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      Drugs & Diseases > Oncology

      Glioblastoma Workup

      Updated: Mar 07, 2023
      • Author: Jeffrey N Bruce, MD; Chief Editor: Herbert H Engelhard, III, MD, PhD, FACS, FAANS  more...
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      Workup

      Laboratory Studies

      Because gliobastoma is currently a molecular diagnosis, genetic studies for IDH and H3 status are essential, and genetic studies for TERT promoter mutation, EGFR gene amplification, and +7/-10 chromosome copy number changes are also important. Furthermore, excluding a metabolic or infectious process with routine laboratory studies is critical in the evaluation of an otherwise healthy patient who presents with new-onset seizures or neurologic deficit.

      Researchers are working to identify a biomarker that could be used to diagnose glioblastoma with a noninvasive liquid biopsy taken from blood or cerebrospinal fluid, but this technology has not been fully realized. [159, 160, 161]

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      Imaging Studies

      Imaging studies of the brain are essential to make the diagnosis of glioblastoma (GBM). For complete discussion, see Imaging in Glioblastoma.

      On computed tomography (CT) scans, glioblastomas usually appear as irregularly shaped hypodense lesions with thick margins, a peripheral ringlike zone of heterogeneous contrast enhancement, and a penumbra of vasogenic edema. Hemorrhage is occasionally seen, while calcification is uncommon. A marked mass effect is typically evident. [158]

      Magnetic resonance imaging (MRI) with and without contrast is the study of choice for the evaluation and diagnosis of glioblastoma (see the images below). [19, 20] These lesions typically have an enhancing ring observed on T1-weighted images and a broad surrounding zone of edema apparent on T2-weighted images. The central hypodense core represents necrosis, the contrast-enhancing ring is composed of highly dense neoplastic cells with abnormal vessels permeable to contrast agents, and the peripheral zone of non-enhancing low attenuation is vasogenic edema containing varying numbers of invasive tumor cells.[ [158] Several pathologic studies have shown that the area of enhancement does not represent the outer tumor border, because infiltrating glioma cells can be identified within, and occasionally beyond, a 2-cm margin. [162]

      A T1-weighted axial MRI without intravenous contra A T1-weighted axial MRI without intravenous contrast demonstrates a hemorrhagic multicentric glioblastoma in the right temporal lobe. Effacement of the ventricular system is present on the right, along with mild impingement of the right medial temporal lobe on the midbrain.
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      A T1-weighted axial MRI with intravenous contrast A T1-weighted axial MRI with intravenous contrast shows heterogeneous enhancement of the lesion within the right temporal lobe. The hypointensity circumscribed within the enhancement is suggestive of necrosis. This radiologic appearance is typical of a multicentric glioblastoma.
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      A T1-weighted coronal MRI with intravenous contras A T1-weighted coronal MRI with intravenous contrast demonstrates a glioblastoma within the medial temporal lobe and the stereotypical pattern of contrast enhancement.
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      A T1-weighted sagittal MRI with intravenous contra A T1-weighted sagittal MRI with intravenous contrast demonstrates a glioblastoma.
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      On T2-weighted axial MRI, the tumor (glioblastoma) On T2-weighted axial MRI, the tumor (glioblastoma) and surrounding white matter within the right temporal lobe show increased signal intensity compared with a healthy brain, suggesting extensive tumorigenic edema.
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      A fluid-attenuated inversion recovery (FLAIR) axia A fluid-attenuated inversion recovery (FLAIR) axial MRI. This image is similar to the T2-weighted image and demonstrates extensive edema in a patient with glioblastoma.
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      Positron emission tomography (PET) is very sensitive at the initial stage of the diagnosis and can be helpful in diagnosing glioblastomas in difficult cases, such as those associated with radiation necrosis or hemorrhage. Compared with standard MRI, PET is better able to identify intra-tumor heterogeneity and delineate tumor extent. [163] Consequently, PET is particularly useful in treatment planning (including, biopsy, surgery, and radiotherapy) and post-treatment monitoring. On PET scans, increased regional glucose metabolism closely correlates with cellularity, and PET volumes have been shown to have a strong prognostic impact. [164, 165]

      Magnetic resonance (MR) spectroscopy has also proved somewhat useful in distinguishing recurrent tumor from radiation necrosis and hemorrhage. [166] In solid enhancing portions of glioblastoma, MR spectroscopy demonstrates an increase in the choline-to-creatine peak ratio (CHO:CR), an increased lactate (LAC) peak, and decreased N-acetylaspartate (NAA) peak (see the image below). [167] As this classic “neoplastic spectrum” is broadly indicative of cell turnover, identification of this pattern in non-enhancing T2/FLAIR regions supports a diagnosis of infiltrative tumor over radiation necrosis/hemorrhage. [167, 168] A choline/NAA index greater than 2 with a concurrently elevated LAC peak is associated with a poor prognosis. [169]

      Magnetic resonance (MR) spectroscopy signal repres Magnetic resonance (MR) spectroscopy signal representative of glioblastoma (GBM) demonstrating a high peak ratio of choline (CHO) to creatine (CR), a decreased N-acetylaspartate (NAA) peak, and an increased lactate (LAC) peak.
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      Cerebral angiograms are not necessary for the diagnosis or clinical management of glioblastomas.

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      Other Tests

      Electroencephalography (EEG) changes observed in the setting of glioblastoma and other CNS tumors result mainly from disruptions in the surrounding neural tissue, as tumor is electrically silent. While EEG patterns are not specific to tumor pathology, some general correlations have been established. For example, compared with slow-growing gliomas, glioblastomas are associated with more overall abnormality and greater impairment and disorganization of background rhythms. Glioblastomas also produce the most widespread, slowest, and largest delta waves and, due to the high incidence of necrosis, tend to demonstrate flat polymorphic delta activity (PDA). [170]

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      Procedures

      While lumbar puncture can be useful in narrowing the differential diagnosis, it may be contraindicated in the setting of a severe mass effect due to the risk of herniation secondary to increased intracranial pressure. 

      Cerebrospinal fluid (CSF) studies do not currently aid in the diagnosis of glioblastoma, but research is being conducted in monitoring of genetic changes in glioblastoma and the presence of circulating tumor DNA. [159, 160, 161]

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      Histologic Findings

      Macroscopic Appearance

      Despite the short duration of symptoms, glioblastomas are often surprisingly large at the time of presentation, occupying much of a cerebral lobe. [2] They are typically unilateral but may cross the corpus callosum. [55, 56, 57] Most glioblastomas of the cerebral hemispheres are clearly intraparenchymal with an epicenter in the white matter, but some extend superficially into cortical gray matter and contact the leptomeninges and dura, occasionally mimicking a metastasis or meningioma. [76, 77]  

      Macroscopically, glioblastomas are poorly delineated, with peripheral grayish to pink tumor cells, central yellowish necrosis from myelin breakdown (comprising up to 80% of the total tumor), and multiple red and brown areas of recent and distant hemorrhages. [2] Cysts, when present, typically contain a turbid fluid of liquefied necrotic tumor tissue. [171, 172] See the image below.

      Coronal section of a glioblastoma in the left temp Coronal section of a glioblastoma in the left temporal lobe with typical coloration: thickened tan cortex overlying a large central region of yellowish necrosis stippled with red and brown lesions from new and old hemorrhage. Courtesy of Wikimedia Commons [author Sbrandner, https://commons.wikimedia.org/wiki/File:Glioblastoma_macro.jpg].
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      Microscopic Appearance

      Glioblastomas are highly cellular tumors composed of poorly differentiated, fusiform, round, or pleomorphic astrocytic cells with marked nuclear atypia and brisk mitotic activity. [172] As discussed in greater detail in Overview/Pathophysiology, microvascular proliferation and necrosis are essential diagnostic features. [2] Necrosis is often, but not always, accompanied by perinecrotic palisading and can be innate, or therapy-induced (ie, radionecrosis) in patients who have received treatment. The distribution of these histologic features varies, but viable tumor cells tend to be located in the periphery whereas necrotic tissue is usually found in the tumor center. [2] Microvascular proliferation occurs throughout the tumor but is most pronounced around necrotic regions and in the infiltrative margins. [2]

      Undoubtedly, glial fibrillary acidic protein (GFAP) remains the most valuable marker for neoplastic astrocytes. Although immunostaining is variable and tends to decrease with progressive dedifferentiation, many cells remain immunopositive for GFAP even in the most aggressive glioblastomas. Vimentin and fibronectin expression are common but less specific. [173]

      The WHO recognizes three histologic patterns characterized by the predominance of a particular cell type: giant cell glioblastoma, gliosarcoma, and epitheliod glioblastoma. These patterns are discussed below. 

      Giant cell glioblastoma

      Large, multinucleated tumor cells are present in many glioblastomas, but only those in which multinucleated giant cells comprise the dominant histopathological feature are designated giant cell glioblastomas. This subtype is rare, accounting for < 1% of all glioblastomas. [174, 175] Giant cell glioblastomas are characterized by an abundance of multinucleated giant cells set against a background of small, often fusiform cells (see the image below). [176]

      Histology section of a giant cell glioblastoma. Se Histology section of a giant cell glioblastoma. Several bizarre, multinucleated giant cells are visible against a background of smaller tumor cells. Courtesy of Wikimedia Commons (author Jensflorian, https://commons.wikimedia.org/wiki/File:Giant_cell_glioblastoma_HE_X200.jpg].
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      The giant cells themselves are bizarre: in some cases, they can be as large as 0.5 mm in diameter and contain more than 20 nuclei. [2] Mitoses are often visible in both the giant cells and smaller tumor cells. A common feature is the formation of pseudorosette-like accumulations of tumor cells around the vasculature. [52] Frequently rich in reticulin, giant cell glioblastomas are firm and well-circumscribed; consequently, these tumors may be mistaken for a metastasis or meningioma when attached to the dura. [2] Although the prognosis in patients with giant cell glioblastoma is poor, it may be slightly better than that of ordinary glioblastoma. [175, 177]

      Gliosarcoma

      The designation of gliosarcoma is reserved for tumors that show prominent mesenchymal metaplasia characterized by alternating areas of glial and mesenchymal differentiation in a biphasic pattern. [2] (See the image below.) This subtype is also rare but slightly more common than giant cell glioblastoma, accounting for roughly 2% of all glioblastomas. [178]

      Histology section of a gliosarcoma with Van Gieson Histology section of a gliosarcoma with Van Gieson’s stain highlighting connective tissue. The classic alternating pattern of gliomatous (pink) and sarcomatous (yellow-brown) tissue is evident. Courtesy of Wikimedia Commons [author Marvin 101, https://commons.wikimedia.org/wiki/File:Gliosarcoma_Histopathology_200x_EVG.jpg].
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      Gliosarcomas are characterized by a mixture of sarcomatous and gliomatous tissues. The sarcomatous component often resembles a spindle cell sarcoma, with long bundles of densely packed spindle cells surrounded by reticulin fibers. Some cases show marked pleomorphism and/or additional lines of mesenchymal differentiation, including cartilage, bone, osteoid-chondroid tissue, smooth and striated muscle, and lipomatous features. [179, 180, 181]

      The glial component typically appears as reticulin-free islands of astrocytic cells; rarely, primitive neuronal components are present. [182] Due to its high connective-tissue content, gliosarcoma—like giant cell glioblastoma—appears as a firm, well-circumscribed mass that may be similarly mistaken for a metastasis or meningioma when attached to the dura. [2] The prognosis in patients with gliosarcoma is very similar to that of classic glioblastoma. [183]

      Epithelioid glioblastoma

      Epithelioid glioblastomas, which often resemble metastatic carcinoma or melanoma, are characterized by sharply demarcated, loosely cohesive aggregates of large epithelioid cells with little intervening neuropil. The epithelioid cells are relatively uniform, with distinct cell membranes, abundant eosinophilic cytoplasm, large vesicular nuclei, and prominent macronucleoli. [2] Rosenthal fibers and eosinophilic granular bodies are rare. In some cases, giant cells, lipidization, cytoplasmic vacuoles, desmoplastic response, and xanthoastrocytoma-like histology can be seen. [184, 185, 186] Necrosis is often present but is more commonly zonal than palisading. [2] The prognosis in patients with epithelioid glioblastomas varies with the presence of various genetic alterations including BRAF mutations, COKN2A deletions, and PDGFRA amplification. [185]

      This glioblastoma is composed of large epithelioid This glioblastoma is composed of large epithelioid cells that are immunoreactive for glial fibrillary acidic protein (GFAP) (hematoxylin and eosin, 40× original magnification). Courtesy of Roger E McLendon, MD.
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      Staging

      Staging of glioblastomas is neither practical nor possible because these tumors do not have clearly defined margins. Rather, they exhibit well-known tendencies to invade locally and spread along compact white matter pathways, such as the corpus callosum, internal capsule, optic radiation, anterior commissure, fornix, and subependymal regions. Despite its rapid infiltrative growth, glioblastomas tend not to invade the subarachnoid space and thus rarely metastasize via cerebrospinal fluid (CSF). Penetration of the dura, venous sinuses, and bone is exceptional, and hematogenous spread to extraneural tissues is very rare in patients who have not had previous surgical intervention. [78, 79, 80, 67, 81] When metastasis does occur, it most commonly affects bones, lymph nodes, liver, and lungs. [82, 83]

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