A 9-year-old boy with known Duchenne type muscular dystrophy (DMD) presented with signs of increased intracranial pressure. Radiological investigations revealed a lesion in the midline of the posterior fossa. Subtotal resection was performed. Pathology findings were consistent with the diagnosis of anaplastic medulloblastoma. The postoperative lumbar CSF was positive for malignant cells. Postoperatively, the patient showed severe neurological deterioration and lost his capacity to walk. He was treated with craniospinal radiation followed by nonintensive chemotherapy. At 30 months postsurgery, he was still in complete remission but had not recovered his walking ability. This is the second report of a malignant brain tumor in a boy with DMD. The possible link between the 2 conditions is discussed, as are ethical considerations regarding the management of medulloblastoma in children with DMD.
Machiel van den Akker, Paul Northcott, Michael D. Taylor, William Halliday, Ute Bartels, and Eric Bouffet
Lucie Lafay-Cousin, Gillian Lindzon, Michael D. Taylor, Walter Hader, Cynthia Hawkins, Robert Nordal, Normand Laperriere, Suzanne Laughlin, Eric Bouffet, and Ute Bartels
Primary CNS sarcomas are very rare pediatric tumors with no defined standard of care.
This study was a retrospective review of children diagnosed with a primary CNS sarcoma and treated at 2 Canadian tertiary care centers between 1995 and 2012. This report focuses on patients with cerebral hemispheric tumor location due to their specific clinical presentation.
Fourteen patients with nonmetastatic primary CNS sarcoma were identified; in 9 patients, tumors were located in the cerebral hemisphere and 7 of these patients presented with intratumoral hemorrhage. One infant who died of progressive disease postoperatively before receiving any adjuvant therapy was not included in this study. The final cohort therefore included 8 patients (4 males). Median patient age at diagnosis was 11.8 years (range 5.8–17 years). All tumors were located in the right hemisphere. Duration of symptoms prior to diagnosis was very short with a median of 2 days (range 3–7 days), except for 1 patient. Three (37.5%) patients had an underlying diagnosis of neurofibromatosis Type 1 (NF1). Gross-total resection was achieved in 5 patients. The dose of focal radiation therapy (RT) ranged between 54 Gy and 60 Gy. Concomitant etoposide was administered during RT. ICE (ifosfamide, carboplatin, etoposide) chemotherapy was administered prior to and after RT for a total of 6–8 cycles. Seven of the 8 patients were alive at a median time of 4.9 years (range 1.9–17.9 years) after treatment.
In this retrospective series, patients with primary CNS sarcomas located in the cerebral hemisphere most commonly presented with symptomatic acute intratumoral hemorrhage. Patients with NF1 were overrepresented. The combination of adjuvant ICE chemotherapy and focal RT provided encouraging outcomes.
Ute Bartels, Cynthia Hawkins, Jing Ma, Michael Ho, Peter Dirks, James Rutka, Derek Stephens, and Eric Bouffet
The authors’ aim in conducting this study was to investigate retrospectively the prognostic significance of angiogenic features in optic pathway/hypothalamic gliomas (OPHGs) in children.
Patients were identified in whom a diagnosis of OPHG was made using pathological analysis at the Toronto Hospital for Sick Children between 1985 and 2002. Tumor specimens were reviewed for diagnostic accuracy and adequacy of the specimen. Sections were immunostained with factor VIII to assess microvessel density (MVD). A ratio of α–smooth muscle actin to factor VIII immunostaining was calculated to arrive at a vascular maturity index (VMI). Vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) immunostaining were performed to evaluate angiogenic factors. In addition, the MIB-1 labeling index (LI) was used to assess proliferation. These factors were evaluated with respect to progression-free survival (PFS).
Forty-one of 60 patients originally identified had adequate samples and follow up for inclusion in the study. Of these, eight patients had coexisting neurofibromatosis Type 1. Twenty-eight patients experienced tumor progression after the initial treatment (surgery with or without adjuvant treatment). Thirty-eight patients are still alive. A high MVD (> 21 vessels/1.2 mm2) was associated with a significantly higher rate of progression compared with a low MVD (< 21 vessels/1.2 mm2; p = 0.017). Microvessel density was also predictive of reduced PFS on multivariate analysis stratified for extent of resection (p = 0.04), and VMI as well as intensity and distribution of VEGF and VEGFR staining and the MIB-1 LI were not significantly associated with PFS.
These findings suggest that MVD is the best current predictor of PFS in incompletely resected OPHGs. This information highlights the importance of angiogenesis in regard to low-grade gliomas.
Report of three cases
Lucie Lafay-Cousin, Ute Bartels, Charles Raybaud, Abhaya V. Kulkarni, Sharon Guger, Annie Huang, and Eric Bouffet
✓Intracystic bleomycin therapy has been proposed as a treatment for predominantly cystic craniopharyngioma. The risks of using this therapy, however, have not been clearly identified. The authors report on three children treated with intracystic bleomycin who developed initially mild symptoms during their course of therapy. They describe the neuroimaging findings from computed tomography (CT) scans and magnetic resonance (MR) images and the medical management of these three cases.
Two patients in whom craniopharyngioma was recently diagnosed and one patient with recurrent craniopharyngioma were treated with a course of 3 mg of intracystic bleomycin three times a week for 5 weeks, followed by once every week for 10 weeks. All patients had a negative reservoir permeability test prior to beginning intracystic bleomycin therapy. Patients were asymptomatic or had mild symptoms at the time of neuroimaging.
Magnetic resonance images revealed extensive vasogenic edema surrounding the cyst in all three patients, consistent with signs of bleomycin leakage. The edema occurred near the time of the 12th injection in two patients, and at the end of treatment in the remaining patient. Subsequently, two patients developed further symptoms suggestive of hypothalamic injury. These two patients received corticosteroids, leading to a rapid and sustained clinical improvement. Follow-up serial MR images showed a progressive regression of the surrounding edema.
Neuroimaging documentation of bleomycin toxicity has been described mainly in adults experiencing severe toxicity. There was no correlation between clinical symptoms and the extent of edema in these three patients. An MR image provides a higher resolution than CT scans for evaluating the adjacent cerebral structures and is very sensitive in detecting early abnormalities, even in asymptomatic patients. Bleomycin therapy requires close clinical monitoring. Imaging evaluation should be performed using MR imaging during treatment to ensure the safety of the therapy. In the authors' experience, the toxicity to bleomycin was transient. Management of the toxicity using high-dose steroid administration appears to contribute to controlling the bleomycin-induced inflammatory process.
Adriana Fonseca, Palma Solano, Vijay Ramaswamy, Uri Tabori, Annie Huang, James M. Drake, Derek S. Tsang, Normand Laperriere, Ute Bartels, Abhaya V. Kulkarni, and Eric Bouffet
There is no consensus on the optimal clinical management of ventriculomegaly and hydrocephalus in patients with diffuse intrinsic pontine glioma (DIPG). To date, the impact on survival in patients with ventriculomegaly and CSF diversion for hydrocephalus in this population remains to be elucidated. Herein, the authors describe their institutional experience.
Patients diagnosed with DIPG and treated with up-front radiation therapy (RT) at The Hospital for Sick Children between 2000 and 2019 were identified. Images at diagnosis and progression were used to determine the frontal/occipital horn ratio (FOR) as a method to measure ventricular size. Patients with ventriculomegaly (FOR ≥ 0.36) were stratified according to the presence of symptoms and categorized as follows: 1) asymptomatic ventriculomegaly and 2) symptomatic hydrocephalus. For patients with ventriculomegaly who did not require CSF diversion, post-RT imaging was also evaluated to assess changes in the FOR after RT. Proportional hazards analyses were used to identify clinical and treatment factors correlated with survival. The Kaplan-Meier method was used to perform survival estimates, and the log-rank method was used to identify survival differences between groups.
Eighty-two patients met the inclusion criteria. At diagnosis, 28% (n = 23) of patients presented with ventriculomegaly, including 8 patients who had symptomatic hydrocephalus and underwent CSF diversion. A ventriculoperitoneal shunt was placed in the majority of patients (6/8). Fifteen asymptomatic patients were managed without CSF diversion. Six patients had resolution of ventriculomegaly after RT. Of 66 patients with imaging at the time of progression, 36 (55%) had ventriculomegaly, and 9 of them required CSF diversion. The presence of ventriculomegaly at diagnosis did not correlate with survival on univariate analysis. However, patients with symptomatic hydrocephalus at the time of progression who underwent CSF diversion had a survival advantage (p = 0.0340) when compared to patients with ventriculomegaly managed with conservative approaches.
Although ventriculomegaly can be present in up to 55% of patients with DIPG, the majority of patients present with asymptomatic ventriculomegaly and do not require surgical interventions. In some cases ventriculomegaly improved after medical management with steroids and RT. CSF diversion for hydrocephalus at the time of diagnosis does not impact survival. In contrast, our results suggest a survival advantage in patients who undergo CSF diversion for hydrocephalus at the time of progression, albeit that advantage is likely to be confounded by biological and individual patient factors. Further research in this area is needed to understand the best timing and type of interventions in this population.
Report of 2 cases
Niketa C. Shah, Amit Ray, Ute Bartels, James Rutka, Eric Bouffet, James Drake, Cynthia E. Hawkins, and Annie Huang
✓ The authors report on 2 newborn infants with the unusual presentation of intrinsic brainstem tumors. Both nondysmorphic, full-term neonates had cranial nerve palsies and hypotonia. Diagnoses of diffuse intrinsic brainstem gliomas were made on the basis of magnetic resonance imaging, which showed large expansive, nonenhancing intrinsic pontine masses. Intrinsic pontine tumors, characteristically seen in school-age children, are most often high-grade gliomas that are almost invariably fatal. However, the microanatomy and natural history of pontine tumors in neonates are unknown. With parental consent, both newborns were treated expectantly with supportive care but died of progressive disease by 2 weeks of age. In one child, postmortem examination revealed a primary brainstem primitive neuroectodermal tumor. The authors conclude that, as in older children, neonatal intrinsic brainstem tumors may be of a highly malignant nature. The rapid tumor progression in both cases indicates that where a diagnostic procedure may pose significant risks, supportive observation can aid in distinguishing malignant from benign tumor growth.
Katrin Scheinemann, Ute Bartels, Annie Huang, Cynthia Hawkins, Abhaya V. Kulkarni, Eric Bouffet, and Uri Tabori
Intramedullary spinal cord low-grade gliomas (LGGs) are rare CNS neoplasms in pediatric patients, and there is little information on therapy for and outcome of these tumors in this population. Furthermore, most patient series combine adult and pediatric patients or high- and low-grade tumors, resulting in controversial data regarding optimal treatment of these children. To clarify these issues, the authors performed a regional population-based study of spinal cord LGGs in pediatric patients.
All pediatric patients with LGGs treated during the MR imaging era (1985–2007) were identified in the comprehensive database of the Hospital for Sick Children in Toronto. Data on demographics, pathology, treatment details, and outcomes were collected.
Spinal cord LGGs in pediatric patients constituted 29 (4.6%) of 635 LGGs. Epidemiological and clinical data in this cohort were different than in patients with other spinal tumors and strikingly similar to data from pediatric patients with intracranial LGGs. The authors observed an age peak at 2 years and a male predominance in patients with these tumors. Histological testing revealed a Grade I astrocytoma in 86% of tumors. Although 5-year progression-free survival for the entire group was 48 ± 9%, all patients were alive at a median follow-up of 8.2 years. Five-year progression-free survival was 88 ± 13% for patients undergoing gross-total resection and 34 ± 11% for those undergoing all other therapies, respectively (p = 0.02). Chemotherapy and radiation therapy showed similar efficacy, achieving sustained tumor control in most patients. However, this excellent survival rate was associated with an 83% rate of significant neurological and orthopedic sequelae.
This study provides basic data on the incidence, clinical course, and outcome of spinal cord LGGs in pediatric patients. The similarities between spinal and intracranial LGGs in pediatric patients showing excellent survival but high morbidity suggest that a less aggressive approach may be the preferable treatment option for these patients.
Lucie Lafay-Cousin, Donald J. Mabbott, William Halliday, Michael D. Taylor, Uri Tabori, Ian D. Kamaly-Asl, Abhaya V. Kulkarni, Ute Bartels, Mark Greenberg, and Eric Bouffet
Choroid plexus carcinomas (CPCs) are rare pediatric tumors with a generally poor prognosis. Although the role of surgery is well recognized, the role of adjuvant chemotherapy and radiation therapy remains unclear. In this paper, the authors' goal was to assess the role of second-look surgery and neoadjuvant ifosfamide, carboplatin, etoposide (ICE) chemotherapy in the management of CPC and to study neurocognitive outcome.
The authors performed an institutional retrospective review of patients in whom CPC was diagnosed between 1985 and 2006 at the Hospital for Sick Children in Toronto. Fourteen patients (7 boys and 7 girls) were included. The median age at diagnosis was 18.6 months (range 1.1–65.3 months). Four patients had evidence of metastatic disease at diagnosis. Two of the 14 patients underwent gross-total resection during initial surgery; 12 of the patients received neoadjuvant chemotherapy, 10 of whom underwent second surgery. In total, of 12 patients who received chemotherapy with a curative intent, 11 underwent a greater than 95% resection. Neoadjuvant ICE chemotherapy was given prior to second surgery (median 4 cycles, range 2–5 cycles) and was continued after second resection for a median total of 7 cycles (range 4–16 cycles).
No tumor progression was observed during chemotherapy prior to second surgery. Five patients subsequently experienced tumor progression/relapse. At a median follow-up of 6.9 years (range 1.9–18.5 years), 8 patients are alive. None of the survivors received radiation therapy. However, 6 of 8 display significant neurocognitive and/or sensorial deficit.
In this experience, second surgery following neoadjuvant ICE chemotherapy led to a high rate of complete or near-complete resection. Chemotherapy appears to facilitate second-look surgery, in particular through a reduction of intraoperative blood loss. Despite radiation avoidance, the majority of survivors experienced significant neurocognitive impairment.
Iska Moxon-Emre, Eric Bouffet, Michael D. Taylor, Normand Laperriere, Michael B. Sharpe, Suzanne Laughlin, Ute Bartels, Nadia Scantlebury, Nicole Law, David Malkin, Jovanka Skocic, Logan Richard, and Donald J. Mabbott
Craniospinal irradiation damages the white matter in children treated for medulloblastoma, but the treatment-intensity effects are unclear. In a cross-sectional retrospective study, the effects of treatment with the least intensive radiation protocol versus protocols that delivered more radiation to the brain, in addition to the effects of continuous radiation dose, on white matter architecture were evaluated.
Diffusion tensor imaging was used to assess fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity. First, regional white matter analyses and tract-based spatial statistics were conducted in 34 medulloblastoma patients and 38 healthy controls. Patients were stratified according to those treated with 1) the least intensive radiation protocol, specifically reduced-dose craniospinal irradiation plus a boost to the tumor bed only (n = 17), or 2) any other dose and boost combination that delivered more radiation to the brain, which was also termed the “all-other-treatments” group (n = 17), and comprised patients treated with standard-dose craniospinal irradiation plus a posterior fossa boost, standard-dose craniospinal irradiation plus a tumor bed boost, or reduced-dose craniospinal irradiation plus a posterior fossa boost. Second, voxel-wise dose-distribution analyses were conducted on a separate cohort of medulloblastoma patients (n = 15).
The all-other-treatments group, but not the reduced-dose craniospinal irradiation plus tumor bed group, had lower fractional anisotropy and higher radial diffusivity than controls in all brain regions (all p < 0.05). The reduced-dose craniospinal irradiation plus tumor bed boost group had higher fractional anisotropy (p = 0.05) and lower radial diffusivity (p = 0.04) in the temporal region, and higher fractional anisotropy in the frontal region (p = 0.04), than the all-other-treatments group. Linear mixed-effects modeling revealed that the dose and age at diagnosis together 1) better predicted fractional anisotropy in the temporal region than models with either alone (p < 0.005), but 2) did not better predict fractional anisotropy in comparison with dose alone in the occipital region (p > 0.05).
Together, the results show that white matter damage has a clear association with increasing radiation dose, and that treatment with reduced-dose craniospinal irradiation plus tumor bed boost appears to preserve white matter in some brain regions.