Anna J. Janss

Incidence, Risks, and Sequelae of Posterior Fossa Syndrome in Pediatric Medulloblastoma

PURPOSE To investigate the incidence, risks, severity, and sequelae of posterior fossa syndrome (PFS) in children with medulloblastoma. METHODS AND MATERIALS Between 1990 and 2007, 63 children with medulloblastoma at Emory University and Childrens Healthcare of Atlanta were treated with craniectomy followed by radiation. Fifty-one patients were assigned to a standard-risk group, and 12 patients were assigned to a high-risk group. Five patients had <1.5-cm(2) residual tumor, 4 had >or=1.5-cm(2) residual tumor, and the remainder had no residual tumor. Eleven patients had disseminated disease. Patients received craniospinal irradiation at a typical dose of 23.4 Gy or 36 Gy for standard- or high-risk disease, respectively. The posterior fossa was given a total dose of 54 or 55.8 Gy. Nearly all patients received chemotherapy following cooperative group protocols. RESULTS Median follow-up was 7 years. PFS developed in 18 patients (29%). On univariate analysis, brainstem invasion, midline tumor location, younger age, and the absence of radiographic residual tumor were found to be predictors of PFS; the last two variables remained significant on multivariate analysis. From 1990 to 2000 and from 2001 to 2007, the proportions of patients with no radiographic residual tumor were 77% and 94%, respectively. During the same eras, the proportions of patients with PFS were 17% and 39%. Only 4 patients had complete recovery at last follow-up. CONCLUSIONS The incidence of PFS increased in the latter study period and is proportional to more aggressive surgery. Children with midline tumors exhibiting brainstem invasion are at increased risk. With the increased incidence of PFS and the permanent morbidity in many patients, the risks and benefits of complete tumor removal in all patients need to be reexamined.

A phase II study of metronomic oral topotecan for recurrent childhood brain tumors

The prognosis for recurrent or refractory brain tumors in children is poor with conventional therapies. Topotecan is a topoisomerase I inhibitor with good central nervous system (CNS) penetration following oral administration. Increased efficacy of topotecan has been demonstrated with prolonged low‐dose daily treatment in pre‐clinical models. To investigate further this drug delivered orally in pediatric CNS malignancies, a phase II study in children with recurrent or refractory brain tumors was performed.

Diffuse leptomeningeal neuroepithelial tumor: 9 pediatric cases with chromosome 1p/19q deletion status and IDH1 (R132H) immunohistochemistry.

Leptomeningeal dissemination in children is typical of high-grade, and occasionally low-grade, neoplasms. Rare cases of widely disseminated oligodendroglia-like leptomeningeal tumors, sometimes with associated spinal cord lesions, have been described that respond to treatment and follow an indolent course. Whether these lesions represent an established tumor category or are a unique entity remains to be established. We present 9 pediatric cases of such diffuse leptomeningeal neuroepithelial tumors (DLNT), 8 with assessment of 2 common genetic alterations seen in oligodendrogliomas, 1p and 19q chromosomal deletions and isocitrate dehydrogenase-1 (IDH1) R132H mutations. Four patients were male and 5 female, with a mean age at presentation of 4 years (range, 2 to 7 y). All presented with signs of increased intracranial pressure and diffuse contrast enhancement of the leptomeninges by magnetic resonance imaging. Three had a cervical or upper thoracic spinal cord tumor, and another had a small cerebellar lesion. Leptomeningeal biopsies showed a thickened and fibrotic arachnoid infiltrated by monotonous cells with round nuclei and prominent perinuclear clearing. All cases were strongly immunoreactive for S100 protein, and most showed faint granular synaptophysin reactivity. Six of 8 cases showed deletions of chromosome arm 1p by fluorescence in situ hybridization, 2 of which also had loss of 19q. None of the lesions reacted with IDH1-R132H antibodies. Although the clinicopathologic features show overlap of these DLNT lesions with oligodendroglioma and extraventricular neurocytoma, they do not exactly match either one, suggesting that DLNTs are a distinct tumor entity.

Congenital glioblastoma: a clinicopathologic and genetic analysis.

Congenital central nervous system (CNS) tumors are uncommon, accounting for 1% of all childhood brain tumors. They present clinically either at birth or within the first 3 months. Glioblastoma (GBM) only rarely occurs congenitally and has not been fully characterized. We examined clinicopathologic features and genetic alterations of six congenital GBMs. Tumors were seen by neuroimaging as large, complex cerebral hemispheric masses. All showed classic GBM histopathology, including diffuse infiltration, dense cellularity, GFAP‐positivity, high mitotic activity, endothelial proliferation and pseudopalisading necrosis. Neurosurgical procedures and adjuvant therapies varied. Survivals ranged from 4 days to 7.5 years; two of the three long‐term survivors received chemotherapy, whereas the three short‐term survivors did not. Paraffin‐embedded tissue sections were used for FISH analysis of EGFR, chromosomes 9p21 (p16/CDKN2A) and 10q ( PTEN/DMBT1); sequencing of PTEN and TP53; and immunohistochemistry for EGFR and p53. We uncovered 10q deletions in two cases. No EGFR amplifications, 9p21 deletions, or mutations of TP53 or PTEN were noted; however, nuclear p53 immunoreactivity was strong in 5/6 cases. Tumors were either minimally immunoreactive (n = 3) or negative (n = 3) for EGFR. We conclude that congenital GBMs show highly variable survivals. They are genetically distinct from their adult counterparts and show a low frequency of known genetic alterations. Nonetheless, the strong nuclear expression of p53 in these and other pediatric GBMs could indicate that p53 dysregulation is important to tumorigenesis.

Successful Retreatment of a Child with a Refractory Brainstem Ganglioglioma with Vemurafenib.

A child with brainstem ganglioglioma underwent subtotal resection and focal radiation. Magnetic resonance imaging confirmed tumor progression 6 months later. Another partial resection revealed viable BRAF V600E‐positive residual tumor. Vemurafenib (660 mg/m2/dose) was administered twice daily, resulting in >70% tumor reduction with sustained clinical improvement for 1 year. Vemurafenib was then terminated, but significant tumor progression occurred 3 months later. Vemurafenib was restarted, resulting in partial response. Toxicities included Grade I pruritus and Grade II rash. Vemurafenib was effectively crushed and administered in solution via nasogastric tube. We demonstrate benefit from restarting vemurafenib therapy.

De novo germline TP53 mutation presenting with synchronous malignancies of the central nervous system

We present a case of a 14‐year‐old male with a germline TP53 mutation who presented with synchronous primitive neuroectodermal tumor and choroid plexus carcinoma. Identification of synchronous brain tumors prompted genetic testing for predisposition to malignancy. Within 5 months of presentation, the child developed widely metastatic alveolar rhabdomyosarcoma. Patient DNA sequencing showed a TP53 allele with a premature stop codon in the oligomerization/nuclear export signal (NES) domain (R342ter). The childs parents, younger brother, paternal grandparents, and maternal grandmother, are without history of malignancy. The patients brother tested negative for TP53 mutations. This case identifies a rare, de novo, germline TP53 mutation presenting with synchronous CNS malignancies and exhibiting a more fulminant course than typical cases of Li–Fraumeni syndrome. Pediatr Blood Cancer 2009; 53:1352–1354.

Seventeen-year-old adolescent with pituitary abscess

Abstract Pituitary abscess is a rare but potentially life-threatening infectious process. Diagnosis is challenging as symptoms are non-specific and signs of infection may be absent. We report the case of a previously healthy 17-year-old male who presented with worsening headaches, polyuria, polydipsia and no clinical signs of infection. On evaluation, he was found to have hypopituitarism with diabetes insipidus, hypothyroidism and adrenal insufficiency. An imaging study revealed a pituitary mass. He underwent transsphenoidal biopsy to rule out tumor. The abscess was drained transsphenoidally and he was treated with parental antibiotics. Magnetic resonance imaging one year later revealed a normal pituitary without any evidence of abscess or mass. He continues to require thyroid, adrenal and anti-diuretic hormone replacements. As with any pituitary lesion, prompt complete hypothalamic pituitary evaluation is essential to avoid potentially life-threatening consequences.

Clinical responses of patients with diffuse leptomeningeal glioneuronal tumors to chemotherapy

IntroductionDiffuse leptomeningeal glioneuronal tumors (DLGT) have been recognized in the most recent WHO classification as a distinct entity.ObjectiveWe describe seven pediatric cases of DLGT and the responses to therapy and outcome.MethodsWe conducted a retrospective review of charts from 1985 to 2013.ResultsDBS is an effective therapeutic modality for intractable TLE, particularly in patients with lateralized EEG A total of seven patients were identified. Median age at diagnosis was 3 years. Three months was the median time from symptom development to diagnosis. Common MRI findings included diffuse leptomeningeal thickening, nodularity, or coating of the subarachnoid or ependymal surfaces. The leptomeningeal lesions often appear cystic and contrast enhancement was variable. Six patients had leptomeningeal involvement of the brain and spine. All patients had a negative CSF cytology. Biopsies demonstrated thickened meninges infiltrated by a monotonous population of oligodendrocyte-like cells. Immunohistochemistry revealed variable features of neuronal and/or glial differentiation. All samples were negative for BRAF V600E mutation by immunohistochemistry. Therapy included one patient treated with craniospinal irradiation followed by vincristine, etoposide, cyclophosphamide, and cisplatin with stable disease for 164 months. Six patients received carboplatin and vincristine with a median duration of response of 20+ months (15–122+). Three patients received temozolomide upfront and progressed at 3, 4, and 27 months. No patients demonstrated complete or partial responses to any chemotherapy regimens. Progression-free survival ranged from 3 to 164+ months; 4/7 patients remained free of progression. All patients are alive.ConclusionsDLGT are rare tumors that lack imaging responses; however, there was clinical/ symptom improvement in 100% of the patients. A better understanding of the tumor biology is necessary to improve the diagnosis and treatment of this rare disease.

Successful treatment of a child with a prolactin secreting macroadenoma with temozolomide

Abstract Prolactinomas are a rare subset of brain tumors in pediatrics. We report a child with a prolactin secreting macroadenoma which was refractory to initial treatment with a dopamine antagonist. Given the location of her tumor she was ineligible for surgical resection. Temozolomide (200 mg/m2×5 days each month) was administered with a dramatic and prolonged response in tumor size, prolactin level, and symptoms, with no side effects from treatment. We demonstrate the benefit of temozolomide in the treatment of a pediatric patient with prolactinoma.

Pineal Region Tumors in Children

The pineal gland, located at the roof of the diencephalon, is a cone-shaped structure dorsal to the midbrain tectum. It is composed of a variety of cells, including astrocytes, ganglion cells, blood vessels, and pinocytes. Pineocytes, the parenchymal cells of this organ, are specialized neurons rich in monoaminergic neurotransmitters, including serotonin, norepinepherin, and melatonin. While retinal proteins such as S-antigen are expressed on some pineocytes, the pineal gland is not photosensitive in humans and higher primates. Collateral projections from the retino-thalamic tract as well as sympathetic fibers from the superior cervical ganglion innervate the pineal gland [3]. Its role in humans and higher primates is controversial, but likely related to synchronizing neuro-endocrine responses to sympathetic and circadian light-dark cycles [32].