Page 18 - Molecular features of low-grade developmental brain tumours

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implicated in SEGAs and targeting both pathways in pLGGs has been suggested 123.
Subependymal giant cell astrocytoma
SEGAs are low-grade glioneuronal tumours classified as WHO grade I and represent 1%-
2% of all pediatric brain tumours 3,23. Since 2012, The International Tuberous Sclerosis
Complex Consensus Conference has defined SEGA as either a lesion that is located at the
caudothalamic groove with a size >1 cm or a subependymal lesion of any size with serial
growth based on consecutive imaging 77. Although SEGAs are benign and slow growing
tumours, extensive growth can cause obstruction of the cerebrospinal fluid tract leading
to hydrocephalus and in some cases even sudden death 124,125.The prevalence of SEGAs in
patients with TSC ranges from 5% to 25% 124,126-129. SEGAs can already be detected in fetal
and neonatal periods, but generally develop during the first two decades of life 97,127,130-134.
The occurrence of de novo SEGAs after the age of 18 years is relatively low, however tumour
growth can still be observed in ~20% of adult patients 134-136. SEGAs are thought to arise
from SENs along the ependymal lining of the lateral ventricles at the height of the foramen of Monro 138-140.
Histologically, SEGAs consist of spindle cells, gemistocytic-like cells and giant cells and are indistinguishable from SEN (Figure 3K). They can also present vascular stroma and parenchymal or vascular calcifications. Initially, it was thought that SEGAs have an astrocytic character, however more recent studies have demonstrated a mixed glio-neuronal phenotype. SEGAs are usually strongly positive for glial fibrillary acid protein (GFAP) and S-100 protein as well as for neuronal markers, i.e. neurofilament proteins (NF) and synaptophysin 141-143. Due to this mixed phenotype, it has been suggested that their origin lies in neural progenitors that normally reside in the subependymal zone 144. The percentage of KI67 positive cells in SEGAs is low at 1-2%, which is in accordance with their benign phenotype 145. However, rare cases with anaplastic features and increased KI67 positivity have been reported 146,147. Positive staining for mTOR activation has been found predominately in giant cells but not in spindle cells of SEGA 108,143,145,148. HLA-DR positive microglial cells localize around giant cells in SEGA, which is interesting considering that the mTOR pathway can activate immune responses 149,150.
At the molecular level little is known about establishment and progression of SEGAs. Evidence of second-hit inactivation of TSC1 or TSC2 has been reported in SEGAs 108,114. However, second hit mutations are not always seen in SEGAs and might already be present in SEN, suggesting that additional molecular mechanisms may play a role in their progression and growth. Recently, it was shown that that the overall mutation burden is low in SEGA, which is consistent with their slow growing character 114. In the same study it was shown that gene ontologies related to cell systems such as inflammation, extracellular matrix organization and synaptic transmission were mainly affected in SEGAs 114. However, it is still unknown how the deregulation of these cell systems could contribute to SEGA pathology and needs to be further investigated.
Treatment options in TSC
The goal of epilepsy treatment in TSC is to prevent and control seizures as soon as possible.