Skip to main content
NCBI home page
Neuro-Oncology logoLink to Neuro-Oncology
. 2012 Jun;14(Suppl 1):i43–i48. doi: 10.1093/neuonc/nos100

EPIDEMIOLOGY

PMCID: PMC3483346
Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-01. ETANTR-TUMOR WITH UNDEFINED BIOLOGY

Soumen Khatua 1, Robert Brown 2, Michael Pearlman 1, Tribhawan Vats 1

Abstract

Embryonal Tumors with Abundant Neuropil and True Rosettes (ETANTR) is a rare variant of a CNS tumor in children and to date less than 75 cases have been reported. The prognosis is dismal and the rarity of this tumor has precluded defining oncogenic signaling pathways and treatment guidelines. We describe a 5 year female who presented at 3 years of age with ptosis of the left eye. MRI showed a large left frontoparietal mass with extension into the ethmoidal and maxillary sinuses. A partial resection of the mass was performed and the pathology was consistent with ETANTR. She received chemotherapy with vincristine, methotrexate, cytoxan, cisplatin, topotecan. As tumor continued to progress she received radiation therapy and adjuvant chemotherapy with temozolomide, etoposide followed by cis-retinoic acid and melatonin for a year. We for the first time, performed molecular tumor profiling using morphoproteomic analysis by quantifying immunohistochemical signaling intensity of major pathways and biological markers in this biomorphic tumor which included medulloepitheliomatous (ME) and the neuroblastic (NB) component. Analysis of the upstream signal transducers, downstream effectors, cell cycle related analytes, antiapoptotic and stem cell markers were performed. We demonstrated constitutive activation of the ras/Raf kinase/ERK pathway as evidenced by the phosphoyrylated ERK 1,2 kinase more seen in the ME portion and the Akt /mTOR pathway both in the nuclear and cytoplasmic compartments of the tumor cells. Constitutive activation of the NF-kappaB pathway was also seen which is consistent with the convergent signaling from the AKT and ERK pathways which showed the likely role of these major pathways in the oncogenesis of this tumor. This preliminary data shows targeting these combined pathways along with careful selection of conventional therapy could improve the prognosis of these rare aggressive tumors and warrants further evaluation in future studies.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-02. ARE MEDULLOBLASTOMAS EXCEPTIONAL IN CHILDREN WITH DOWN SYNDROME? EVIDENCE FROM A 13-COUNTRY EPIDEMIOLOGICAL STUDY

Daniel Satge 1, Charles Stiller 2, Stefan Rutkowski 3, Andre O von Bueren 4, Brigitte Lacour 5, Danièle Sommelet 6, Motoi Nishi 7, Maura Massimino 8, Maria-Luisa Garré 9, Florencia Moreno 10, Henrik Hasle 11, Zsuzsanna Jakab 12, Mark Greenberg 13, Nicolas von der Weid 14, Claudia Kuehni 15, Oscar Zurriaga 16, Maria-Luisa Vicente 17, Rafael Peris-Bonet 18, Martin Benesch 19, Michel Vekemans 20, Sheena Sullivan 21, Christian Rickert 22

Abstract

As persons with Down syndrome (DS) have a unique tumor profile with a reduced frequency of solid tumors, we aimed at evaluating the distribution and frequency of specific types of brain tumors. Medulloblastomas, Central Nervous System Primitive Neuroectodermal Tumors (CNS-PNETs) and gliomas were collected from cancer registries or brain tumor registries in 13 countries of Europe, America, Asia and Oceania. The observed number of children with DS having medulloblastomas, CNS-PNETs or glial tumors was compared to the expected number. The number of DS children with each category of tumor, medulloblastomas, CNS-PNETs and gliomas was treated as a Poisson variable with 0.000884 times the number of tumor cases in that category. Among 8,043 neural tumors: 6,882 medulloblastomas and 1,161 CNS-PNETs, only one patient with DS had a medulloblastoma, while respectively 6.08 (p = 0.016) and 7.11 (p = 0.0066) children with DS were expected. Among 13,797 children with gliomas, 10 had DS, whereas 12.2 were expected. Children with DS seem specifically protected against primary neural cell embryonal tumors of the CNS, whereas gliomas seem to occur at the same frequency as in the general population. Since a protection against neuroblastoma, another neural cell embryonal tumor has been observed in DS, our data strengthens the idea that additional genetic material on the supernumerary chromosome 21 could protect against neural cell tumor development.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-03. HAZARDOUS AIR POLLUTANTS AND RISK OF CHILDHOOD CENTRAL NERVOUS SYSTEM TUMORS IN CALIFORNIA

Paul Graham Fisher 1, Julie Von Behren 2, David O Nelson 2, Peggy Reynolds 1

Abstract

PURPOSE: We examined the relationship of estimated perinatal exposures to hazardous air pollutants with respect to childhood CNS tumor risk in a large, ethnically diverse population-based sample. METHODS: Cases were selected from the California Cancer Registry, diagnosed in children ages 0 to 10 years, from 1996 through 2006. Using probabilistic record linkage (LinkPlus), we matched cases to California birth certificates. Four controls were matched to each case by birth date and gender. Maternal residential addresses at birth were geocoded. Estimated levels of hazardous air pollutants were assigned based on census tract using the Assessment System for Population Exposure Nationwide model (ASPEN), from the U.S. Environmental Protection Agency (EPA). For those variables identified in tree-based exploratory methods as important predictors, we estimated effect sizes by calculating odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression. RESULTS: 1028 cases and 4112 controls were analyzed. Half of cases occurred in Hispanic children. The most common tumors were the gliomas (n = 457; 291 low-grade and 166 high-grade) and medulloblastomas (n = 142), followed by PNET (n = 82) ependymomas (n = 82), and germ cell tumors (n = 21). Exploratory methods suggested no evidence for an overall increased risk for CNS tumors associated with residential levels of hazardous air pollutants during the perinatal period. There were, however, suggestions of increased risk for medulloblastoma (OR associated with total exposure score = 2.3, 95% CI = 1.3-4.3), PNET (OR for area exposure sources = 6.3, 95% CI = 2.3-17.5), and in germ cell tumors (OR for area exposure sources = 3.3, 95% CI = 1.1-13.9). CONCLUSIONS: While no overall increased risk for CNS tumors was observed in relationship to residential hazardous air pollutants, the increased risk noted in the poorly differentiated tumors medulloblastoma, PNET, and germ cell tumors underscores the importance of accounting for both the heterogeneity of CNS tumors and the complexity of data from air toxics models available from the EPA.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-04. DURATION OF SYMPTOMS PRIOR TO DIAGNOSIS IN PEDIATRIC BRAIN TUMORS IN JAPAN: IMPACT ON PROGNOSIS

Kohei Fukuoka 1, Takaaki Yanagisawa 1, Tomonari Suzuki 1, Tomoyuki Koga 2, Kenji Wakiya 2, Jyun-ichi Adachi 2, Kazuhiko Mishima 2, Takamitsu Fujimaki 2, Masao Matsutani 2, Ryo Nishikawa 2

Abstract

BACKGROUND: The initial presentation of brain tumors in children frequently mimics other more common and less serious conditions, resulting in diagnostic difficulty and a prolonged time to diagnosis. Delay in diagnosis can be associated with increased morbidity. There are some reports from Western countries analyzing the pre-diagnostic symptomatic interval (PSI) and its impact on prognosis. It remains unclear whether earlier diagnosis can contribute to better prognosis. There are few reports on this subject from Japan where neuroimagings, such as magnetic resonance imaging are available best in the world. OBJECT: To examine the PSI and its impact on prognosis in brain tumors in children. METHODS: Data was abstracted from the charts of 141 patients under 18 years presenting with brain tumor, treated in Saitama Medical University (from December 1993 to March 2007) and Saitama Medical University International Medical Center (from April 2007 to October 2011). RESULTS: The median age at diagnosis was 8.0 years (0 month to 17.3 years). The male to female ratio was 71:70. The pathological diagnosis was low grade glioma in 36, germ cell tumors in 34, ependymoma in 14, medulloblastoma in 13, brain stem tumor in 12 patients. The median PSI is 6.0 weeks (0 week to 204 weeks). There were no statistically differences on overall survival and progression free survival in the shorter PSI patients compared to the longer PSI patients. On both univariate and multivariate analysis, worse histological grading was statistically correlated with shorter PSI. CONCLUSIONS: PSI in this study was shorter than those described in previous studies. Shorter PSI was significantly associated with high grade tumors. Earlier diagnosis did not lead to better prognosis in brain tumors in children. We should seek other factors to improve outcome.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-05. THREE CHILDREN WITH BRAIN TUMORS AND CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY SYNDROME: HOW TO RECOGNIZE A TUMOR PREDISPOSITION SYNDROME?

Corrie Gidding 1, Jolanda Schieving 2, Pieter Wesseling 3, Marjolijn Ligtenberg 4, Nicoline Hoogerbrugge 4, Marjolijn Jongmans 4

Abstract

BACKGROUND: In children with cancer an underlying Tumor Predisposition Syndrome (TPS) may influence response to treatment and outcome. Early recognition may lead to better treatment options, avoidance of induction and early detection of second tumors. Additionally, family members can be advised about surveillance and prenatal diagnosis. TPS is not always easy to recognize. Therefore we developed a questionnaire to screen for TPS. We describe three patients and the questionnaire. MATERIALS AND METHODS: Three children with brain tumors and the TPS: Constitutional Mismatch Repair Deficiency syndrome (C-MMRD) are described. The questionnaire is based on literature study. RESULTS: Patient 1 developed two malignancies (Atypical Teratoid / Rhabdoid Tumor and NHL) before she was diagnosed with C-MMRD: which predisposes not only for brain tumors and hematological malignancies but also for colorectal cancer. Patient 2 and 3 are sisters. The diagnosis C-MMRD was made after both developed a Glioblastoma Multiforme. All three had pigmented skin lesions, a negative family history for malignancies, no NF-1 (pat 2 and 3), nor SMARCB1 (pat 1) aberration. QUESTIONNAIRE: Many tumor predisposition syndromes are characterized by skin features as well as other associated abnormalities like congenital anomalies, growth disturbances, intellectual disability, and also with adult type tumors at young age. Therefore our questionnaire is based on the patients history, family history and the phenotype of the patient. At the end of the online questionnaire referral for genetic counseling is not only advised for children with more than one malignancy or a positive family history but also for patients with the above mentioned associated characteristics, for children with adult type tumors, and for children with tumor types that are highly associated with specific genetic syndromes or TPS. CONCLUSION: Recognition of C-MMRD only after 2 malignancies implies diagnostic delay. Early recognition is important and our questionnaire may provide this.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-06. A NATIONAL FEASIBILITY STUDY OF REAL-TIME CENTRAL PATHOLOGY REVIEW AND MOLECULAR DIAGNOSTICS FOR MEDULLOBLASTOMA

Stephen Crosier 1, Sarah Leigh Nicholson 3, Keith Robson 2, Thomas Jacques 3, Stephen Wharton 4, Nick Bown 1, Antony Michalski 3, Barry Pizer 5, Steven Clifford 1

Abstract

The Children's Cancer and Leukaemia Group (CCLG) recently instigated a biological study to establish feasibility of rapid collection, consent, transportation and centralised molecular biological analysis of prognostic biomarkers, alongside central pathological review (CPR), from patients with medulloblastoma in the UK. This study established systems for participation in the forthcoming pan-European PNET5 MB clinical trial (commencing Autumn 2012), which will (i) stratify therapy according to risk defined by clinical, pathological and biological disease features, (ii) mandate submission of snap-frozen tumour material for biological testing. The study is based upon CCLG centres informing the study coordinator of newly diagnosed patients, consenting and submitting tissue for study. A target time-frame of 30 days post-surgery was set to undertake CPR and assess favourable (b-catenin status by immunohistochemistry) and high-risk (MYC/MYCN amplification by FISH) molecular biomarkers and return test outcomes to centres, prior to commencement of adjuvant therapy. To date (Feb 2009-Jan 2012), 90 patients have been registered from 16 CCLG centres. CPR and successful analysis of all biomarkers was achieved in 81% (73/90), with small sample size the most common cause of technical failure. Results were returned to centres within 28 days (mean); delayed submission from local to reference centre was the most common reason for exceeding the 30-day guideline. MYCN/MYC amplification was observed in 12 cases (13%), which would elevate them to ‘high-risk' status, while 4 favourable-risk b-catenin positive tumours were identified (4%). Histopathological sub-classification was modified in 8 (9%), indicating that CPR will influence risk-stratification in the trials setting. CPR and molecular diagnostics for medulloblastoma have been established for the UK, which will underpin forthcoming molecularly-driven clinical trials. Delayed sample submission and/or submission of small frozen tumour biopsies represent significant risks to successful analysis. Ongoing support from all trials centres will be essential to allow strong recruitment to these international trials.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-07. ANALYSIS OF CLUSTER OF DIFFERENTIATION (CD) MARKERS IN PEDIATRIC BRAIN TUMORS CAN BE USED AS A DIAGNOSTIC AND PROGNOSTIC TOOL

Emma Sanden 1, Edward Visse 1, Peter Siesjo 1, Anna Darabi 1

Abstract

BACKGROUND: Malignant pediatric brain tumors constitute a heterogeneic group of central nervous system tumors, and general markers of diagnosis and prognosis are not available. Recently, a panel of CD markers (CD15, CD24, CD29) was used to define increasing neural differentiation of embryonic stem cells. Although these CD markers have been associated with worse prognosis due to presence of tumor propagating cells, alterations in adhesion and migration in various cancer types, no studies of multiple CD markers in pediatric brain tumors have been performed. METHODS: We have collected tumors, including medulloblastomas (MB), ependymomas (EP) and juvenile astrocytomas, from >20 pediatric brain tumor patients. Frozen tumor sections and cultured tumor cells were stained for CD15, CD24 and CD29 and analyzed using fluorescence microscopy or flowcytometry. RESULTS: MB contained a mixture of cells with strong CD15 labeling inside vessels and cells with diffuse CD15 staining in the parenchyma of the tumor tissue. Cells strongly labeled with CD15 were also positive for the leukocyte marker CD45. The previously proposed association between CD15 expression and prognosis in MB could instead of reflecting abundance of tumor propagating cells depend on infiltrating immune cells. In low-grade pediatric tumors and EP, larger areas stained weakly for CD15 while few cells displayed strong staining. CD24 was expressed on the vast majority of cells in pediatric brain tumors, despite grade of malignancy. MB, however, displayed an intense and aberrant staining for CD24. Computerized image analysis of frozen tumor sections showed that proliferation of cells and the expression of CD29 correlated in a sub-group of MB. CONCLUSIONS: Our preliminary data show that CD15, CD24 and CD29 are differentially expressed in high- and low-malignant pediatric brain tumors in vivo. By defining the patterns of CD antigen expression in different pediatric tumors their relationship to biological behavior and thus prognosis can be established.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-08. A FAMILY-BASED PILOT STUDY OF DETOXIFICATION AND DNA REPAIR GENES AND THE RISK OF PEDIATRIC MEDULLOBLASTOMA

Darryl Nousome 1, Philip J Lupo 1, Michael E Scheurer 2

Abstract

INTRODUCTION: Although little is known about the etiology of medulloblastoma, studies suggest a genetic component to risk. Additionally, as the peak incidence occurs between 3 and 6 years of age, evaluating exposures that occur in utero may be critical. Important limitations of population-based epidemiological studies used to evaluate the genetic determinants of medulloblastoma are: 1) population stratification bias and 2) the inability to account for maternal genetic effects (a proxy for the intrauterine environment). An underutilized family-based approach in the epidemiology of medulloblastoma, the case-parent triad design, accounts for these limitations, while eliminating the need for a control group. Because of this, we are building a cohort of medulloblastoma case-parent triads and have conducted a pilot study to assess the role of detoxification and DNA repair genes on pediatric medulloblastoma risk. METHODS: Medulloblastoma case-parent triads (n = 27) were recruited from Texas Children's Hospital. DNA samples were genotyped using the Sequenom iPLEX MassARRAY for 23 candidate single nucleotide polymorphisms (SNPs) in 9 detoxification and 6 DNA repair genes. Log-linear modeling was used to examine associations between medulloblastoma and maternal and case genotypes. RESULTS: There were 6 variants where p < 0.10: maternal SNPs XPA rs1800975, XRCC1 rs25487, and EPHX1 rs1051740 and case SNPs APEX rs1130409, CYP1B1 rs1800440, and NAT2 rs1799930. The maternal genotype for EPHX1 rs1051740 (RR = 3.26 95% CI: 1.12-9.53, p = 0.01) and the case genotype for APEX1 rs1130409 (RR = 2.99, 95% CI: 0.96-9.31, p = 0.04) were associated with medulloblastoma. CONCLUSIONS: To our knowledge, this is the first assessment of maternal genetic effects and the risk of medulloblastoma. This study will inform our future analyses as we continue to build a cohort of medulloblastoma case-parent triads for the assessment of maternal and case genetic effects. Additionally, our results provide preliminary evidence that pediatric medulloblastoma risk is influenced by genetic variation in DNA repair and detoxification genes.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-09. PREGNANCY OUTCOME AND CHILD NEURODEVELOPMENT FOLLOWING IN UTERO EXPOSURE TO TREATMENT FOR MATERNAL CANCER

Irena Nulman 1, Maru Barrera 1, Cynthia Maxwell 3, Gideon Koren 1

Abstract

INTRODUCTION: With delayed childbearing, the incidence of cancer in pregnancy will continue to increase. Prenatal cancer creates a conflict between optimal maternal management and fetal safety. Currently, limited data exists on cancer-complicated pregnancy outcomes and management guidelines are inconsistent. This report outlines existing knowledge of perinatal cancer and presents pediatric and neurodevelopmental outcomes of children exposed in utero to maternal malignancy. METHODS: Under the Canadian Consortium of Cancer in Pregnancy Evidence (CCoPE), twenty-four children prenatally exposed to maternal malignancy were assessed at Motherisk. Information on maternal malignancy, its treatment, and obstetric and pediatric outcomes was documented. Children's neurodevelopment was assessed using standardized psychological tests. Descriptive and inferential statistical analyses were used. RESULTS: Fifteen children were exposed to chemotherapy and/or radiation. Nine children exposed to maternal cancer or surgery served as controls. Children's ages ranged from three to twelve years. When compared to treatment-exposed children, control children presented with shorter gestations (37.2 weeks vs. 35.2 weeks) and lower birth weights (3115 grams vs. 2600 grams). Children from both groups were similar in their developmental milestones and anthropometric measurements at testing. There were no statistically significant group differences in children's Full-scale, Verbal, and Performance IQs (105vs104; 106vs.104; and 98vs.101) or CBCL scores. DISCUSSION: Exposure to chemotherapy or maternal malignancy did not adversely affect children's long-term neurodevelopment, which fell within population norms. All children achieved normal physical milestones at time of testing. Shorter gestations and low birth weights in the control group were due to planned deliveries in order to start treatment. Iatrogenic prematurity, which is associated with increased child morbidity and mortality, should be minimized. These reported results are reassuring and should be considered when weighing the benefits of timely versus postponed maternal treatment. More research is needed to support these results and ensure optimal maternal treatment and fetal safety.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-10. BRAIN TUMORS IN INFANTS: A REPORT ON 103 CASES

Serge Gorelyshev 1, Kaspot Matuev 1, Andrey Lubnin 1, Mikhail Laskov 2, Natali Lemeneva 1, Nadezhda Mazerkina 1, Elena Khuhlaeva 1

Abstract

Brain tumors are rare in infants, still can be challenging to be treated surgically and late outcomes are far from being satisfactory. 103 infants with intracranial tumors were treated at the Burdenko Neurosurgical Institute from 2000 to 2010 (4% of all children operated during the same time). Dermoid cysts and other skull base lesions were excluded from this study. Supratentorial tumors occurred most frequently (87 cases), while subtentorial tumors were revealed more rare (16 cases). The most preferred histology was glioma (26%) and choroid plexus tumor (26%), followed by ependymoma (14%), glioneuronal tumors (9%), PNET (7%), teratoma (6%), ATRT (4%), and pineoblastoma (4%). Surgical removal of tumors was performed in 81 (78.6%) infants, CSF shunting - in 11 (10.7%), and stereotactic radiosurgery in 1 patient. In 10 (9.7%) patients surgical treatment was not performed due to the giant size of tumors. Total removal was performed in 58 (71.6%) cases, subtotal - in 11 (13.6%), partial - in 9 (11.1%), biopsy - in 3 (3.7%). 4 intraoperative and 3 early postoperative deaths occurred (8.6%). In 27 (33.3%) cases giant and/or highly vascularized tumors were imaged. Preoperative embolization of afferent vessels and intraoperative injection of recombinant factor VIIa (rFVIIa) as well as other methods significantly reduced blood loss during surgical removal of the tumor. Histology is known in 81 operated infant. Tumors Gr II-IV were revealed in 60 patients, tumors Gr I - in 21 patient. Chemotherapy was given according to different chemotherapeutic protocols (HIT SKK 2000, SIOP 2000/LGG, Baby-POG). During the follow-up period 10 deaths (12%) were recorded in the group of operated infants. The overall mortality for the whole group is 20%. We conclude that radical removal of brain tumors in infants including giant and/or highly vascularized tumors is possible. The appropriate adjuvant therapy may remarkably improve the long term results.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-11. WHAT‘S IN A PNET? PRIMARY INTRACRANIAL P-PNET AND CNS-PNET ARE NOT THE SAME - AN EXTREMELY RARE BUT INSIDIOUS PITFALL IN THE RADIO-THERAPEUTIC MANAGEMENT OF PEDIATRIC BRAIN TUMORS

Klaus Müller 1, Frank Bruns 2, Torsten Pietsch 3, Stefan Rutkowski 4, Rolf-Dieter Kortmann 1

Abstract

Primary intracranial peripheral primitive neuroectodermal tumor (p-PNET) of the Ewing tumor family is extremely rare. According to the best of our knowledge less than thirty cases have been published to date. In the busy everyday of oncological care primary intracranial p-PNET can easily be confused with the much more frequent central nervous system primitive neuroectodermal tumor (CNS-PNET). Moreover the histopathological distinction may be challenging because both entities consist of undifferentiated small round cells and cannot be distinguished under the microscope without further immunohistochemical or genetic analyses. According to the accepted thought however, the correct histopathological diagnosis is crucial for the appropriate radio-therapeutic management because primary intracranial p-PNET and CNS-PNET are said to depict different clinical courses and to require different treatment strategies. For primary intracranial p-PNET local irradiation is recommended whereas CNS-PNET requires irradiation of the cranio-spinal axis with a focal boost to the tumor site. While recommendations for chemotherapy are established for CNS-PNET, little is known about chemotherapy for intracranial p-PNET. Here we present a case of pediatric primary intracranial p-PNET of the Ewing tumor family in a 5 year old boy, comment on its specific immunohistochemical and genetic features and finally discuss its appropriate radio-therapeutic management having searched the sparse literature for the evidence of the currently recommended treatment concept: We identified and assessed twenty-seven case reports of primary intracranial p-PNET published between 1996 and 2011. After a median follow-up time of 1,1 years (range 0 to 20 years) 3 patients died. 10-year overall survival was 79 ± 11%. In 17/27 cases (63%) radio-therapeutic and in 16/27 cases (59%) chemo-therapeutic treatments were reported.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-12. DETAILED DEMOGRAPHIC PROFILE OF MOLECULAR SUBTYPES OF INDIAN MEDULLOBLASTOMA PATIENTS

Rahul Krishnatry 1, Neelam Shirsat 2, Ratika Kunder 2, Sridhar Epari 1, Tejpal Gupta 1, Purna Kurkure 1, Tushar Vora 1, B Arora 1, Alisagar Moiyadi 1, Rakesh Jalali 1

Abstract

AIM: To discuss the detailed demographic profiles of various molecular subtypes in Indian meduloblastoma patients. METHODS: The molecular sub-typing for 78 consecutive patients of medulloblastoma presenting at a single institute neuro-oncology clinic (2003-11) was done by mRNA expression levels of select set marker genes using real time RT-PCR. The demographic details of these patients including age, sex and histological type were obtained from electronically maintained prospective database and analysed using descriptive statistics. RESULTS: The mean age at presentation was 10.8yrs (median-8.5; range1-45) with 12% infants(0-3yrs), 71% children (4-15yrs) and 17% adults(>15yrs). Males were predominant with only 24 females (30.8%). The most common histology was classical 66(84.6%) followed by 6 desmoplastic & 6 anaplastic types. On molecular subtyping there were 18(23%) WNT, 20(25.6%) SHH, 13(16.7%) C and 27(34.6%) D. The mean (median; range) age in various molecular subtypes were 15 yrs(10;7-45) WNT, 13yrs(8;1-36)SHH, 5.6yrs(5;2-11) C and 8.6yrs(8.5;3-21) D. In infants 44% were SHH and C type each, with 12% D. In children 43% were D, 23% WNT, 18% C and 16% SHH. In adults 54% were SHH, 38.5% WNT and 7.5% D. There were no infants in WNT and none > 11 yrs in C. There was a bimodal age distribution of 1-10 yrs(50%) and 20-36 yrs(50%) in SHH. Out of 24 females in total 38% were SHH, 33% WNT, 21% C and 8% D. The male were more common in all subgroups. All patients were of classical histology in WNT; 25% were desmoplastic & 10% anaplastic in SHH; 31% anaplastic in C and only one patient desmoplastic in D; rest all being classical. CONCLUSION: The demographic profiles of Indian medulloblastoma is similar to described in western literature; except that various age of presentation in all subgroups is older by 2-3 years and males are much more common than females.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-13. PRIMARY CNS TUMOURS IN CHILDREN AND ADOLESCENTS. OWN EXPERIENCE.

Ewa Swieszkowska 1, Bozenna Dembowska-Baginska 1, Monika Drogosiewicz 1, Iwona Filipek 1, Marta Perek-Polnik 1, Wieslawa Grajkowska 2, Danuta Perek 1

Abstract

Adolescents aged 15-19 years with CNS tumours are a specific group of patients. Tumour epidemiology in this group is different than in younger children and there is scarce data on the treatment outcome in this population. The aim of our study was to describe distribution and treatment results of brain tumours in adolescents and younger children in our centre and depict the differences between the two age groups. MATERIAL AND METHODS: Out of 2420 pts with solid tumours treated in our department between 1998-2008 there were 2057pts< 15 yrs and 363pts>15 yrs of age. In the younger group CNS tumours constituted 32% whereas in adolescents 5.3%. Analysis of gender, tumour type distribution and treatment results in both groups was performed. RESULTS: Out of 913pts with CNS tumours 783pts(85.76%) were < 15yrs of age (430 boys, 354 girls) and 130pts(14.23%) were adolescents (72 boys, 58 girls). In children < 15 yrs of age 255pts(32.6%) had medulloblastoma/PNET, 142pts(18.1%) low-grade glioma and 95pts(12.1%) high-grade glioma. In patients > 15 years of age 29pts(22.3%) presented with high-grade glioma and 28pts(21.6%) medulloblastoma/PNET. 430pts(54.9%) from younger group, are alive, from 1.5yrs-14yr3m (median 8yrs 4m) from diagnosis. 71(54.6%) adolescent patients are alive from 1yr9 m to 13.5yrs (median 6yrs9m) from diagnosis. Treatment results of most common CNS tumours in adolescents and younger children are respectively as follows: high-grade glioma 15.3%vs27.3%, medulloblastoma/PNET 45.7%vs61.9%, intracranial germ cell tumours 69.6%vs78.4%, low-grade glioma 88.8%vs88.6%, ependymoma 73.3%vs64.4%, brain stem glioma 50%vs20.8%. CONCLUSIONS: Our analysis shows that CNS tumours were more frequent in children than in adolescents and that the most common malignant tumours in younger children and adolescent were medulloblastoma and high-grade glioma respectively. Adolescents with high-grade glioma, medulloblastoma/PNET and brain stem glioma had a worse outcome comparing to younger patients. Supported by The National Centre for Research and Development.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-14. INCIDENCE OF MEDULLOBLASTOMA IN CANADIAN CHILDREN

Donna Johnston 1, Janelle Cyr 1, Douglas Strother 2, Lucie Lafay-Cousin 2, Chris Fryer 3, Katrin Scheinemann 4, Anne-Sophie Carret 5, Adam Fleming 6, Valerie Larouche 7, Eric Bouffet 8

Abstract

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. It has been perceived by many Canadian pediatric oncologists that the number of children diagnosed with medulloblastoma has decreased over the past decade. For this reason the Canadian Pediatric Brain Tumor Consortium undertook an epidemiological survey to examine the yearly incidence of this disease in children in Canada. HYPOTHESIS: The incidence of medulloblastoma declined between the two time periods of 1990–2000 and 2001–2010. METHODS: All patients under the age of 18 years diagnosed with medulloblastoma from 1990-2010 inclusive were included. Data collected included date of diagnosis, age at diagnosis, gender, stage, pathology, treatment, recurrence, and current status. Analysis was done using SPSS. RESULTS: Data were obtained on 431 patients from 9 centers in Canada. Significantly more patients were diagnosed from 2001-2010 (56.6%) compared to 1990-2000 (p = 0.018). During the earlier period (1990-2000) the incidence per 100,000 population under the age of 14 was 29.1, and for the later period (2001-2010) was 39.8. For the entire study time period, the mean age at diagnosis was 6.6 years, and 60% of cases were male. The majority of cases were stage M0 (62%), with 12% M1, 7% M2, 16% M3 and 1% M4. Classic medulloblastoma was found in 61% of patients; of the remaining patients, 14% had anaplastic or large cell medulloblastoma, and 13% had medulloblastoma with extensive nodularity. 41% of patients were enrolled on a clinical trial, while 44% were not enrolled but treated according to a clinical trial. The majority (64.9%) of patients are still alive. CONCLUSIONS: Contrary to our hypothesis, the incidence of medulloblastoma increased significantly in the years 2001-2010 compared to 1990-2000. It will be prudent to obtain data from the other Canadian centers to ensure that this trend is not due to a redistribution of cases.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-15. WHAT IS THE REAL INCIDENCE OF PEDIATRIC BRAIN TUMORS? 10 YEAR EXPERIENCE OF THE GERMAN NATIONAL PEDIATRIC BRAIN TUMOR NETWORK HIT

Carsten Friedrich 1, Astrid K Gnekow 2, Gudrun Fleischhack 3, Christof M Kramm 4, Michael C Fruehwald 2, Hermann L Müller 5, Gabriele Calaminus 6, Uwe Kordes 1, Andreas Faldum 7, Torsten Pietsch 8, Monika Warmuth-Metz 9, Rolf D Kortmann 10, Irene Jung 11, Peter Kaatsch 11, Stefan Rutkowski 1

Abstract

BACKGROUND: The HIT-network was established in the year 2000 in Germany as a consortium of prospective nation-wide studies or registries with concerted central reference institutions for neuropathology, neuroradiology, CSF diagnostics, radiotherapy, and biometrics, aiming to improve diagnostic assessments, therapeutic recommendations, and ultimately the prognosis of children and adolescents with brain tumors. PROCEDURES: The numbers of patients registered from 2001-2010 with low-grade glioma (HIT-LGG 96, SIOP-LGG 04), high-grade glioma, pontine glioma (HIT-GBM-C/D, HIT-HGG 2008), medulloblastoma, CNS-PNET, pineoblastoma, ependymoma (HIT 2000, HIT-REZ 97/05), atypical teratoid rhabdoid tumors (EU-RHAB), germ cell tumors (SIOP-CNS GCT 96, SIOP-CNS-GCT-II), craniopharyngeoma (HIT-Endo, KRANIOPHARYNGEOM 2000/2007), and choroid plexus tumors (CPT-SIOP-2000) with different upper age limits were centrally assessed. Numbers of newly diagnosed patients were compared with those of the German Childhood Cancer Registry (GCCR) for intracranial and intraspinal tumor of patients <15 years with residency in Germany. RESULTS: The annual numbers of patients registered by more than 100 different local institutions within the HIT-network have increased linear (R2 = 0.71) from 441 patients (2001) to 652 patients (2010), with a yearly gain of around 20 additional patients. 62% of the newly registered patients had low-grade glioma, 18% high-grade glioma and 17% AT/RT. The incidence rate of the GCCR increased linear from 3.4 to 4.3 per 100.000 children (R2 = 0.57) in the same period. CONCLUSIONS: The annual numbers of patients registered within the HIT-network have increased by 51% within 10 years, partly due to an increase of low-grade glioma patients who frequently do not need adjuvant treatment at diagnosis. The incidence rates of the GCCR have increased in parallel but less pronounced, and are already higher than rates reported by other registries, such as SEER from 2001-2008. The high profile and broad acceptance of the HIT-network may have contributed to this effect towards population based data collection. Supported by Deutsche Kinderkrebsstiftung

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-16. HISTOPATHOLOGICAL HETEROGENEITY IN DIFFUSE INTRINSIC PONTINE GLIOMA

Viola Caretti 1, Marianna Bugiani 2, Ilja Boor 3, Pepijn Schellen 1, W Peter Vandertop 4, David P Noske 5, Gertjan Kaspers 6, Thomas Wurdinger 5, Pieter Wesseling 2

Abstract

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric neoplasm. Since surgery and biopsy are not routinely performed, detailed histopathological studies on this disease are lacking. AIM: To investigate the histopathological spectrum of DIPGs. METHODS: Recently, a Dutch nation-wide (‘brain only’) autopsy protocol was developed. Within two years after implementation, six autopsies have been performed and all brain areas affected by the tumour have been studied in detail. RESULTS: All patients showed tumor dissemination beyond the brainstem in the cerebellum and, except for one patient, in supratentorial areas (incl. thalamus, frontal and occipital lobe). In three patients, tumor growth was more prevalent in the gray as compared to the white matter. The DIPG cell phenotype varied widely, ranging from small cells with little visible cytoplasm, via prototype astrocytic tumor cells with ample eosinophilic cytoplasm and/or eosinophilic cell processes, to giant (astrocytic) tumor cells with monstrous nuclei. Interestingly, in three patients the tumor focally showed a ‘subependymoma-like’ component. Tumor growth in the leptomeningeal compartment was detected in two patients. In all cases, while large areas of the tumors still showed the histopathology of low grade diffuse glioma, other areas were characterized by increased mitotic activity, variable necrosis and/or occasionally florid microvascular proliferation, warranting histopathological grading of the lesion as WHO grade IV (glioblastoma). We are currently performing detailed immunohistochemical investigation of the tumor in the pons and in all other brain areas infiltrated by the malignancy. CONCLUSION: DIPGs are characterized by diffuse infiltrative growth in the preexistent brain tissue and show significant intra- and inter-tumoral heterogeneity. This latter phenomenon has important consequences for the interpretation of small biopsy specimens obtained from these lesions. It remains to be assessed if the grading system used for ‘adult diffuse gliomas’ can be readily applied to DIPGs.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-17. MEDULLOMYOBLASTOMA AND MELANOTIC MEDULLOBLASTOMA FORM A HISTOLOGIC SPECTRUM AND A DISTINCT MOLECULAR SUBGROUP OF MEDULLOBLASTOMA

Giles Robinson 1, Murali Chingtagumpala 2, Adekunle Adesina 2, James Dalton 1, Mariarita Santi 3, Angela Sievert 3, Karen Wright 1, Gregory Armstrong 1, Daniel Boue 4, Randal Olshefski 4, Suzanne Scott 4, Annie Huang 5, Richard Cohn 6, Sridharan Gururangan 7, Daniel Bowers 8, Richard Gilbertson 1, Amar Gajjar 1, David Ellison 1

Abstract

BACKGROUND: A few children are diagnosed each year with a medulloblastoma that exhibits rhabdomyoblastic or melanocytic differentiation. While these tumors have been anecdotally reported to have a poor outcome, the literature is limited to small case series and single case reports. Recent studies have shown medulloblastoma to be a heterogeneous tumor, subcategorized into four molecular subgroups that have distinct clinical and biologic features. The aim of this study was to determine whether these rare variants are aligned to any of these subgroups. METHODS: We have retrospectively collected the largest case series (n = 17) of patients with rhabdomyoblastic or melanocytic variants; 11 tumors from three institutional trials (SJMB03, SJYC07, SJMB96) and 6 from pathology consults/multi-institutional collaborations. Molecular subgroup was determined by immunohistochemistry and in a few cases (n = 4) by gene expression profiling. RESULTS: Histopathologically, seven tumors were classified as medullomyoblastomas, seven as melanotic medulloblastomas, and three displayed a mixed phenotype. Median age at diagnosis was 5 years (range 10months-19yrs), and 41% (7/17) patients had disseminated/high-risk disease. Overall survival and progression free survival at 2 yrs post-diagnosis were 71% and 57%, respectively. A trend toward worse outcome could not be identified to be independent from young age at diagnosis and metastatic disease. Immunohistochemical studies capable of distinguishing SHH, WNT and non-SHH/WNT tumors were often confounded by a mixed phenotype and thus inconclusive. Furthermore, unbiased hierarchical clustering of mRNA expression profiles suggested that these tumors form a distinct subgroup. CONCLUSIONS: We present data to suggest that the rare melanotic medulloblastoma and medullomyoblastoma form a histopathologic spectrum and should be considered as a fifth molecular subgroup of disease. Since no major clinical variation is seen with this differentiation pattern in comparison to larger medulloblastoma cohorts, we recommend continued treatment of these patients with standard of care therapy until further investigational studies can be completed.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-18. DILEMNA: HOW TO BEST OBTAIN SNAP FROZEN TISSUE AT DIAGNOSIS

Elizabeth Chick 1, Andrew Donson 1, Emily Owens 2, Amy A Smith 2, Jennifer R Madden 1, Nicholas K Foreman 1

Abstract

BACKGROUND: It is quickly becoming standard of care for snap frozen tissue to be obtained on all pediatric neuro-ocology patients at tumor resection. This tissue is becoming a priority in genetic based diagnoses and targeted therapies. Many institutions are unable to obtain this tissue effectively. It is difficult to know whether the responsibility lies with the NeuroOncology, Neurosurgery, or Pathology service to obtain and store these specimens. Other obstacles include how to establish a database that correlates the specimen with a patient number. In addition, consenting the patient and family must be done in a timely fashion. A clinical research assistant and/or research nurse are critical in achieving this important task. METHODS: To ascertain the magnitude of this need, we reviewed our database of tumor specimens collected during a six month period; August 2011 to January 2012. RESULTS: During that time 31patients presented with an operable central nervous system (CNS) tumors. Only 1 of those 31 declined consent for tissue sample collection. Twenty-nine of the 30 surgical patients had adequate biopsy tissue to obtain a snap frozen sample. Of those, 28 (97%) of the samples obtained were snap frozen and of those, 5 were collected off business hours. For comparison, a recent multi-center trial collected only 34 snap frozen samples of 77 enrolled patients (44%). CONCLUSIONS: The experience nationally has proven difficult to obtain snap frozen tumor samples, with less than half of centers participating in a cooperative group trial submitting appropriate tissue. Our experience shows that it is possible to obtain nearly all tumor specimens at time of resection. However, it requires a dedicated laboratory staff and timely coordination between operating room staff, NeuroOncology, and NeuroSurgery.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-19. FEASIBILITY AND EFFICACY OF AN INTERNATIONAL COLLABORATION TO TEST CLINICAL, PATHOLOGICAL AND GENETIC DETERMINATES OF THE BIALLELIC MISMATCH REPAIR SYNDROME

Doua Bakry 1, Melyssa Aronson 2, Carol Durno 2, Rimawi Hala 3, Roula Farah 4, Nisreen Amayiri 11, Qasim Alharbi 12, Ashraf Shamvil 5, Shay Ben-Shachar 13, Shlomi Constantini 14, Dvir Rina 15, Jordan Ellise 6, Steve Keiles 7, Aaron Pollet 17, Ibrahim Qaddoumi 8, Steve Gallinger 2, David Malkin 16, Eric Bouffet 9, Cynthia Hawkins 10, Uri Tabori 9

Abstract

INTRODUCTION: Individuals with germline biallelic mismatch repair gene mutations (bMMR) develop multiple childhood malignancies, including brain tumors, haematological and early-onset gastrointestinal (GI) cancers. These patients usually succumb to their cancers and rarely reach adulthood. We have initiated an international collaboration to improve diagnosis and treatment, and offer early detection to these patients and their at-risk family members. MATERIALS AND METHODS: We established a central clinical database and tissue bank, including blood and tumour samples. Review of pathology is conducted, tumours are stained for all four MMR genes (PMS2, MSH6, MLH1, MSH2) and tested for microsatellite instability. Germline DNA is sequenced and genetic counselling and surveillance are offered to these families accordingly. RESULTS: Twenty-two children from 14 families developed 29 tumors. Seventeen brain tumors developed in sixteen patients of the twenty two patients (72%) and 76% of the brain tumors were high grade gliomas. All patients with brain tumors (including 4 with multiple malignancies) had pre-existing Café-au-lait spots. Out of all genetic alterations detected in our group one novel deletion and one novel missense somatic mutation in PMS2, one novel deletion mutation in MSH6 and one complex genetic alteration were found. Germline mutations were detected in all patients whose tumor samples stained negative for the specific gene. A comparison between microsatellite instability and immunostaining is currently being performed. Pre- and post-test genetic counselling was conducted and clinical surveillance protocol was able to detect two brain tumours, multiple GI malignancies, and premalignant lesions. CONCLUSION: We demonstrate the feasibility and efficacy of an international consortium for bMMR carriers. Brain tumors are by far the most common cancer in this syndrome. Immunostaining of these tumors is a simple and reliable method to screen for bMMR in suspected patients. Finally, surveillance may improve survival for at-risk family members once a germline mutation is discovered.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-20. CNS TUMOURS IN THE FIRST YEAR OF LIFE, THE LEEDS EXPERIENCE

M Trivedi 1, J Goodden 1, P Chumas 1, A Tyagi 1, R O'kane 1

Abstract

INTRODUCTION: Tumours in very young children are rare. We have studied tumour types, treatment & outcomes in children under one year-old, treated at Leeds General Infirmary. METHODS: Patients identified from the neuro-oncology database from January 2010 to December 2011. Retrospective analysis of presentation, surgery, resection extent, histology and patient journey. RESULTS: Seven patients were diagnosed and treated during the study period. Median age at diagnosis was 7 months (range 1- 12). There were 3 boys and 4 girls. Four were supratentorial and three were infratentorial. Tumour types were Mature Teratoma (2), Immature Teratoma (1), Glioblastoma Multiforme (1), Atypical Teratoid Rhabdoid Tumour (ATRT) (1), Pilomyxoid astrocytoma (1), and Medulloblastoma (1). Surgery types included endoscopic biopsy (2), craniotomy & subtotal tumour debulking (5), craniotomy & total macroscopic excision of tumour (2). During surgery, we noted difficult access due to small patient size, and large tumour volume, providing challenges for both the surgeon and anaesthetist. One patient had craniotomy after endoscopic biopsy. The patient with Glioblastoma currently has stable, disease-free imaging following 2 operations and chemotherapy. The two patients with mature teratoma are stable on follow-up (1 complete and 1 incomplete excision). The patient with medulloblastoma had partial resection due to brainstem involvement, followed by adjuvant therapy. Three patients succumbed to their disease - patients with ATRT, immature teratoma and medulloblastoma. Comparison will be made between this series and current literature when presented in full. CONCLUSIONS: This series demonstrates the varied nature of diagnosis for infantile tumours. Obtaining tissue for diagnosis is vital to guide subsequent therapy. The surgical challenges of these tumours can be considerable. Good outcomes can be achieved in this age-group - refuting some authors' nihilism.

Neuro Oncol. 2012 Jun;14(Suppl 1):i43–i48.

EP-21. CENTRAL NERVOUS SYSTEM TUMOURS IN INFANTS AND EARLY CHILDHOOD

M Trivedi 1, J Goodden 1, P Chumas 1, A Tyagi 1, R O'Kane 1, D Crimmins 1, S Picton 1, M Elliott 1

Abstract

INTRODUCTION: Central nervous system (CNS) tumours in infants (under 3 years-old) present significant treatment challenges. In particular, the desire to limit radiotherapy (to none, or focal radiotherapy) in this group has made the extent of surgical resection critical. We describe the surgical outcome and impact on different tumour types in children under 3, treated at Leeds General Infirmary. METHOD: Children under 3 years old with CNS tumours were identified from the neuro-oncology databases. Retrospective data was collected from January 2006 to December 2011 (6 years). We studied tumour type, surgical resection extent, post-operative treatment and outcome. RESULTS: Twenty-two patients were treated during this period. Median age 20 months (range 1-35 months). Seven were under 1 (31.8%), 9 were 1-2 years old (41%) and 6 were 2-3 years old (27.2%). Male: Female ratio was 1:1.4. The commonest tumours were pilocytic astrocytoma (3, 13.6%), medulloblastoma (7, 31.8%) and ependymoma (3, 13.6%). Some tumours were seen predominantly in the under 1's - notably teratoma, glioblastoma multiforme, pilomyxoid astrocytoma and atypical teratoid rhabdoid tumour (ATRT). Other pathological types included DNET, PNET, ganglioglioma and neuroblastoma. Seven patients died, of which 3 had rapid progression of medulloblastoma. Two died due to tumour progression - ATRT (1), and ependymoma (1). A patient with brainstem pilocytic astrocytoma died from respiratory problems 7 months post-operatively. 30-day mortality was 1 (4.5%) - treatment-limiting decision made due to severe metabolic/endocrine problems following surgery for immature teratoma. CONCLUSION: This series of children under 3 years old reflects a wide variety of tumour subtypes ranging from low to high grade. Complete surgical resection remains the therapeutic mainstay in the management of early childhood brain tumours, especially with the desire to limit radiotherapy to the developing brain - an ongoing challenge in this age-group.

Articles from Neuro-Oncology are provided here courtesy of Society for Neuro-Oncology and Oxford University Press

RESOURCES