My Journey.

This is the life story of Dr. Lucy B. Rorke-Adams, who was raised in the rural Midwest of the United States by Armenian immigrant parents during the Depression. The youngest in a family of five girls, she was lovingly nurtured by her parents and sisters. She was encouraged to become educated in order to lead a worthwhile life and contribute to society. She chose medicine, specifically the specialty of pediatric neuropathology, and over her long career succeeded in advancing the field. In particular, she made major contributions to understanding childhood brain tumors, central nervous system (CNS) malformations, and pathophysiology of abusive CNS injury in infants and children.

Childhood Optic Nerve Glioma: Vision Loss Due to Biopsy.

Two children without neurofibromatosis type 1 presented with unilateral decreased vision and MRI revealing optic nerve tumors. In the first case, chemotherapy was initiated empirically for presumed optic pathway glioma, but the lesion increased in size with associated clinical worsening, raising concern for a possible alternate diagnosis. Biopsy of the involved optic nerve resulted in worsening of vision due to a branch retinal artery occlusion and showed a grade I pilocytic astrocytoma. In the second case, sudden symptom onset and rapid tumor growth prompted an optic nerve biopsy, resulting in vision loss due to a central retinal artery occlusion and revealing grade I pilocytic astrocytoma. In both cases, tissue diagnosis did not alter the course of management. Instead, biopsy was associated with additional vision loss, highlighting the risk of biopsy in children with isolated optic nerve tumors and imaging that is most consistent with an optic pathway glioma.

Chromosome band 7q34 deletions resulting in KIAA1549-BRAF and FAM131B-BRAF fusions in pediatric low-grade Gliomas.

The majority of pediatric low-grade gliomas (LGGs) are characterized by constitutive activation of the mitogen-activated protein kinase (MAPK) pathway through various mechanisms including BRAF mutations, inactivation of NF1, and KIAA1549-BRAF and FAM131B-BRAF fusions. The KIAA1549-BRAF fusion typically results from a 2.0 Mb tandem duplication in chromosome band 7q34. In the present study, single nucleotide polymorphism (SNP)-based array analysis of three LGGs demonstrated deletions in 7q34 that resulted in a BRAF fusion. Case 1 was likely a pilocytic astrocytoma (PA) with three deletions in 7q33q34 and an exon 15-9 KIAA1549-BRAF fusion. SNP array analysis of case 2, a possible dysembryoplastic neuroepithelial tumor (DNT), revealed a 2.6 Mb deletion, which included the 5' end of BRAF and extended to the 3' end of FAM131B. In case 3, deletions involving BRAF and FAM131B were observed in both a primary and a recurrent PA. RNA-based sequence analysis of cases 2 and 3 confirmed a fusion between FAM131B exon 2 and BRAF exon 9. The presence of fusion transcripts in these three LGGs highlights the utility of SNP array analysis to identify deletions that are suggestive of fusion proteins. BRAF fusions can result from multiple non-overlapping deletions, suggesting various complex mechanisms of formation.

Clinical, pathologic, and mutational spectrum of dystroglycanopathy caused by LARGE mutations.

Dystroglycanopathies are a subtype of congenital muscular dystrophy of varying severity that can affect the brain and eyes, ranging from Walker-Warburg syndrome with severe brain malformation to milder congenital muscular dystrophy presentations with affected or normal cognition and later onset. Mutations in dystroglycanopathy genes affect a specific glycoepitope on α-dystroglycan; of the 14 genes implicated to date, LARGE encodes the glycosyltransferase that adds the final xylose and glucuronic acid, allowing α-dystroglycan to bind ligands, including laminin 211 and neurexin. Only 11 patients with LARGE mutations have been reported. We report the clinical, neuroimaging, and genetic features of 4 additional patients. We confirm that gross deletions and rearrangements are important mutational mechanisms for LARGE. The brain abnormalities overshadowed the initially mild muscle phenotype in all 4 patients. We present the first comprehensive postnatal neuropathology of the brain, spinal cord, and eyes of a patient with a homozygous LARGE mutation at Cys443. In this patient, polymicrogyria was the predominant cortical malformation; densely festooned polymicrogyria were overlaid by a continuous agyric surface. In view of the severity of these abnormalities, Cys443 may be a functionally important residue in the LARGE protein, whereas the mutation p.Glu509Lys of Patient 1 in this study may confer a milder phenotype. Overall, these results expand the clinical and genetic spectrum of dystroglycanopathy.

Diagnostic application of high resolution single nucleotide polymorphism array analysis for children with brain tumors.

Single nucleotide polymorphism (SNP) array analysis is currently used as a first tier test for pediatric brain tumors at The Children's Hospital of Philadelphia. The results from 100 consecutive patients are summarized in the present report. Eighty-seven percent of the tumors had at least one pathogenic copy number alteration. Nineteen of 56 low grade gliomas (LGGs) demonstrated a duplication in 7q34, which resulted in a KIAA1549-BRAF fusion. Chromosome band 7q34 deletions, which resulted in a FAM131B-BRAF fusion, were identified in one pilocytic astrocytoma (PA) and one dysembryoplastic neuroepithelial tumor (DNT). One ganglioglioma (GG) demonstrated a 6q23.3q26 deletion that was predicted to result in a MYB-QKI fusion. Gains of chromosomes 5, 6, 7, 11, and 20 were seen in a subset of LGGs. Monosomy 6, deletion of 9q and 10q, and an i(17)(q10) were each detected in the medulloblastomas (MBs). Deletions and regions of loss of heterozygosity that encompassed TP53, RB1, CDKN2A/B, CHEK2, NF1, and NF2 were identified in a variety of tumors, which led to a recommendation for germline testing. A BRAF p.Thr599dup or p.V600E mutation was identified by Sanger sequencing in one and five gliomas, respectively, and a somatic TP53 mutation was identified in a fibrillary astrocytoma. No TP53 hot-spot mutations were detected in the MBs. SNP array analysis of pediatric brain tumors can be combined with pathologic examination and molecular analyses to further refine diagnoses, offer more accurate prognostic assessments, and identify patients who should be referred for cancer risk assessment.

Varicella zoster virus pneumonitis and brainstem encephalitis without skin rash in an immunocompetent adult.

Varicella zoster virus (VZV) pneumonitis and brainstem encephalitis developed in an immunocompetent adult without rash. Chest computed tomography exhibited nodularity; lung biopsy revealed multinucleated giant cells, Cowdry A inclusions, VZV antigen, and DNA. Varicella zoster virus central nervous system disease was verified by cerebrospinal fluid (CSF) anti-VZV IgG antibody with reduced serum/CSF ratios.

Memoir: curiosity rewarded!

EDITORS' INTRODUCTION: The following reminiscence by Lucy Balian Rorke-Adams is the eighth autobiography in a series published in the Journal of Neuropathology and Experimental Neurology. These have been solicited from senior members of the neuropathology community who have been noted leaders and contributors to neuroscience and to the American Association of Neuropathologists (AANP) and have a historical perspective of the importance of neuropathology in diagnosis, education, and research. It is hoped that this series will entertain, enlighten, and present members of the AANP with a better sense of the legacy that we have inherited, as well as reintroduce our respected neuroscientists as humans having interesting lives filled with joys and sorrows and allow them to present their lives in their own words.MNH, RAS.

Optic pathway gliomas: neoplasms, not hamartomas.

IMPORTANCE: Optic pathway gliomas are an important neuro-ophthalmic cause of vision loss in children. Their management depends on whether they are considered neoplasms or hamartomas. OBJECTIVE: To outline the evidence that optic pathway gliomas are slowly growing neoplasms and not hamartomas. DESIGN: Review of relevant studies in the literature. SETTING: The authors are from a pediatric tertiary referral center. RESULTS: The growth patterns and histopathology of optic pathway gliomas are more consistent with those of neoplasms. Spontaneous regression, thought to be a characteristic of hamartomas, can be seen in neoplasms of other types as well as in optic pathway gliomas. Chemotherapy used in low-grade gliomas has been shown to halt or improve vision loss in optic pathway gliomas in many cases. CONCLUSIONS AND RELEVANCE: Optic pathway gliomas are not hamartomas but truly are neoplasms. Thus, patients should be followed up closely, and chemotherapies should be used when clinical progression occurs. Other more directed therapies will certainly be used in the future.

Phase II study of pre-irradiation chemotherapy for childhood intracranial ependymoma. Children's Cancer Group protocol 9942: a report from the Children's Oncology Group.

PURPOSE: Standard therapy for childhood intracranial ependymoma is maximal tumor resection followed by involved-field irradiation. Although not used routinely, chemotherapy has produced objective responses in ependymoma, both at recurrence and in infants. Because the presence of residual tumor following surgery is consistently associated with inferior outcome, the potential impact of pre-irradiation chemotherapy was investigated. METHODS: Between 1995 and 1999, the Children's Cancer Group undertook a Phase II trial of pre-irradiation chemotherapy in children 3-21 years of age with intracranial ependymoma and radiological evidence of post-operative residual tumor. RESULTS: Of 84 patients, 41 had residual tumor, and were given four cycles of cisplatin-based chemotherapy prior to irradiation. Of 35 patients fully evaluable for response to chemotherapy, 14 (40%) demonstrated complete response, 6 (17%) partial response, 10 (29%) minor response or stable disease, and 5 (14%) demonstrated progressive tumor growth. For the entire group, 5-year overall survival (OS) and event-free survival (EFS) was 71 ± 6%, and 57 ± 6%, respectively. The pre-irradiation chemotherapy group demonstrated EFS comparable to that of patients with no residual tumor who received irradiation alone (55 ± 8% vs. 58 ± 9%, P = 0.45). Any benefit of chemotherapy was restricted to patients with greater than 90% tumor resection. CONCLUSIONS: Children with near total resection of ependymoma may benefit from pre-irradiation chemotherapy. Patients with subtotal resection have inferior outcome despite responses to chemotherapy, and should be considered for second-look surgery prior to irradiation. Pediatr Blood Cancer 2012; 59: 1183-1189. © 2012 Wiley Periodicals, Inc.

A distinct Smoothened mutation causes severe cerebellar developmental defects and medulloblastoma in a novel transgenic mouse model.

Deregulated developmental processes in the cerebellum cause medulloblastoma, the most common pediatric brain malignancy. About 25 to 30% of cases are caused by mutations increasing the activity of the Sonic hedgehog (Shh) pathway, a critical mitogen in cerebellar development. The proto-oncogene Smoothened (Smo) is a key transducer of the Shh pathway. Activating mutations in Smo that lead to constitutive activity of the Shh pathway have been identified in human medulloblastoma. To understand the developmental and oncogenic effects of two closely positioned point mutations in Smo, we characterized NeuroD2-SmoA2 mice and compared them to NeuroD2-SmoA1 mice. While both SmoA1 and SmoA2 transgenes cause medulloblastoma with similar frequencies and timing, SmoA2 mice have severe aberrations in cerebellar development, whereas SmoA1 mice are largely normal during development. Intriguingly, neurologic function, as measured by specific tests, is normal in the SmoA2 mice despite extensive cerebellar dysplasia. We demonstrate how two nearly contiguous point mutations in the same domain of the encoded Smo protein can produce striking phenotypic differences in cerebellar development and organization in mice.

Meningiomas in children and adolescents: a meta-analysis of individual patient data.

BACKGROUND: The epidemiological, prognostic, and therapeutic features of child and adolescent meningioma are poorly defined. Clinical knowledge has been drawn from small case series and extrapolation from adult studies. This study was done to pool and analyse the clinical evidence on child and adolescent meningioma. METHODS: Searches of PubMed, Medline, and Embase identified 35 case series of child and adolescent meningioma completed over the past 21 years. Individual patient data were obtained from 30 studies via direct communication with investigators. Primary outcomes were relapse-free survival (RFS) and overall survival. Prognostic variables were extent of initial surgery, use of upfront radiotherapy, age, sex, presence of neurofibromatosis, tumour location, and tumour grade. RFS and overall survival were analysed using Kaplan-Meier survival curves and multivariable Cox regression models. FINDINGS: From a total of 677 children and adolescents with meningioma, 518 were eligible for RFS analysis and 547 for overall survival analysis. Multivariable analysis showed that patients who underwent initial gross-total resection had better RFS (hazard ratio 0·16, 95% CI 0·10-0·25; p<0·0001) and overall survival (0·21, 0·11-0·39; p<0·0001) than those who had subtotal resection. No significant benefit was seen for upfront radiotherapy in terms of RFS (0·59, 0·30-1·16; p=0·128) or overall survival (1·10, 0·53-2·28; p=0·791). Patients with neurofibromatosis type 2 (NF2) had worse RFS than those without neurofibromatosis (2·36, 1·23-4·51; p=0·010). There was a significant change in overall survival with time between patients with NF2 compared with those without neurofibromatosis (1·45, 1·09-1·92; p=0·011); although overall survival was initially better for patients with NF2 than for those without neurofibromatosis, overall survival at 10 years was worse for patients with NF2. Patients with WHO grade III tumours had worse RFS than those with WHO grade I (3·90, 2·10-7·26; p<0·0001) and grade II tumours (2·49, 1·11-5·56; p=0·027). INTERPRETATION: Extent of initial surgical resection is the strongest independent prognostic factor for child and adolescent meningioma. No benefit for upfront radiotherapy was noted. Hence, aggressive surgical management, to achieve gross-total resection, is the initial treatment of choice. In the event of a subtotal resection, repeat resection is recommended to achieve maximum extirpation. Close observation is warranted for patients who have a subtotal resection or who have WHO grade III tumours. Patients without neurofibromatosis should have a minimum 10-year follow-up, whereas patients with NF2 should be considered a special risk category, necessitating life-long follow-up. FUNDING: None.

Malignant rhabdoid tumors express stem cell factors, which relate to the expression of EZH2 and Id proteins.

Malignant rhabdoid tumors (MRTs) are highly aggressive pediatric tumors associated with loss of expression of SMARCB1, commonly occurring in the central nervous system [referred to as atypical teratoid/rhabdoid tumors (AT/RTs)] and in the kidney and soft tissues. Histologically, MRTs are characterized by immunohistochemical evidence of primitive neuroectodermal, mesenchymal, and epithelial differentiation. The ability of MRTs to differentiate along multiple lines, as evidenced by both histologic features and polyphenotypic immunohistochemical staining, and the proliferative nature of MRT cells are characteristics shared with the self-renewal and plasticity of embryonic stem cells (ES). To test the hypothesis that MRTs share similarities with ES, we used immunohistochemistry to evaluate the expression of various stem cell markers in a tissue microarray containing 26 AT/RTs and 16 non-central nervous system MRTs (NCMRTs). Staining intensity was scored as negative (0), low (1+), moderate (2+), and strong (3+) and was multiplied by the percentage of positive tumor cells to establish a semiquantitative measure for each marker. In AT/RT, strong-to-low expression was noted with glypican-3 (20 of 26, 77%), Sall4 (23 of 26, 88%), T-cell leukemia/lymphoma 1 (25 of 26, 96%), and undifferentiated embryonic cell transcription factor 1 (19 of 26, 73%). Markers that showed low expression in AT/RT were Sox2 (8 of 26, 31%), Nanog (7 of 26, 27%), Klf4 (10 of 26, 38%), Zfp206 (5 of 26, 19%), and musashi-1 (21 of 26, 81%). Similarly, in NCMRT, expression was noted with glypican-3 (12 of 16, 75%), Sall4 (13 of 16, 81%), T-cell leukemia/lymphoma 1 (16 of 16, 100%), undifferentiated embryonic cell transcription factor 1 (12 of 16, 75%), Sox2 (5 of 16, 31%), Nanog (8 of 16, 50%), Klf4 (8 of 16, 50%), Zfp206 (13 of 16, 81%), and musashi-1 (11 of 16, 75%). Placental alkaline phosphatase, Oct4, c-KIT, CD30, α-fetoprotein, and ß- -human chorionic gonadotrophin were not expressed in all cases. Markers that regulate the expression of stem cell transcription factors were also expressed in MRT. AT/RT cases showed expression of Id proteins: Id1 (17 of 26, 65%), Id2 (24 of 26, 92%), Id3 (22 of 26, 85%), and Id4 (22 of 26, 85%). Low expression was observed with EZH2 (15 of 26, 58%). Similarly, NCMRT cases showed expression of Id1 (15 of 16, 94%), Id2 (16 of 16, 100%), Id3 (16 of 16, 100%), Id4 (13 of 16, 81%), and EZH2 (13 of 16, 81%). Finally, regression analysis revealed a significant relationship between the expression of stem cell markers and EZH2 (P<0.0001), Id1 (P=0.0087), Id2 (P=0.0002), Id3 (P=0.0033), and Id4 (P<0.0001). These data suggest that MRTs express many stem cell-associated transcription factors, which may be regulated by the expression of EZH2 and the Id family of proteins. This study underscores similarities between MRTs and stem cells and may help elucidate common biologic pathways that could serve in advancing more effective therapeutic strategies to treat MRTs.

Neuropathology of vaccination in infants and children.

AIMS: Documentation of clinical-pathological features of 37 infants/children whose parents alleged a relationship between vaccination and death or permanent central nervous system (CNS) damage, and sought compensation through the National Vaccine Injury Compensation Program. SCOPE: Of the 5545 claims filed during the 10-year period (1990-1999), CNS tissue was available for evaluation by a pediatric neuropathologist in 37; 33 died and 4 had a biopsy or lobectomy. Most commonly implicated vaccines were DTP/DTaP, followed by MMR and IPV/OPV, but almost all of the vaccines currently given to infants/children were alleged to be responsible for the illness/death. No lesions were found in 5 of 37 (13.5%). The most frequent abnormality consisted of acute anoxic encephalopathy (14 of 37 - 37.8%), consequent to several different causes, such as positional asphyxia, cardio-respiratory arrest during status epilepticus, etc. The remaining children manifested other lesions, including inflammation (5 of 37 - 13.5%), vascular and developmental anomalies (4 each of 37 or 10.6%), cerebral edema and system degeneration (2 each of 37 or 5.4%), and one case of heavy metal exposure in a child living near an abandoned mine (2.2%). CONCLUSIONS: There was no obvious relationship between type of vaccine (or vaccines simultaneously administered) to time of onset of symptoms, nature of symptoms or the lesions found.

Ganglioglioma arising from dysplastic cortex.

We report the case of a child who presented at 3 months of age with complex partial seizures, a linear facial nevus, and magnetic resonance imaging (MRI) showing delayed myelination and thickened cortex in the left temporal, parietal, and occipital regions. A repeat 3Tesla MRI scan with and without contrast at 6 months again showed cortical dysplasia of the left hemisphere. No other abnormalities were seen. A third scan at 3 years 6 months showed a 2.5 cm, round, hyperintense lesion on both T(2) and T(1) sequences. The lesion and surrounding dysplastic cortex were resected. Palmini grade IIA dysplasia and a ganglioglioma were diagnosed. These findings suggest that cellular components of cortical dysplasias have oncogenic potential.

Eye findings in X-linked lymphoproliferative disorder.

BACKGROUND: X-linked lymphoproliferative disorder typically presents as an Epstein-Barr virus-specific immune defect with a poor prognosis. Herein we present the clinical and pathologic findings for the first known case of X-linked lymphoproliferative disorder with visual symptoms at initial presentation. METHODS: Retrospective chart review, clinicopathologic correlation (brain biopsy and postmortem brain and eye tissue), and literature review. RESULTS: An 18-year-old boy had a unique presentation of X-linked lymphoproliferative disorder with visual symptoms and retinal findings. He subsequently developed central nervous system vasculitis. He never had evidence of Epstein-Barr virus infection during his clinical course, but in situ hybridization was positive in scattered cells in the brain postmortem. Eye pathologic examination at autopsy showed ischemic changes, but no inflammation. CONCLUSION: When a young patient presents with cotton wool spots, a thorough workup must be done, and immunologic disorders should be considered in the differential diagnosis. X-linked lymphoproliferative disorder-associated eye findings may not always be associated with Epstein-Barr virus infection and, as demonstrated by this case, can be indicative of an underlying vasculitic process.

Head injury, diagnostic X-rays, and risk of medulloblastoma and primitive neuroectodermal tumor: a Children's Oncology Group study.

OBJECTIVE: A comprehensive case-control study was conducted to determine potential risk factors for medulloblastoma/primitive neuroectodermal tumor (PNET), a common brain tumor in children. This analysis evaluated possible associations between previous head injury and ionizing radiation exposure through diagnostic X-rays and medulloblastoma/PNET. METHODS: Mothers of 318 cases <6 years of age at diagnosis between 1991 and 1997 and registered with the Children's Oncology Group were interviewed. Mothers of 318 matching controls were selected through random digit dialing and interviewed. RESULTS: An association was not detected between previous head injury (OR: 0.78, 95% CI: 0.40-1.5) or head X-ray for any reason including head injury with medulloblastoma/PNET. A statistically non-significant excess of cases reported having an X-ray for reason other than head injury (OR 2.3, 95% CI 0.91-5.7). When cases that received an X-ray for a common symptom of medulloblastoma/PNET were considered unexposed this association weakened (OR: 1.3, 95% CI: 0.49-3.7). No dose-response relationship was observed. CONCLUSIONS: Head injury and exposure to diagnostic head X-rays were not associated with medulloblastoma/PNET in this study. Future studies should investigate all imaging procedures with ionizing radiation exposure including computed tomography scans and utilize radiation dose estimations.

Neck injuries in young pediatric homicide victims.

OBJECT: In this study, the authors estimate the prevalence of injuries to the soft tissue of the neck, cervical vertebrae, and cervical spinal cord among victims of abusive head trauma to better understand these injuries and their relationship to other pathophysiological findings commonly found in children with fatal abusive head trauma. METHODS: The population included all homicide victims 2 years of age and younger from the city of Philadelphia, Pennyslvania, who underwent a comprehensive postmortem examination at the Office of the Medical Examiner between 1995 and 2003. A retrospective review of all available postmortem records was performed, and data regarding numerous pathological findings, as well as the patient's clinical history and demographic information, were abstracted. Data were described using means and standard deviations for continuous variables, and frequency and ranges for categorical variables. Chi-square analyses were used to test for the association of neck injuries with different types of brain injury. RESULTS: The sample included 52 children, 41 (79%) of whom died of abusive head trauma. Of these, 29 (71%) had primary cervical cord injuries: in 21 there were parenchymal injuries, in 24 meningeal hemorrhages, and in 16, nerve root avulsion/dorsal root ganglion hemorrhage were evident. Six children with abusive head trauma had no evidence of an impact to the head, and all 6 had primary cervical spinal cord injury (SCI). No child had a spinal fracture. Six of 29 children (21%) with primary cervical SCIs had soft-tissue (ligamentous or muscular) injuries to the neck, and 14 (48%) had brainstem injuries. There was a significant association of primary cervical SCI with cerebral edema (p = 0.036) but not with hypoxia-ischemia, infarction, or herniation. CONCLUSIONS: Cervical SCI is a frequent but not universal finding in young children with fatal abusive head trauma. In the present study, parenchymal and/or root injury usually occurred without evidence of muscular or ligamentous damage, or of bone dislocation or fracture. Moreover, associated brainstem injuries were not always seen. Although there was a significant association of primary cervical cord injury with cerebral edema, there was no direct relationship to brainstem herniation, hypoxia-ischemia, or infarction. This suggests that cervical spinal trauma is only 1 factor in the pathogenesis of these lesions.