Low-grade developmental and epilepsy associated brain tumors: a critical update 2020

Abstract

Brain tumors represent the second most frequent etiology in patients with focal seizure onset before 18 years of age and submitted to epilepsy surgery. Hence, this category of brain tumors, herein defined as low-grade, developmental, epilepsy-associated brain tumors (LEAT) is different from those frequently encountered in adults as (A): 77% of LEAT occur in the temporal lobe; (B): the vast majority of LEAT are of low malignancy and classified as WHO I°; (C): LEAT are often composed of mixed glial and neuronal cell components and present with variable growth patterns including small cysts or nodules; (D): LEAT do not share common gene driving mutations, such as IDH1 or 1p/19q co-deletions. Characteristic entities comprise the ganglioglioma (GG), the dysembryoplastic neuroepithelial tumor (DNT), the angiocentric glioma (AG), the isomorphic diffuse glioma (IDG) and the papillary glio-neuronal tumor (PGNT), representing 73.2% of 1680 tumors collected in a large German series of 6747 patients submitted to epilepsy surgery. In the realm of exciting discoveries of genetic drivers of brain tumors new genes have been also reported for LEAT. BRAF V600E mutations were linked to GG with CD34 expression, FGFR1 mutations to DNT, MYB alterations to AG and also IDG and PRKCA fusions to PGNT, suggesting the possibility to also develop a genetically driven tumor classification scheme for LEAT. Rare availability of LEAT in a single center is a challenging obstacle, however, to systematically unravel the neurobiological nature and clinical behavior of LEAT. Other challenges in need of clarification include malignant tumor progression of LEAT entities, seizure relapse in patients following bulk tumor resection and the controversial issue of associated focal cortical dysplasia as additional pathomechanism. In order to advance our understanding and promote reliable diagnostic work-up of LEAT, we recommend, therefore, international collaboration to achieve our goals.

Keywords: Astrocytoma; Ganglioglioma; Oligodendroglioma; Pathology; Seizure.

Fig. 1

Histopathologically and genetically defined LEAT. Legend to Figure: Selected LEAT entities in which a common gene driving mutation has been discovered. a-d: a papillary glio-neuronal tumor (PGNT) with the characteristic presentation of papillary growth pattern (A – HE), glial (B – GFAP) and neuronal components (C – MAP2 and D – Synaptophysin). This tumor was included in the study by Hou et al. describing its distinct DNA methylation profile and SLC44A1-PRKCA fusion [31]. e-h: a dysembryoplastic neuroepithelial tumor (DNT) with the characteristic histological presentation of a specific glio-neuronal element (E – HE), lack of GFAP immunoreactivity in the clear-cell component (F - GFAP), floating neurons (G – MAP2) and a newly discovered p16 immunoreactivity shown in H, helpful to distinguish the DNT from other LEAT entities (unpublished observation, courtesy of Dr. Roland Coras, Erlangen, Germany). This tumor would typically present as FGFR1 altered CD34 negative DNT (not yet genetically confirmed in this tumor sample). j-m: a ganglioglioma (GG) with a characteristic glial-neuronal phenotype and small calcifications (J – HE), a predominant astroglial component (K-GFAP), dysplastic neurons (L-MAP2) and CD34 immunoreactivity in the tumor mass lesion shown in lower right corner as well as in diffusely infiltrated peritumoral grey and white matter (M-CD34). This tumor was included in the study of Blumcke et al. describing the distinct DNA methylation patterns of BRAF V600E mutated CD34 positive GG vs. CD34 negative DNT [3]. n-r: an angiocentric glioma (AG) with characteristic growth pattern around blood vessels (N-HE), a predominant astroglial phenotype (O-GFAP), enriched neuronal matrix (P-MAP2) and EMA-dots similar to ependymoma (R-EMA). This tumor showed a MYB fusion as previously described by Qaddomi et al. [58]. s-w: an isomorphic and diffusely infiltrating glioma (IDG) of low cellularity (S-HE), a predominant astroglial phenotype (T-GFAP), only few contained and pre-existing neurons (U-MAP2) and lack of IDH1R132H mutations (W-IDH mutation specific antibody). This tumor showed a MYBL1 fusion and was previously described by Wefers et al. [75]