Clinical, demographic, anatomopathological, and molecular findings in patients with medulloblastoma treated in a single health facility / Achados clínicos, demográficos, anatomopatológicos e moleculares de portadores de meduloblastoma tratados em uma única instituição

ABSTRACT Objective: To describe the clinical, demographic, anatomopathological, molecular, and survival characteristics of patients with medulloblastoma. Methods: Retrospective study based on patient information obtained from the review of medical records. Overall and event-free survival were analyzed using the Kaplan-Meier estimator, and the curves were compared by the log-rank test. Results: Among the patients investigated, 70 were male (66%), and age at diagnosis ranged from 2 months to 22 years. The most frequent signs and symptoms were headache (80.8%) and vomiting (75.8%). Regarding treatment, most patients (63.2%) underwent complete surgical resection, with a predominance of classic histology (63.2%). The 5-year overall survival rate was 67.9%, and the 10-year rate was 64.2%. Patients with molecular profile characteristic of the wingless (WNT) subgroup had a better prognosis, with 5-year overall survival of 75%. Conclusions: The clinical, demographic, anatomopathological, and molecular characteristics of patients with medulloblastoma described in the present study were mostly similar to those reported in the literature. Patients submitted to complete tumor resection had better clinical outcomes than those who underwent incomplete resection/biopsy. Patients classified as high-risk showed worse overall and event-free survival than those in the standard-risk group, and the presence of metastasis at diagnosis was associated with recurrence.

RESUMO Objetivo: Descrever as características clínicas, demográficas, anatomopatológicas, moleculares e de sobrevida de pacientes portadores de meduloblastoma. Métodos: Estudo retrospectivo, no qual as informações dos pacientes foram obtidas pela revisão dos prontuários médicos. Análises de sobrevida global e de sobrevida livre de eventos foram realizadas por meio da construção de curvas de Kaplan-Meier e a comparação entre as curvas foi feita pelo teste log-rank. Resultados: Entre os pacientes analisados, 70 pertenciam ao sexo masculino (66%) e a idade ao diagnóstico variou de dois meses a 22 anos. Os sinais e sintomas de maior frequência foram cefaleia (80,8%) e vômitos (75,8%). Em relação ao tratamento, a maioria (63,2%) dos pacientes foi submetida à ressecção cirúrgica total e apresentava como histologia predominante a forma clássica (63,2%). A taxa de sobrevida global em cinco anos foi de 67,9% e, em 10 anos, de 64,2%. Os pacientes com perfil molecular característico do subgrupo wingless (WNT) apresentaram melhor prognóstico, com sobrevida global em cinco anos de 75%. Conclusões: As características clínicas, demográficas, anatomopatológicas e moleculares dos pacientes com meduloblastoma descritas no presente estudo foram majoritariamente semelhantes às descritas na literatura. Pacientes submetidos à ressecção completa do tumor tiveram melhor evolução clínica do que aqueles com ressecção incompleta/biópsia. Pacientes estratificados como de alto risco apresentaram pior sobrevida global e livre de eventos do que o grupo standard e a presença de metástases ao diagnóstico se mostrou associada à ocorrência de recidiva da doença.

Risk factors for the prognosis of pediatric medulloblastoma: a retrospective analysis of 40 cases

OBJECTIVES: In this study, we evaluated the association of molecular subtypes, clinical characteristics and pathological types with the prognosis of patients with medulloblastoma. METHODS: We analyzed forty patients with medulloblastoma who underwent surgical resection at our center between January 2004 and June 2014. Risk factors associated with survival, disease progression and recurrence were analyzed with a univariate Cox regression analysis, and the identified significant risk factors were further analyzed by Kaplan-Meier survival curves. RESULTS: Factors associated with overall survival included M stage (p=0.014), calcification (p=0.012), postoperative treatment, postoperative Karnofsky Performance Scale (KPS) score (p=0.015), and molecular subtype (p=0.005 for WNT and p=0.008 for SHH). Number of symptoms (p=0.029), M stage (p<0.001), and postoperative radiotherapy (p=0.033) were associated with disease progression. Patients with the WNT or SHH subtype had better survival outcomes than patients with non-WNT/SHH subtypes. Risk factors for disease progression-free survival were symptoms >2 and ≥M1 stage without postoperative radiotherapy. The risk of recurrence increased with advanced M stage. Protective factors for recurrence included M0 stage and a combination of chemotherapy and radiotherapy. CONCLUSION: We identified the risk factors associated with survival, disease progression and recurrence of medulloblastoma patients. This information is helpful for understanding the prognostic factors related to medulloblastoma.

Análise de sobrevida e fatores prognósticos de pacientes pediátricos com tumores cerebrais / Analysis of survival and prognostic factors of pediatric patients with brain tumor

OBJETIVOS: Realizar análise de sobrevida e avaliar, através de análise multivariada, a influência de diversas variáveis na sobrevida, definindo fatores prognósticos de pacientes pediátricos com tumores do sistema nervoso central (SNC) tratados em um único centro. MÉTODOS: Analisamos, retrospectivamente, a sobrevida de 103 crianças portadoras de tumores cerebrais primários, diagnosticadas consecutivamente no período entre janeiro de 2000 e dezembro de 2006. Análise multivariada de fatores influenciando a sobrevida global por regressão de Cox foi usada para definir possíveis fatores prognósticos. RESULTADOS: A mediana e a média de idade foram de 7,2 e 7,6 anos. Houve predominância do sexo masculino (relação 1,22:1). A maioria dos pacientes tinha meduloblastoma ou tumores neuroectodérmicos primitivos (PNET, 38 por cento) ou astrocitomas de baixo grau (18 por cento). As topografias mais comuns foram cerebelar (49 por cento) e tronco cerebral (21 por cento). A sobrevida, 5 anos após o diagnóstico, foi de 84 por cento para astrocitomas de baixo grau e 51 por cento para meduloblastomas e PNET. Fatores prognósticos para a sobrevida global foram histopatológico (astrocitomas de alto grau e ependimomas, razão de risco entre 3,7 e 3,9), cirurgia (razão de risco 0,5 para tumores completamente ressecados) e radioterapia (razão de risco 0,5 para pacientes que receberam radioterapia). CONCLUSÕES: A sobrevida global de pacientes pediátricos com tumores cerebrais neste estudo é comparável àquela dos registros populacionais dos Estados Unidos e Europa. Os fatores de prognóstico definidos para sobrevida global também se assemelham àqueles previamente publicados.

OBJECTIVES: To estimate survival and evaluate prognostic factors of pediatric patients with central nervous system (CNS) tumors treated in a single center. METHODS: Retrospective analysis of survival of 103 children with primary brain tumors diagnosed consecutively from January 2000 to December 2006. Cox regression was used for multivariate analysis of factors that affect overall survival to define possible prognostic factors. RESULTS: Median and mean ages were 7.2 and 7.6 years. There was a male predominance (1.22:1). Most patients had medulloblastomas or primitive neuroectodermal tumors (PNET, 38 percent), or low-grade astrocytomas (18 percent). The anatomic site of most tumors was the cerebellum (49 percent) and the brain stem (21 percent). Five-year survival after diagnosis was 84 percent for low-grade astrocytomas and 51 percent for medulloblastomas and PNET. Prognostic factors for overall survival were histopathological type (high-grade astrocytomas and ependymomas; hazard ratio = 3.7 to 3.9), surgery (hazard ratio of 0.5 for completely resected tumors) and radiotherapy (hazard ratio of 0.5 for patients who underwent radiotherapy). CONCLUSIONS: Overall survival of pediatric patients with brain tumors in this study was similar to that found in populations of the United States and Europe. The prognostic factors defined for overall survival are also similar to those published in previous studies.

Immunohistochemical expression of markers Ki-67, neun, synaptophysin, p53 and HER2 in medulloblastoma and its correlation with clinicopathological parameters / Expressão imunoistoquímica dos marcadores Ki-67, neun, sinaptofisina, p53 e HER2 em meduloblastoma e sua correlação com os parâmetros clínico-patológicos

Medulloblastoma (MB) is the most common malignant brain tumor in childhood. The alterations found include: presence of oncoproteins p53 and HER2, elevated mitotic index, and presence of neuronal differentiation. The aim of this study was to determine the immunohistochemical expression of markers Ki-67, NeuN, synaptophysin, HER2 and p53 in 40 MB samples and their correlation with clinicopathologic parameters and survival. In 29 patients (72.5 percent), >20 percent of cells were positive for Ki-67. Males showed greater ki-67 expression (p=0.02) and smaller survival rates (p=0.002). NeuN and synaptophysin were negative in 16 (40 percent) and 8 (20 percent) cases, respectively. P53 was positive in 18 (45 percent) cases, with 11 (61 percent) weakly positive and 7 (39 percent) strongly positive. HER2 was positive in 23 (57.5 percent) of the samples and did not show statistical association with survival (p=0.07).

Meduloblastoma (MB) é o tumor maligno encefálico mais freqüente na infância. dentre as alterações encontradas estão: a presença das oncoproteínas p53 e HER2, elevado índice mitótico e presença de diferenciação neuronal. o objetivo deste estudo foi determinar a expressão imunoistoquímica (IMQ) dos marcadores Ki-67, NeuN, sinaptofisina, HER2 e p53 em 40 amostras de MB, correlacionando-as com parâmetros clinicopatológicos e com a sobrevida. Vinte e nove pacientes (72,5 por cento) apresentaram 20 por cento ou mais das células positivas para Ki-67. os pacientes do sexo masculino apresentaram maior expressão do Ki-67 (p=0,02) e também menor sobrevida (p=0,002). NeuN e sinaptofisina foram negativos em 16 (40 por cento) e 8 (20 por cento) casos, respectivamente. P53 foi positivo em 18 (45 por cento) casos, sendo 11 (61 por cento) fracamente positivos e 7 (39 por cento) fortemente positivos. HER2 foi positivo em 23 (57,5 por cento) das amostras e não demonstrou associação estatística com a sobrevida (p=0.07).

Meduloblastoma, caracterización de los últimos 10 años en el Hospital Guillermo Grant Benavente, Concepción / Meduloblastoma, characterization in the last 10 years in Guillermo Grant Benavente Hospital, Concepción

Meduloblastoma, tumor maligno del SNC de origen discutido pero se admite en células neuroepiteliales germinales del techo del cuarto ventrículo. Incidencia 5,7/1.000.000 niños de 0-14 años. Corresponde a un 15-20 por ciento de todos los tumores intracraneales infantiles, más frecuentes en hombres con peak en primera década y 20-30 años. Tiene mal pronóstico con 56 por ciento sobrevida a 5 años. Objetivo: caracterizar pacientes diagnosticados de meduloblastoma en últimos 10 años. Materiales y métodos: Estudio descriptivo, observacional de prevalencia, se analizaron todos los diagnósticos histológicos de Meduloblastoma entre 1/08/95 y 31/07/05 en Patología Hospital Clínico Regional Concepción. Resulados: Nuestro universo fueron 17 pacientes con 64,7 hombres con promedio edad 17,76 años con desviación estándar de 16.82. Un 70,6 por ciento fueron pediátricos y 29,4 por ciento mayores de 15 años. Un 29,4 por ciento presentaron sólo cefalea al diagnóstico. El tratamiento fue en 88,2 por ciento cirugía total más radioterapia y quimioterapia. Desde 1995 hasta 2000 se presentaron sólo 35,29 por ciento de los casos de los últimos 10 años con promedio de edad 23,83 años y desviación estándar de 23,95 con 83,3 por ciento hombres y 16,7 por ciento mujeres. En cambio en quinquenio entre 2000 y 2005 corresponden a 64,71 por ciento de todos los casos con promedio de edad de 14,45 por ciento años y desviación estándar de 11 con 58,3 por ciento de hombres y 41,6 por ciento mujeres. Esto demuestra no sólo el aumento de casos en los últimos 5 años, sino también de aumento de casos en mujeres. En 83,3 por ciento se realizó acceso clásico suboccipital. Un 52,9 por ciento de pacientes con meduloblastoma estaba fallecido a 10 años. La sobrevida promedio de pacientes fallecidos por meduloblastoma fue de 14,22 meses con desviación estándar de 12,97.

Meduloblastoma, is a malignant tumor of the CNS of discussed origin but it is admitted in germinal neuroepiteliales cells of the ceiling of the fourth ventricle. Incidence 5,7/1.000.000 children of 0-14 years. It corresponds to a 15-20 percent of all the infantile intracraneles tumor, but it frequents in men with peak in first decade and 20-30 years. It has bad I foretell with 56 percent sobrelife to 5 years. Objective: to characterize patients diagnosed of meduloblastoma in last 10 years. Material and methods: Cross-sectional, descriptive and observational study. We analyzed all diagnose histologic of Meduloblastoma between 1/08/05 and 31/07/05 in Pathology Clinical Hospital Regional Concepciòn. Results: Our universe men with average were 17 patients with 64.7 percent age 17.76 years with s.d. 16,,82. A 70,6 percent were pediatrics and greater 29,4 percent older than15 years. A 29,4 percent presented only migraine at diagnose. Th treatment was in 88,2 percent total surgery plus radiotherapy and chemotherapy. Since 1995 up to 2000 appeared only 35.29 percent of the cases of last the 10 years from the total with 23.83 years and s.d. 23.95 83,3 percent men and 16.7 percent women. However in quinquennium between 2000 and 2005 correspond to 64.71 percent of all cases 14.45 years and d.s. 11 with 58,3 percent of men and 41,6 percent women. This demosnstrate not only a increase in cases, but also an increase in the number of women. In 83,3 percent classic access was made suboccipital. A 52,9 percent of patients with meduloblastom died to 10 years. The survival average of patients who died by Meduloblastoma was of 14.22 months with s.d. 12.97.

Medulloblastomas: clinical profile, treatment techniques and outcome - an institutional experience.

The present series reports an audit on the patterns of presentation, radiation treatment techniques, failure pattern and outcome in the 36 patients treated at a single institution. Patients were accrued between October 1991 and September 1999. They underwent total or subtotal resection along with craniospinal irradiation. The dose to the cranium ranged from 30 to 43Gy (median- 36Gy), to the spine from 20 - 36Gy (median- 36Gy) and the posterior fossa boost, which was delivered in 32 cases, ranged from 14 to 24Gy (median -18Gy). Simulator film evaluation was carried out at the time of analysis based on the French Medulloblastoma Group guidelines, which revealed a significant under-dosage in the region of posterior fossa and cribriform plate in 27% and 19% respectively. Adjuvant chemotherapy was administered in 7 patients. Salvage treatment in the form of chemotherapy (5 cases) and re-irradiation (2 cases) were attempted but were ineffective. The overall survival (OS) and progression free survival (PFS) rates were 54% and 40% respectively, with the median being 75 and 29 months respectively. Amongst all the prognostic factors considered, on univariate analysis, duration of symptoms was significant for PFS with a trend towards significance for OS, while extent of debulking had a trend towards significance for PFS. No factor emerged significant on multivariate analysis.

The effect of isochromosome 17q presence, proliferative and apoptotic indices, expression of c-erbB-2, bcl-2 and p53 proteins on the prognosis of medulloblastoma

Medulloblastoma accounts for 20 to 25+ACU- of all intracranial neoplasms in children. The significance of the presence of isochromosome 17q (i(17q)), proliferative potential, apoptotic activity, and expression of c-erbB-2, bd-2, and p53 proteins in predicting long-term survival of patients with medulloblastomas was investigated. Twenty children were divided into two groups (favorable and poor outcome groups). Ten children with favorable outcome (FO) were disease-free during the follow-up period (median: 61.5 months). The other ten children with poor outcome (PO) died of disease progression, having a median survival of 18 months. Fluorescent in situ hybridization (FISH) for i(17q), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), and immunohistochemistry for Ki-67, c-erbB-2, bcl-2, and p53 proteins was performed in these patients. Nine out of 17 children showed i(17q). There was no difference in the rate of positive i(17q) between the FO and PO groups. The presence of i(17q) was not significantly related to biological factors that we investigated. Unlike the prominent presence of the proliferative potential and p53 expression in children with PO, apoptotic activity and expression of c-erbB-2 and bcl-2 had no correlation with the outcome.

The effect of isochromosome 17q presence, proliferative and apoptotic indices, expression of c-erbB-2, bcl-2 and p53 proteins on the prognosis of medulloblastoma

Medulloblastoma accounts for 20 to 25+ACU- of all intracranial neoplasms in children. The significance of the presence of isochromosome 17q (i(17q)), proliferative potential, apoptotic activity, and expression of c-erbB-2, bd-2, and p53 proteins in predicting long-term survival of patients with medulloblastomas was investigated. Twenty children were divided into two groups (favorable and poor outcome groups). Ten children with favorable outcome (FO) were disease-free during the follow-up period (median: 61.5 months). The other ten children with poor outcome (PO) died of disease progression, having a median survival of 18 months. Fluorescent in situ hybridization (FISH) for i(17q), terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), and immunohistochemistry for Ki-67, c-erbB-2, bcl-2, and p53 proteins was performed in these patients. Nine out of 17 children showed i(17q). There was no difference in the rate of positive i(17q) between the FO and PO groups. The presence of i(17q) was not significantly related to biological factors that we investigated. Unlike the prominent presence of the proliferative potential and p53 expression in children with PO, apoptotic activity and expression of c-erbB-2 and bcl-2 had no correlation with the outcome.

Análise e fatores prognósticos do meduloblastoma e sua forma desmoplásica / Analysis and prognostic factors of the medulloblastomas and desmoplasic medulloblastomas

O Meduloblastoma cerebelar, tumor neuroectodérmico primitivo do sistema nervoso central, tem origem no véu medular posterior medial do vermis cerebelar ou, nos casos laterais, na camada granular externa de Obersteimer dos hemisférios cerebelosos. É caracterizado por grande controvérsia na literatura. Dentre suas variantes morfológicas, verifica-se o meduloblastoma desmoplásico, descrito por Rubinstein, em substituiçao ao sarcoma aracnóideo cerebelar de Forster & Gagel, de topografia predominantemente hemisférica, consistência fibrótica, padrao histológico rico em reticulina, incidência maior no adulto, e menor agressividade oncobiológica. Um tipo destes tumores, com melhor prognóstico, é o meduloblastoma desmoplásico do adulto, de topografia lateral, com evoluçao pré-operatória mais longa. A radioterapia de todo neuroeixo, com dose maior ou igual a 5500 rads na fossa posterior participa como fator importante de melhor prognóstico nestes tumores. Recentemente, a quimioterapia vem oferecendo melhores resultados como tratamento adjuvante associado pré ou pós-radioterapia no meduloblastoma. Finalmente, depreende-se dos dados retirados da literatura pela similitude entre o meduloblastoma clássico e o desmoplásico, em relaçao ao quadro clínico e natureza histológica, destacando a maior sobrevida aos 2 e 5 anos neste último, nao justificando tratamento diferenciado em relaçao ao primeiro.