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. 2019 Jun 10;21(6):800-808.
doi: 10.1093/neuonc/noz037.

Septal dysembryoplastic neuroepithelial tumor: a comprehensive clinical, imaging, histopathologic, and molecular analysis

Jason C H Chiang  1 , Julie H Harreld  2 , Ryuma Tanaka  3 , Xiaoyu Li  1 , Ji Wen  1 , Chenran Zhang  4   5 , Daniel R Boué  6 , Tracy M Rauch  7 , J Todd Boyd  8 , Jie Chen  9 , Joseph C Corbo  9 , Thomas W Bouldin  10 , Scott W Elton  11 , Le-Wen L Liu  12 , Deborah Schofield  13 , Sunhee C Lee  14 , John-Paul Bouffard  15 , Maria-Magdalena Georgescu  16 , Rimal H Dossani  17 , Maria A Aguiar  13 , Richard A Sances  18 , Ali G Saad  19 , Frederick A Boop  5 , Ibrahim Qaddoumi  1 , David W Ellison  3
Affiliations

Septal dysembryoplastic neuroepithelial tumor: a comprehensive clinical, imaging, histopathologic, and molecular analysis

Jason C H Chiang et al. Neuro Oncol. .

Abstract

Background: Dysembryoplastic neuroepithelial tumors (DNETs) are uncommon neural tumors presenting most often in children and young adults and associated with intractable seizures. Rare midline neoplasms with similar histological features to those found in DNETs have been described near the septum pellucidum and termed "DNET-like neoplasms of the septum pellucidum." Due to their rarity, these tumors have been described in just a few reports and their genetic alterations sought only in small series.

Methods: We collected 20 of these tumors for a comprehensive study of their clinical, radiological, and pathological features. RNA sequencing or targeted DNA sequencing was undertaken on 18 tumors, and genome-wide DNA methylation profiling was possible with 11 tumors. Published cases (n = 22) were also reviewed for comparative purposes.

Results: The commonest presenting symptoms and signs were related to raised intracranial pressure; 40% of cases required cerebrospinal fluid diversion. Epilepsy was seen in approximately one third of cases. All patients had an indolent disease course, despite metastasis within the neuraxis in a few cases. Radiologically, the septum verum/septal nuclei were involved in all cases and are the proposed site of origin for septal DNET (sDNET). Septal DNET showed a high frequency (~80%) of mutations of platelet derived growth factor receptor A (PDGFRA), and alterations in fibroblast growth factor receptor 1 (FGFR1) and neurofibromatosis type 1 (NF1) were also identified. In a genomic DNA methylation analysis alongside other neural tumors, sDNETs formed a separate molecular group.

Conclusions: Genetic alterations that are different from those of cerebral DNETs and a distinct methylome profile support the proposal that sDNET is a distinct disease entity.

Keywords: FGFR1; NF1; PDGFRA; DNET; septum verum.

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Figures

Fig. 1
Fig. 1
Clinical Features of sDNET. (A) Although the SJCRH series shows slight male predilection, there is no gender predilection in the combined series. (B) Box and scatter plots of age at diagnosis. (C) Frequencies of presenting symptoms; MS = mental status, IV = intraventricular. (D) Due to its location, gross total resection (GTR) of sDNET was possible in only a portion of cases. STR = subtotal resection. (E) Cases showed metastasis within the neuraxis at presentation or during follow-up. (F) Most cases of sDNET were managed by observation alone after surgery. (G) Progression-free survival of patients with sDNET; median time to progression was 19 months for the SJCRH series. (H) Overall survival of patients with sDNET.
Fig. 2
Fig. 2
Anatomy of sDNET. (A) Axial, (B) sagittal, and (C) coronal T1-weighted images (T1WI) show the normal anatomy of the septum verum (SV) and surrounding structures. The diagonal band of Broca (DbB, containing Ch2 nuclei) is visible at the anterior, medial, and inferior aspect of the SV. The septum pellucidum (SP) is a thin membrane above the SV. CC = corpus callosum, FX = fornix, AC = anterior commissure, SCA = subcallosal area, GP = globi pallidi. Typical sDNET (*) located in the SV, in this case on the right, is shown on (D) axial, (E) sagittal, and (F) coronal T1WI. Typically, sDNET appears hyperintense on T2-weighted images (G) and non-enhancing on T1WI with contrast (T1WI+C) (H), and partially suppressed on T2-weighted FLAIR images (I). (J) Axial gradient recalled echo images show no susceptibility suggestive of hemorrhage. (K) Sagittal images from FIESTA (Fast Imaging Employing Steady-state Acquisition) show almost fluid-like signal. (L) On ADC map, the tumor is hyperintense, consistent with absence of restricted water diffusion seen as low signal on diffusion-weighted image (inset).
Fig. 3
Fig. 3
Characteristic histopathologic and immunophenotype of sDNET. (A) The presence of numerous OLCs is a feature of sDNET. (B) Neurons that appear to “float” in mucin pools are an uncommon finding. (C) Septal DNET has a tendency for an infiltrative growth pattern, revealed by the presence of numerous entrapped axons and neurons. (D) Infiltration beneath the ependyma is also another characteristic finding. (E) The tumor cells in sDNET are positive for Olig2 and GFAP (F). (G) Ki67 immunolabeling is generally low but can reach a moderate level in focal areas in a few cases (H). Scale bar = 50 µm.
Fig. 4
Fig. 4
Molecular alterations in sDNET. Nearly 80% (14/18) of tumors with available tissue for sequencing harbor alterations in PDGFRA Ig-like domain 4, especially in the K385 residue (13/14, 92.9%). (B) FGFR1 alterations, including hotspot double mutations (K656E and A638G, and K656M and T658P) in the tyrosine kinase domain (TKD) and internal tandem duplication (ITD) of the TKD are found in 3 other tumors. (C) An NF1 mutation in the Ras-GTPase activating (GAP) domain is identified in 1 tumor; number of cases in circles. Diagram and domain information were obtained from Pediatric Cancer Data Portal (PeCan) of St Jude Children’s Research Hospital (https://pecan.stjude.cloud/home).
Fig. 5
Fig. 5
Septal DNET is a molecularly distinct entity. Both unsupervised cluster analysis (A) and a t-SNE plot (B) of methylation profiles of sDNET and pediatric low-grade neuroepithelial tumors (LGNETs) highlighted sDNET as a molecularly distinct disease entity; AG = angiocentric glioma, DA = diffuse astrocytoma, O = oligodendroglioma.
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