Low-grade epilepsy-associated neuroepithelial tumors: Tumor spectrum and diagnosis based on genetic alterations

Abstract

Brain tumors can always result in seizures when involving the cortical neurons or their circuits, and they were found to be one of the most common etiologies of intractable focal seizures. The low-grade epilepsy-associated neuroepithelial tumors (LEAT), as a special group of brain tumors associated with seizures, share common clinicopathological features, such as seizure onsets at a young age, a predilection for involving the temporal lobe, and an almost benign course, including a rather slow growth pattern and thus a long-term history of seizures. Ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNET) are the typical representatives of LEATs. Surgical treatments with complete resection of tumors and related epileptogenic zones are deemed the optimal way to achieve postoperative seizure control and lifetime recurrence-free survival in patients with LEATs. Although the term LEAT was originally introduced in 2003, debates on the tumor spectrum and the diagnosis or classification of LEAT entities are still confusing among epileptologists and neuropathologists. In this review, we would further discuss these questions, especially based on the updated classification of central nervous system tumors in the WHO fifth edition and the latest molecular genetic findings of tumor entities in LEAT entities.

Keywords: brain tumor; diagnosis; epilepsy; neuroepithelial; pathology.

FIGURE 1

RAS-RAF-MAPK signaling pathway with molecular genetic alterations affected in LEATs. Genetic alterations detected in LEAT entities mainly involve two signaling cascades, namely, RAS-RAF-MAPK (left/pink) and PI3K-AKT-mTOR (right/blue). Signals begin at the insulin-like growth factor-1 (IGF-1) receptor at the cell surface, as well as the epidermal growth factor (EGF) receptor, and transmit to the downstream canonical cascades of the MAPK pathway (through RAS, RAF, and MEK1/2 to ERK1/2) and the mTOR pathway (through PI3K, PDK-1, AKT, and TSC1-TSC2-TBC1D7 complex to mTORC1/2). The specific genetic alterations are listed in the figure (light red), including the FGFR1 alteration and BRAF^V600E mutation detected in GG and DNET and the MYB/MYBL1 fusions found in AG and IDG, with the activation of the RAS-RAF-MAPK signaling pathway to control DNA transcriptions for cell proliferation and differentiation. In particular, the MAPK pathway activation is regulated by substrates of the PI3K-AKT-mTOR signaling cascade, which, in turn, was controlled by the components from RAS-RAF-MAPK cascades to determine the protein synthesis (dashed lines).