Biomarcadores radiológicos en RM para una aproximación al diagnóstico molecular en gliomas IDH-mutados (grado II y III) / MR Imaging Biomarkers for a Diagnostic Approach of IDH-mutated Gliomas (Grades II/III)

Resumen Objetivo: Analizar características por resonancia magnética (RM) de gliomas IDH-mutados (grado II y III) en base a parámetros cualitativos, a fin de valorar el rendimiento del signo del mismatch T2-FLAIR y otras características morfológicas de los tumores, en predecir el estado del 1p/19q y su reproducibilidad interobservador. Métodos Estudio retrospectivo, descriptivo y analítico sobre una cohorte de 53 gliomas IDH-mutados (grado II y III) y molecularmente definidos respecto al 1p/19q, seleccionados a partir de la base de datos de la institución, durante el periodo 2014- 2019. Dos neuroradiólogos evaluaron características imagenológicas de forma independiente y enmascarada al diagnóstico: mismatch T2-FLAIR, localización tumoral, bordes, señal, infiltración cortical e inhomogeneidad en T2. Los casos discordantes fueron evaluados por un tercer neuroradiólogo de mayor experiencia. Resultados: Treinta de 53 (56,6%) gliomas fueron no codelecionados, y 23/53 (43,4%) codelecionados. El signo del mismatch T2-FLAIR fue positivo en 16/53 (30,18%) pacientes, 15/16 (93,75%) no codelecionados y 1/16 (6,25%) codelecionado (Exacto de Fisher p = <,0001). Los dos evaluadores demostraron una concordancia interobservador casi perfecta para ese signo, κ =,907 (95% CI, 0,781 a 1,0). La especificidad y el valor predictivo positivo del signo para predecir la ausencia de la codeleción fue de un 95,7% y un 93,8% respectivamente. Discusión: La reciente actualización en la clasificación de los gliomas los clasifica acorde a su perfil molecular. En los últimos años, varios investigadores han estudiado características morfológicas por RM de los tumores con la intención de predecir las características moleculares de los mismos. Conclusión: En nuestra población, el signo del mismatch T2-FLAIR es el único biomarcador radiológico que muestra asociación estadísticamente significativa en predecir la ausencia de codeleción en los gliomas IDH-mutados (grado II y III), con una alta especificidad y un alto valor predictivo positivo.

Abstract Objective: To analyze magnetic resonance (MR) characteristics of IDH-mutated gliomas (grades II/III) utilizing qualitative parameters with the goal of assessing the performance of the T2-FLAIR mismatch sign and other morphological characteristics of tumors in predicting the 1p/19q co-deletion status as well as inter-observer reproducibility. Methods: Retrospective and descriptive study analyzing a cohort of 53 IDH-mutated lower-grade (grades II/III) gliomas with known 1p/19q co-deletion status. Patients meeting selection criteria for this study were taken from our institutional data from 2014-2019. Two neuroradiologists assessed the following imaging characteristics independently, and blinded from the diagnosis: T2-FLAIR mismatch, tumor location, borders, signal characteristics, cortical infiltration and T2* inhomogeneity. In the event of discordant interpretations, a third senior neuroradiologist also evaluated the case. Results: 23 of the 53 (43.4%) gliomas demonstrated 1p/19q co-deletion and 30 of 53 (56.6%) did not. T2-FLAIR mismatch was positive in 16 of 53 cases (30.2%) with 15 of 16 (93.8%) demonstrating no co-deletion and 1/16 (6.25%) with co-deletion (Fisher's exact p = < .0001). The two readers showed an almost perfect interreader agreement for this sign κ = 0.907 (95% CI, 0.781 to 1.0). Specificity and positive predictive value of the sign to predict the absence of co-deletion was 95.7% and 93.8% respectively. Discussion: The recent update in classification of lower-grade gliomas segregates gliomas according to molecular profile. In the recent past, many researchers have studied MR morphologic characteristics of these tumors with the intention of predicting molecular features of said tumors Conclusion: In our patient population, T2-FLAIR mismatch sign is the only radiologic biomarker that shows statistically significant association with the absence of 1p/19q co-deletion in lower-grade gliomas, with high specificity and positive predictive value.

Perfil Anatomopatológico e Imuno-histoquímico de Gliomas de Pacientes da Região de Maringá-PR / Anatomopathological and Immunohistochemical Profile of Gliomas of Patients in the Region of Maringá-PR / Perfil Anatomopatológico e Inmunohistoquímico de Gliomas en Pacientes la Región de Maringá-PR

Introdução: Os gliomas representam 80% dos tumores do sistema nervoso central. A Organização Mundial da Saúde (OMS) adicionou, em 2016, critérios moleculares na classificação dos gliomas. A fisiopatologia e os fatores de risco desses tumores ainda não são totalmente conhecidos. Objetivo: Realizar uma análise retrospectiva dos laudos anatomopatológicos e imuno-histoquímicos de gliomas. Método: Estudo transversal, retrospectivo e descritivo, a partir de exames anatomopatológicos e imuno-histoquímicos realizados entre janeiro de 2014 e dezembro de 2018 em um laboratório de anatomia patológica na cidade de Maringá-PR. Dos 234 laudos relacionados com o termo glioma, 204 foram selecionados para este estudo. Resultados: Foram encontrados tumores astrocitários, ependimários e oligodendrogliais, sendo que os astrocitomas corresponderam à maioria (86,8% dos casos encontrados). A média de idade ao diagnóstico foi de 51,8 anos e houve maior prevalência desses tumores no sexo masculino. Também foram analisadas mutações detectáveis por imuno-histoquímica como p53 (mutada em 66,7% dos testados), isocitrato desidrogenase (IDH) (28,6% mutados), X-linked alpha-thalassemia mental retardation (ATRX) (21,0%) e marcadores diagnósticos como o epithelial membrane antigen (EMA) positivo em todos os ependimomas analisados. Conclusão: É inegável a necessidade de novas pesquisas sobre os gliomas tanto no campo epidemiológico, tendo em vista a nova classificação, quanto no escopo fisiopatológico e clínico, com o objetivo de melhorar o entendimento sobre a patologia e o tratamento dos pacientes

Introduction: Gliomas represent 80% of the central nervous system tumors. World Health Organization (WHO) has added, in 2016, molecular features to the classification of gliomas. The pathophysiology and risk factors of these tumors are not yet fully understood. Objective: Perform a retrospective analysis of immunohistochemical and anatomopathological reports of gliomas. Method: Cross-sectional, retrospective and descriptive study carried out from anatomopathological and immunohistochemical exams made between January 2014 and December 2018 in a pathological anatomy laboratory in the city of Maringá-PR. Of the 234 reports related to the term glioma, 204 were selected for this study. Results: Astrocytic, ependymal and oligodendroglial tumors were found, with astrocytomas accounting for the majority (86.8% of the cases found). Mean age at diagnosis was 51.8 years and the prevalence was higher in men. Furthermore, immunohistochemically detectable mutations were analyzed, such as p53 (mutated in 66.7% of those tested), isocitrate dehydrogenase (IDH) (28.6% mutated), X-linked alpha-thalassemia mental retardation (ATRX) (21.0%) and diagnostic markers such as positive epithelial membrane antigen (EMA) in all analyzed ependymomas. Conclusion: The necessity of further researches on gliomas is undeniable , both epidemiologically considering the new classification and within the clinical and pathophysiological scope in order to improve the understanding of the pathology and the treatment for the patients

Introducción: Los gliomas representan 80% de los tumores del sistema nervioso central. La Organización Mundial de la Salud (OMS) agregó, en 2016, criterios moleculares sobre como clasificar los gliomas. La fisiopatología y los factores de riesgo de estos tumores aún no se comprenden completamente. Objetivo: Realizar un análisis retrospectivo de informes inmunohistoquímicos y anatomopatológicos de gliomas. Método: Estudio transversal, retrospectivo y descriptivo con base em pruebas anatomopatológicas e inmunohistoquímicas realizadas entre enero de 2014 y diciembre de 2018 en un laboratorio de anatomía patológica de la ciudad de Maringá-PR. De los 234 informes relacionados con el término glioma, se seleccionaron 204 para este estudio. Resultados: Se encontraron tumores astrocíticos, ependimarios y oligodendrogliales, siendo los astrocitomas la mayoría (86,8% de los casos encontrados). La edad media al diagnóstico fue de 51,8 años y hubo una mayor prevalencia de estos tumores en el sexo masculino. También se analizaron mutaciones detectables inmunohistoquímicamente, como p53 (mutado en 66,7% de los analizados), isocitrato desidrogenase(IDH) (28,6% mutado), X-linked alpha-thalassemia mental retardation (ATRX) (21,0%) y marcadores de diagnóstico como epithelial membrane antigen (EMA) positivo en todos los ependimomas analizados. Conclusión: Es innegable la necesidad de profundizaren las investigaciones sobre los gliomas, tanto en el campo epidemiológico, ante la nueva clasificación, como en el ámbito fisiopatológico y clínico, con el objetivo de mejorar el conocimiento sobre la patología y el tratamiento de los pacientes

Semi-quantitative evaluation of brain gliomas in adults: A focus on neuropathological characteristics

Introduction: Gliomas are neoplasms with high recurrence and mortality. Due to the difficulty to apply the World Health Organization (2016) classification, developing countries continue to use histological evaluation to diagnose and classify these neoplasms. Objective: To develop a semi-quantitative scale to numerically grade gliomas by its morphological characteristics. Method: A cohort of patients with gliomas was assessed and followed for 36 months. Tumor tissue sections were analyzed and graded, including aspects such as cell line, cellularity, nuclear pleomorphism, mitosis, endothelial hyperplasia, hypoxic changes, apoptotic bodies, necrosis, hemorrhage and proliferation index. Results: 58 cases were analyzed. Low-grade gliomas median score was 12 points (9 and 13.5 for percentiles 25 and 75, respectively), whereas for high-grade gliomas it was 17 points (16 and 20.5 for percentiles 25 and 75, respectively) (p < 0.0001). Thirty-six-month survival of patients with low (13/17) and high grade gliomas (6/41) was also significantly different (p < 0.0001). Conclusions: The semi-quantitative morphological scale allows an objective evaluation of gliomas, with an adequate correlation between the score, tumor grade and survival time.

Current concepts in the pathology and genetics of gliomas.

In recent years, there has been a marked improvement in our understanding of molecular genetics of gliomas. These advancements offer hope for development of tailored therapies targeting a tumor's unique molecular profile, and may also translate into improved classification and identification of newer prognostic markers. This review focuses on the neuropathological features of different types of glial neoplasms according to the World Health Organization classification, and the recent advances in their molecular biology with emphasis on the genetic mechanisms underlying tumor progression, diagnostic and prognostic markers and potential therapeutic targets.

Current concepts and newer developments in the treatment of malignant gliomas.

Primary malignant brain tumors account for only 2% of all adult cancers but they cause a disproportionately high cancer-related disability and death. Survival of malignant glioma patients has changed only modestly over the past three decades despite the emergence of new treatment strategies for these tumors. In this review, we describe the standard treatment modalities for malignant glioma, which include surgery, radiation therapy and chemotherapy, as well as the status of novel therapies that have been developed to target various aspects of glioma cell biology. We also address this issue of drug delivery as a factor limiting the efficacy of systemic administration of therapeutics and attempts to overcome this barrier. Further progress towards a cure for malignant gliomas will require a greater understanding of the underlying mechanisms driving the growth, and resistance to therapy, of these challenging tumors.

Gliomas de alto grado en adultos / High grade gliomas in adults

Malignant gliomas represent 80 percent of primary malignant central nervous system tumors. It generally presents with headache, epilepsy, cognitive change, dysphasia, or progressive hemiparesia. Current standard treatment for malignant glioma includes: surgical resection or biopsy, radiation therapy and/or chemotherapy. The prognosis of malignant gliomas is still dismal despite aggressive treatment attempts. Understanding the molecular pathogenesis of glioma may lead to a rational development of new therapies. This review summarizes the diagnosis and management of these tumors in adults.

Estado actual de la terapia antiangiogénica en el manejo de gliomas de alto grado / Present state of the antiangiogenic therapy in the management of gliomas of high degree

High grade gliomas are lethal cancers. Despite recent advances in surgery, radiotherapy and chemotherapy, the overall survival is 15 months for glioblastoma. They are among the most vascular of human tumors, making them especially attractive targets for angiogenesis inhibitors. Most clinical trials of these agents as monotherapy have failed to demonstrate survival benefit in unselected high grade glioma patient populations. Several mechanisms of treatment failure have been postulated. In response, there are new intervention strategies on course: the combination of target therapy with classic chemotherapy, multitargeted kinase inhibitors and combinations of single-targeted kinase inhibitors and the identification of correlative biomarkers. These advances provide real opportunities for the development of effective therapies for high grade gliomas.

Expression of cytokeratins in gliomas.

Metastatic carcinoma, which is a common malignant tumor seen in the central nervous system is often difficult to distinguish from glioblastoma multiforme. In general, neoplastic cells maintain fidelity in the expression of parent cell intermediate filament and immunohistochemistry remains the mainstay in diagnosis. A panel consisting of GFAP (usually positive for astrocytic tumors) and cytokeratin (usually positive for metastatic carcinomas) is most commonly used for this purpose. However, co-expression of two or more classes of intermediate filament proteins by neoplasms is a widespread phenomenon and there are reports of glial neoplasms expressing keratin markers. Our aims and objectives were to analyse the expression of both cytokeratin and GFAP in different glial tumors and metastatic carcinomas. Cases were collected for a period of two years. All the cases were diagnosed as primary or metastatic intracranial tumors. Formalin-fixed paraffin-embedded thin sections were taken on egg-albumin coated slides and immunostaining with GFAP and polyclonal cytokeratin was done. Forty-five tumors were analysed, including 35 glial neoplasms and 10 metastatic carcinomas of which 7 of the 32 astrocytic neoplasms (22%) showed focal immunoreactivity with pancytokeratin. All of the glial tumors but none of the metastatic carcinomas were positive with GFAP. So our conclusion was that co-expression of GFAP and CK is a fairly common phenomenon, especially in case of undifferentiated and high grade gliomas and this must be kept in mind while differentiating these cases from metastatic carcinoma, as CK positivity does not rule out the diagnosis of a glial neoplasm. Further studies with an expanded panel of CK is most useful for this.

Role of survivin in glioma progression: a clinico-pathological study

Gliomas are among the most aggressive of all human malignancies. Glioblastoma multitbrme is the most malignant histopathological subtype. Survivin is one of the inhibitors of apoptosis. It is over-expressed in many human cancers. We performed clinical and pathological study aimed to clarify its role in glioma progression. Gliomas are among the most aggressive of all human malignancies. Glioblastoma multiforme is the most malignant histo-pathological subtype. Survivin is one of the inhibitors of apoptosis. It is over-expressed in many human cancers. We performed clinical and pathological study aimed to clarify its role in glioma progression. This study included 34 glioma patients. Clinical evaluation including age, sex, clinical presentation and location of the tumor, was done. Sections from glioma specimens were stained with H and E, classified and graded according to WHO classification, [2000] and then immunostained to detect Survivin protein expression. The study included 34 glioma cases. Survivin was expressed to a variable extent in most groups of gliomas [in 21/24, 1/4, 1/1 and 5/5 cases of astrocytomas, oligodendrogliomas, mixed oligoastrocytoma and ependymomas respectively]. Survivin expression showed gradual up-regulation with increasing grade of astrocytomas from pilocytic astrocytomas [66.7%] [right arrow] diffuse astrocytomas [77.8%] [right arrow] anaplastic astrocytomas [100%] [right arrow] glioblastoma multiforme [100%]. This study showed that there is a strong correlation between the distribution and staining intensity of Survivin protein expression and the tumor grade [P< value< 0.01 and < 0.00 respectively]. Also there is a strong correlation hetueen Survivin protein expression as evidenced by immunoreactivity score [IRS] and tumor grade and proliferative activity [P value< 0.00 and <0.002 respectively]. Survivin plays an important role in the initiation of gliomas and their progression towards higher grades

Gliomas múltiplos: casos ilustrativos de quatro formas de apresentação / Multiple gliomas: illustrative cases of 4 different presentations

Os gliomas múltiplos são relativamente raros e podem ser classificados didaticamente de acordo com: a) a época da apresentação, em precoces (quando presentes desde o diagnóstico inicial) ou tardios (quando presentes durante a evolução); e b) as características dos exames de imagem, em multifocais (quando há evidência de contiguidade das lesões) ou multicêntricos (quando não é possível identificar contiguidade das lesões). Entre os 212 pacientes com diagnóstico anatomopatológico de glioma, acompanhados prospectivamente no setor de neuro-oncologia de março/90 a setembro/99, 15 (7 por cento) apresentaram lesões múltiplas. Descrevemos 4 casos característicos de cada uma das possíveis apresentações: multicêntrico precoce, multicêntrico tardio, multifocal precoce e multifocal tardio, com ênfase nas características de imagem e possíveis diagnósticos diferenciais. O diagnóstico diferencial das lesões múltiplas no sistema nervoso central inclui doenças inflamatórias e infecciosas, além de metástases. A possibilidade de tratar-se de tumores de origem glial, entretanto, deve ser sempre lembrada, mesmo naqueles pacientes com diagnóstico de neoplasia sistêmica conhecida, conforme já descrito na literatura. O diagnóstico histológico se impõe, uma vez que as características de imagem não permitem diagnóstico de certeza.

Brain stem gliomas, clinico radiological study: a classification system with "prognostic significance" is suggested

In the present study 21 patients with the clinico-radiological diagnosis of brain stem glioma are included [13 males and 8 females]. Patients were subjected to [1] Full clinical examination [2] MRI and/or CT scan of the brain with and without intravenous contrast enhancement. CT myelography was also done to patients presented with cervicomedullary gliomas. According to the duration of symptomatology before clinical presentation, the anatomical localization of the brain stem gliomas [diffuse versus focal, Cystic versus sold], the pattern of contrast enhancement [non, diffuse, ring or patchy enhancement], the pattern of response to radiotherapy and the overall prognosis during a one year follow up, patients were classified into five groups. Group [1] patients with diffuse brain stem gliomas and with a relatively better prognosis [10 patients, 47.5%], group [2] patients with diffuse brain stem gliomas and with a relatively worse prognosis [4 patients, 19%], group [3] patients with focal pontine or midbrain gliomas [4 patients, 19%], group [4] patients with cervicomedullary gliomas [2 patients, 9.5%] and group [5] a single patient [5%] with probable brain stem metastasis. The clinical and radiological findings in the various groups will presented and discussed. Lines of treatment, clone to each group, and the result of a one year follow up will also be presented and discussed

Estudio estructural comparativo de los blastomas gliales del sistema nervioso central / Comparative structural study of the glial blastomas of the central nervous system

El OBJETIVO de nuestro trabajo es comparar 2 métodos diagnósticos, y demostrar las semejanzas de las distintas Clasificaciones de los Tumores Gliales del Sistema Nervioso Central. Se realizaron técnicas de inmunomarcación para proteína gliofibrilar ácida (GFAP), e impregnaciones argénticas especiales para confrontar los hallazgos según las últimas interpretaciones histogenéticas. Estudiamos 95 Gliomas con hematoxilina-eosina y técnicas argénticas, y en 58 casos tomados al azar realizamos además la técnica para GFAP. Con ambos métodos obtuvimos resultados iguales en el diagnóstico de tumores gliales cuyas células poseen gliofibrillas: Glioepiteliomas (Ependimonas), Glioblastomas, Astroblastomas y Astrocitomas. En los Oligodendrogliomas cuyas células no poseen gliofibrillas pero sí microtúbulos, las técnicas argénticas marcaron estas células y sus prolongaciones, no así la técnica para GFAP. Hay semejanzas al comparar la Clasificación de Del Río Horttega-Polak con la de la OMS y la de otros autores, en lo referente a los Gliomas. Sólo hay diferencias en la nomenclatura de algunos tumores o en su interpretación histogenética, que no son sustanciales y están limitados, que no son sustanciles y están limitados al "Espongioblastoma Polar" y al "Gliosarcoma". Por lo tanto, creemos que la revalorización de la Clasificación de Del Río Hortega-Polak está justificada.

Tumores sellares y suprasellares que afectan al quiasma y nervios ópticos. III. Gliomas diencefálicos de nervios y quiasma ópticos, ependimomas y subependimomas, espongioneuroblastomas, hemangionas diencefálicos, alteraciones inflamatorias / Sellar and suprasellar tumors afecting chiasma and optic nerves. Part III. Diencephalic gliomas of the chiasma and optic nerve, ependimomas ans subepondimomas, spongioneuroblastomas, diencephalic hemangiomas and inflamatory alterations

Las vías visuales anteriores pueden dañarse por: Tumores que se originen del quiasma y nervio óptico (astrocitoma y glioblastoma multiforme), adenomas pituitarios y arqueoblastomas, gliomas diencefálicos, espongioneuroblastoma, ependimomas y excepcionalmente por parásitos o procesos inflamatorios, granulomatosos que actúan como una masa ocupativa intracraneana. Es necesario tener en mente estos padecimientos en el diagnóstico diferencial. Es frecuentemente que los pacientes acudan primero con el optometrista o el oftalmólogo, en este último es en quien recae la responsabilidad más importante en la prontitud del diagnóstico

Ependimoma mixopapilar con erosión e invasión de la columna vertebral. Presentación de dos casos / Myxopapillary ependymoma with vertebral invansion and erosion. A report of two cases

El ependimoma es el tumor intramedular más frecuente de los segmentos torácico, lumbar y sacro. De las tres variedades descritas por Kernohan, la mixopapilar es la que afecta casi exclusívamente al cono medular y al filum terminale. Excepcionalmente erosiona e invade a la columna vertebral. En este informe se presentan dos casos en los que se demuestra erosión e invasión, en uno por medio de estudio post-mortem, y en otro por medio de estudios de imagen y biopsia