PTPS-13STUDY OF CLINICOPATHOLOGICAL CHARACTERISTICS, BRAF V600E MUTATION, AND MTOR SIGNALING PATHWAY ACTIVATION IN DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS (DNET)

Abstract

Dysembryoplastic Neuroepithelial Tumor (DNET) is a WHO Grade I glioneuronal tumor of children and young adults. BRAFV600E mutation has been identified in DNETs. More recently, mTOR-pathway has been implicated in molecular pathogenesis of glioneuronal tumors. We aimed to evaluate the presence of enhanced mTOR-pathway signalling, incidence of BRAFV600E mutation, and to compare the results with clinicopathological features. Immunohistochemistry for markers of mTOR-pathway activation, viz. pS6 and p4EBP1, was performed. Sequencing for BRAFV600E mutation was done in cases with adequate tissue. Sixty-seven cases of DNET were identified, accounting for 5% of patients with drug-refractory epilepsy. Mean age of patients was 16.1 years (range: 2-38 years); male preponderance was noted. Majority (68.7%) of patients were in pediatric age group (<18 years). Duration of seizures ranged from 1-22 years (mean = 7.5 years). All patients underwent ECOG-guided resection. Histopathologically, tumors were characterized by the presence of floating neurons within a specific glioneuronal element. Associated lesions such as cortical dysplasia (19%) and mesial temporal sclerosis (1.5%) were seen. Four cases were composite lesions with DNET, ganglioglioma and cortical dysplasia. pS6 immunopositivity was seen in 91% cases, while p4EBP1 was positive in 26%. Interestingly, pS6 positivity was also seen in neurons in the adjacent dysplastic cortex. Sequencing revealed BRAF V600E mutation in 11% of cases examined. Overall seizure-free survival was 87% (n = 55). Notably, of 51 patients undergoing complete resection, 48 (94%) had good outcome (Engel grade I). All four patients who underwent incomplete resection had Engel grade II-III outcomes. Thus, DNETs are rare, surgically curable neoplasms. Identification of these tumors has prognostic as well as therapeutic implications, as most patients remain seizure-free after complete resection. Evidence of mTOR-pathway activation suggests a role for mTOR signalling in their pathogenesis, and supports the use of mTOR inhibitors in DNET patients, particularly those having persistent seizures after incomplete resection.