Concurrent ependymal and ganglionic differentiation in a subset of supratentorial neuroepithelial tumors with EWSR1-PLAGL1 rearrangement

Abstract

Neuroepithelial tumors with fusion of PLAGL1 or amplification of PLAGL1/PLAGL2 have recently been described often with ependymoma-like or embryonal histology respectively. To further evaluate emerging entities with PLAG-family genetic alterations, the histologic, molecular, clinical, and imaging features are described for 8 clinical cases encountered at St. Jude (EWSR1-PLAGL1 fusion n = 6; PLAGL1 amplification n = 1; PLAGL2 amplification n = 1). A histologic feature observed on initial resection in a subset (4/6) of supratentorial neuroepithelial tumors with EWSR1-PLAGL1 rearrangement was the presence of concurrent ependymal and ganglionic differentiation. This ranged from prominent clusters of ganglion cells within ependymoma/subependymoma-like areas, to interspersed ganglion cells of low to moderate frequency among otherwise ependymal-like histology, or focal areas with a ganglion cell component. When present, the combination of ependymal-like and ganglionic features within a supratentorial neuroepithelial tumor may raise consideration for an EWSR1-PLAGL1 fusion, and prompt initiation of appropriate molecular testing such as RNA sequencing and methylation profiling. One of the EWSR1-PLAGL1 fusion cases showed subclonal INI1 loss in a region containing small clusters of rhabdoid/embryonal cells, and developed a prominent ganglion cell component on recurrence. As such, EWSR1-PLAGL1 neuroepithelial tumors are a tumor type in which acquired inactivation of SMARCB1 and development of AT/RT features may occur and lead to clinical progression. In contrast, the PLAGL2 and PLAGL1 amplified cases showed either embryonal histology or contained an embryonal component with a significant degree of desmin staining, which could also serve to raise consideration for a PLAG entity when present. Continued compilation of associated clinical data and histopathologic findings will be critical for understanding emerging entities with PLAG-family genetic alterations.

Keywords: EWSR1-PLAGL1; PLAGL1; PLAGL2; Ependymal-like; Ganglionic differentiation; Neuroepithelial tumor.

Fig. 1

Representative pre-operative brain MRI images of neuroepithelial tumors with PLAG-family genetic alterations are shown. Cases #1–6 have EWSR1-PLAGL1 rearrangement, while Case #7 and #8 have PLAGL2 amplification or PLAGL1 amplification respectively. The top row demonstrates post-contrast T1-weighted sequences, the middle row demonstrates T2-weighted sequences, and the bottom row shows apparent diffusion coefficient maps. Heterogeneous enhancement and diffusion restriction of the solid component are the most common findings, except for tumor #5, which was multicystic and showed no enhancement or diffusion restriction. Tumor cysts were present in case #5, 6, and 8. Additional imaging details are available in supplementary Table 1

Fig. 2

Histology of neuroepithelial tumors with EWSR1-PLAGL1 rearrangement. Concurrent ependymal and ganglionic differentiation was observed on initial resection in 4/6 cases with EWSR1-PLAGL1 rearrangement in this series. The most prominent example occurred in a tumor with combined ependymoma/subependymoma-like histology (Case #4) including areas with intermixed clusters of ganglion cells (A–E). Paranuclear dot-like staining for EMA was only convincingly present in Case #4 (B). Case #5 also showed lower-grade histologic features and had interspersed dysmorphic ganglion cells of low to moderate frequency among otherwise subtly ependymal-like histology; the ganglion cells were small in size (F–G). Case #3 contained ganglion cells in regions of lower-cellularity with occasional microcalcifications, the adjacent areas with greater ependymal quality showed smaller sized cells and variable cellularity (H–I). Case #6 was predominantly ependymal-like with focal areas containing ganglionic cells, there was regionally increased cellularity (J–K). Case #1 lacked a ganglion cell component on initial resection, and showed higher-grade histologic features with increased cellularity (L), elevated Ki-67 labeling and mitotic index, as well as areas of necrosis

Fig. 3

Neuroepithelial tumor with EWSR1-PLAGL1 fusion and subclonal INI1 loss. On initial resection of case #2 a majority of the neoplasm demonstrated ependymal-like architecture (A). However, a selected region of the tumor with increased cellularity contained small clusters of embryonal or rhabdoid cells (B) and showed loss of INI1 by immunostaining (C). The patient received chemotherapy per ACNS0334 and developed multifocal intracranial disease, with additional resection at 7 months showing dense leptomeningeal involvement including a prominent ganglion cell component (D). There was loss of INI1 staining in most neoplastic cells of the second resection, including the small cell component and ganglionic cells (E). The patient died of disease progression 11 months after initial resection

Fig. 4

Histology of high-grade neuroepithelial/embryonal tumors with PLAGL1 or PLAGL2 amplification. Case #8 (PLAGL1 amplification) demonstrated divergent differentiation with a prominent embryonal component, glial elements, and myogenic differentiation (A–F). A loose perivascular/pseudopapillary architecture of primitive cells was seen in selected areas (A), with higher magnification showing small hyperchromatic crowded nuclei with nuclear molding (B). The histology varied with other areas having a greater degree of eosinophilic cytoplasm and glial fibrillarity (C) or spindled cells in fascicular arrangement (D). Desmin immunostaining was positive in a significant percentage of neoplastic cells (E), with myogenic qualities in rare cells with densely eosinophilic cytoplasm or elongation (F). Case #7 (PLAGL2 amplification) showed primitive cells with a vaguely perivascular arrangement and occasional foci of myxoid material (G–H); desmin positivity also involved a significant percentage of neoplastic cells (I)