GLIOBLASTOMA MULTIFORME
 

The graded anaplasia of the glioma group reaches its extreme in glioblastoma multiforme. Most authors consider this lesion to be a neoplasm of astrocytes because (1) the glioblastoma merges as a clinical entity with the two better-differentiated astrocytomas and anaplastic astrocytomas, (2) pathologically the glioblastoma sometimes evolves out of a better-differentiated astrocytic tumor, and (3) it often contains neoplastic astrocytes. It is recognized, however, that many glioblastomas appear to arise de novo, some are totally undifferentiated, and a rare glioblastoma evolves out of another glioma such as an oligodendroglioma.

In any site, the glioblastoma expresses its outright anaplasia as the induration and sometimes fleshy grayness of high cellularity and the hemorrhagic necrosis of rapid growth. These features are most apparent in the cerebral hemispheres of adults, where the characteristically deep-seated lesion is most common, but can also be observed in the brain stem or in the rare lesion of the spinal cord. The gray fleshiness is typical of any markedly cellular lesion and is often most apparent in areas of invaded cortical gray matter. The necrotic regions are usually more centrally placed and are known for distinctive variegation by reds, browns, and yellows. Unlike the well-differentiated astrocytoma, the mass often appears well defined, and any cysts are filled with dirty brown, rather than clear yellow, fluid. The neoplastic cells diffuse freely through the white matter and can funnel into fiber pathways such as the corpus callosum, internal capsule, or anterior commissure. Expansion into the opposite cerebral hemisphere then produces the classic butterfly lesion.

At surgery, the circumscription of the glioblastoma can be sufficiently pronounced, especially in the giant cell variant. to suggest a metastatic carcinoma. The deposition of collagen, either as a reactive process or as part of a neoplastic proliferation of fibroblasts ("gliosarcoma"), can enhance this definition and produce a discrete, firm mass. In general, however, the glioblastoma's infiltrating border, large size, and prominent central area of necrosis are distinguishing features. The soft necrotic character of some glioblastomas can be simulated by the primary cerebral lymphoma or the occasional infarct that comes to surgery. The latter shows prominent softening of the cerebral cortex and lacks the fleshy grayness of the glioma. A rare patient with a glioblastoma has the acute effects of a large intratumoral hemorrhage, although the incidence of this event in this neoplasm is much lower than in metastatic neoplasms such as malignant melanoma and choriocarcinoma. The incidence is high enough, however, to justify pathologic study of tissue fragments adherent to intracranial hematomas.

Microscopically, most of the viable neoplastic cells in the glioblastoma are concentrated in a region of high cellularity that circumscribes a central area of necrosis. In less-advanced neoplasms, only scattered smaller areas of necrosis may be seen. The cellular areas are apparent macroscopically as the fleshy rim and radiographically as the ring of contrast enhancement. Peripherally, the neoplastic cells diffuse away into the surrounding edematous brain for distances that must be considerable in light of the failure of large en bloc resections to cure the lesion. In contrast to the well-differentiated astrocytoma, calcification is rare.

The cytologic composition of the glioblastoma includes a remarkably heterogeneous array of cell types such as fibrillary astrocytes, gemistocytes, larger and more pleomorphic astrocytes, and large bizarre cells with extreme pleomorphism. For the most part these elements have characteristics generally attributed to astrocytes; that is, they have stellate processes as in the fibrillary and gemistocytic astrocytes and a prominent glassy cytoplasm as in the more bizarre astrocytes and giant cells. With immunoperoxidase staining, the fibrillary and gemistocytic astrocytes are often positive, whereas the pink cytoplasm of the other cells shows a variable positivity. By electron microscopy, the positivity with immunoperoxidase is correlated with the presence of the cytoplasmic "glial" filaments. These are numerous in the fibrillary astrocytes and unpredictably present in the large glassy cytoplasm of the remaining cell types.

A cell that often predominates in the glioblastoma but is present also in limited numbers in the anaplastic astrocytoma is a small anaplastic form with a round to elongated nucleus. These cells proliferate to a remarkably high density and are usually responsible for gray, fleshy areas. They also are extremely mobile and diffuse freely through the corpus callosum or other fiber tracts, invade the cortex to surround neurons, and aggregate in a subpial position. In addition, they often are prominent about areas of necrosis, suggesting that this distinctive peripheral concentration of cells could be a consequence of their motility by which they accumulate at the edge because they are unable to pass through the necrotic center.

Some glioblastomas contain many large, bizarre cells, and such neoplasms have been variously referred to as giant cell glioblastoma, giant cell fibrosarcoma, or a type of gliosarcoma. Most authors would classify most of these lesions as gliomas and have noted that, in spite of their alarming microscopic appearance, the survival rate for patients with these lesions is somewhat more favourable than for those with the typical glioblastoma. This may relate to their well-circumscribed nature and ease of surgical excision and/or to the reduced biological aggressiveness of bizarre giant cells.

Reactive fibroblasts populate some glioblastomas, whereas neoplastic fibroblasts proliferate in others. In either setting, mesenchymal cells are distinguished from the glial component by the former's polarity, association with reticulin and collagen, and absence of GFAP. A higher incidence in the temporal lobes has been suggested for the mixed neoplastic lesions known as gliosarcomas. It is worth noting that the distinction between reactive and neoplastic fibroblasts is often quite subjective: what is a gliosarcoma to one observer may be a glioblastoma with reactive fibrosis to another. The distinction appears largely academic, however, because the presence of a sarcomatous component does not seem to modify the prognosis.

For diagnostic purposes, the histologic diagnosis of glioblastoma is usually made as much on the basis of two distinctive secondary features as on cytologic characteristics. The first of these is vascular proliferation, by which vascular cells divide to produce coiled masses resembling renal glomeruli. These new vessels often have a directional orientation, as the coils point toward a common site such as an area of high cellularity or necrosis. A response to an angiogenic factor liberated by the neoplasm has been suggested. The phenomenon is often referred to as endothelial proliferation or vascular endothelial proliferation (VEP); however, several immunohistochemical studies have demonstrated that other vascular elements, such as vascular smooth muscle cells, pericytes, and perivascular fibroblasts, are major participants in the proliferative process. The term microvascular proliferation, which has achieved some currency, is more accurate.

Microvascular proliferation is an important feature differentiating glioblastoma multiforme from the well­differentiated fibrillary astrocytoma and the anaplastic astrocytoma, although a small amount of this proliferation is acceptable within the latter lesion. Although characteristic of the glioblastoma, microvascular proliferation is found also in limited extent in other neoplasms, such as pilocytic astrocytoma, cerebellar astrocytoma, oligodendroglioma, and medulloblastoma.

The second diagnostically helpful feature in glioblastoma is necrosis. This feature, with or without associated pseudopalisading of neoplastic cells, is a firm differential point distinguishing glioblastoma from anaplastic astrocytoma. In lesions that have been previously treated with radiation therapy, of course, necrosis may not have this diagnostic value. A distinctive feature of necrotic areas in glioblastoma multiforme, especially the smaller foci, is a concentration of neoplastic cells that jostle with one another at the periphery. Because these cells are often elongated and oriented perpendicularly to their tangents with the necrotic area, the term palisade or pseudopalisade is applied. In a cerebral hemispheric glioma, this pseudopalisading is virtually diagnostic of glioblastoma. Neither the presence nor the absence of pseudopalisading, however, affects the prognostic or diagnostic value of necrosis.

The pathologic diagnosis of the glioblastoma is usually not difficult in generous specimens but can be problematic in small ones. The pathologist's need for an adequate specimen cannot be over­emphasized. More diagnostic problems can be resolved by larger specimens than by application of special stains, including available immunologic techniques. Although purists contend that glioblastoma should be diagnosed only in the presence of necrosis and/or vascular proliferation, in practice there is a justifiable temptation in surgical material to diagnose glioblastoma multiforme on the basis of extreme cellularity or pleomorphism alone, especially in the face of typical clinical and radiographic findings. This is not condoned in the less cellular lesions, however. The size of some small specimens also makes it difficult to exclude other malignant neoplasms such as a metastatic carcinoma. For this reason it is desirable to submit to the pathologist specimens from the edge of the most cellular areas. Such tissues define the relationship of the neoplasm to the surrounding brain-a relationship that in the case of glioblastoma is one of diffuse infiltration and in metastatic carcinoma is the expansion of a cohesive mass. The diagnostically helpful microvascular proliferation and necrosis with pseudopalisading are also often prominent in this peripheral region. A positive GFAP stain indicates a glial, rather than an epithelial, neoplasm, but, like other special stains, it is often negative in the anaplastic lesion where its diagnostic value is most needed.

Radio- and chemotherapy produce marked changes in the glioblastoma that may be encountered at reoperation. Radiotherapy destroys small cells, leaving better differentiated astrocytes behind, and induces pleomorphism in residual neoplastic or reactive glia. Macroscopically, such treated lesions in remission are discrete, fibrotic, necrotic, and sometimes calcified. Cysts some-times form. The subsequent phenomenon of recurrence relates largely to the regrowth of the small anaplastic cells discussed above. At this point, such cells are widely invasive and frequently extend down, or in the case of brain stem lesions up, the cerebral peduncles. Perhaps 10 percent of the lesions seed the ventricular and subarachnoid spaces. In such cases, cytologic study of the cerebrospinal fluid (CSF) can be an effective diagnostic tool.