Gliomas in children and adolescents: investigation of molecular alterations with a potential prognostic and therapeutic impact.

PURPOSE: Gliomas represent the most frequent central nervous system (CNS) tumors in children and adolescents. However, therapeutic strategies for these patients, based on tumor molecular profile, are still limited compared to the wide range of treatment options for the adult population. We investigated molecular alterations, with a potential prognostic marker and therapeutic target in gliomas of childhood and adolescence using the next-generation sequencing (NGS) strategy. METHODS: We selected 95 samples with initial diagnosis of glioma from patients treated at Pediatric Oncology Institute-GRAACC/UNIFESP. All samples were categorized according to the 2021 World Health Organization Classification of Tumors of the CNS, which included 39 low-grade gliomas (LGGs) and 56 high-grade gliomas (HGGs). Four HGG samples were classified as congenital glioblastoma (cGBM). NGS was performed to identify somatic genetic variants in tumor samples using the Oncomine Childhood Cancer Research Assay® (OCCRA®) panel, from Thermo Fisher Scientific®. RESULTS: Genetic variants were identified in 76 of 95 (80%) tumors. In HGGs, the most common molecular alteration detected was H3F3A c.83A > T variant (H3.3 K27M) and co-occurring mutations in ATRX, TP53, PDGFRA, MET, and MYC genes were also frequently observed. One HGG sample was reclassified as supratentorial ependymoma ZFTA-fusion positive after NGS was performed. In LGGs, four KIAA1549-BRAF fusion transcripts were detected and this alteration was the most recurrent genetic event and favorable prognostic factor identified. Additionally, genetic variants in ALK and NTRK genes, which provide potential targets for therapy with Food and Drug Administration-approved drugs, were identified in two different cases of cGBM that were classified as infant-type hemispheric glioma, a newly recognized subgroup of pediatric HGG. CONCLUSION: Molecular profiling by the OCCRA® panel comprehensively addressed the most relevant genetic variants in gliomas of childhood and adolescence, as these tumors have specific patterns of molecular alterations, outcomes, and effectiveness to therapies.

Diagnostic challenges of an incidental finding: case report of definitely-congenital glioblastoma multiforme in a very preterm infant.

BACKGROUND: Congenital brain tumors are extremely rare in the neonatal population, and often associated with a poor prognosis. The diagnostic suspicion is often aroused at antenatal scans or postnatally, if clinical signs and symptoms of increased intracranial pressure become evident. We present a case of definitely congenital glioblastoma multiforme incidentally diagnosed in a preterm infant, aiming to raise clinical awareness on this condition and to highlight the challenges of the related diagnostic work-up. CASE PRESENTATION: This female infant was born at 31 weeks' gestation after an uneventful pregnancy. No abnormalities were detected at antenatal ultrasound scans and genetic tests. Head circumference at birth was on the 25th centile. A routine brain ultrasound scan performed on day 1 revealed a large, inhomogeneous lesion in the right cerebral hemisphere, with contralateral midline shift, which was confirmed by brain magnetic resonance imaging (MRI). Eye fundus and routine blood exams, including platelets count, coagulation screening and C-reactive protein, were normal. Given the high risk of complications, surgical biopsy of the lesion was temporarily hold and a daily sonographic follow-up was undertaken. Although head circumference growth was steady on the 25th centile, progressive changes of the lesion were detected by cranial ultrasound. The repeat MRI scans showed a significant enlargement of the mass, with contralateral midline shift and signs of intralesional and intraventricular bleeding. In view of this worsening, surgical resection was performed. The histological examination of the lesion biopsy documented a GFAP+ highly cellular neoplasm, with no mutation on SMARCB1 gene. At the molecular analysis, mutations on IDH and H3F3A genes were absent, whereas MGMT promoter was unmethylated. The diagnosis was grade IV glioblastoma IDH wild-type. CONCLUSIONS: Congenital glioblastoma multiforme is an extremely rare but highly aggressive neoplasm. Since intralesional biopsy is not often feasible in affected neonates, knowledge of the associated clinical and neuroradiological features is particularly important, as they can also add useful information on the neoplasm behavior. Specimens from open surgical resection allow to perform a definite histological analysis and an extended molecular characterization, with relevant prognostic implications.

Congenital Glioblastoma Multiforme with Long-Term Childhood Survival: A Case Report and Systematic Review.

BACKGROUND: Congenital glioblastoma multiforme (cGBM) is an infrequent primary central nervous system tumor occurring within the first few months of life with a reported poor overall prognosis. Our objective was to describe our own clinical case of cGBM and review the literature of cGBM cases with prolonged survival. CASE DESCRIPTION: We report a case of cGBM with prolonged survival at 4 years. A systematic review was conducted on cases of cGBM with long-term childhood survival. We searched online databases until August 2019 for relevant articles. The patient underwent an emergency right hemicraniectomy with excision and biopsy of the right cerebral hemisphere mass and insertion of a ventriculoperitoneal shunt. At present, she is a 52-month-old child with good speech and minimal left hemiparesis and able to ambulate, with a Functional Independence Measure for Children score of 109. Out of 160 articles screened, there were 10 articles included. A total of 15 patients, including the present case, were analyzed qualitatively. The age at presentation ranged from 30 weeks' gestation to 35 days. Most patients underwent surgical excision (n = 13, 86.7%) and adjuvant chemotherapy (n = 10, 66.7%). The reported range of survival of these patients was from 27 to 110 months. CONCLUSIONS: Limited evidence from 15 cases of cGBM suggests that surgical excision and/or chemotherapy may prolong the survival of patients. Therefore, these interventions may be offered and performed to patients with cGBM on a case-by-case basis. Larger clinical studies or registry-based information are necessary to substantiate the implications of our review.

Congenital Glioblastoma with Distinct Clinical and Molecular Characteristics: Case Reports and a Literature Review.

BACKGROUND: The molecular diagnosis of brain tumors is important in classifying tumors and determining appropriate treatment. Congenital glioblastoma multiforme (GBM) is a rare tumor that occurs in infants, and the prognosis is poor. Approximately 60 patients diagnosed with congenital GBM have been reported. However, few reports have conducted molecular analyses of congenital GBM. CASE DESCRIPTION: We describe 2 congenital GBM patients treated in our hospital, and report results of immunohistochemistry, fluorescent in situ hybridization (FISH), direct sequencing, and methylation analyses. Surgery was performed on both patients at 2 months old, and the cases were diagnosed as glioblastoma. Immunohistochemical staining, FISH, and direct sequencing were positive for glial fibrillary acidic protein and ATRX, partially positive for p53, showed no alteration of isocitrate dehydrogenase 1 R132H, H3F3A, HIST1H3B, and BRAF, and indicated no codeletion of 1p and 19q. Methylation analysis of 1 patient identified copy number aberrations of 4 genes: deletions of CDK6 and CDKN2A/B, and a fusion of MET. One patient received chemotherapy consisting of ranimustine, interferon-beta, carboplatin, and etoposide, whereas the other patient received chemotherapy with the modified Children's Cancer Group study-9921 protocol. Residual tumors in both patients were decreased, and they achieved 18-year- and 9-month progression-free survival, respectively. In addition, we reviewed 65 previously reported congenital GBM patients, and found they have better prognosis than pediatric and adult GBM, and long-term survival can be expected. CONCLUSIONS: Congenital GBM demonstrates clinical and molecular characteristics that are different from those of pediatric or adult GBM.

Congenital Glioblastoma multiforme and eruptive disseminated Spitz nevi.

BACKGROUND: Glioblastoma multiforme (GBM) is the deadliest malignant primary brain tumor in adults. GBM develops primarily in the cerebral hemispheres but can develop in other parts of the central nervous system. Its congenital variant is a very rare disease with few cases described in literature. CASE PRESENTATION: We describe the case of a patient with congenital GBM who developed eruptive disseminated Spitz nevi (EDSN) after chemotherapy. Few cases of EDSN have been described in literature and this rare clinical variant, which occurs predominantly in adults, is characterized by multiple Spitz nevi in the trunk, buttocks, elbows and knees. There is no satisfactory treatment for EDSN and the best therapeutic choice is considered the clinical observation of melanocytic lesions. CONCLUSION: We recommend a close follow-up of these patients with clinical observation, dermoscopy and reflectance confocal microscopy (RCM). However, we suggest a surgical excision of the lesions suspected of being malignant.