Central Nervous System Embryonal Tumors Research Articles

Isochromosome 17q, MYC amplification and large cell/anaplastic phenotype in a case of medullomyoblastoma with extracranial metastases

Medullomyoblastoma (MMB) is a rare variant of medulloblastoma, a member of the family of central nervous system (CNS) embryonal tumors. The outcome of standard therapy for CNS embryonal tumors is often unpredictable in the setting of MMB. Here, we present the clinical course and treatment of an almost 4-year-old girl with MMB that was characterized by MYC amplification, isochromosome 17q and large cell/anaplastic histopathology.

Molecular diagnostics of brain tumors

Knowledge about the molecular aberrations driving the development and progression of primary central nervous system tumors is steadily increasing, including recent discoveries of novel genetic aberrations in both pediatric and adult brain tumors, such as the frequent mutations in the isocitrate dehydrogenase 1 (IDH1) gene in diffuse gliomas or the aberrant activation of BRAF signaling in pilocytic astrocytomas. Importantly, evidence is accumulating that certain molecular changes are closely associated with therapy response and/or patient survival, thus making them attractive targets for molecular diagnostic testing aiming to improve treatment stratification and prognostic assessment of the individual patient. Prominent examples of molecular markers that have elicited substantial clinical interest are the association of MGMT promoter methylation with sensitivity to alkylating chemotherapy and longer survival in glioblastoma patients as well as the combined complete loss of chromosomal arms 1p and 19q as a powerful prognostic marker in patients with (oligodendro)glial tumors. Furthermore, assessment of the mutation status of IDH1, either by immunohistochemistry or by DNA sequencing, has been identified as a powerful diagnostic and prognostic marker in diffuse gliomas, while the detection of BRAF aberrations may facilitate the diagnosis of pilocytic astrocytomas [1]. Similarly, recent studies on embryonal central nervous system (CNS) tumors have shown that medulloblastomas can be molecularly subdivided into pathogenetically distinct subgroups based on mRNA profiles indicative of aberrant activation of different signaling pathways, such as the sonic hedgehog or wingless signaling cascades. Furthermore, several genetic and chromosomal markers have been identified that are closely linked to the survival of medulloblastoma patients, most notably amplification of MYC and MYCN, mutation/nuclear accumulation of bcatenin, copy number changes of chromosome 6, and aberrations of chromosome 17. Combined assessment of these markers allows for a greatly improved risk stratification of medulloblastoma patients that will likely be implemented into upcoming clinical trials. Moreover, characteristic molecular alterations have been identified for certain less common embryonal tumor entities, including mutation and loss of expression of SMARCB1 (INI1/ hSNF5) in atypical teratoid/rhabdoid tumors as well as focal amplification of a micro-RNA cluster at chromosome 19q13.42 in ependymoblastoma/embryonal tumor with abundant neuropil and true rosettes, respectively [2]. Traditionally, the classification and grading of brain tumors is based on the assessment of histopathological and immunohistochemical features under the light microscope according to the criteria defined in the World Health Organization (WHO) classification of tumors of the central nervous system. This morphological analysis, however, tells only ‘part of the story’ of a tumor. There is no problem as long as the information generated by the educated analysis of a histological slide (which is in fact a ‘systematic artifact’ created by fixation, further tissue processing, cutting and staining of tumor tissue) leads to a highly reproducible diagnosis that conveys the information required for the assessment of prognosis and therapeutic decision-making. However, the WHO criteria for typing and grading of tumors are not always precise, G. Reifenberger (&) Department of Neuropathology, Heinrich-Heine-University, Dusseldorf, Germany e-mail: reifenberger@med.uni-duesseldorf.de

Liposomal cytarabine for central nervous system embryonal tumors in children and young adults

To assess the tolerability and efficacy of liposomal cytarabine (LC), an encapsulated, sustained-release, intrathecal (IT) formulation of cytosine arabinoside, in de novo and relapsed central nervous system (CNS) embryonal tumors in children and young adults. We studied retrospectively all patients less than age 30 at our institution treated consecutively with LC for medulloblastoma (MB), primitive neuroectodermal tumor (PNET), and atypical teratoid rhabdoid tumor (ATRT). Seventeen patients received LC (2 mg/kg up to 50 mg, every 2 weeks to monthly) at diagnosis of high-risk CNS embryonal tumor (2 PNET, 3 ATRT) or relapse of MB (12 MB; 9 had leptomeningeal metastases). Sixteen patients received concurrent systemic chemotherapy. A total of 108 doses were administered (IT 82, intraventricular 26) with a mean of six (range 1-16) treatments per patient. Only three administrations were associated with adverse effects of arachnoiditis or headache. None developed malignant cerebrospinal fluid (CSF) cytology while receiving LC. All the six evaluable patients with malignant CSF cytology and treated with at least two doses cleared their CSF (mean 3 doses, range 1-5). Median overall survival in relapse patients was 9.1 months. Five patients (4 de novo and 1 relapsed) remain alive in complete remission for a median 26.8 months from first LC. Liposomal cytarabine is an easily administered, well-tolerated, and active drug in patients with high-risk embryonal neoplasms. One-third of our cohort remains in remission from otherwise fatal diagnoses. Our findings warrant a phase II trial of LC in newly diagnosed or recurrent CNS embryonal tumors.

Incidence of atypical teratoid/rhabdoid tumors in children

Atypical teratoid/rhabdoid tumors are highly malignant embryonal central nervous system (CNS) tumors that were defined as an entity in 1996. As compared with other malignant CNS tumors, their biological behavior is particularly aggressive, but patients may benefit from an intensified treatment. Atypical teratoid/rhabdoid tumors display a complex histomorphology, which renders them prone to misdiagnosis. They occur predominantly in young children, with an estimated prevalence of 1% to 2% among all pediatric CNS tumors. However, population-based data on the incidence of these tumors are not yet available. A nation-wide survey of malignant high-grade CNS tumors (World Health Organization grade III/IV), diagnosed in children (aged birth to 14 years) from 1996 to 2006 was conducted by the Austrian Brain Tumor Registry. A central histopathology review was performed including the assessment of SMARCB1 (INI1) protein status. A total of 311 newly diagnosed, malignant CNS tumors were included. Atypical teratoid/rhabdoid tumors constituted the sixth most common entity (6.1%), referring to an age-standardized incidence rate of 1.38 per 1,000,000 person-years in children. Peak incidence was found in the birth to 2 years age group, where they were as common as CNS primitive neuroectodermal tumors and medulloblastomas. A total of 47.4% of atypical teratoid/rhabdoid tumors were initially diagnosed, whereas 52.6% were retrospectively detected by the central review. The 5-year survival of atypical teratoid/rhabdoid tumor patients was 39.5%, with 66.7% in the correctly diagnosed group versus 15.0% in the not recognized group (P = .0469). Clinicians and pathologists should be aware of the high incidence of atypical teratoid/rhabdoid tumors in young children to optimize diagnostic and therapeutic management of patients with these tumors.

Embryonal tumor with abundant neuropil and true rosettes (ETANTR): a new distinctive variety of pediatric PNET: a case-based update

Embryonal central nervous system (CNS) tumors are currently classified into three types: medulloblastoma, atypical rhabdoid/teratoid tumors, and primitive neuroectodermal tumor (PNET). A distinctive subtype of PNET called "embryonal tumor with abundant neuropil and true rosettes" (ETANTR) was reported in 2000. ETANTR is a recently described variety of PNET that combines microscopic features of neuroblastoma and ependymoblastoma, demonstrating areas of fine fibrillary neuropil intermingled with cellular zones and ependymoblastic rosettes. It has been suggested that this neoplasm should be considered as a separate entity. ETANTR is an eminently pediatric tumor that has been reported exclusively in children younger than 4 years. A 9-month-old girl underwent subtotal resection of a brainstem neoplasm. A 23-month-old girl was submitted to surgery for a frontoparietal tumor. In both instances, the histopathological diagnosis confirmed ETANTR. Both children were treated with chemotherapy and one with radiotherapy. Death in both patients occurred after a mean period of 10 months. By reporting these two new instances of ETANTR, we want to contribute to the knowledge of this highly malignant CNS embryonal neoplasm that occurs only in young children, given its present lethal prognosis, the scarcity of reported cases, and the lack of treatment guidelines.

Infectious exposure in the first years of life and risk of central nervous system tumours in children: analysis of birth order, childcare attendance and seasonality of birth

Background:An infective, mostly viral basis has been found in different human cancers. To test the hypothesis of a possible infectious aetiology for central nervous system (CNS) tumours in children, we investigated the associations with proxy measures of exposure to infectious disease.Methods:In a large case–control study nested in the populations of Denmark, Norway, Sweden, and Finland of 4.4 million children, we studied the association of birth order and seasonal variation of birth with subsequent risk for CNS tumours. We identified 3983 children from the national cancer registries, and information on exposure was obtained from the high-quality national administrative health registries. We investigated the association between childcare attendance during the first 2 years of life and the risk for CNS tumours in a subset of Danish children with CNS tumours, using information from the Danish Childcare database.Results:We observed no association between birth order and risk of CNS tumours overall (odds ratio (OR) for second born or later born vs first born, 1.03; 95% confidence interval (CI), 0.96–1.10) or by histological subgroup, and children with CNS tumours did not show a seasonal variation of birth that was distinct from that of the background population. Childcare attendance compared with homecare showed a slightly increased OR (1.29; 95% CI, 0.90–1.86) for CNS tumours, with the highest risk observed in children attending a crèche. The strongest association was observed for embryonal CNS tumours. We found no effect of age at enrolment or duration of enrolment in childcare.Conclusion:These results do not support the hypothesis that the burden of exposure to infectious disease in early childhood has an important role in the aetiology of paediatric CNS tumours.

Central nervous system

Several different types of tumors, benign and malignant, have been identified in the central nervous system (CNS). The prognoses for these tumors are related to several factors, such as the age of the patient and the location and histology of the tumor. In adults, about half of all CNS tumors are malignant, whereas in pediatric patients, more than 75% are malignant. For most benign CNS tumors that require treatment, neurosurgeons can offer curative resections or at least provide significant relief from mass effect. Unfortunately, we still lack effective treatments for most primary and secondary malignant CNS tumors. However, the past decade has witnessed an explosion in the understanding of the early molecular events in malignant primary CNS tumors, and for the first time in history, oncologists are seeing that a plethora of new therapies targeting these molecular events are being tested in clinical trials. There is hope on the horizon for the fight against these deadly tumors. The distribution of CNS tumors by location has remained constant for numerous years. The majority of primary CNS tumors arise in the major cortical lobes. Twenty nine percent of primary CNS tumors arise from the dural meninges that encase the CNS structures. The vast majority of these are meningiomas, of which over 90% are benign. About 10% of primary CNS tumors are found in the sella turcica region, where the pituitary gland resides. Other much less common sites of primary CNS tumors include the pineal region, ventricular system, cerebellum, brain stem, cranial nerves, and spinal cord. The distribution of CNS tumors by histology has seen a slight increase in more malignant tumors over the past decade, possibly due to increased neuroimaging practices or environmental exposures. Arising from glial cells, gliomas represent over 36% of all primary CNS tumors and consist of astrocytomas, oligodendrogliomas, ependymomas, mixed gliomas, and neuroepithelial tumors. The benign meningiomas make up 32% of primary CNS tumors, followed by nerve sheath tumors and pituitary tumors. Primary CNS lymphomas, embryonal tumors, and craniopharyngiomas are uncommon. The most common gliomas are astrocytomas, and these tumors are typically classified by the World Health Organization (WHO) as Grades I through IV. Grade IV, the most malignant grade of astrocytoma, includes glioblastoma multiforme (GBM), the most common malignant primary CNS glioma in adults, which represents 51% of all CNS gliomas. GBM is unfortunately the most challenging to effectively treat and has the worst patient survival. This chapter is therefore primarily devoted to the current understanding of this topic. Here we describe the molecular and cellular events associated with malignant glioma initiation and progression. We also review the importance of glioma stem cell biology and tumor immunology in early gliomagenesis. In addition, we present a brief description of the most common malignant primary CNS glioma in pediatric patients - medulloblastoma, as well as familial cancer syndromes that include gliomas as part of the syndrome.

Mouse models of CNS embryonal tumors

Central nervous system (CNS) embryonal tumors are devastating cancers in children, consisting of medulloblastomas, CNS primitive neuroectodermal tumors, and atypical teratoid/rhabdoid tumors. One of the reasons that CNS embryonal tumors remain difficult to treat is their rarity, which makes conducting clinical trials for these tumors difficult. Recent advances of molecular biology have led us to identify molecular and genetic causality of brain tumors. Based on the genetic alterations found in humans, multiple models of human CNS embryonal tumors have been generated in genetically engineered mice. These mouse models are valuable tools for understanding brain tumor biology and discovering novel therapeutic targets and drugs. In this article, we review molecular and cytogenetic characteristics of human CNS embryonal tumors and corresponding mouse models that have been developed. These findings indicate that common genetic abnormalities are seen in variants of human CNS embryonal tumors, and multiple histological variants of these tumors can be generated from a single set of genetic abnormalities in mice. These data provide insight into the biology and classification of CNS embryonal tumors.

Ultrastructural evidence of ependymal differentiation in a genetically proven atypical teratoid/rhabdoid tumor

We describe a case of genetically proven atypical teratoid/rhabdoid tumor (ATRT), showing ultrastructural evidence of ependymal differentiation. Such differentiation has not been reported so far in ATRT. This finding supports the concept that ATRTs as the majority of central nervous system embryonal tumors may derive from an immature and pluripotent neuroectodermal cell capable of differentiating along multiple lineages.

Fanconi anemia and biallelic BRCA2 mutation diagnosed in a young child with an embryonal CNS tumor

Medulloblastoma, the most common pediatric malignant brain tumor often arises sporadically; however, in a subgroup of patients, there exist familial conditions such as Fanconi anemia with biallelic BRCA2 mutation that predispose patients to developing medulloblastoma. Biallelic inactivation of BRCA2 in Fanconi anemia has been previously described in only 11 patients with medulloblastoma in the literature to date. Here we report two siblings diagnosed with central nervous system embryonal tumors at an early age in association with biallelic BRCA2 inactivation, including the first reported case of a spinal cord primitive neuroectodermal tumor (PNET) in a BRCA2/FANCD1 kindred.

Carboplatin‐based primary chemotherapy for infants and young children with CNS tumors

A carboplatin-based chemotherapy regimen was used as primary postoperative therapy in infants with central nervous system (CNS) tumors to limit renal and ototoxicity and to target systemic exposure. Fifty-three patients aged <age 3 years with embryonal CNS tumor medulloblastoma (n = 20), ependymoma (EP, n = 21), choroid plexus carcinoma (CPCA, n = 5), and primitive embryonal neoplasms including atypical teratoid rhabdoid tumors (n = 7) were treated with cyclophosphamide, etoposide, and carboplatin. Radiation therapy was used only for residual disease at the end of chemotherapy or disease progression. The response rate after 2 cycles of chemotherapy was 34% (complete response, 13.8%; partial response, 20.7%). Myelosuppression was the dominant toxicity; 2 patients had toxic deaths related to thrombocytopenia with trauma. The 5-year overall survival (OS) was 49% +/- 7%, and the progression-free survival (PFS) was 31% +/- 7%, with a median follow-up of 11.4 years (range, 5.2-15.0 years). For medulloblastoma, the 5-year PFS was 26% +/- 9%; for EP it was 33% +/- 10%; for CPCA it was 80% +/- 18%; and for primitive neuroectodermal and atypical teratoid rhabdoid tumors it was 0%. Localized EP patients with gross total resection who did not undergo radiotherapy had a 5-year PFS of 57% +/- 17% and OS of 71% +/- 16%. Two patients developed late second malignancies; 1 was associated with germline p53 mutation. The results confirm that carboplatin has similar activity to cisplatin in otherwise similar regimens. Five-year survival data are comparable to those reported in other recent studies, including high-dose chemotherapy studies. Of note is the marked activity in CPCA and gross totally resected EP.

Efficacy and tolerability of intrathecal liposomal cytarabine for central nervous system embryonal tumors

2064 Background: Liposomal cytarabine (DepoCyt) is a sustained-release intrathecal (IT) preparation of cytarabine, formulated by encapsulating the drug in spherical aqueous chambers within a lipid matrix. While proven effective in lymphomatous meningitis, this drug has shown some activity in medulloblastoma (MB) with spinal metastases in limited pediatric phase I study. Methods: We reviewed all patients at our institution treated with liposomal cytarabine for primary central nervous system (CNS) embryonal tumors-MB, primitive neuroectodermal tumor (PNET), and atypical teratoid rhabdoid tumor (ATRT). Results: A cohort of 17 patients were treated with liposomal cytarabine at diagnosis of CNS embryonal tumor (2 PNET, 3 ATRT) or relapse (12 MB [7 average-risk, 5 high-risk]); nine had leptomeningeal metastases. Drug was dosed at 2 mg/kg up to 50, every 2 weeks to monthly, along with dexamethasone. Concurrent systemic chemotherapy was given in 16 patients. Median age at first dose was 10.8 years (range 0.9 to 27.9 years). A total of 102 doses were administered (lumbar IT 76, Ommaya intraventricular 36) with a mean of six treatments (range 1–16). Only three administrations were associated with adverse effects of arachnoiditis or headache; no dose reductions were required. Median overall survival from relapse was 11.8 months. All six evaluable patients with malignant cerebrospinal fluid (CSF) cytology and treated with at least two doses cleared their spinal fluid (mean 3 doses, range 1–5). No patient developed malignant CSF cytology while receiving liposomal cytarabine. Ten patients developed progressive disease and died, with only one later recurrence in the spinal fluid. Seven patients remain alive (4 initial and 3 relapse) with five in continuous complete remission (2 ATRT) for a median 13.7 months from first liposomal cytarabine. Conclusions: Liposomal cytarabine was well tolerated and easily administered. All patients with neoplastic meningitis cleared malignant cells from their spinal fluid after treatment with IT liposomal cytarabine and systemic chemotherapy. One-third of our cohort remains in remission from otherwise fatal diagnoses. Our findings warrant a phase II trial of liposomal cytarabine in newly diagnosed or recurrent CNS embryonal tumors. [Table: see text]

Embryonal Tumors With Abundant Neuropil and True Rosettes

Embryonal neoplasms of the central nervous system (CNS) generally arise in the early years of life and behave in a clinically aggressive manner, but vary somewhat in their microscopic appearance. Several groups have reported examples of an embryonal tumor with combined histologic features of ependymoblastoma and neuroblastoma, a lesion referred to as "embryonal tumor with abundant neuropil and true rosettes" (ETANTR). Herein, we present 22 new cases, and additional clinical follow-up on our 7 initially reported cases, to better define the histologic features and clinical behavior of this distinctive neoplasm. It affects infants and arises most often in cerebral cortex, the cerebellum and brainstem being less frequent sites. Unlike other embryonal tumors of the CNS, girls are more commonly affected than boys. On neuroimaging, the tumors appear as large, demarcated, solid masses featuring patchy or no contrast enhancement. Five of our cases (18%) were at least partly cystic. Distinctive microscopic features include a prominent background of mature neuropil punctuated by true rosettes formed of pseudo-stratified embryonal cells circumferentially disposed about a central lumen (true rosettes). Of the 25 cases with available follow-up, 19 patients have died, their median survival being 9 months. Performed on 2 cases, cytogenetic analysis revealed extra copies of chromosome 2 in both. We believe that the ETANTR represents a histologically distinctive form of CNS embryonal tumor.

Geographic risk modeling of childhood cancer relative to county-level crops, hazardous air pollutants and population density characteristics in Texas

BackgroundChildhood cancer has been linked to a variety of environmental factors, including agricultural activities, industrial pollutants and population mixing, but etiologic studies have often been inconclusive or inconsistent when considering specific cancer types. More specific exposure assessments are needed. It would be helpful to optimize future studies to incorporate knowledge of high-risk locations or geographic risk patterns. The objective of this study was to evaluate potential geographic risk patterns in Texas accounting for the possibility that multiple cancers may have similar geographic risks patterns.MethodsA spatio-temporal risk modeling approach was used, whereby 19 childhood cancer types were modeled as potentially correlated within county-years. The standard morbidity ratios were modeled as functions of intensive crop production, intensive release of hazardous air pollutants, population density, and rapid population growth.ResultsThere was supportive evidence for elevated risks for germ cell tumors and "other" gliomas in areas of intense cropping and for hepatic tumors in areas of intense release of hazardous air pollutants. The risk for Hodgkin lymphoma appeared to be reduced in areas of rapidly growing population. Elevated spatial risks included four cancer histotypes, "other" leukemias, Central Nervous System (CNS) embryonal tumors, CNS other gliomas and hepatic tumors with greater than 95% likelihood of elevated risks in at least one county.ConclusionThe Bayesian implementation of the Multivariate Conditional Autoregressive model provided a flexible approach to the spatial modeling of multiple childhood cancer histotypes. The current study identified geographic factors supporting more focused studies of germ cell tumors and "other" gliomas in areas of intense cropping, hepatic cancer near Hazardous Air Pollutant (HAP) release facilities and specific locations with increased risks for CNS embryonal tumors and for "other" leukemias. Further study should be performed to evaluate potentially lower risk for Hodgkin lymphoma and malignant bone tumors in counties with rapidly growing population.

High‐dose chemotherapy with autologous stem cell transplantation in adults with recurrent embryonal tumors of the central nervous system

Embryonal central nervous system (CNS) tumors (medulloblastoma, cerebral neuroblastoma, pineoblastoma, and primitive neuroectodermal tumors) are rare in adults. Recurrent disease has an extremely poor outcome. The use of high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has demonstrated promising results in children with recurrent disease, but there are only limited data regarding its role in adults. The purpose of the current study was to evaluate adult patients with embryonal CNS tumors who were treated with HDC with ASCT and compare their outcomes with those of patients who received conventional-dose chemotherapy. The authors reviewed the medical records of 23 adult patients (age >or= 18 years) who were treated at the Mayo Clinic for recurrent embryonal CNS tumors between 1976 and 2004. The authors compared treatment with HDC with ASCT (10 patients) with an historic control of patients treated with conventional-dose chemotherapy (nitrosourea based, cisplatin based, or both) (13 patients). HDC with ASCT was associated with increased survival (P= .044) and a longer time to disease progression (TTP) (P= .028). The conventional-dose chemotherapy group had a median TTP of 0.58 years and a median survival of 2.00 years. The HDC with ASCT group had a median TTP of 1.25 years and a median survival of 3.47 years. When restricted to patients receiving ASCT after first disease recurrence, the median TTP was 2.5 years and the median survival was 4.16 years. Toxicities were similar in both groups. Improvements in the median TTP and survival noted with the administration of HDC with ASCT, as well as the acceptable toxicity of this regimen, supports consideration of its use in adults with recurrent embryonal CNS tumors.

Hedgehog Signaling Promotes Medulloblastoma Survival via BclII

Activation of the Hedgehog (Hh) pathway has been identified in several cancers, including medulloblastoma, but the mechanisms by which this pathway affects tumor survival and growth are incompletely understood. We investigated whether Hedgehog might promote survival of medulloblastoma cells via up-regulation of BclII. We found that mRNA levels of the Hedgehog pathway effector Gli1 were significantly associated with BclII expression in medulloblastoma and that Gli1 and BclII are both present in regions of decreased apoptosis in nodular medulloblastoma. Transient overexpression of Gli1 and Gli2 in medulloblastoma cultures induced a BclII transcriptional reporter and increased BclII protein levels, whereas stable overexpression of Gli1 was associated with increased BclII mRNA. The Hedgehog antagonist cyclopamine blocked expression of the Hh pathway targets PTCH1 and Gli1, lowered BclII levels, and increased apoptosis in DAOY and UW228 medulloblastoma cells. Apoptotic induction caused by cyclopamine could be rescued in part by enforced expression of Gli1 or BclII. Hh pathway blockade also sensitized medulloblastoma to the effects of the proapoptotic agent lovastatin. These data demonstrate that BclII is an important mediator of Hh activity in medulloblastoma and suggest new strategies for combined chemotherapeutic regimens.

Immunohistochemical Analysis of INI1 Protein in Malignant Pediatric CNS Tumors: Lack of INI1 in Atypical Teratoid/Rhabdoid Tumors and in a Fraction of Primitive Neuroectodermal Tumors without Rhabdoid Phenotype

Immunohistochemical lack of nuclear INI1 protein expression has been recently described as characteristic finding in atypical teratoid/rhabdoid tumors (AT/RTs), and has been suggested as useful marker to distinguish AT/RTs from other malignant pediatric central nervous system (CNS) tumors. In this study, we examined a large series of malignant pediatric CNS tumors to determine the immunohistochemical expression of INI1 protein in different malignant pediatric tumor entities. Archival paraffin-embedded biopsy specimens of 289 malignant pediatric CNS tumors including medulloblastomas, supratentorial primitive neuroectodermal tumors, glioblastomas, anaplastic astrocytomas, anaplastic ependymomas, choroid plexus carcinomas, germ cell tumors, and AT/RTs were analyzed immunohistochemically for expression of nuclear INI1 protein. Positive INI1 staining was observed in 263 tumors. Lack of INI1 protein was detectable in 26 tumors. Seventeen of the 26 tumors showed morphologically characteristic features of AT/RTs, whereas 9 embryonal tumors did not display rhabdoid features. Tumors without rhabdoid phenotype but lack of INI1 showed an aggressive clinical course and poor response to conventional treatment regimens. In summary, immunohistochemical expression of INI1 protein is lacking in tumors displaying characteristic morphologic features of AT/RT. Furthermore, a certain number of embryonal tumors without rhabdoid features but lack of INI1 protein and aggressive biologic behavior can be detected. We conclude that INI1 protein analysis should be routinely performed in all malignant pediatric embryonal CNS tumors to detect cases with lack of INI1 protein, because patients with these tumors are likely to benefit from intensified treatment.

Late Relapse of Pediatric Medulloblastoma

Medulloblastoma (MB), the most common malignant brain tumor of childhood, is classified according to pathomorphologic characteristics in the group of central nervous system embryonal tumors, but both its pathogenesis and biologic behavior remain unknown. In addition, the relationship of MB to other embryonal brain tumors is debated and response to therapy is difficult to predict. The authors report an uncommon case of unfavorable late relapse, local as well as distant, in a 26-year old male patient, who was free of disease and without treatment-related morbidity for fifteen years after combined therapy for pediatric MB.

Chromosome 17 Abnormalities in Pediatric Neuroblastic Tumor With Abundant Neuropil and True Rosettes

Although as a group, embryonal central nervous system tumors share a common background of primitive round cells, numerous distinctive histologic features allow for further subclassification. One tumor with a unique microscopic appearance is the recently described pediatric neuroblastic tumor with abundant neuropil and true rosettes (PNTANTR). We report 2 additional cases of this unusual tumor; both arose in 4-year-old children, one a midpontine tumor and the other a large cerebral lesion. The tumors contained hypercellular sheets of undifferentiated cells, broad zones of neuropil, and scattered perivascular, Homer Wright, and multilayered ependymoblastic-like rosettes. Isochromosome 17q was detected in multiple samples from one tumor, while the other tumor showed polysomy 17. No deletions of INI1 or amplifications of MYC or MYCN were detected. This report adds 2 cases to our experience of PNTANTR and is the first to demonstrate isochromosome 17q, a molecular alteration typical of medulloblastomas.

Chromosome 17 Abnormalities in Pediatric Neuroblastic Tumor With Abundant Neuropil and True Rosettes

Although as a group, embryonal central nervous system tumors share a common background of primitive round cells, numerous distinctive histologic features allow for further subclassification. One tumor with a unique microscopic appearance is the recently described pediatric neuroblastic tumor with abundant neuropil and true rosettes (PNTANTR). We report 2 additional cases of this unusual tumor; both arose in 4-year-old children, one a midpontine tumor and the other a large cerebral lesion. The tumors contained hypercellular sheets of undifferentiated cells, broad zones of neuropil, and scattered perivascular, Homer Wright, and multilayered ependymoblastic-like rosettes. Isochromosome 17q was detected in multiple samples from one tumor, while the other tumor showed polysomy 17. No deletions of INI1 or amplifications of MYC or MYCN were detected. This report adds 2 cases to our experience of PNTANTR and is the first to demonstrate isochromosome 17q, a molecular alteration typical of medulloblastomas.