Multiple Intraspinal Gangliogliomas in a Child With Neurofibromatosis Type 1: Case Report and Literature Review.

Neurofibromatosis type 1 (NF1)-associated primary intramedullary spinal cord ganglioglioma has only rarely been reported. Because of frequent nonresectability, they pose significant management challenges despite clinical indolence. This report describes a 4-year-old girl with NF1 who was found to have multiple discrete, infiltrative intramedullary cord masses, and biopsy demonstrated World Health Organization grade I ganglioglioma. Panel-based next-generation sequencing showed her previously identified germline NF1 mutation and a second somatic NF1 mutation. This represents the first report of multiple primary intramedullary gangliogliomas in a child with NF1 and demonstrates how biopsy with panel-based next-generation sequencing provides potential targets for MAPK/MEK/BRAF pathway inhibitor therapy.

Ganglioglioma of brain stem and cervicomedullary junction: A 50years review of literature.

Gangliogliomas are rare low-grade brain tumors composed of both neoplastic glial and neuronal cell elements. The treatment modalities are relatively different in this location and hence factors affecting outcome are poorly understood. We identified 142 brain stem GG patients across 46 studies. The average age was 11.4years with significant difference b/w males and females under the age of 20 (p=0.001). 100% of tumors in the CMJ while, 72% of type I and 86% of type II tumors demonstrated contrast enhancement. 72% of type I and 86% of type II tumors demonstrated contrast enhancement. All BRAF mutation positive tumors demonstrated contrast enhancement. Medulla and pons was the most favorable location followed by medulla alone, and the CMJ. In all tumors "gross total resection" (GTR, 16%), "subtotal resection" (STR, 48%) or "partial resection" (PR, 36%) was achieved. Most subtypes II and III were partially resected (86% and 66%), while, subtype I underwent STR (66%). Only 55% of the patients were positive for the BRAF V600E mutation. The overall survival dropped from 50% at 24 to 10% at 60months, postoperatively. Through this review, we found that an early diagnosis, location, and with the imaging characteristics are vital part of the preoperative planning. Surgical resection is highly dependent on location in the brain stem with radical resection only limited to the most contrast enhancing portion of these tumors. BRAF V600E mutation status should be considered to allow the possibility of targeted therapy in case of a residual tumor and/or regrowth.

Longitudinal mutational analysis of a cerebellar pilocytic astrocytoma recurring as a ganglioglioma.

A cerebellar pilocytic astrocytoma (PA) in a child recurred first with a PA histology and then with features of a ganglioglioma (GG). Molecular genetic analyses of the tumors confirmed a BRAF V600E mutation in all. They also all harbored a T202M mutation in ERK1, a kinase downstream of BRAF that is implicated in glial versus neuronal differentiation. The GG sample contained several variants that were not present in the PA samples; in particular, it had a truncating mutation in MAP2. These findings not only underscore the role of BRAF as oncogenic driver but also suggest that other genes may influence tumor morphology.

An Unusual Case of Constitutional Mismatch Repair Deficiency Syndrome With Anaplastic Ganglioglioma, Colonic Adenocarcinoma, Osteosarcoma, Acute Myeloid Leukemia, and Signs of Neurofibromatosis Type 1: Case Report.

BACKGROUND AND IMPORTANCE: Constitutional mismatch repair deficiency (CMMRD) syndrome is a disorder with recessive inheritance caused by biallelic mismatch repair gene mutations, in which mismatch repair defects are inherited from both parents. This syndrome is associated with multiple cancers occurring in childhood. The most common tumors observed with CMMRD include brain tumors, digestive tract tumors, and hematological malignancies. The aim of this study was to report new phenotypic expressions of CMMRD syndrome and add new insight to the existing knowledge about this disease. A review of the literature was conducted and recommendation for surveillance and follow-up in patients with CMMRD are proposed. CLINICAL PRESENTATION: We report for the first time in the literature, the case of a 22-year-old female patient who was diagnosed with CMMRD syndrome, with the development of 2 unusual tumors: an anaplastic ganglioglioma and an osteosarcoma. She presented initially with an anaplastic ganglioglioma and later developed several malignancies including colonic adenocarcinoma, osteosarcoma, and acute myeloid leukemia. The patient had an atypical course of her disease with development of the initial malignancy at an older age and a remarkably long survival period despite developing aggressive tumors. CONCLUSION: Many aspects of this disease are still unknown. We identified a case of CMMRD in a patient presenting with an anaplastic ganglioglioma, who underwent successful surgical resection, chemotherapy, and radiotherapy and has had one of the longest survival periods known with this disease. This case broadens the tumor spectrum observed with CMMRD syndrome with anaplastic ganglioglioma and osteosarcoma as new phenotypic expressions of this genetic defect.

Ganglioglioma arising from dysplastic cortex.

We report the case of a child who presented at 3 months of age with complex partial seizures, a linear facial nevus, and magnetic resonance imaging (MRI) showing delayed myelination and thickened cortex in the left temporal, parietal, and occipital regions. A repeat 3Tesla MRI scan with and without contrast at 6 months again showed cortical dysplasia of the left hemisphere. No other abnormalities were seen. A third scan at 3 years 6 months showed a 2.5 cm, round, hyperintense lesion on both T(2) and T(1) sequences. The lesion and surrounding dysplastic cortex were resected. Palmini grade IIA dysplasia and a ganglioglioma were diagnosed. These findings suggest that cellular components of cortical dysplasias have oncogenic potential.

Desmoplastic infantile ganglioglioma: novel aspects in clinical presentation and genetics.

BACKGROUND: Desmoplastic infantile ganglioglioma is a rare tumor occurring mainly in infants and young children. Both radiological and histopathological appearances may resemble malignancy, although its clinical course is mainly benign. METHODS: Altogether, 5 cases of DIG have been operated on in our hospital since the first diagnosis of DIG in Finland in 1993. We evaluated their presenting symptoms, radiological and surgical findings, histologic characteristics, and follow-up. RESULTS: All patients were male. Three were less than 18 months old, and 2 were 35 and 79 months old. The most common presenting symptoms were epileptic seizures (4 cases). In 4 cases, there was a histopathologically verified single cystic tumor. In 1 case, DIG was operatively diagnosed in 2 separate locations. This patient, moreover, had 2 other lesions suspected of being DIG, including a mass originating from the ophthalmic nerve. None of the patients received adjuvant therapies. All our patients are alive after 7 to 120 months of follow-up. There were no recurrences in any of the patients after tumor resection. For the first time, we describe EGFR and MYCN amplifications in tumors which are, respectively, of their mixed glial and neuronal origin. CONCLUSION: The clinical presentation of DIG may be more often associated with epileptic seizures than previously thought. The radiological appearance of DIG may vary from cystic to solid and from contrast-enhancing to nonenhancing. Even multiple locations of DIG have been encountered. Increasing evidence supports surgery as the treatment of choice for DIG, although oncogene amplifications have been described.

Ganglioglioma arising in a Peutz-Jeghers patient: a case report with molecular implications.

The Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder caused by inactivating germline mutations in the serine-threonine kinase gene LKB1, is characterized by mucocutaneous pigmentation, multiple gastrointestinal hamartomatous polyps, and by an increased risk for developing tumors involving several different organs. To date, no brain tumors have been described in PJS patients. In this report, we describe a case of ganglioglioma in a 22-year-old PJS patient. Single-strand conformation polymorphism-Heteroduplex analysis evidenced an abnormal pattern in exon 6 of the LKB1 gene. Sequencing revealed a 821delTinsAC mutation creating a termination codon 29 nucleotides downstream (p.Asn274fsX11). RNA studies showed an out-of-frame LKB1 isoform derived from the wild type allele and generated by exon 4 skipping. Since the LKB1 gene is expressed in the fetal and adult brain, our data would suggest its likely involvement in the pathogenesis of a subset of gangliogliomas.

[The onset of an anaplastic ganglioglioma during the post-natal period with signs of toxemia of pregnancy]. / Inicio de un ganglioglioma anaplásico durante un puerperio con signos de toxemia gravídica.

INTRODUCTION: Gangliogliomas are infrequent neuronoglial tumours which present in youngsters and are usually located in the temporal lobe. They usually appear with epileptic seizures and prognosis after surgical excision is usually good. The anaplastic forms are even less frequent and prognosis is poorer. The onset of epileptic seizures during the early post-natal period means that the clinician has to resort to a broad differential diagnosis. CASE REPORT: Hours after a preterm birth, at the 32nd week of gestation, a 35-year-old primipara began to suffer seizures and also presented arterial hypertension, proteinuria and a low platelet count. A cranial computerized tomography scan was carried out where a left frontal hypodense lesion was observed. Transcranial echo Doppler scan showed medium speeds and suggested eclampsia. The seizures, however, recurred during the days that followed and a magnetic resonance scan of the head revealed a lesion with nodular contrast enhancement, which was excised, and finally an anatomopathological diagnosis of an anaplastic ganglioglioma was reached. DISCUSSION: The toxemia of pregnancy, which gave rise to a vasogenic cerebral edema, accelerated the clinical onset of a brain tumour during the post-natal period. A ganglioglioma, although infrequent, is always a possibility to be borne in mind in young patients.

Lhermitte-Duclos disease is a clinical manifestation of Cowden's syndrome.

BACKGROUND: Lhermitte-Duclos disease (LDD) is a hamartomatous overgrowth of cerebellar ganglion cells, which replace granular cells and Purkinje cells. In recent years several cases involving the association between LDD and Cowden's syndrome (CS), an autosomal dominant condition characterized by multiple hamartomas and neoplastic lesions in skin and internal organs, have been reported. METHODS: We reviewed the medical records and imaging studies of six patients with LDD who were treated at our institution, and we looked at other possible symptoms of CS. RESULTS: Other clinical findings suggestive of CS were apparent in five patients: These included mucocutaneous lesions, acral keratosis, thyroid adenoma, fibrocystic disease, ovarian cyst, intestinal polyposis, and arteriovenous malformation. Only in the youngest patient, a 5-year-old boy, were no cutaneous or other signs found, despite extensive clinical and ultrasound examination. CONCLUSION: Our observations strengthen the hypothesis that LDD is a neurological manifestation of CS. Patients with LDD should receive a thorough dermatological and systemic screening, because some of the lesions (breast, etc...) can develop into malignant tumors.

Ganglion cells in the posterior pituitary: result of ectopia or transdifferentiation?

Histologic examination revealed large ganglion cells within the posterior pituitary of an 80-year-old woman who died of myocardial infarction. Apparently fully mature, the cells were an incidental finding scattered within hyperplastic foci of pars intermedia (PI)-derived cells (basophil invasion) on histologic examination of the pituitary obtained at autopsy. Immunocytochemistry showed staining reactivity for neuron-specific enolase, synaptophysin, alpha subunit of the glycoprotein hormones and beta-endorphin. The presence of these ganglion cells with features similar to those of magnocellular hypothalamic neurons could be considered the result of abnormal migration during the early phase of embryonic life, or differentiation/maturation of neuroblasts, presumed to occur in the embryonic neurohypophysis. Alternatively, transdifferentiation from proliferating PI cells may explain the emergence of neurons; a hypothesis supported by the proximity and shared alpha subunit, and beta-endorphin immunoreactivities of the two cell types.

Evidence for developmental precursor lesions in epilepsy-associated glioneuronal tumors.

The etiology and pathogenesis of epilepsy-associated local lesions remain largely unknown. Histopathologically, the most frequent lesions comprise gangliogliomas and glioneuronal malformations, i.e., hamartias or hamartomas, with a preferred location in the temporal lobe of young patients. A characteristic histopathological admixture of glial and neuronal elements, the focal appearance and the benign clinical behaviour suggest a malformative nature. So far, no molecular genetic alterations specifically involved in the pathogenesis of these glioneuronal lesions have been identified. However, immunohistochemical analysis revealed distinct distribution patterns of oncofetal antigens. The embryonic form of the neural cell adhesion molecule is present within glioneuronal hamartias, indicating an early migrational disorder. Recently, we have observed immunoreactivity for the stem cell marker CD34 in the majority of gangliogliomas and glioneuronal hamartomas. Based on these findings, we propose a common origin of gangliogliomas and glioneuronal hamartomas from a bipotent precursor that undergoes abnormal glioneuronal development.

Neoplasias asociadas a epilepsia fármaco-resistente crónica: ¿un nuevo concepto en tumores cerebrales? / Neoplasms associated to chronic pharmaco-resistant epilepsy: a new concept in brain tumors?

La epilepsia fármaco resistente crónica (EFRC) se asocia frecuentemente a lesiones neoplásicas (LN). El diagnóstico precoz de las LN ha aumentado desde la introducción de la resonancia magnética (RM) en el estudio rutinario de la epilepsia refractaria. Los pacientes con EFRC presentan un espectro de LN muy diferente al observado normalmente en otros pacientes neuroquirúrgicos portadores de tumores cerebrales. Las LN están presentes en alrededor de un 30 por ciento de los pacientes operados por EFRC, en los cuales la epilepsia es frecuentemente el único síntoma y con una historia clínica que supera los 10 años con crisis parciales complejas (con o sin generalización secundaria). La RM suele revelar una señal anormal en todos los pacientes, sin mostrar efecto de masa o edema. La cirugía consiste en resección de la LN, incluyendo el tejido epileptógeno perilesional, determinado por video-electroencefalografía digital o eventualmente por electrocorticografía en casos no concluyentes. Las LN más frecuentes encontradas son: gangliogliomas, gliomas de bajo grado (especialmente astrocimas) y tumores disembrioplásticos neuroepiteliales. La larga duración preoperatoria de la EFRC indica que la mayoría de las LN han permanecido largo tiempo en el encefálo y que han crecido muy lentamente o bien han permanecido estáticas. El control post-operatorio de las crisis así como la sobrevida sugiere que las LN en las EFC tienen un excelente pronóstico. Sin embargo un seguimiento más largo es necesario para establecer el pronóstico rela de las LN en el área de la RM

Gangliogliomas: revisión de la literatura / Gangliogliomas: review of the literature

El ganglioglioma es un tumor infrecuente del sistema nervioso central (SNC), compuesto por una mezcla de neuronas maduras situadas en una matriz glial usualmente astrocitaria. El ganglioglioma se puede ubicar en cualquier lugar del SNC, es más frecuente en la región supratentorial y con preferencia y con preferencia en el lóbulo temporal donde suele asociarse a epilepsia refractaria. El origen del ganglioglioma es desconocido, probablemente se debe a una falla del desarrollo embrionario. Su conducta biológica es generalmente benigna, y la anaplasia es un hecho altamente infrecuente. La resonancia magnética es el examen de elección; ésta evidencia generalmente una lesión quística, con porciones sólidas ocasionalmente calcificaciones asociadas. El tratamento de elección es la resección completa de la lesión, la cula en los casos sin anaplasia es considerada curativa. Si existe epilepsia refractaria asociada se debe además localizar y resecar el foco epileptógeno