RESUMEN
OBJECTIVES: To elucidate the relationship between DNA methylation profiling (DMP) and pathological diagnosis (PD) in pediatric glial and glioneuronal tumors with B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations, addressing their diagnostic challenges. METHODS: This retrospective study, conducted in Saudi Arabia, analyzed 47 cases from the Children's Brain Tumor Network online database using scanned images, next-generation sequencing data, and methylation profiles processed using the Heidelberg methylation brain tumor classifiers v12.5 and v12.8. The data was last access on 10 November 2023. RESULTS: The highest prevalence of BRAF mutations was observed in pilocytic astrocytoma and ganglioglioma. The DMP was consistent with PD in 23 cases, but discrepancies emerged in others, including diagnostic changes in diffuse leptomeningeal glioneuronal tumor and polymorphous low-grade neuroepithelial tumor of the young. A key inconsistency appeared between a pilocytic astrocytoma MC and a glioneuronal tumor PD. Two high-grade astrocytomas were misclassified as pleomorphic xanthoastrocytomas. Additionally, low variant allelic frequency in gangliogliomas likely contributed to misclassifications as control in 5 cases. CONCLUSION: This study emphasized the importance of integrating DMP with PD in diagnosing pediatric glial and glioneuronal tumors with BRAF mutations. Although DMP offers significant diagnostic insights, its limitations, particularly in cases with low tumor content, necessitate cautious interpretation, as well as its use as a complementary diagnostic tool, rather than a definitive method.
Asunto(s)
Neoplasias Encefálicas , Metilación de ADN , Mutación , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas B-raf , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/diagnóstico por imagen , Niño , Masculino , Femenino , Metilación de ADN/genética , Estudios Retrospectivos , Preescolar , Ganglioglioma/genética , Ganglioglioma/patología , Ganglioglioma/diagnóstico por imagen , Adolescente , Glioma/genética , Glioma/patología , Glioma/diagnóstico , Astrocitoma/genética , Astrocitoma/patología , Astrocitoma/diagnóstico por imagen , Astrocitoma/diagnóstico , Lactante , Arabia SauditaRESUMEN
Objective: To investigate the clinical, radiological, and pathological features of anaplastic gangliogliomas (AGGs) and to determine whether these tumors represent a distinct entity. Methods: Consecutive 667 cases of ganglioglioma (GG) diagnosed at the Xuanwu Hospital, Capital Medical University, Beijing, China between January 2015 and July 2023 were screened. Among these cases, 9 pathologically confirmed AGG cases were identified. Their clinical, radiological, treatment, and outcome data were analyzed retrospectively. Most of the tumor samples were subject to next-generation sequencing, while a subset of them were subject to DNA methylation profiling. Results: Among the 9 patients, there were five males and four females, with a median age of 8 years. Epileptic seizures (5/9) were the most frequently presented symptom. Radiological examinations showed three types of radiological manifestations: four cases showed abnormal MRI signals with no significant mass effects and mild enhancement; two cases demonstrated a mixed solid-cystic density lesion with peritumoral edema, which showed significant heterogeneous enhancement and obvious mass effects, and one case displayed cystic cavity formation with nodules on MRI, which showed evident enhancements. All cases exhibited mutations that were predicted to activate the MAP kinase signaling pathway, including seven with BRAF p.V600E mutation and two with NF1 mutation. Five AGGs with mutations involving the MAP kinase signaling pathway also had concurrent mutations, including three with CDKN2A homozygous deletion, one with a TERT promoter mutation, one with a H3F3A mutation, and one with a PTEN mutation. Conclusions: AGG exhibits a distinct spectrum of pathology, genetic mutations and clinical behaviors, differing from GG. Given these characteristics suggest that AGG may be a distinct tumor type, further expansion of the case series is needed. Therefore, a comprehensive integration of clinical, histological, and molecular analyses is required to correctly diagnose AGG. It will also help guide treatments and prognostication.
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Neoplasias Encefálicas , Metilación de ADN , Ganglioglioma , Imagen por Resonancia Magnética , Mutación , Fosfohidrolasa PTEN , Proteínas Proto-Oncogénicas B-raf , Humanos , Ganglioglioma/patología , Ganglioglioma/genética , Masculino , Femenino , Niño , Estudios Retrospectivos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Proteínas Proto-Oncogénicas B-raf/genética , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Telomerasa/genética , Histonas/genética , Histonas/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Epilepsia/patología , Epilepsia/genéticaAsunto(s)
Neoplasias Encefálicas , Ganglioglioma , Neoplasias Meníngeas , Humanos , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/diagnóstico por imagen , Diagnóstico Diferencial , Ganglioglioma/patología , Ganglioglioma/diagnóstico , Ganglioglioma/terapia , Imagen por Resonancia Magnética , Neoplasias Meníngeas/patología , Neoplasias Meníngeas/diagnósticoRESUMEN
Ganglioglioma (GG) with anaplasia (anaplastic ganglioglioma) is a rare and controversial diagnosis. When present, anaplasia involves the glial component of the tumor, either at presentation or at recurrence. To date, most published cases lack molecular characterization. We describe the histologic and molecular features of 3 patients presenting with BRAF p. V600E-mutant GG (CNS WHO grade 1) with high-grade glial transformation at recurrence. The tumors occurred in pediatric patients (age 9-16 years) with time to recurrence from 20 months to 7 years. At presentation, each tumor was low-grade, with a BRAFV600E-positive ganglion cell component and a glial component resembling pleomorphic xanthoastrocytoma (PXA) or fibrillary astrocytoma. At recurrence, tumors resembled anaplastic PXA or high-grade astrocytomas without neuronal differentiation. CDKN2A homozygous deletion (HD) was absent in all primary tumors. At recurrence, 2 cases acquired CDKN2A HD; the third case showed loss of p16 and MTAP immunoexpression, but no CDKN2A/B HD or mutation was identified. By DNA methylation profiling, all primary and recurrent tumors either grouped or definitely matched to different methylation classes. Our findings indicate that malignant progression of the glial component can occur in GG and suggest that CDKN2A/B inactivation plays a significant role in this process.
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Neoplasias Encefálicas , Ganglioglioma , Humanos , Ganglioglioma/genética , Ganglioglioma/patología , Adolescente , Niño , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Masculino , Femenino , Proteínas Proto-Oncogénicas B-raf/genética , Epigénesis Genética , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patologíaRESUMEN
To analyse the imaging findings of papillary glioneuronal tumors (PGNTs), in order to improve the accuracy of preoperative diagnosis of this tumor. The clinical and imaging manifestations of 36 cases of PGNT confirmed by pathology were analyzed retrospectively. A total of 17 males and 19 females, averaging 22.47 (± 11.23) years. Initial symptoms included epilepsy in ten, headache in seven, and others in 19 cases. 97.2% (35/36) of the lesions were located in the supratentorial area, and 80.5% (29/36) in the intraventricular or deep white matter adjacent to the lateral ventricles. Twenty-four of the lesions (66.7%) were mixed cystic and solid, four (11.1%) were cystic with mural nodules, four (11.1%) were cystic, and four (11.1%) were solid. Four cases of PGNT of cystic imaging showed a "T2-FLAIR mismatch" sign. 69.4% (25/36) had septations. Nine lesions (25%) were accompanied by edema, and 9 (25%) of the mixed cystic and solid lesions were accompanied by hemorrhage. Among the 18 patients who underwent computed tomography (CT) or susceptibility-weighted imaging (SWI), nine had lesions with calcification. PGNTs mostly manifest as cystic mass with mural nodules or mixed cystic and solid mass in the white matter around the supratentorial ventricle, and the cystic part of the lesion is mostly accompanied by septations. Pure cystic lesions may exhibit the sign of "T2-FLAIR mismatch". PGNT is rarely accompanied by edema but sometimes by calcification and hemorrhage. Patients often present with seizures, headaches, and mass effect symptoms.
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Neoplasias Encefálicas , Imagen por Resonancia Magnética , Humanos , Masculino , Femenino , Adulto , Adolescente , Adulto Joven , Niño , Estudios Retrospectivos , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Tomografía Computarizada por Rayos X , Persona de Mediana Edad , Ganglioglioma/cirugía , Ganglioglioma/patología , Ganglioglioma/diagnóstico por imagen , PreescolarRESUMEN
AIM OF THE STUDY: To assess whether the middle temporal gyrus (MTG) approach to mesial temporal lobe (MTL) tumours is an effective procedure for the treatment of epilepsy in children. CLINICAL RATIONALE FOR THE STUDY: MTL tumours are a common cause of drug-resistant epilepsy in children. There is as yet no consensus regarding their treatment. One possibility is resection via a MTG approach. MATERIAL AND METHODS: We assessed the medical records of patients treated at the Department of Neurosurgery, Children's Memorial Health Institute,Warsaw, Poland between 2002 and 2020. A prospectively maintained database including clinical, laboratory, and radiographic presentation, as well as pre- and post-operative course, was analysed. Patients with at least a one- -year follow-up were included. RESULTS: There were 14 patients aged 4-18 years who underwent a MTG approach for a MTL tumour. All presented with epileptic seizure, and none had neurological deficit on admission to hospital. Median follow-up was 2.5 years. Neuronavigation was used to adjust the approach, localise the temporal horn, and achieve radical resection of the tumour and the hippocampus. Gross total resection was performed in all cases. In most patients, histopathological examination revealed ganglioglioma. One patient had transient aphasia. Two patients developed hemiparesis after surgery, which later improved. One of them also experienced visual disturbances. Acute complications were more frequent in younger patients (p = 0.024). In all cases, MRI confirmed complete resection and there was no tumour recurrence during the follow-up period. 13/14 patients remained seizure-free (Engel class I). CONCLUSIONS AND CLINICAL IMPLICATIONS: The MTG approach to MTL tumours is an effective procedure for the treatment of epilepsy in children. It avoids removal of the lateral temporal lobe and poses only a minor risk of permanent neurological complications.
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Neoplasias Encefálicas , Lóbulo Temporal , Humanos , Niño , Femenino , Masculino , Adolescente , Preescolar , Lóbulo Temporal/cirugía , Lóbulo Temporal/patología , Lóbulo Temporal/diagnóstico por imagen , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/cirugía , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Polonia , Procedimientos Neuroquirúrgicos/métodos , Resultado del Tratamiento , Ganglioglioma/cirugía , Ganglioglioma/patología , Ganglioglioma/diagnóstico por imagen , Epilepsia Refractaria/cirugía , Neuronavegación/métodosRESUMEN
To describe the natural history of spinal gangliogliomas (GG) in order to determine the most appropriate neuro-oncological management. A Medline search for relevant publications up to July 2023 using the key phrase "ganglioglioma spinal" and "ganglioglioma posterior fossa" led to the retrieval of 178 studies. This corpus provided the basis for the present review. As an initial selection step, the following inclusion criteria were adopted: (i) series and case reports on spinal GG; (ii) clinical outcomes were reported specifically for GG; (iii) GG was the only pathological diagnosis for the evaluation of the tumor; (iv) papers written only in English was evaluated; and (v) papers describing each case in the series were included. The World Health Organization (WHO) 2021 grading criteria for gangliogliomas were applied. A total of 107 tumors were evaluated (63 from male patients and 44 from female patients; 1.43 male/1.0 female ratio, mean age 18.34 ± 15.84 years). The most common site was the cervical spine, accounting for 43 cases (40.18%); GTR was performed in 35 cases (32.71%) and STR in 71 cases (66.35%), while this information was not reported in 1 case (0.94%). 8 deaths were reported (7.47%) involving 2 males (25%) and 6 females (75%) aged 4-78 years (mean 34.27 ± 18.22) years. GGs located on the spine displayed the same gender ratio as these tumors in general. The most frequent symptom was pain and motor impairment, while the most prevalent location was the cervical spinal cord. GTR of the tumor posed a challenge for neurosurgeons, due to the difficulty of resecting the lesion without damaging the spinal eloquent area, explaining the lower rate of cure for this tumor type.
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Neoplasias Encefálicas , Ganglioglioma , Humanos , Masculino , Femenino , Preescolar , Niño , Adolescente , Adulto Joven , Adulto , Ganglioglioma/cirugía , Ganglioglioma/diagnóstico , Ganglioglioma/patología , Resultado del Tratamiento , Recurrencia Local de Neoplasia/patología , Neoplasias Encefálicas/cirugíaRESUMEN
Neuropil-like islands (NIs) are a histologic hallmark of glioneuronal tumors with neuropil-like islands (GTNIs), but GTNIs are presently not considered a homogeneous entity. The essence of GTNI is likely its glial component, and NIs are now considered aberrant neuronal differentiation or metaplasia. The case we report herein is a 41-year-old woman who was synchronously affected by two brain tumors: one was a glioblastoma (glioblastoma multiforme, GBM), of isocitrate dehydrogenase (IDH)-wild type, with NIs in the left parietal lobe, and the other was histologically a composite gangliocytoma (GC)/anaplastic ganglioglioma (GG) with NIs in the right medial temporal lobe. While both tumors were genetically wild type for IDH, histone H3, and v-raf murine sarcoma viral oncogene homolog B1 (BRAF), the former tumor, but not the latter, was mutated for telomerase reverse transcriptase promoter gene (TERT). A recent systematic study using DNA methylation profiling and next-generation sequencing showed that anaplastic GG separate into other WHO tumor types, including IDH-wild-type GBM. It suggested a diagnostic scheme where an anaplastic GG is likely an IDH-wild-type GBM if it is a BRAF wild type, IDH wild type, and TERT promoter mutant tumor. The likely scenario in this patient is that the GBM results from the progression of GC/anaplastic GG due to the superimposed TERT promoter mutation and the propagation of newly generated GBM cells in the contralateral hemisphere. A systematic analysis using DNA methylation profiling and next-generation sequencing was not available in this study, but the common presence of NIs histologically noted in the two tumors could support this scenario. Although a sufficient volume of molecular and genetic testing is sine qua non for the accurate understanding of brain tumors, the importance of histologic observation cannot be overemphasized.
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Neoplasias Encefálicas , Ganglioglioma , Ganglioneuroma , Glioblastoma , Telomerasa , Femenino , Ratones , Animales , Humanos , Adulto , Glioblastoma/complicaciones , Glioblastoma/genética , Glioblastoma/patología , Ganglioglioma/patología , Proteínas Proto-Oncogénicas B-raf/genética , Ganglioneuroma/patología , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neurópilo/patología , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Mutación , Telomerasa/genéticaRESUMEN
Gangliogliomas (GGs) represent the most frequent glioneuronal tumor entity associated with chronic recurrent seizures; rare anaplastic GGs variants retain the glioneuronal character. So far, key mechanisms triggering chronic hyperexcitability in the peritumoral area are unresolved. Based on a recent mouse model for anaplastic GG (BRAFV600E, mTOR activation and Trp53KO) we here assessed the influence of GG-secreted factors on non-neoplastic cells in-vitro. We generated conditioned medium (CM) from primary GG cell cultures to developing primary cortical neurons cultured on multielectrode-arrays and assessed their electrical activity in comparison to neurons incubated with naïve and neuronal CMs. Our results showed that the GG CM, while not affecting the mean firing rates of networks, strongly accelerated the formation of functional networks as indicated increased synchrony of firing and burst activity. Washing out the GG CM did not reverse these effects indicating an irreversible effect on the neuronal network. Mass spectrometry analysis of GG CM detected several enriched proteins associated with neurogenesis as well as gliogenesis, including Gap43, App, Apoe, S100a8, Tnc and Sod1. Concomitantly, immunocytochemical analysis of the neuronal cultures exposed to GG CM revealed abundant astrocytes suggesting that the GG-secreted factors induce astroglial proliferation. Pharmacological inhibition of astrocyte proliferation only partially reversed the accelerated network maturation in neuronal cultures exposed to GG CM indicating that the GG CM exerts a direct effect on the neuronal component. Taken together, we demonstrate that GG-derived paracrine signaling alone is sufficient to induce accelerated neuronal network development accompanied by astrocytic proliferation. Perspectively, a deeper understanding of factors involved may serve as the basis for future therapeutic approaches.
Asunto(s)
Neoplasias Encefálicas , Ganglioglioma , Humanos , Animales , Ratones , Ganglioglioma/complicaciones , Ganglioglioma/metabolismo , Ganglioglioma/patología , Neoplasias Encefálicas/metabolismo , Alta del Paciente , Convulsiones/complicaciones , Neuronas/metabolismoRESUMEN
Long-term epilepsy-associated tumors (LEATs) include a series of neoplasms that commonly occur in children, adolescents, or young adults, have an astrocytic or glioneuronal lineage, are histologically benign (WHO grade1) with a neocortical localization predominantly situated in the temporal lobes. Clinically, chronic refractory epilepsy is usually the unique symptom. Gangliogliomas (GG) and dysembryoplastic neuroepithelial tumors (DNT) are the most common representative entities besides pilocytic astrocytomas (PA) and angiocentric gliomas (AG). Recent molecular studies have defined new clinicopathological entities, which are recognized by the WHO 2021 classification of brain tumors. Some of them such as diffuse astrocytoma MIB or MYBL1 altered, polymorphous low-grade neuroepithelial tumor of the young (PLNTY), and multilocular and vacuolating neuronal tumor (MVNT) are currently considered LEATs. The relationship between LEATs and epilepsy is still a matter of debate, and there is a general agreement about the beneficial effects of an early neurosurgical intervention on the clinical outcome.
Tumores associados a epilepsia de longa duração constituem uma série de neoplasias asatrocitárias ou glioneuronais que comumente incidem em crianças, adolescentes e jovens adultos e que são histologicamente benignos (OMS grau 1), de localização neocortical e predominantemente situados nos lobos temporais. Clinicamente, a epilepsia crônica refratária é, de modo geral, o único sintoma. Gangliogliomas (GG) e tumores neuroepiteliais disembrioplásticos (DNT) são as entidades mais representativas associadas a astrocitomas pilocíticos (AP) e gliomas angiocêntricos (GA). Estudos moleculares recentes permitiram a definição de novas entidades clínico-patológicas reconhecidas pela classificação de tumores cerebrais da OMS 2021. Algumas delas, como o astrocitoma difuso MIB ou MIBL1 alterados, o tumor neuroepitelial polimorfo do jovem (PLNTY) e o tumor neuronal multilocular e vacuolizado (MVNT) são atualmente considerados tumores associados a epilepsia de longa duração. A relação entre este grupo de tumores e epilepsia é ainda debatida e há um consenso geral sobre o benefício prognóstico de intervenção cirúrgica precoce.
Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Epilepsia , Ganglioglioma , Glioma , Neoplasias Neuroepiteliales , Adolescente , Adulto Joven , Humanos , Niño , Epilepsia/etiología , Glioma/patología , Neoplasias Encefálicas/patología , Ganglioglioma/patología , Astrocitoma/patología , Neoplasias Neuroepiteliales/patologíaRESUMEN
AIM: To report a series of patients diagnosed with gangliogliomas (GG) in unusual locations; and to review the clinical and imaging features as well as surgical treatment and outcomes. MATERIAL AND METHODS: A series of consecutive patients who underwent surgery for GGs at unusual locations, such as intraventricular region and posterior fossa, from 2010 to 2022 were included in the study. RESULTS: Nine patients with GGs located in unusual areas, one in the intraventricular region and 8 in the posterior fossa, were included. There were 5 males and 4 females, with a mean age 31±8.5 years. We performed GTR in 6 cases and STR in 3 cases. Seven tumors were grade I WHO while the remaining two were anaplastic. Five patients also had preoperative hydrocephalus. We found a positive correlation between midline GG of the posterior fossa and solid aspect of the tumor (p=0.05). Univariate analysis found no other statistically significant associations, but this was due to the small patient sample. Recurrence was seen in 2 cases with STR, after 1 and 10 years, respectively. CONCLUSION: GG should be considered in the differential diagnosis of patients with tumors in the intraventricular region or posterior fossa. Maximal tumor resection and restoration of CSF flow pathways ensure a good outcome. Growth patterns correlate with resection and can help choose the best candidates for surgery. However, further studies on large patient samples are needed.
Asunto(s)
Neoplasias Encefálicas , Ganglioglioma , Hidrocefalia , Masculino , Femenino , Humanos , Adulto Joven , Adulto , Ganglioglioma/diagnóstico por imagen , Ganglioglioma/cirugía , Ganglioglioma/patología , Hidrocefalia/diagnóstico por imagen , Hidrocefalia/etiología , Hidrocefalia/cirugía , Diagnóstico Diferencial , Estudios Retrospectivos , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/cirugíaRESUMEN
Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low-grade glial-glioneuronal tumors. We present the associated clinical, histopathologic and molecular features. Patients were all female, aged 8 years, 15 months, and 10 months at diagnosis. All tumors were located in the cerebral hemispheres and predominantly cortical, with leptomeningeal involvement in 2/3 patients. Similar to previously described activating RAF1 fusions, the breakpoints in RAF1 all occurred 5' of the kinase domain, while the breakpoints in the 3' partner preserved the N-terminal kinesin-interacting domain and coiled-coil motifs of TRAK1. Two of the three cases demonstrated methylation profiles (v12.5) compatible with desmoplastic infantile ganglioglioma (DIG)/desmoplastic infantile astrocytoma (DIA) and have remained clinically stable and without disease progression/recurrence after resection. The remaining tumor was non-classifiable; with focal recurrence 14 months after initial resection; the patient remains symptom free and without further recurrence/progression (5 months post re-resection and 19 months from initial diagnosis). Our report expands the landscape of oncogenic RAF1 fusions in pediatric gliomas, which will help to further refine tumor classification and guide management of patients with these alterations.
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Astrocitoma , Neoplasias Encefálicas , Ganglioglioma , Glioma , Niño , Femenino , Humanos , Proteínas Adaptadoras del Transporte Vesicular , Astrocitoma/genética , Astrocitoma/patología , Neoplasias Encefálicas/patología , Ganglioglioma/patología , Glioma/genética , Glioma/patología , Fusión de OncogenesRESUMEN
Recent epigenomic analyses have revealed the existence of a new DNA methylation class (MC) of infant-type hemispheric glioma (IHG). Like desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA), these tumors mainly affect infants and are supratentorial. While DIG/DIA is characterized by BRAF or RAF1 alterations, IHG has been shown to have receptor tyrosine kinase (RTK) gene fusions (ALK, ROS1, NTRK1/2/3, and MET). However, in this rapidly evolving field, a more comprehensive analysis of infantile glial/glioneuronal tumors including clinical, radiological, histopathological, and molecular data is needed. Here, we retrospectively investigated data from 30 infantile glial/glioneuronal tumors, consecutively compiled from our center. They were analyzed by two experienced pediatric neuroradiologists in consensus, without former knowledge of the molecular data. We also performed a comprehensive clinical, and histopathological examination (including molecular evaluation by next-generation sequencing, RNA sequencing, and fluorescence in situ hybridization [FISH] analyses), as well as DNA methylation profiling for the samples having sufficient material available. The integrative histopathological, genetic, and epigenetic analyses, including t-distributed stochastic neighbor embedding (t-SNE) analyses segregated tumors into 10 DIG/DIA (33.3%), six IHG (20.0%), three gangliogliomas (10.0%), two pleomorphic xanthoastrocytomas (6.7%), two pilocytic astrocytomas (6.7%), two supratentorial ependymomas, ZFTA fusion-positive (6.7%), two supratentorial ependymomas, YAP1 fusion-positive (6.7%), two embryonal tumors with PLAGL2-family amplification (6.7%), and one diffuse low-grade glioma, MAPK-pathway altered. This study highlights the significant differential features, in terms of histopathology (leptomeningeal infiltration, intense desmoplasia and ganglion cells in DIG/DIA and necrosis, microvascular proliferation, and siderophages in IHG), and radiology between DIG/DIA and IHG. Moreover, these results are consistent with the literature data concerning the molecular dichotomy (BRAF/RAF1 alterations vs. RTK genes' fusions) between DIG/DIA and IHG. This study characterized histopathologically and radiologically two additional cases of the novel embryonal tumor characterized by PLAGL2 gene amplification.
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Astrocitoma , Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Ependimoma , Ganglioglioma , Neoplasias Neuroepiteliales , Humanos , Ganglioglioma/genética , Ganglioglioma/patología , Neoplasias Encefálicas/patología , Proteínas Proto-Oncogénicas B-raf/genética , Estudios Retrospectivos , Hibridación Fluorescente in Situ , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas/genética , Astrocitoma/genética , Astrocitoma/patología , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética , Proteínas de Unión al ARNRESUMEN
Exome-wide sequencing studies recently described PTPN11 as a novel brain somatic epilepsy gene. In contrast, germline mutations of PTPN11 are known to cause Noonan syndrome, a multisystem disorder characterized by abnormal facial features, developmental delay, and sporadically, also brain tumors. Herein, we performed a deep phenotype-genotype analysis of a comprehensive series of ganglioglioma (GG) with brain somatic alterations of the PTPN11/KRAS/NF1 genes compared to GG with common MAP-Kinase signaling pathway alterations, i.e., BRAFV600E. Seventy-two GG were submitted to whole exome sequencing and genotyping and 84 low grade epilepsy associated tumors (LEAT) to DNA-methylation analysis. In 28 tumours, both analyses were available from the same sample. Clinical data were retrieved from hospital files including disease onset, age at surgery, brain localization, and seizure outcome. A comprehensive histopathology staining panel was available in all cases. We identified eight GG with PTPN11 alterations, copy number variant (CNV) gains of chromosome 12, and the commonality of additional CNV gains in NF1, KRAS, FGFR4 and RHEB, as well as BRAFV600E alterations. Histopathology revealed an atypical glio-neuronal phenotype with subarachnoidal tumor spread and large, pleomorphic, and multinuclear cellular features. Only three out of eight patients with GG and PTPN11/KRAS/NF1 alterations were free of disabling-seizures 2 years after surgery (38% had Engel I). This was remarkably different from our series of GG with only BRAFV600E mutations (85% had Engel I). Unsupervised cluster analysis of DNA methylation arrays separated these tumours from well-established LEAT categories. Our data point to a subgroup of GG with cellular atypia in glial and neuronal cell components, adverse postsurgical outcome, and genetically characterized by complex alterations in PTPN11 and other RAS-/MAP-Kinase and/or mTOR signaling pathways. These findings need prospective validation in clinical practice as they argue for an adaptation of the WHO grading system in developmental, glio-neuronal tumors associated with early onset focal epilepsy.
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Epilepsia , Ganglioglioma , Humanos , Epilepsia/patología , Ganglioglioma/genética , Ganglioglioma/patología , Mutación/genética , Fenotipo , Proteína Tirosina Fosfatasa no Receptora Tipo 11/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Genes ras , Sistema de Señalización de MAP QuinasasRESUMEN
Gangliogliomas are brain tumors composed of neuron-like and macroglia-like components that occur in children and young adults. Gangliogliomas are often characterized by a rare population of immature astrocyte-appearing cells expressing CD34, a marker expressed in the neuroectoderm (neural precursor cells) during embryogenesis. New insights are needed to refine tumor classification and to identify therapeutic approaches. We evaluated five gangliogliomas with single nucleus RNA-seq, cellular indexing of transcriptomes and epitopes by sequencing, and/or spatially-resolved RNA-seq. We uncovered a population of CD34+ neoplastic cells with mixed neuroectodermal, immature astrocyte, and neuronal markers. Gene regulatory network interrogation in these neuroectoderm-like cells revealed control of transcriptional programming by TCF7L2/MEIS1-PAX6 and SOX2, similar to that found during neuroectodermal/neural development. Developmental trajectory analyses place neuroectoderm-like tumor cells as precursor cells that give rise to neuron-like and macroglia-like neoplastic cells. Spatially-resolved transcriptomics revealed a neuroectoderm-like tumor cell niche with relative lack of vascular and immune cells. We used these high resolution results to deconvolute clinically-annotated transcriptomic data, confirming that CD34+ cell-associated gene programs associate with gangliogliomas compared to other glial brain tumors. Together, these deep transcriptomic approaches characterized a ganglioglioma cellular hierarchy-confirming CD34+ neuroectoderm-like tumor precursor cells, controlling transcription programs, cell signaling, and associated immune cell states. These findings may guide tumor classification, diagnosis, prognostication, and therapeutic investigations.
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Neoplasias Encefálicas , Ganglioglioma , Células-Madre Neurales , Niño , Humanos , Ganglioglioma/patología , Transcriptoma , Placa Neural/patología , Células-Madre Neurales/patología , Neoplasias Encefálicas/patologíaRESUMEN
INTRODUCTION: The recently updated World Health Organization classification of central nervous system (CNS) tumors, 5th edition, (CNS5) reclassifies pediatric tumors according to their distinct molecular drivers, recognizing a new entity-infant-type hemispheric glioma (IHG). Defined by its unique epigenetic signature, and/or genomic fusions in ALK, ROS1, NTRK, or MET gene, IHG subsumes many cases previously classified as congenital glioblastoma (cGBM). Histologic features of IHG are still poorly defined with known overlap with a clinic radiologically similar entity-desmoplastic infantile ganglioglioma/astrocytoma (DIG). METHODS: We revisited our cohort of cGBMs and DIGs, now reclassifying them according to CNS5 and compared the clinical, radiologic, molecular and histologic features between the two. RESULTS: 3/6 cases of cGBM that underwent targeted NGS fusion mutation panel were positive for ALK fusions (involving MAP4, MZT2Bex2, and EML4 genes as fusion partners), and 1/6 showed GOPC:ROS1 fusion. Interestingly, GOPC:ROS1 fusion was also shared by 1/5 cases of histologically defined DIG. DNA methylation profiling using the Heidelberg classifier (v12.3) recategorized 2/5 DIG cases as IHG (including the case with ROS1 alteration). CONCLUSION: In conclusion, histology alone is insufficient to distinguish IHG from DIG, necessitating epigenomic and genomic testing for the diagnosis of early-life gliomas.
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Astrocitoma , Neoplasias Encefálicas , Ganglioglioma , Glioblastoma , Lactante , Niño , Humanos , Glioblastoma/diagnóstico por imagen , Glioblastoma/genética , Ganglioglioma/diagnóstico por imagen , Ganglioglioma/genética , Ganglioglioma/patología , Proteínas Tirosina Quinasas/genética , Epigenómica , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Proteínas Proto-Oncogénicas/genética , Astrocitoma/genética , Genómica , Proteínas Tirosina Quinasas ReceptorasRESUMEN
Gangliogliomas (GGs), composed of dysmorphic neurons and neoplastic astroglia, represent the most frequent tumor entity associated with chronic recurrent epileptic seizures. So far, a systematic analysis of potential differences in neurochemical profiles of dysmorphic tumoral neurons as well as neurons of the peritumoral microenvironment (PTME) was hampered by the inability to unequivocally differentiate between the distinct neuronal components in human GG biopsies. Here, we have applied a novel GG mouse model that allows to clearly resolve the neurochemical profiles of GG-intrinsic versus PTME neurons. For this purpose, glioneuronal tumors in mice were induced by intraventricular in utero electroporation (IUE) of piggyBac-based plasmids for BRAFV600E and activated Akt (AktT308D/S473D, further referred to as AktDD) and analyzed neurochemically by immunocytochemistry against specific marker proteins. IUE of BRAFV600E/AktDD in mice resulted in tumors with the morphological features of human GGs. Our immunocytochemical analysis revealed a strong reduction of GABAARα1 immunoreactivity in the tumor compared to the PTME. In contrast, the extent of NMDAR1 immunoreactivity in the tumor appeared comparable to the PTME. Interestingly, tumor cells maintained the potential to express both receptors. Fittingly, the abundance of the presynaptic vesicular neurotransmitter transporters VGLUT1 and VGAT was also decreased in the tumor. Additionally, the fraction of parvalbumin and somatostatin nonneoplastic interneurons was reduced. In conclusion, changes in the levels of key proteins in neurotransmitter signaling suggest a loss of synapses and may thereby lead to neuronal network alterations in mouse GGs.
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Neoplasias Encefálicas , Epilepsia , Ganglioglioma , Humanos , Ratones , Animales , Ganglioglioma/complicaciones , Ganglioglioma/metabolismo , Ganglioglioma/patología , Convulsiones , Neuronas/metabolismo , Epilepsia/complicaciones , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Microambiente TumoralRESUMEN
Anaplastic gangliogliomas of the spinal cord are extremely rare with only four cases reported in the literature. Here we present the case of a 22-year-old female who presented acutely with quadraparesis and urinary retention. Radiographic imaging demonstrated an intramedullary lesion within the cervical spine. She underwent a cervical laminectomy and resection of the lesion under neurophysiological monitoring. Post-operatively, she regained some function, but remained paraparetic. Histopathology demonstrated an anaplastic ganglioglioma (WHO Grade 3). She subsequently underwent radiotherapy. Following surgery, she remained stable and had MRC Grade 3 Power in all four limbs. Herein, we describe a previously undescribed case of cervical anaplastic ganglioglioma and review the existing literature.
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Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Ganglioglioma , Neoplasias de la Médula Espinal , Femenino , Humanos , Adulto Joven , Adulto , Ganglioglioma/diagnóstico por imagen , Ganglioglioma/cirugía , Ganglioglioma/patología , Neoplasias de la Médula Espinal/diagnóstico por imagen , Neoplasias de la Médula Espinal/cirugía , Neoplasias de la Médula Espinal/patología , Neoplasias Encefálicas/cirugía , Radiografía , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Most patients with glioneuronal tumors present with seizures. Although several studies have shown that greater extent of resection improves overall patient survival, few studies have focused on postoperative seizure outcome after resection of these tumors. The aim of this study was to characterize seizure control rates in patients undergoing glioneuronal tumor resection and evaluate the association between poor seizure outcome and tumor recurrence or progression. METHODS: The study population included patients who had undergone resection of glioneuronal tumors between 2014 and 2019 at our institution. Seizure outcome was assessed using Engel grading. Preoperative seizure characteristics, tumor characteristics, surgical factors, and postoperative seizure outcomes were reviewed. RESULTS: Twenty-six patients (N.=16, temporal lobe; N.=6, frontal lobe; N.=4, parietal lobe) with mean seizures duration of 56.9-months, were assessed. Histopathologically, N.=15 dysembryoplastic neurepithelial tumor, N.=7 ganglioglioma and N.=4 Diffuse lepto-meningeal neuroepithelial tumor. There were 2 cases of complex DNET and one case of DLMNT had associated cortical dysplasia. At mean follow-up of 49.7 months, N.=20 Engel 1, N.=4 Engel 2 and N.=2 had Engel 3 outcome. N.=20 underwent gross total excision (N.=18 Engel 1 and N.=2 Engel 2) and N.=6 sub-total excision. Among the 4 patients who needed re-surgery, two were in Engel 2 and another two were in Engel 3. CONCLUSIONS: Good seizure-outcome is likely associated with extent of resection. Younger age of patient, less than one-year of seizure duration and absence of generalization of seizure are good prognostic indicators. The best seizure-control can be achieved by early surgical intervention.