tissue diagnosis and, therefore, surgical biopsy. We have reviewed the results of biopsy for DIPGs in children at a single institution and compared our results to those available in the literature to elucidate the utility of biopsy for DIPGs. METHODS: A historical cohort study was performed using medical records of patients under the age of 18 who underwent surgical biopsy of a DIPG at a single institution. RESULTS: Nine patients were included, four males and five females. Age at presentation ranged from 8 months to 10 years (average 5.7 years). Pathologic diagnoses included five high grade (WHO grade III or IV) gliomas and four low grade (WHO grade II) astrocytomas. There were no intraoperative complications, and only one patient developed a new postoperative neurologic deficit. CONCLUSIONS: Stereotactic biopsy of DIPGs is essential to obtain a pathologic diagnosis and is associated with low morbidity. This technique is important to elucidate biological characteristics of these tumors in order to direct multidisciplinary treatment plans possibly involving chemotherapy, radiation therapy, or other future clinical trial interventions for children with DIPGs.

The potential effect of gender in CYP1A1 and GSTM1 genotype-specific associations with pediatric brain tumor.

Brain tumors are the common site for solid tumors in childhood. Very few studies have investigated genes with low penetrance in relation to pediatric brain tumor (pBT) development. Brain tumors do occur more frequently in males compared to females regardless of age, tumor histology, or region of the world. Taken into account these facts, we have designed a study aimed to analyse the contribution of some genetic factors to pBP in males and females. Patients with glial and embryonic brain tumors (160 males, 124 females) and healthy controls (277 males, 187 females) were included in the study. All subjects were genotyped for eight polymorphic variants in the genes of xenobiotics detoxification CYP1A1 (rs2606345, rs4646903, rs1048943), GSTM1 (Ins/del), GSTT1 (Ins/del), repair ERCC2 (rs1799793, rs13181), and folate pathway MTHFR (rs1801133). Genotype-specific risks of pBT were sex-dependent. GSTM1 deletion and dual deletions in GSTM1-GSTT1 loci were associated with brain tumor in males (P = 1.2 × 10(-5); odds ratio (OR) = 2.56; 95 % confidence interval (CI), 1.45-3.85 and P = 4.9 × 10(-4); OR = 3.09; 95 % CI, 1.63-5.89, relatively). The increased risk of brain tumors was evident for CYP1A1 rs2606345 (P = 0.0028; OR = 2.06; 95 % CI, 1.27-3.34) and minor haplotypes rs2606345-rs1048943-rs4646903 in females (global haplotype association P value, 0.0011). This study provides first evidence for the different pronounced pBT associations in males and females. This phenomenon possibly reflects the sexual dimorphism as an important determinant of brain tumor biology.

Brainstem glioma: a review.

Brainstem gliomas (BGs) are a heterogenous group of gliomas that occur predominately in children. They can be separated into groups on the basis of anatomy and clinical behavior: diffuse intrinsic pontine glioma (DIPG), exophytic medullary glioma, and tectal glioma. DIPG is the commonest BG. Median age at onset is 6.5 years and median survival is less than 1 year. Adults with DIPG survive longer, suggesting a less aggressive and biologically different tumor from that in children. Patients present with cranial nerve dysfunction, long tract signs, or ataxia, either in isolation or in combination. Magnetic resonance imaging shows an infiltrative lesion occupying most of the pons and contrast enhancement is usually not prominent. Standard treatment is fractionated radiotherapy. Platelet-derived growth factor receptor alpha and epidermal growth factor receptor mutations have been identified. Inhibitors of these growth factor receptors are being evaluated in clinical trials. Exophytic medullary and tectal gliomas are relatively indolent tumors that can often be followed closely without treatment.