Epithelioid Glioblastomas and Anaplastic Epithelioid Pleomorphic Xanthoastrocytomas--Same Entity or First Cousins?

Abstract

Epithelioid glioblastoma (eGBM) and pleomorphic xanthoastrocytoma (PXA) with anaplastically transformed foci (ePXA) show overlapping features. Eleven eGBMs and 5 ePXAs were reviewed and studied immunohistochemically. Fluorescence in situ hybridization for EGFR amplification, PTEN deletion and ODZ3 deletion was also performed, with Ilumina 450 methylome analysis obtained in five cases. The average age for eGBM was 30.9 (range 2-79) years, including five pediatric cases and a M : F ratio of 4.5. The ePXA patients had a M : F ratio of 4 and averaged 21.2 (range 10-38) years in age, including two pediatric cases. Six eGBMs and two ePXAs recurred (median recurrence interval of 12 and 3.3 months, respectively). All tumors were composed of solid sheets of loosely cohesive, "melanoma-like" cells with only limited infiltration. ePXAs showed lower grade foci with classic features of PXA. Both tumor types showed focal expression of epithelial and glial markers, retained INI1 and BRG1 expression, occasional CD34 positivity, and lack of mutant IDH1 (R132H) immunoreactivity. BRAF V600E mutation was present in four eGBMs and four ePXAs. ODZ3 deletion was detected in seven eGBMs and two ePXAs. EGFR amplification was absent. Methylome analysis showed that one ePXA and one eGBM clustered with PXAs, one eGBM clustered with low-grade gliomas, and two eGBMs clustered with pediatric-type glioblastomas. Common histologic, immunohistochemical, molecular and clinical features found in eGBM and ePXA suggest that they are closely related or the same entity. If the latter is true, the nomenclature and WHO grading remains to be resolved.

Keywords: BRAFV600E; ODZ3; epithelioid; glioblastoma; pediatric; pleomorphic; prognosis; xanthoastrocytoma.

Figure 1

A. Post‐gadolinium t1 axial magnetic resonance image demonstrating a well‐defined enhancing superficial ePXA in the right temporal lobe, involving mostly the cortex; surrounding edema is not seen. B. Post‐gadolinium magnetic resonance t1 axial image demonstrating a well‐defined, heterogeneously enhancing superficial eGBM with marked surrounding edema.

Figure 2

A. Hematoxylin–eosin‐stained (H&E) section of an epithelioid area in a case of ePXA (case 5), demonstrating sheets of loosely cohesive cells with abundant eosinophilic cytoplasm, large, occasionally eccentric nuclei, occasional nucleoli and distinct cellular borders (melanoma‐like features). A high mitotic rate is observed. B. A high‐power microscopic field of an eGBM (case 6), demonstrating epithelioid cells with the same features as described above. Occasional cells with paranuclear globular inclusions are seen (rhabdoid features); furthermore, there are occasional cells with enlarged red macronucleoli (melanoma‐like features).

Figure 3

Comparison of morphologic and immunohistochemical features of  PXA  (left) and epithelioid (right) areas in a single case of ePXA (case 5). A. Illustrates an area composed of spindled and oval cells with irregular nuclear contours and variably vacuolated (lipidized) cytoplasm. Eosinophilic granular bodies and occasional bizarre, large cells are also seen. B. Shows the epithelioid regions of anaplastic transformation. The PXA areas were extensively positive for GFAP (cytoplasmic and fibrillary pattern) (C), whereas the epithelioid areas showed mostly loss of GFAP expression (D). Occasional tumor cells in the PXA areas demonstrated CD34 expression in an arborescent pattern (E). The epithelioid areas also contained occasional CD34‐positive tumor cells (F). Both areas demonstrated BRAF  V600E mutant protein expression (G,H). The Ki67 immunostain revealed a low proliferation index in the PXA areas (I), and a considerably higher labeling index in the epithelioid areas (J).

Figure 4

A. Illustrates a non‐neoplastic control case with two CEP4 signals (green) and two ODZ3 signals (red) in most nuclei. B. Illustrates a case of eGBM in which the majority of nuclei contain one ODZ3 (red) and two CEP4 (green) signals.