Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway

Abstract

Epileptogenic tumors affecting children and young adults are a morphologically diverse collection of neuroepithelial neoplasms that, as a group, exhibit varying levels of glial and/or neuronal differentiation. Recent advances in molecular profiling technology, including comprehensive DNA sequencing and methylation analysis, have enabled the application of more precise and biologically relevant classification schemes to these tumors. In this report, we describe a morphologically and molecularly distinct epileptogenic neoplasm, the polymorphous low-grade neuroepithelial tumor of the young (PLNTY), which likely accounts for a sizable portion of oligodendroglioma-like tumors affecting the pediatric population. Characteristic microscopic findings most notably include infiltrative growth, the invariable presence of oligodendroglioma-like cellular components, and intense immunolabeling for cluster of differentiation 34 (CD34). Moreover, integrative molecular profiling reveals a distinct DNA methylation signature for PLNTYs, along with frequent genetic abnormalities involving either B-Raf proto-oncogene (BRAF) or fibroblast growth factor receptors 2 and 3 (FGFR2, FGFR3). These findings suggest that PLNTY represents a distinct biological entity within the larger spectrum of pediatric, low-grade neuroepithelial tumors.

Keywords: BRAF; Epilepsy; FGFR2; FGFR3; Low-grade neuroepithelial tumor; Oligodendroglioma.

Fig. 1

Radiographic features of PLNTY. Typical appearance of a unifocal abnormality best seen on FLAIR sequence (a; case 1). Frequent calcifications appreciated on CT scan (b; case 2). Focal contrast enhancement was seen in two cases (c–f) as demonstrated by FLAIR (c, d) and T1 post-contrast (e, f) images for cases 6 (c, e) and 2 (d, f). Cystic change was also seen in case 6 (c, e)

Fig. 2

Morphological features of PLNTY. Oligodendroglial (a, b), fibrillary astrocytic (c, d), and spindled astrocytic (e, f) features as seen in cases 3 (a, c, e) and 6 (b, d, f). Vague perivascular pseudorosetting (g, h) as seen in case 5 by smear preparation (g) as well as sectioning (h)

Fig. 3

Immunohistochemical features of PLNTY. Strong labeling for GFAP as seen in case 3 (a), OLIG2 positivity as seen in case 2 (b), negativity for HuC/HuD as seen in case 6, and expression of BRAF V600E as seen in case 3. Diffuse strong expression of CD34 in both tumor cells (e, f) and peripherally associated ramified neural elements (g, h) as seen in case 3 (e, g) and case 6 (f, h)

Fig. 4

FGFR fusions in PLNTY. Schematics showing the tandem duplication and deletion events resulting in FGFR3-TACC (a), FGFR2-KIAA1598 (b), and FGFR2-CTNNA3 (b) fusions. c Copy number profiles from chromosome 10 showing causative deletion events for FGFR2-KIAA1598 (upper) and FGFR2-CTNNA3 (lower) fusions in two ArcherDx-confirmed cases (5 and 7). Red and green indicate relative copy number loss and gain respectively. The genomic positions of CTNNA3, KIAA1598, and FGFR2 are indicated. d Both fusion events are recapitulated in two additional cases identified in the DFKZ database. In the case of the likely FGFR2-CTNNA3 fusion (lower), noise precludes definitive segmentation of the deletion event (blue line)

Fig. 5

Global methylation profiling delineates PLNTY from other epileptogenic tumors of children and young adults. Heat map (red increase methylation, blue decreased methylation) showing distinct CpG methylation signature for PLNTY. Histopathologic and genetic correlates are shown. GG ganglioglioma, PA pilocytic astrocytoma, DNET dysembryoplastic neuroepithelial tumor, LGG NOS low-grade glioma, not otherwise specified. Red squares indicate DFKZ samples not in the original MSKCC cohort