Reactivos de inmunohistoquímica para diagnóstico diferencial oncológico de neoplasias del sistema nervioso central / Immunohistochemical reagents for differential cancer diagnosis of central nervous system neoplasms

INTRODUCCIÓN: El Departamento de Equipo Funcional de Patología Quirúrgica y Necropsia del Instituto Nacional de Enfermedades Neoplásicas, en relación a nuevos reactivos de inmunohistoquímica para diagnóstico oncológico de tumores del sistema nervioso central, ha solicitado la opinión técnica de la UFETS. 2. Existen neoplasias del sistema nervioso central que presentan una pobre respuesta al tratamiento estandarizado y un peor pronóstico, por lo cual ameritan un diagnóstico eficaz y temprano. Los marcadores para inmunohistoquímica H3 K27M, H3 K27m3, GAB-1, YAP-1, H3.3G34R y MAP-2 permitirían un diagnóstico más eficaz e incluso influiría en su tratamiento y seguimiento. Estrategia de búsqueda de información: a) Pregunta Clínica: Sección A: SNC: En la población con tumores de SNC, ¿Cuál es la utilidad de los marcadores de H3 K27m3, GAB-1, YAP-1, H3.3G34R y MAP-2 como diagnóstico oncológico en tumores del SNC? b) Recolecciòn de los Manuscritos a Revisar: Tipos de estudios: La estrategia de búsqueda sistemática de información científica para el desarrollo del presente informe se realizó siguiendo las recomendaciones de la Pirámide jerárquica de la evidencia propuesta por Haynes y se consideró los siguientes estudios: Sumarios y guías de práctica clínica. Revisiones sistemáticas y/o meta-análisis. Ensayos Controlados Aleatorizados (ECA) Estudios Observacionales (cohortes, caso y control, descriptivos) No hubo limitaciones acerca de la fecha de publicación o el idioma para ningún estudio. DISCUSION: Tomando los criterios para un marco de valor de la Health Technology Assessment International (2018)13 para la toma de decisiones y formulación de la recomendación, se encontró una serie de estudios de los cuales no se encontraron revisiones sistemáticas ni estudios diagnósticos. La calidad de evidencia evaluada con metodología GRADE fue baja en todos los estudios evaluados, considerando el diseño de estudio observacional, y por el pequeño tamaño de las muestras estudiadas. Esta valoración indica que los resultados obtenidos en el mundo real por la aplicación de estas tecnologías pueden ser significativamente diferentes a los resultados diagnósticos de los estudios presentados. Los estudios que evaluaron el H3K27M y H3K27me3 evaluaron la utilidad diagnóstica de los anticuerpos para detección de estas mutaciones. El diagnóstico de glioma de línea media con mutación K27M permite reconocer una entidad de peor pronóstico y sólo se logra con la aplicación de estos marcadores. Si bien existe una cantidad limitada de evidencia, los estudios llevados por Tina Huang y col. evaluaron el rendimiento diagnóstico de estos marcadores comparándolos con estudios de mutación en muestras de tejido con diagnóstico de glioma (n=69) y tejido sano (n=4) en población pediátrica. Otro estudio por Sriram Venneti y col. tomaron como población 290 muestras de cáncer con mutación H3F3A K27M conocida. Los estudios reportan una sensibilidad 100% y una especificidad 100% para el marcador H3K27M y Sriram Venneti reportó una sensibilidad 100% y especificidad 98% para H3K27me3. Ambos marcadores cuentan con una utilidad diagnóstica importante su aplicación permitiría diagnosticar precozmente una enfermedad con mal pronóstico en edad pediátrica y adulta. El GAB-1 y el YAP-1 intervienen en el proceso de desarrollo del cáncer a nivel de sistema nervioso central. La detección de ambas mutaciones por inmnohistoquimica permite la clasificación molecular del meduloblastoma en SHH, WNT y no-SHH/WNT. El determinar el subtipo molecular es importante ya que cada uno cuenta con un pronóstico diferente y su reconocimiento permitiría realizar un mejor diagnóstico y hasta influir en el tipo de tratamiento que recibiría. David W. Ellison y su equipo reconocer al meduloblastoma como una enfermedad heterogenea y a través de inmunohistoquímica determinan los subtipos de meduloblastoma en una cohorte de 235 muestras en pacientes de un rango de edad 0.4 ­ 52 años. Los subtipos moleculares SHH, WNT, y no SHH/WNT correspondían al 31%, 14%, y 55% de los casos. Hye Sook Min y col. evaluaron la detección de mutaciones a través de anticuerpos para inmunohistoquímica en cada subtipo molecular de meduloblastoma. El GAB-1 fue hallado en el 100% de los subtipos SHH y en sólo el 25% del subtipo WNT. El YAP-1 se encontró en el 50% de los subtipos WNT, el 80%de SHH y sólo el 2% en los subtipos no-SHH/WNT. Ambos marcadores son relevantes para poder clasificar adecuadamente cada subtipo molecular de meduloblastoma. Las mutaciones H3.3G34R y MAP-2 están asociadas con la progresión de enfermedad oncológica. Farhana Haque y col. evaluaron la eficacia de la inmunotinción para la detección de H3.3G34R en una cohorte de 22 muestras de tumores incluidos en parafina con mutación H3.3 G34R conocida. 17 eran tumores supratentoriales de alto grado, 2 gangliomas anaplasicos, 2 oligoastrocitomas grado III y 1 glioma de alto grado. La IHC detectó con éxito la proteína mutante correspondiente en todos los casos (11/11 G34R). Los resultados demostraron una concordancia adecuada entre estudio diagnóstico con inmunohistoquímica y estudio mutacional correspondiente. Se reportó una sensibilidad del 100% y especificidad del 98% para diagnóstico. Con respecto al estudio de inmunohistoquímica del MAP-2, Ingmar Blümcke y su grupo de estudio demostraron que el análisis por inmunohistoquímica presentó una sensibilidad del 98% y una alta especificidad para la detección de esta mutación, la cual está asociada con la progresión de tumores astrocíticos de alto grado en el sistema nervioso central. En este momento el INEN no cuenta con marcadores que puedan diagnosticar los gliomas de línea media con mutación K27M, una entidad de pobre repuesta al tratamiento y peor pronóstico y que por ende ameritaría un diagnóstico precoz. De la misma forma, la clasificación molecular de los meduloblastomas es algo importante. Cada subtipo molecular cuenta con un pronóstico diferente lo cual podría impactar en el tratamiento y la forma de seguimiento de los pacientes. Tampoco se cuenta con una forma de detección de la mutación 3.3 G34R y el MAP-2 cuenta con una alta eficacia diagnóstica para el diagnóstico de astrocitomas de alto grado. Ninguno de estos procedimientos diagnósticos está siendo realizado en este momento por lo cual la aplicación de estos marcadores supone un impacto positivo al considerar la población de pacientes diagnosticados que contarían con un tratamiento adecuado. Todos estos marcadores se integrarían al arsenal diagnóstico, sin reemplazar otro marcador que ya se esté aplicando en el INEN. El impacto económico de esta prueba para el INEN es incierto y es necesario realizar un análisis de impacto presupuestario para estimar cuantitativamente el gasto sanitario del uso de esta prueba en la población con linfomas. CONCLUSIONES: Algunas patologías oncológicas del sistema nervioso centran tienen una mala respuesta al tratamiento convencional, lo cual les da un peor pronóstico y un curso más agressivo. Los marcadores H3 K27M y H3 K27m3 presentan una alta sensibilidad y especificidad para el diagnóstico de gliomas de la línea media con mutación K27M. Esta entidad cuenta con una peor respuesta a tratamiento y peor pronóstico. Su detección temprana podría permitir un mejor tratamiento y optimizar las pautas de seguimiento. Los marcadores H3.3G34R y MAP-2 reconocen mutaciones que intervienen con el desarrollo del cáncer. Ambos cuentan con una alta sensibilidad y especificidad para el diagnóstico de tumores astrocíticos de alto grado. Los marcadores GAB-1 y YAP-1 se utilizan para determinar los subtipos moleculares de meduloblastoma, teniendo el GAB-1 una sensibilidad alta para el tipo SHH. Cada subtipo molecular de meduloblastoma cuenta con un pronóstico diferente lo cual podría influenciar en la forma de tratamiento que recibirían. Los marcadores de inmunohistoquímica permitirían un eficaz y temprano diagnóstico, lo cual influiría positivamente en el pronóstico de los pacientes con estas patologías, las cuales hasta la fecha no han sido diagnosticadas adecuadamente.

Intra-Axial Metastatic Angiosarcoma of the Central Nervous System Associated with Anemia, Pulmonary Tuberculosis and Short Survival

Introduction Angiosarcoma (AG) is a malignant mesenchymal neoplasm that predominantly affects the soft tissues and, to variable degrees, expresses themorphological and functional characteristics of the endothelium. The incidence of sarcomas of the central nervous system(CNS) is low (0.5% to 2.7%), and AGs involving the brain are even rarer. Case Description A 45-year-old male patient presented with complaints of headache, nausea, and vomiting. An examination showed bilateral papilledema and a right lung pleurotomy. The patient's previous history included drug addiction, pulmonary tuberculosis, lung abscess, pleural empyema, and pulmonary artery embolization for severe hemoptysis. Computed tomography/magnetic resonance imaging scans revealed a large intra-axial lesion extending into the right parietal and temporal lobes, with hemorrhagic zones. The patient underwent surgical resection of the lesion. Microscopy showed a poorly-differentiated, high-grade malignant tumor composed of plump/epithelioid cells forming small vascular spaces and solid nests, compatible with AG.In the postoperative period, the patient developed recurrent hemoptysis. A biopsy of the tissues adjacent to the pleurotomy determined the diagnosis of pulmonary AG. At 30 days after the resection, the patient died from hemoptysis, hemothorax, lung atelectasis, and intracranial hypertension related to the recurrence of the brain tumor. Conclusion Angiosarcoma is a rare neoplasia related to short survival due to the high proliferative index, which must be considered in patients presenting hemorrhagic tumors. No specific genetic abnormalities have been described for this neoplasia.

Estudio restrospectivo de 48 casos de linfoma primario del sistema nervioso central / Retrospective study of 48 cases of primary central nervous system lymphoma

Los linfomas primarios del sistema nervioso central (LPSNC) son neoplasias infrecuentes confinadas al SNC. Más del 90% son de tipo B y afectan principalmente a pacientes entre 50-70 años. La inmunodeficiencia es el factor de riesgo más importante. El objetivo de nuestro trabajo fue evaluar las características demográficas, estado inmunológico y los hallazgos en los estudios complementarios de pacientes con LPSNC. Se realizó el análisis retrospectivo de 48 casos estudiados en nuestro centro desde enero 1992 a mayo 2015. La edad mediana de presentación fue 61 años (25-84); la relación hombre:mujer 2.1:1. El 85% (41 casos) fueron inmunocompetentes al momento del diagnóstico. El 94% (45 casos) tuvo compromiso parenquimatoso, 4% (2 casos) meníngeo y 2% (1 caso) ocular. El lóbulo más afectado fue el frontal (43%) y 35% tuvieron compromiso ganglio basal. En RM, el 89% mostró realce con contraste y 55% restricción en difusión. El síndrome piramidal fue la manifestación inicial más frecuente (56%). El LCR fue inflamatorio en el 72%, aunque solo 11.1% presentó examen citológico positivo. El tipo más frecuente de LPSNC fue no-Hodgkin B (96%) y el subtipo difuso de células grandes el más habitual (83%). En nuestra serie la ausencia de inmunocompromiso fue una característica frecuente y la presentación clínico-radiológica fue muy pleomórfica. La sospecha inicial permitiría arribar a un diagnóstico temprano, evitando tratamientos empíricos que puedan confundir o retrasar el diagnóstico.

Primary central nervous system lymphoma (PCNSL) is an infrequent form of non-Hodgkin lymphoma restricted to the CNS. More than 90% are type B and mainly affect patients aged 50-70 years. Immunodeficiency is the most important risk factor. The aim of our study was to evaluate the immune status, clinical presentation and findings in complementary studies of PCNSL patients. A retrospective analysis of 48 cases treated in our center between January 1992 and May 2015 was performed. Median age at diagnosis was 61 years (range 25-84); with male predominance (2.1:1). Forty one cases (85%) were immunocompetent patients. Brain MRI findings showed parenchymal involvement in 45 cases (94%), 43% with frontal lobe and 35% basal ganglia, 4% had meningeal involvement and 2% had ophthalmic involvement at diagnosis. Fifty-five percent had restricted signal on diffusion weighted imaging and contrast enhancement was found in 89%. Pyramidal syndrome was the main initial clinical manifestation (56%). There were abnormal findings in 62% of CSF samples, but in only 11.1% positive cytology results were detected. The most frequent type was diffuse large B-cell lymphoma (83%), being B-cell type the most common form between them (96%). In our series PCNSL was more frequent in immunocompetent elderly male subjects. At initial evaluation, clinical manifestations and MRI findings were variable. The initial suspicion of this entity would allow an early diagnosis, avoiding empirical treatments that may confuse or delay diagnosis.

Characteristics and Outcomes of Second Malignant Neoplasms after Childhood Cancer Treatment: Multi-Center Retrospective Survey

This retrospective study investigated the clinical characteristics and outcomes of second malignant neoplasms (SMNs) in survivors of childhood cancer from multiple institutions in Korea. A total of 102 patients from 11 institutions who developed SMN after childhood cancer treatment between 1998 and 2011 were retrospectively enrolled. The most common primary malignant neoplasms (PMNs) were central nervous system (CNS) tumors (n = 17), followed by acute lymphoblastic leukemia (n = 16), non-Hodgkin lymphoma (n = 13), and osteosarcoma (n = 12). The most common SMNs were therapy-related myeloid neoplasms (t-MNs; acute myeloid leukemia [AML], 29 cases; myelodysplastic syndrome [MDS], 12 cases), followed by thyroid carcinomas (n = 15) and CNS tumors (n = 10). The median latency period was 4.9 years (range, 0.5-18.5 years). Among 45 patients with solid tumors defined as an SMN, 15 (33%) developed the lesion in a field previously subjected to radiation. The 5-year overall survival (OS) rate of patients with an SMN was 45% with a median follow-up time of 8.6 years. Patients with AML, MDS, and CNS tumors exhibited the poorest outcomes with 5-year OS rates of 18%, 33%, and 32%, respectively, whereas those with second osteosarcoma showed comparable outcomes (64%) to patients with primary counterpart and those with second thyroid carcinoma had a 100% OS rate. Further therapeutic efforts are recommended to improve the survival outcomes in patients with SMNs, especially in cases with t-MNs and CNS tumors.

Characteristics and Outcomes of Second Malignant Neoplasms after Childhood Cancer Treatment: Multi-Center Retrospective Survey

This retrospective study investigated the clinical characteristics and outcomes of second malignant neoplasms (SMNs) in survivors of childhood cancer from multiple institutions in Korea. A total of 102 patients from 11 institutions who developed SMN after childhood cancer treatment between 1998 and 2011 were retrospectively enrolled. The most common primary malignant neoplasms (PMNs) were central nervous system (CNS) tumors (n = 17), followed by acute lymphoblastic leukemia (n = 16), non-Hodgkin lymphoma (n = 13), and osteosarcoma (n = 12). The most common SMNs were therapy-related myeloid neoplasms (t-MNs; acute myeloid leukemia [AML], 29 cases; myelodysplastic syndrome [MDS], 12 cases), followed by thyroid carcinomas (n = 15) and CNS tumors (n = 10). The median latency period was 4.9 years (range, 0.5-18.5 years). Among 45 patients with solid tumors defined as an SMN, 15 (33%) developed the lesion in a field previously subjected to radiation. The 5-year overall survival (OS) rate of patients with an SMN was 45% with a median follow-up time of 8.6 years. Patients with AML, MDS, and CNS tumors exhibited the poorest outcomes with 5-year OS rates of 18%, 33%, and 32%, respectively, whereas those with second osteosarcoma showed comparable outcomes (64%) to patients with primary counterpart and those with second thyroid carcinoma had a 100% OS rate. Further therapeutic efforts are recommended to improve the survival outcomes in patients with SMNs, especially in cases with t-MNs and CNS tumors.

Análise de sobrevida de pacientes portadores de tumores do sistema nervoso central / Survival analysis of patients with central nervous tumor

Objetivos: analisar a sobrevida de pacientes com diagnóstico de tumores do sistema nervoso central (SNC) em um serviço de referência em Oncologia Pediátrica, sua apresentação clínica, evolução e influência de fatores prognósticos. Métodos: estudo de coorte histórica. Foram estudados pacientes menores de 19 anos, no período de março de 2003 a dezembro de 2009. O método de Kaplan-Meier foi utilizado para estimar a probabilidade de sobrevida global (SGLO). O teste de log rank e o modelo de regressão de Cox foram usados nas análises univariada e multivariada. Resultados: foram incluídos 159 pacientes, com mediana de tempo de seguimento de 13 meses. O intervalo entre o início dos sintomas e o diagnóstico teve mediana de 1,9 mês; 52% eram do gênero masculino. A mediana de idade ao diagnóstico foi de 7,2 anos. Os diagnósticos histológicos mais frequentes foram glioma de baixo grau (27%), meduloblastoma (19,5%) e tumor de tronco encefálico (17,6%). Cefaleia foi o sintoma mais frequente ao diagnóstico. A localização primária mais comum dos tumores foi a infratentorial (55,3%). A SGLO aos cinco anos foi de 42% (IC 95, 33 a 53%). Na análise univariada, foi observada associação significativa entre tempo de surgimento dos sintomas e o diagnóstico (p=0,046) e diagnóstico histológico (p<0,001). Na análise multivariada, esses fatores mantiveram-se e foram acrescidos da localização primária do tumor. Discussão: a SGLO observada neste estudo foi claramente inferior às descritas na literatura internacional, porém semelhante à de dois outros centros de referência nacionais. Estudos multicêntricos em nível nacional são necessários para confirmação desses resultados.

Objetives: To evaluate outcome of patients with the diagnosis of Central Nervous System tumors at a local reference pediatric oncology service, their clinical presentation, evolution and influence of prognostic factors. Methods: Patients enrolled in this retrospective study between March,2003 and December,2009, were less than nineteen years old at the time of the diagnosis. Kaplan-Meier method was used to estimate the overall survival (OS). Log rank test and Cox?s method were used in the statistical analysis. Results: Study population consisted of 159 patients with median follow up period of 13 months. Median of the time between onset of symptoms and diagnosis was 1,9 months. Boys comprised 52% of the studied population. Median age at diagnosis was 7,2 years. Most common diagnostic subtypes were low grade glioma (27%), medulloblastoma (19,5%) and brain stem tumors (17,6%). Headache was the most frequent symptom (57%) and infratentorial tumors correspond to 55,3% of the cases. An estimated OS of 42% (CI 95%, 33% to 53%) was observed for the role group. An association between outcome and the following variables was observed: interval between the time of onset of symptoms and diagnosis (p=0,046)and histological classification of the tumors (p<0,001). In the multivariate analysis, these variables were sustained, added of the primary location of the tumor in the Central Nervous System. Discussion: Overall survival detected in this study was clearly worse when compared with international centers rates, although were similar to other Brazilian studies. It?s important to develop multicentric studies to confirm data showed in this study

A Case of Isolated Lymphoblastic Relapse of the Central Nervous System in a Patient with Chronic Myelogenous Leukemia Treated with Imatinib

No abstract available.

Cerebrospinal fluid approach on neuro-oncology / Estudo do liquido cefalorraquiano em neuro-oncologia

Central nervous system (CNS) involvement is a major complication of haematological and solid tumors with an incidence that ranges from 10% in solid malignances up to 25% in specific leukaemia or lymphoma subtypes. Cerebrospinal fluid (CSF) patterns are unspecific. Though CSF cytology has a high specificity (up to 95%), its sensitivity is generally less than 50% and no diagnostic gold standard marker is available, yet. New technologies such as flow cytometry, molecular genetics and newer biomarkers may improve diagnostic sensitivity and specificity, leading to the CNS involvement diagnosis, and consequently, to an effective prophylaxis and successful treatment.

O envolvimento do sistema nervoso central (SNC) é uma das maiores complicações das neoplasias de linhagem hematológica e dos tumores sólidos, com uma incidência que varia de 10% nestes últimos até 25% nas leucemias e subtipos de linfomas. Os padrões do líquido cefalorraquiano (LCR) nestes casos é inespecífico. Embora a citologia do LCR tenha uma alta especificidade (acima de 95%), sua sensibilidade é geralmente menor que 50%, e nenhum marcador biológico de padrão-ouro é disponível até o momento. Novas tecnologias, como a citologia de fluxo, a genética molecular e novos biomarcadores poderão aumentar a sensibilidade e especificidade no diagnóstico, levando ao diagnóstico de envolvimento do SNC, e consequentemente a profilaxia efetiva e tratamento bem sucedido.

Primary central nervous system lymphoma: what a neurologist/neurosurgeon should know? / Linfoma primário de sistema nervoso central: o que um neurologista/neurocirurgião deve saber?

Primary central nervous system lymphoma is a rare disease, with bad prognosis. Neurologists and neurosurgeons should be familiar with the diagnostic,and biologic features, as well as the initial management of patients. A correct approach to these patients is mandatory for a better outcome.

Linfoma primário do sistema nervoso central é uma doença rara, com prognóstico ruim. Neurologistas e neurocirurgiões devem estar familiarizados com os aspectos do diagnóstico, características biológicas e do manuseio inicial dos pacientes. A abordagem correta desses pacientes é essencial para obter melhores resultados.

Intracranial cavernous malformation in children: a single-centered experience with 30 consecutive cases / Angiomas cavernosos intracranianos em crianças: experiência de um único centro em 30 casos consecutivos

Objectives: To determine the clinical presentation and treatment outcome of pediatric intracranial cavernous malformation (CM) in a single-centered institution. Methods: Clinical data review of 30 patients under 18 years-old who had undergone surgery for cavernous malformation from January 1993 to December 2011. Results: The Study Group included 18 males and 12 females (mean age: 8.7 years-old). Symptoms at presentation were seizures (16/30, 53.3%), headache (15/30, 50.0%), and focal neurological deficits (11/30, 36.6%). Multiple cavernous malformations were found in 5/30 (16.6%). According to location, patients were classified in groups: (G1) brain-steam in 5/30 (16.6%), (G2) cerebellum in 2/30 (6.6%), (G3) supratentorial associated with seizures in 16/30 (53.3%), and (G4) supratentorial without seizures in 7/30 (23.3%). Surgical resection was performed in 26 out of 30 (86.6%) patients. The mean follow-up period was 4.1 years. Of 15 children followed-up with preoperative seizures, all were rendered seizure-free after surgery. Conclusions: For symptomatic solitary cavernous malformation, the treatment of choice is complete microsurgical excision preceded by careful anatomical and functional evaluation. For multiple cavernous malformation or asymptomatic patients, the treatment modalities must be cautiously considered. .

Objetivos: Determinar a apresentação clínica e o acompanhamento do tratamento em crianças com angioma cavernoso intracraniano numa única instituição. Métodos: Revisão de dados clínicos de 30 pacientes menores de 18 anos com que passaram por uma cirurgia de angioma cavernoso intracraniano entre janeiro de 1993 a dezembro de 2011. Resultados: O grupo de estudo incluiu 18 sujeitos masculinos e 12 femininos (idade média: 8,7 anos). Os sintomas iniciais eram convulsões (16/30, 53,3%), cefaleia (15/30, 50,0%) e déficits neurológicos focais (11/30, 36,6%). Havia angiomas cavernosos intracranianos múltiplos em 5 de 30 (16.6%). A classificação foi feita em grupos de acordo com a localização: (G1) tronco cerebral em 5/30 (16,6%); (G2) cerebelo em 2/30 (6,6%); (G3) supratentoriais associados a convulsões em 16/30 (53,3%) e (G4) supratentoriais sem convulsões em 7/30 (23,3%). Ressecção cirúrgica foi realizada em 26 de 30 (86,6%) pacientes, com seguimento médio de 4,1 anos. De 15 crianças com convulsões pré-operatórias, todas ficaram livres das crises após a cirurgia. Conclusões: Para angioma cavernoso intracraniano solitário e sintomático, o tratamento de escolha é excisão microcirúrgica total precedida de avaliação funcional e anatômica meticulosa. Para angiomas cavernosos intracranianos múltiplos ou pacientes assintomáticos, as modalidades terapêuticas devem ser consideradas cautelosamente. .

Glioblastoma multicêntrico originado em dois locais incomuns: cerebelo e tálamo / Multicentric glioblastoma arising in two unusual sites: cerebellum and thalamus

Multicentric glioblastomas (MGBM) arising in infra/supratentorial regions are uncommon lesions. The authors report a case of MGBM in a 61 year-old female patient, who presented a sudden onset of left hemiplegia. The magnetic resonance imaging (MRI) showed two expansive large lesions affecting cerebellum and thalamus, with strong contrast enhancement. The patient underwent resection of the cerebellar lesion. Microscopy revealed a high grade glial neoplasm exhibiting high mitotic index, areas of necrosis and microvascular proliferation. The neoplastic cells showed positive immunoexpression for glial fibrillary acidic protein (GFAP). The morphological findings were consistent with glioblastoma (GBM). The patient was referred to radiotherapy, with discrete signs of tumor regression after a 60-day clinical follow-up.

Glioblastomas multicêntricos (GBMM) originados em regiões infra/supratentoriais são lesões incomuns. Os autores relatam um caso de GBMM em paciente do sexo feminino, 61 anos de idade, que apresenta quadro súbito de hemiplegia esquerda. O exame de ressonância magnética (RM) mostrou duas lesões expansivas volumosas, com forte impregnação pelo contraste no cerebelo e no tálamo. A paciente foi submetida à ressecção da lesão cerebelar. À microscopia, foi identificada uma neoplasia glial de alto grau exibindo alto índice mitótico, áreas de necrose e proliferação microvascular. As células neoplásicas revelaram imunoexpressão positiva para proteína glial acídica (GFAP). O conjunto das alterações morfológicas foi consistente com glioblastoma. A paciente foi encaminhada para radioterapia, com sinais discretos de regressão tumoral após acompanhamento clínico de 60 dias.

Astrocitoma pilocítico da região selar/suprasselar determinando manifestações endócrinas / Pilocytic astrocytoma of sellar/suprasellar region determining endocrine manifestations

Pilocytic astrocytoma (PA) is a grade I glial neoplasm arising mainly in the cerebellum of children. Herein, the authors report a case of PA in a 21 year-old male patient, who presented headache, vomiting and delayed pubertal development. Serum level of cortisol and testosterone corresponded to 32.8 ug/dl and 0.19 ng/ml, respectively. The computed tomography/magnetic resonance (CT/RM) imaging showed an expansive process compromising suprasellar/hypothalamic region and determining hydrocephalus. The patient underwent resection of the process. Histological evaluation revealed a glial neoplasm constituted by loose glial tissue, small microcysts, areas of dense piloid tissue and Rosenthal fibers. The neoplastic cells were immunoreactive for glial fibrillary acidic protein (GFAP) and negative for chromogranin and synaptophysin. The diagnosis of PA was then established.

O astrocitoma pilocítico (AP) é uma neoplasia glial grau I encontrada principalmente no cerebelo de crianças. Os autores relatam um caso de AP em paciente masculino, 21 anos de idade, que apresenta cefaleia, vômitos e retardo do desenvolvimento puberal. Os níveis séricos de cortisol e testesterona corresponderam a 32,8 ug/dl e 0,19 ng/ml. A tomografia computadorizada/ressonância magnética (TC/RM) identificaram um processo expansivo que comprometia a região suprasselar/hipotalâmica e determinava hidrocefalia.O paciente foi submetido à ressecção do processo. À microscopia, foi identificada uma neoplasia glial constituída por tecido glial frouxo, pequenos microcistos, áreas de tecido piloide denso e fibras de Rosenthal. As células neoplásicas foram imunopositivas para glial fibrillary acidic protein (GFAP) e negativas para cromogranina e sinaptofisina. O diagnóstico de AP foi, então, estabelecido.

Linfomatosis intravascular cerebral como causa de demencia rápidamente progresiva: reporte de un caso / Cerebral intravascular lymphomatosis as cause of subacute dementia: report of a case

Cerebral Intravascular Lymphomatosis is a type of non Hodgkin Lymphoma, generally composed with B cells, its ocurrence is infrequent, clinically progressive and has a fatal course. Vascular damage is related with tumoral infiltration and small caliber occlusion, with results in multi infarcts. Neurological symptoms and signs are frequently the first clinical manifestation, which include sub acute encephalopathy, cognitive impairment, delirium, aphasia, hemipharesis, visual disturbances, paraplegia, paresthesia and cranial nerves involvement. MRI shows images of vasculitis from CNS. Cerebral Intravascular Lymphomatosis must be considered in differential diagnosis of rapid and subacute dementias, and clinical cases with small vessel recurrent multi infarct of unusual etiology. We present the clinical case of a patient with rapid progressive dementia and systemic disease manifestation. The CNS involvement was characterized as a subacute encephalopathy, with confusion and agitation, seizures, motor disturbances, bilateral plantar extensor reflexes and cerebellar signs. The clinical symptomatic course was progressive, with weight loss and fluctuant fever. The patient had a fatal course after he was treated with Methylprednisolone. Postmortem pathologic examination revealed a diffuse non Hodgkin lymphoma of B cells, intravascular variant, with brain compromise, cerebellum, suprarenal glands, pancreas, myocardium, thyroid gland, lung kidney and the lever...

La linfomatosis intravascular cerebral es un tipo de Linfoma no Hodgkin generalmente de células B, de presentación infrecuente, curso clínico progresivo y fatal. El daño vascular es producto de oclusión de vasos de pequeño calibre por infiltración tumoral, con resultado de múltiples infartos. Las manifestaciones neurológicas suelen ser la forma de presentación clínica inicial, caracterizadas por un amplio espectro que incluye encefalopatía subaguda, deterioro cognitivo, delirio, afasia, hemiparesia, trastornos visuales, paraplejia, parestesias y compromiso de pares craneanos. Los estudios de RNM evidencian alteraciones indistinguibles de las vasculitis del SNC. La linfomatosis intravascular debe considerarse en el diagnóstico diferencial de las demencias rápidamente progresivas y en los cuadros de multi infarto cerebral de pequeño vaso de etiología inusual y recurrente. Se presenta el caso de un paciente con demencia rápidamente progresiva, con manifestaciones neurológicas de deterioro cognitivo y enfermedad sistémica. El compromiso del SNC se expresó como encefalopatía subaguda con confusión, agitación, y crisis convulsivas, trastornos motores con reflejo cutáneo plantar extensor bilateral y compromiso cerebeloso, de curso clínico sintomático progresivo, con baja de peso y fiebre fluctuante. El paciente fue sometido a tratamiento con metilprednisolona a pesar del cual falleció. El estudio necrópsico demostró alteraciones por Linfoma no Hodgkin difuso de células B, variante intra vascular, con compromiso del cerebro, cerebelo, glándulas suprarrenales, páncreas, miocardio, tiroides, pulmón riñón e hígado...

Central nervous system lymphoma: magnetic resonance imaging features at presentation / Linfoma do sistema nervoso central: características da imagem de ressonância magnética à apresentação

OBJECTIVE: This paper aimed at studying presentations of the central nervous system (CNS) lymphoma using structural images obtained by magnetic resonance imaging (MRI). METHODS: The MRI features at presentation of 15 patients diagnosed with CNS lymphoma in a university hospital, between January 1999 and March 2011, were analyzed by frequency and cross tabulation. RESULTS: All patients had supratentorial lesions; and four had infra- and supratentorial lesions. The signal intensity on T1 and T2 weighted images was predominantly hypo- or isointense. In the T2 weighted images, single lesions were associated with a hypointense signal component. Six patients presented necrosis, all of them showed perilesional abnormal white matter, nine had meningeal involvement, and five had subependymal spread. Subependymal spread and meningeal involvement tended to occur in younger patients. CONCLUSION: Presentations of lymphoma are very pleomorphic, but some of them should point to this diagnostic possibility.

OBJETIVO: Este trabalho teve como objetivo estudar as apresentações do linfoma do sistema nervoso central (SNC) por meio de imagens estruturais, obtidas por ressonância magnética (RM). MÉTODOS: Foram analisadas as características das imagens por RM, à apresentação, de 15 pacientes diagnosticados com linfoma do SNC em um hospital universitário, entre janeiro de 1999 e março de 2011, pela frequência e por tabulação cruzada. RESULTADOS: Todos os pacientes apresentaram lesões supratentoriais; em quatro (27 por cento) havia lesões infra e supratentoriais. A intensidade do sinal em T1 e T2 foi predominantemente hipo ou isointensa. Lesões únicas foram associadas ao componente de sinal hipointenso nas imagens ponderadas em T2. Seis pacientes apresentaram necrose. Foram encontrados: alteração de sinal da substância branca perilesional em todos os pacientes, acometimento meníngeo em nove e disseminação subependimária em cinco. Disseminação subependimária e acometimento meníngeo tenderam a ocorrer nos pacientes mais jovens. CONCLUSÃO: As apresentações do linfoma no SNC são pleomórficas, mas algumas delas podem apontar para essa possibilidade diagnóstica.

Tumores primarios del sistema nervioso central en personas de 15 años o más / Primary tumors of the central nervous system in people aged 15 years and older

Objetivo general: generar recomendaciones basadas en la mejor evidencia disponible acerca del manejo de personas con tumores primarios del sistema nervioso central o que hayan sido tratados por ello. Objetivos específicos: personas con tumores primarios del sistema nervioso central o que hayan sido tratados por ello, que reciben atención en el nivel secundario y nivel terciario de salud en el sector público y privado de salud. Usuarios de la guía: Médicos Generales, de Urgencia, Neurólogos, Neurocirujanos, Oncólogos, Radioterapeutas, y otros médicos y profesionales que participan en la atención integral de los pacientes con tumores primarios del sistema nervioso central o tratados por ello.

value of touch preparation for rapid diagnosis of brain tumors as an intraoperative consultation

The touch preparation technique is an accurate and rapid method, and when used as intraoperative consultation examination technique it preserves a good amount of tissue for paraffin embedded sections. This study aimed at examining the accuracy of the touch preparation technique by comparing its diagnosis with that of final pathological diagnosis made by microscopic examinations. The diagnoses of 139 central nervous system lesions by touch preparation technique and paraffin-embedded sections were compared. Touch preparation technique diagnosed correctly 118 [84%] of the lesions. However, the technique failed to correctly diagnose 12% of the cases. The highest rate of accurate diagnosis [100%] was observed in five types out of 11 types of tumor examined. However, the technique was not able to diagnose hydatid cysts correctly. The findings indicate that touch preparation technique may be useful in diagnosing tumor type during surgical operations. Touch preparation technique is very accurate for intraoperative diagnosis. However, adequate clinical history, neuroimaging details, and the intraoperative impressions of the neurosurgeons, if provided, help the pathologists to improve the diagnostic accuracy of the technique

Análise de expressão do gene ADAM23 em tumores do sistema nervoso central (SNC) e estudo de sua função em gliomas e em melanomas / Analysis of ADAM23 gene expression in tumors of the central nervous system (CNS) and study of its function in melanoma and glioma

O gene ADAM23 está epigeneticamente silenciado em tumores de mama de estágios mais avançados e o seu silenciamento nesses tumores confere ao paciente um maior risco de desenvolvimento de metástases e um pior prognóstico. O silenciamento do gene ADAM23 na linhagem tumoral de mama MDA-MB-435 reduz a capacidade proliferativa e aumenta a capacidade migratória e invasiva das células em modelo tridimensional de cultura. No entanto, paradoxalmente, o silenciamento do gene ADAM23 nessa linhagem reduz a capacidade tumorigênica e metastática das células em ensaios in vivo utilizando animais imunodeficientes. Ensaios subsequentes utilizando misturas de células positivas e negativas para a expressão de ADAM23 revelaram que as células negativas estimulam a proliferação, migração e invasão das células positivas e que a heterogeneidade tumoral em relação à expressão de ADAM23 é importante para a disseminação e colonização metastática. Este trabalho teve como objetivo validar a associação entre o silenciamento do gene ADAM23 em tumores primários e a progressão tumoral, e também encontrar um modelo celular alternativo para a realização de ensaios funcionais que comprovassem o papel do gene ADAM23 na proliferação, migração, e invasão celular, bem como a existência de interação celular entre células ADAM23 positivas e negativas. A análise da expressão do gene ADAM23 em amostras de gliomas de diferentes estágios através de PCR em Tempo Real revelou que a expressão desse gene diminui ao longo da progressão tumoral e está bastante reduzida em tumores de grau avançado. Porém, ao contrário do observado em tumores de mama, o silenciamento do gene ADAM23 em gliomas não é causado por hipermetilação de sua região promotora nem por mutações em sua região codificante, ou perda de heterozigose. Infelizmente, não foi possível selecionar clones derivados da linhagem celular de glioblastoma U87MG com silenciamento estável do gene ADAM23 para a realização de ensaios funcionais. Aparentemente, o silenciamento de ADAM23 nessa linhagem resulta na parada do ciclo celular na fase G0/G1, impedindo a seleção de clones com silenciamento estável do gene. O mesmo fenômeno não foi observado na linhagem de melanoma SKmel-37, permitindo a seleção de clones com silenciamento estável de ADAM23 e a realização de ensaios funcionais. Curvas de proliferação em monocamada e ensaios de incorporação de MTT em modelo tridimensional in vitro demonstraram que o silencimento de ADAM23 na linhagem SKmel-37 diminui sua taxa de proliferação em 20-50%. Ensaios de citometria de fluxo demonstraram que o silenciamento de ADAM23 interfere na expressão das integrinas αvß3 e αvß5 na membrana celular, resultando em diminuição de 50% na afinidade aos ligantes de matriz e aumento significativo na capacidade de migração e invasão no colágeno. Ensaios in vitro e in vivo utilizando misturas de células SKmel-37 ADAM23 positivas e negativas também confirmaram a existência de interação entre os dois subtipos celulares. Ensaios in vitro de migração e invasão no colágeno revelaram que células ADAM23 negativas induzem a migração e a invasão de células positivas e, em ensaios de tumorigienese in vivo, observamos que os tumores formados a partir da injeção de uma mistura de células positivas e negativas apresentam crescimento semelhante ao dos tumores formados a partir da injeção de células ADAM23 positivas

The ADAM23 gene is epigenetically silenced in breast tumors of more advanced stages and its silencing in these tumors gives the patient a greater risk of developing metastasis and a worse prognosis. The ADAM23 gene silencing in the MDA-MB-435 breast tumor cell line reduces the proliferative capacity and increases migratory and invasive abilities of cells in three-dimensional culture models. Yet, paradoxically, the ADAM23 gene silencing in this line reduces tumorigenic and metastatic abilities of cells in in vivo assays using immunodeficient animals. Subsequent tests using ADAM23 positive and negative cells mixtures revealed that negative cells stimulate proliferation, migration and invasion of positive cells and the heterogeneity of ADAM23 expression in tumors is important for the spreading and metastatic colonization. This study aimed to validate the association between ADAM23 gene silencing in primary tumors and tumor progression as well as find an alternative cellular model for performing functional tests to prove the role of the ADAM23 gene in proliferation, migration and cell invasion, and to prove the existence of cell interaction between ADAM23 positive and negative cells. The analysis of ADAM23 gene expression in samples from different stages of gliomas by RT-PCR revealed that the expression of this gene decreases over tumor progression and is greatly reduced in tumors of advanced degree. However, unlike that observed in breast tumors, the ADAM23 gene silencing in gliomas is not caused by hypermethylation of its promoter region or by mutations in its coding region, or by loss of heterozygosity. Unfortunately, it was not possible to select clones derived from the U87MG glioblastoma cell line with stable silencing of the gene ADAM23 for the functional testing. Apparently, the silencing of ADAM23 in this cell line results in cell cycle arrest in G0/G1 phase, preventing the selection of clones with stable gene silencing. The same phenomenon was not observed in SKmel-37 melanoma cell line, allowing selection of clones with stable silencing of ADAM23 and functional testing. Monolayer proliferation curves and in vitro MTT incorporation assays in three-dimensional models showed that ADAM23 silencing in the SKmel-37 cell line reduces their rate of proliferation by 20-50%. Flow cytometry assays demonstrated that ADAM23 silencing interferes with the expression of αvß3 and αvß5 integrins in the cell membrane, resulting in a 50% decrease in binding afinity to the matrix and a significant increase in migratory and invasive abilities on collagen. In vitro and in vivo assays using ADAM23 positive and negative SKmel-37 cell mixtures also confirmed the existence of interaction between the two cell subsets. In vitro invasion and migration on collagen assays revealed that ADAM23 negative cells induce migration and invasion of positive cells. Furthermore, in in vivo tumorigenic tests we found that tumors formed from injection of a mixture of positive and negative cells exhibit growth similar to the tumors formed after injection of ADAM23 positive cells

Successful Treatment of Primary Central Nervous System Lymphoma without Irradiation in Children: Single Center Experience

Primary CNS lymphoma (PCNSL) is a very uncommon disease in children, and usually treated by chemotherapy, combined with focal or craniospinal radiotherapy (RT). However, adverse effects of RT are a concern. We evaluated the outcomes of childhood PCNSL, treated with systemic and intrathecal chemotherapy, but without RT. For fifteen years, six patients among 175 of non-Hodgkin lymphoma were diagnosed as PCNSL in Seoul National University Children's Hospital and we analyzed their medical records retrospectively. Their male:female ratio was 5:1, and median age was 10.1 yr. The primary sites were the sellar area in three patients, parietal area in one, cerebellum in one, and multiple areas in one. Their pathologic diagnoses were diffuse large B-cell lymphoma in three patients, Burkitt lymphoma in two, and undifferentiated B-cell lymphoma in one. Five were treated with the LMB96 treatment protocol, and one was treated with the CCG-106B protocol. None had RT as a first-line treatment. One patient had a local relapse and received RT and salvage chemotherapy, without success. No patient had treatment-related mortality. Their estimated 5-yr event-free and overall survival rates were both 83.3%. In conclusion, PCNSL is a rare disease in childhood, but successfully treated by chemotherapy without RT.