47‐Year‐Old Female with Left Upper Extremity Weakness and 28‐Year‐Old Male Motor Vehicle Accident Victim

Clinical History

Case 1: A 47‐year‐old right‐handed female presented with sudden onset of left arm and hand weakness. Examination found a mild left facial droop, dysarthria and mildly decreased left arm grip strength (4/5) with numbness. MRI revealed a contrast‐enhancing tumor (Figure 1a). CT scans of the chest, abdomen and pelvis were unrevealing of other lesions.

Figure 1.

 

Case 2: Four months after this, a 28‐year‐old male had a motor vehicle accident. He had no recollection of events prior to his crash. Neurologic examination was non‐focal, with full strength in all extremities and no sensory deficits. MRI revealed a contrast‐enhancing tumor (Figure 1b). Subsequent CT scans of the chest, abdomen and pelvis showed no other lesions.

Microscopic Pathology

Case 1: Intraoperative smears showed a high‐grade tumor (Figure 1c). Microscopic features of the tumor are shown in Figures 1c–1g. No increased reticulin deposition is seen. GFAP staining is shown in Figure 1h. Immunostains for pan‐cytokeratin and epithelial membrane antigen are negative.

Case 2: Microscopic features of the tumor are shown in Figures 1i‐1k. Immunostains for GFAP (Figure 1l) and S‐100 protein (Figure 1m) are positive, but those for pan‐cytokeratin and AE1/AE3 were negative. Ki‐67 stain is shown in figure 1n. Reticulin deposition is absent with a reticulin stain. What are your diagnoses?

Diagnosis

Epithelioid Glioblastoma, IDH‐wildtype (WHO grade IV).

Discussion

Glioblastoma is the most frequent primary brain tumor of adults, exhibiting a diverse morphologic spectrum. It has recently been sub‐classified based on molecular alterations, specifically with respect to the mutational status of isocitrate dehydrogenase (IDH) which serves as both, prognostic and predictive markers. Nevertheless, some morphologic variants of glioblastomas are still recognized and when identified, prompt further attempts at additional molecular characterization, based on frequently associated observations (1, 2). In these two cases, the diagnosis of glioblastoma was initially substantiated on the basis of immunoreactivity for S‐100 and GFAP, markers associated with glial and astrocytic differentiation, respectively. Morphologic features supported the diagnosis of epithelioid glioblastoma. Both tumors were negative for IDH1 and IDH2 mutations. As approximately half of epithelioid glioblastomas have been shown harbor the BRAF V600E mutation (1, 2, 4), further analyses were performed; the tumor from our 47‐year‐old female showed no evidence of a BRAF V600E mutation, while this mutation was detected in the lesion from the 28‐year‐old male.

Epithelioid glioblastoma, a variant of IDH‐wildtype glioblastoma, is especially aggressive (2, 4). They occur more frequently in younger patients, have a tendency to recur early and may show leptomeningeal infiltration (4). The morphologic differential diagnosis typically includes metastatic carcinoma and melanoma. The clinical scenario of a younger patient, the absence of a neoplastic infiltrates detected elsewhere in the body by radiographic examination, and immunoreactivity for GFAP facilitate a diagnosis of an astrocytoma. From such a point, further differential diagnostic considerations would include giant cell glioblastoma and pleomorphic xanthoastrocytoma (1, 2), a lower grade lesion that interestingly also have a frequent association with BRAF V600E mutations. At such a diagnostic junction, the absence of reticulin deposition, along with features generally associated with high‐grade histology (microvascular proliferation, necrosis, elevated Ki‐67 proliferative index), would direct towards a diagnosis of epithelioid glioblastoma (2).

It is important to note that expression of epithelial markers can pose diagnostic nuances, particularly when attempting to distinguish metastatic carcinoma from gliomas in some clinical settings. This is due to the fact that morphologic epithelial and pseudoepithelial differentiation, along with expression of various cytokeratins, have been well established in glioblastomas (3). Rodriguez and colleagues previously subclassified glioblastomas based on the nature of the epithelioid morphology and keratin expression. Under this scheme, adenoid glioblastoma (A‐GBM) shows nests, cords and occasional pseudoglandular/cribiform spaces, without reactivity for low molecular weight keratins or polyclonal carcinoembryonic antigen (pCEA). Glioblastomas with true epithelial differentiation (TE‐GBM) should demonstrate epithelial morphology, with squamous nests or true glandular structures, accompanied by immunoreactivity for keratin. Epithelioid glioblastoma (E‐GBM) would show large, round cells with abundant cytoplasm, but would lack both, glandular architecture and expression of markers generally associated with epithelial differentiation (3). Under this classification scheme, our two cases would both qualify as epithelioid glioblastoma (E‐GBM).

Although molecular classifications have gained significant traction in the assessment of CNS tumors, the subclassification of IDH‐wildtype glioblastoma as an epithelioid glioblastoma, rests on morphologic and immunohistochemical characteristics, and currently does not depend on whether the BRAF V600E mutation is tested for, or even detected. As such, in summary, these two cases demonstrate that although this rare tumor may share in common an early age of presentation, circumscribed imaging findings, morphologic and immunohistochemical features and even absence of IDH mutational, diversity still exists for other molecular alterations. The detection of BRAF V600E mutation, although not required for diagnosis under current classification schemes, may facilitate increased diagnostic confidence, and may lead to consideration of future therapy with directed agents.