Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?

Abstract

Multinodular and vacuolating neuronal tumor (MVNT) is a new pattern of neuronal tumour included in the recently revised WHO 2016 classification of tumors of the CNS. There are 15 reports in the literature to date. They are typically associated with late onset epilepsy and a neoplastic vs. malformative biology has been questioned. We present a series of ten cases and compare their pathological and genetic features to better characterized epilepsy‐associated malformations including focal cortical dysplasia type II (FCDII) and low‐grade epilepsy‐associated tumors (LEAT). Clinical and neuroradiology data were reviewed and a broad immunohistochemistry panel was applied to explore neuronal and glial differentiation, interneuronal populations, mTOR pathway activation and neurodegenerative changes. Next generation sequencing was performed for targeted multi‐gene analysis to identify mutations common to epilepsy lesions including FCDII and LEAT. All of the surgical cases in this series presented with seizures, and were located in the temporal lobe. There was a lack of any progressive changes on serial pre‐operative MRI and a mean age at surgery of 45 years. The vacuolated cells of the lesion expressed mature neuronal markers (neurofilament/SMI32, MAP2, synaptophysin). Prominent labelling of the lesional cells for developmentally regulated proteins (OTX1, TBR1, SOX2, MAP1b, CD34, GFAPδ) and oligodendroglial lineage markers (OLIG2, SMI94) was observed. No mutations were detected in the mTOR pathway genes, BRAF, FGFR1 or MYB. Clinical, pathological and genetic data could indicate that MVNT aligns more with a malformative lesion than a true neoplasm with origin from a progenitor neuro‐glial cell type showing aberrant maturation.

New clinicopathological associations and histoprognostic markers in ILAE types of hippocampal sclerosis

“…Among CD34+ cases, we described three cases of hippocampal MVNT. The tumoral or dysplastic etiology of this lesion is debated . We confirmed the absence of BRAF V600E mutation and the CD34 and INA immunopositivity of MVNT .…”

“…The tumoral or dysplastic etiology of this lesion is debated . We confirmed the absence of BRAF V600E mutation and the CD34 and INA immunopositivity of MVNT . We identified an association between the “CD34+ nodular” group and dysmnesic auras suggesting that the CD34+ cells are associated with a pre‐ictal activity in the hippocampus.…”

Multinodular and vacuolating neuronal tumour of the cerebrum: a rare neuroimaging incidentaloma or a potentially treatable cause of focal epilepsy?

“…MVNTs are of particular interest to the clinician/epileptologist, not only because of the frequent association with epileptic seizures, but also as an operatively treatable cause of epilepsy. A total of 96 cases (including the current case) have been described in the literature to date (Ratilal et al, 2007;Huse et al, 2013;Bodi et al, 2014;Fukushima et al, 2015;Nagaishi et al, 2015;Yamaguchi et al, 2016;Alsufayan et al, 2017;Badat et al, 2017;Cathcart et al, 2017;Gökç e, 2017;Monté et al, 2017;Nunes et al, 2017;Gonzalez-Quarante et al, 2018;Kapucu et al, 2018;Lobo and Srinivasan, 2018;Pekmezci et al, 2018;Thom et al, 2018) (supplementary table 1), of which 37 were histopathologically verified (HV) (38.54%). A slight female predominance was noticed in both non-HV and HV cases (M:F=2:3 and M:F=9:11, respectively).…”

“…Therefore, epilepsy is probably less frequently associated with MVNT compared to DNET and other low-grade epilepsy-associated tumours (van Breemen et al, 2007). Nevertheless, some cases of MVNTs could have been misdiagnosed as other more prevalent lesions that share histological similarities, based on epilepsy series (Thom et al, 2018). Considering seizure semiology, temporal lobe tumours (the most common [71.79%] localization in MVNT and epilepsy cases) presented with epigastric and déjà vu aura, as well as automotor and dialeptic seizures.…”

“…V. Baščarević, et al Some authors speculated that MVNT is rather a dysplastic hamartomatous malformation of cortical development than a low-grade neoplasma (Cathcart et al, 2017;Thom et al, 2018). However, recent findings by Pekmezci et al (2018) suggest that MVNT is a clonal neoplasm characterized by solitary pathogenic alterations that cause activation in signal transduction pathways (Ras-Raf-MAP kinase signalling pathway), and as such, this tumour is genetically similar to gangliogliomas (MVTN was present with gangliogliomas in 25% of their series), pilocytic astrocytomas, and dysembrioplastic-neuroepithelial tumours (DNET), although without the respective typical mutations.…”