Glioblastoma Multiforme

Radiologic-Pathologic Correlation

Abstract Introduction Clinical Presentation Historical Perspective

Etiology and Genetics Pathologic Characteristics Radiologic-Pathologic Correlation

Therapy and Prognosis Conclusions Source Information References

Radiologic-Pathologic Correlation

As the name implies, GBMs are notorious for a wide variety of appearances, both by location and by feature. However, the single most important unifying characteristic, recognized both at radiologic and gross pathologic examination, is the presence of hemorrhage or necrosis. The primary cellular component of the tumor is frequently of low attenuation on unenhanced CT scans and low signal intensity on T1-weighted MR images, primarily because of excess water in both the intra- and extracellular compartments. The presence of hemorrhage and necrosis bordering on areas of viable neoplastic tissue, however, frequently creates a mixed or heterogeneous pattern, which is clearly demonstrated on gadolinium-enhanced MR images (Figure 4). This heterogeneity may be caused by blood products in various stages of liquidity and oxidation or by complex fluid collections containing water with various concentrations of proteinaceous debris.

In the following subsections, we present many of the more classic appearances of these tumors and also some of their less common manifestations. Some of the variations depicted may also be seen in the lower grades of diffuse astrocytoma, and thus the only differentiating radiologic feature may be the presence of hemorrhage or necrosis.

Hemispheric GBM

The most common imaging appearance of GBM is a large mass located in the supratentorial white matter, usually in the centrum semiovale. The GBM is typically heterogeneous, with central areas of necrosis surrounded by thick irregular walls of solid, living, neoplastic tissue (Figure 1). The gross tumor is surrounded by extensive, perilesional, vasogenic edema ("fingers of edema") and usually exerts considerable mass effect. The imaging appearance in these cases correlates well with the gross pathologic findings, and the correct diagnosis can usually be suggested on the basis of imaging features. Additional diagnostic considerations for this imaging appearance (although they are less likely) include solitary metastasis, tumefactive demyelinating lesion ("singular sclerosis"), and atypical abscess.

Before the availability of cross-sectional imaging, angiography and pneumoencephalography were more widely performed in the work-up of these patients. Nowadays, findings from angiograms can be correlated with those from MR images. On angiograms, prominent, wildly irregular neovascularity, often with early draining veins, was considered typical of GBM (Figure 5). In the example shown, fairly mild vascular changes are seen. In more extreme cases, areas of arterial narrowing and widening, with diffuse arteriovenous shunting could be seen and, in some cases, could be difficult to distinguish from a primary arteriovenous malformation.

These vascular features can also be correlated with findings at positron emission tomography (PET) (Figure 6). This imaging technique most commonly uses radioactively labeled glucose (usually fluorine-18 fluorodeoxyglucose) and can demonstrate both blood flow and metabolic activity (37). Although not commonly used in the evaluation of GBM, PET is a useful research tool and may have practical applicability in evaluating tumor recurrence versus benign enhancing scar tissue (38) or radiation gliosis (39).

Although a GBM typically has thick, irregular walls (Figure 7), occasionally the pattern of necrosis results in a round, thin-walled structure, with scant edema (Figure 8). In such cases, a more extensive differential diagnosis is warranted, including abscess, necrotic metastasis, lower-grade or cystic glioma, resolving hematoma, or focal encephalomalacia caused by an infarct. Some helpful features that may suggest abscess are the presence of multiple lesions (particularly if centered at the border between gray and white matter) and a clinical history of altered immune status, pulmonary arteriovenous malformation or other right-to-left shunt, foreign travel, or high-risk behavior such as intravenous drug abuse. Differentiation from a low-grade cystic astrocytoma may be aided by considerations such as the patient's age and location of the lesion. Usually, despite atypical imaging features, the pathologic analysis is very clear-cut, although in rare cases reactive gliosis surrounding an abscess has been mistaken for a low-grade glioma.

Although most GBMs arise in the deep white matter, these tumors are by no means limited to these regions and may be seen in peripheral locations (Figure 9, Figure 10), potentially resembling a dural-based process. Differential diagnosis in such a case could include atypical meningioma, hemangiopericytoma, dural metastasis, or another dural-based process.

Distinctly uncommon is a GBM that appears as a smooth-walled cyst with a mural nodule (Figure 11). This "cyst with a nodule" morphology is more suggestive of benign lesions, such as pilocytic astrocytoma, ganglioglioma, or pleomorphic xanthoastrocytoma. These largely circumscribed lesions usually occur in children (pilocytic astrocytoma) and tend to occur in specific locations such as the cerebellum or optic tracts, or they are superficially located in children and young adults (pleomorphic xanthoastrocytoma). Hemangioblastomas may also resemble a cyst with a mural nodule; however, these lesions are seen mainly in the posterior fossa and spinal cord.

A potential pitfall is the GBM that manifests primarily as a large intraaxial hemorrhage. Because vasogenic edema takes time to spread, any acute hemorrhage with evidence of extensive or distant edema should be suspected of being a neoplasm. In these cases, additional radiologic study with use of contrast material will usually demonstrate some areas of solid enhancing tissue, and biopsy would be recommended for definitive diagnosis. Differential diagnosis for a large intraparenchymal hemorrhage would include a hypertensive hemorrhage, vascular malformation, hemorrhagic metastasis, or hemorrhagic primary neoplasm (Figure 12). Other considerations such as amyloid angiopathy or traumatic hemorrhage are considered less likely on the basis of the imaging appearance.

Patterns of Dissemination.-Three major patterns of dissemination are seen with GBM. Most frequently, they metastasize from their original location by direct extension, commonly along white matter tracts. One classic example is the spread from a primary lesion in the temporal lobe to the frontal lobe via the uncinate fasciculus (Figure 13).

Less commonly, GBM, like other central nervous system neoplasms, may spread via cerebrospinal fluid pathways (Figure 14). Less than 2% of GBMs exhibit cerebrospinal fluid seeding, either within the central nervous system or through ventriculoperitoneal or ventriculopleural shunts. Subependymal spread of GBM is another uncommon but characteristic pattern of dissemination (Figure 14) that correlates with a poor prognosis.

Perhaps the least common mode of dissemination is hematogenous spread to extraneural sites. This pattern is so rare that Bailey and Cushing asserted that it did not occur (40). This pathway is a rare cause of dense, osteoblastic bone lesions (Figure 15) and is seen primarily in patients who have undergone surgical treatment of GBM.

Multifocal GBM.-There are three pathways that can result in multifocal GBM. First, a primary GBM may spread, usually through cerebrospinal fluid pathways or through white matter, to other locations as discussed (Figure 14; see also Figure 24). Usually, when this occurs, the primary lesion is clearly seen or may have been previously known. Occasionally, it is necessary to image the entire neuraxis to locate the primary tumor.

Second, in a patient with a diffuse, low-grade astrocytoma, multiple areas of malignant degeneration may occur. All astrocytomas, other than grade I circumscribed astrocytomas, to some degree infiltrate through nearby white matter tracts, regardless of their apparent demarcation on radiologic images. Occasionally, within a large area of brain infiltrated by a diffuse but low-grade astrocytoma, multiple areas of malignant transformation occur, giving rise to multifocal GBM. In these cases, the presence of the underlying diffuse astrocytoma may be occult on images, but several distinct foci of ring-enhancing lesions will be seen, suggestive of high-grade tumor or metastases. One clue to the true nature of the abnormality is that the lesions of multifocal GBM tend to be largely within the deep white matter, whereas multiple metastases are usually centered at or near the gray matter-white matter junction (Figure 16).

If a diffuse astrocytoma is hemispheric, or even bihemispheric, the term gliomatosis cerebri is used. In the WHO II grading scale of biologic potential, gliomatosis cerebri is considered a grade III-IV lesion. Even without evidence of focal malignant change, such a diffuse abnormality is presumed to have a high degree of biologic aggressivity, although this point has not been accepted universally. Occasionally, the underlying diffuse neoplasm is clinically occult and the patient comes to clinical attention because of focal or multifocal areas of degeneration to a more typical GBM (Figure 17).

Third, in a patient with a genetic abnormality, multiple areas of GBM may arise de novo, without the presence of an underlying low-grade lesion. These tumors may arise from cells that, although not neoplastic in themselves, are nevertheless "primed" by an inherited or acquired genetic defect.

GBM of the Corpus Callosum

One common and usefully characteristic appearance for a diffuse astrocytoma is the so-called butterfly glioma. Because GBMs are thought to arise from preexisting low-grade diffuse astrocytomas, they too may extend through the commissural white matter tracts, crossing the midline in more than half the cases. Extension through the corpus callosum may occur in a relatively symmetric pattern, giving rise to a butterfly-like appearance (Figure 18, Figure 19). Because the corpus callosum is relatively resistant to infiltration by edema or infection, any lesion seen extending across the midline in this way, whether symmetric or asymmetric, should always be suspected of being a diffuse astrocytoma. Other considerations in the differential diagnosis include primary central nervous system lymphoma, particularily if the patient has acquired immunodeficiency syndrome (AIDS). Cavitation and necrosis are relatively uncommon in central nervous system lymphoma; however, in the setting of AIDS, these atypical features are somewhat more common.

GBM may arise in any part of the corpus callosum and may grow exophytically into the lumen of the ventricle (Figure 20). This type of manifestation may lead, erroneously, into the differential diagnosis of masses of primary intraventricular origin, including choroid plexus papilloma, meningioma (both of which attach to the choroid plexus), central neurocytoma (which attaches to the pellucid septum), and subependymal giant cell astrocytoma (which attaches to the lateral ventricular surface in the region of the head of the caudate nucleus). Usually, careful analysis of imaging findings will prevent this mistake. The appearance of a broad-based abnormality extending into a ventricle with evidence of extraventricular enhancement or mass effect should heighten the suspicion for an exophytic GBM (Figure 21).

Posterior Fossa GBM

The most common astrocytoma in the posterior fossa is the juvenile pilocytic astrocytoma, which occurs most often in the cerebellum, hypothalamus, and optic nerve and tracts. Juvenile pilocytic astrocytomas are distinct from diffuse astrocytomas and do not undergo progressive transformation from low-grade to high- grade gliomas.

The prevalence of primary GBM of the cerebellum is extremely small, especially compared with the prevalence of this lesion in the supratentorial location. The imaging features of this tumor, when it does occur, are relatively similar to those of GBM in other locations (Figure 22). Differential diagnosis includes metastases, hemangioblastoma, or possibly an atypical medulloblastoma.

Astrocytoma of the brain stem is classically seen in children and most commonly is a diffuse, fibrillary tumor of low histologic grade (Figure 23). This tumor does progress to GBM, however, and the tendency for this progression may be slightly increased after radiation therapy. GBM of the brain stem is also seen in the adults. These tumors represent a significant challenge for clinical management. Because even the initial surgical biopsy is associated with risk of injury to vital structures, some clinicians have advocated use of radiation therapy without biopsy in selected cases.

Extraaxial GBM

Both benign and malignant glial neoplasms occasionally manifest as a diffuse leptomeningeal process, usually as a result of dissemination through the cerebrospinal fluid from a primary intraaxial tumor. Primary leptomeningeal glioblastomatosis is a rare neoplastic condition that may originate from ectopic neuroglial cell rests within the pia mater and arachnoid (41).

Radiologic features in cases of primary leptomeningeal glioblastomatosis consist of either a diffuse or focal thickening of the leptomeninges, usually with contrast material enhancement (Figure 24). The differential diagnosis for pathologic conditions with this appearance is broad: Inflammatory disease, both infectious (tuberculosis) and noninfectious (Langerhans cell histiocytosis or sarcoidosis); metastatic deposits (especially from breast carcinoma and lymphoma); and cerebrospinal fluid spread of a primary central nervous system neoplasm such as medulloblastoma, germinoma, or pineoblastoma all may have this radiologic appearance. In addition, surgical scarring, as well as old subarachnoid hemorrhage or even a diagnostic lumbar puncture, can produce enhancing leptomeningeal tissue. Almost any of these other possibilities is more common than leptomeningeal gliomatosis (whether in the form of GBM or another tumor, such as oligodendroglioma), and a careful search for other causes is mandatory before the diagnosis is established. In fact, the diagnosis of leptomeningeal glioblastomatosis is generally made by the pathologist to the amazement of all others.

Even more uncommon is the occurrence of leptomeningeal gliosarcomatosis (Figure 25), whose imaging features are virtually indistinguishable from those of leptomeningeal glioblastomatosis. Theoretically, if leptomeningeal gliosarcomatosis contained enough of a nodular component, one might be able to see a slightly higher degree of attenuation on unenhanced CT scans, but in practical terms, it is very difficult to make this claim prospectively. Again, this diagnosis generally requires tissue examination by the neuropathologist.

Spinal GBM

The most common glioma of the spinal cord is the ependymoma; however, GBMs are also found to arise within the white matter tracts of the spinal cord. The most common location reported is the cervical region, which is also the most frequent location for lower-grade astrocytic neoplasms, including juvenile pilocytic astrocytoma. At radiologic examination, a spinal GBM is seen as an intramedullary mass enlarging the spinal cord; the mass demonstrates variable contrast enhancement and evidence of hemorrhage and necrosis (Figure 26).

Gliosarcoma and Fibrosarcoma

Gliosarcoma, which contains a substantial proportion of malignant mesenchymal cells, is very similar to other GBMs in most imaging characteristics with one important exception. On unenhanced CT scans, most GBMs are of low to intermediate attenuation except in areas of hemorrhage; in contrast, gliosarcoma may display high attenuation within the viable portion of the tumor (due to the presence of fibrous tissue) and low attenuation only within the necrotic center (Figure 27).

Gliosarcoma can occur in any location where GBM occurs, but it is usually found in the central white matter tracts or corpus callosum. One unusual and extreme example of this tumor type occurs if virtually the entire tumor bulk is composed of mesenchymal cells, with a minimal glial component. This tumor is referred to as a central nervous system fibrosarcoma (Figure 28), which represents an infrequent, highly specialized outcome of gliosarcomatous degeneration.

Pediatric and Congenital GBM

Although GBM occurs most frequently in patients aged 65-75 years, it has been reported in patients of every age, including newborns (Figure 16). The imaging and pathologic features of GBM in pediatric patients are similar to those of GBMs found in older patients.

The pathogenesis of congenital GBM is somewhat controversial in that one would expect that more time would be required for the maturation and subsequent dedifferentiation of these cells into GBM. More likely, a "congenital GBM" represents malignant glial differentiation within a primitive neuroectodermal tumor. Considered simply from an etymologic perspective, such a tumor may be the only true GBM. It is possible that future investigations will show that young patients with these tumors inherited a very active oncogene, or possibly an extremely potent spontaneous mutation will be found to be responsible. Happily, these cases are extremely rare.

Abstract Introduction Clinical Presentation Historical Perspective

Etiology and Genetics Pathologic Characteristics Radiologic-Pathologic Correlation

Therapy and Prognosis Conclusions Source Information References