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Over the years, numerous attempts have been made to grade astrocytomas in a manner that correlates accurately and reproducibly with biologic behavior and aggressivity. Kernohan and Sayre in the first series AFIP fascicle of 1952 (31) advocated a four-tiered grading system, which is still commonly referenced. Their scale was based simply on histologic features and unified many different descriptive names for astrocytic tumors into one continuum that correlated with patient outcome and survival time. Since then, numerous revisions have been made as more information about the clinical behavior of these tumors has been gathered and as neuropathologic techniques have increased in sophistication. In the modern era, widespread use of immunohistochemical staining-wherein antibodies to certain molecular components are attached to chromogenic (color-producing) materials-has allowed much greater uniformity and specificity in the diagnosis and classification of neoplasms.
The WHO has pioneered the effort to arrive at reproducible, uniform, international standards for classification and grading of these relatively common neoplasms. This effort culminated in the 1993 publication of the WHO II system (32). Within this all-inclusive classification scheme, WHO II incorporates a four-tiered grading system that applies to astrocytomas as well as other central nervous system neoplasms. This scale combines histopathologic criteria with clinical and prognostic information about biologic behavior and correlates only partially with purely histologic features of tumors (Table 1). The WHO II system recognizes distinct tumor subtypes, both within astrocytomas and within other tumor groups, which may exhibit distinct clinical and histopathologic features.
Astrocytic tumors are divided into two basic categories: circumscribed (grade I) or diffuse (grades II, III, and IV). Grade I tumors, such as pilocytic astrocytoma and subependymal giant cell astrocytoma, are generally well circumscribed and have low rates of recurrence after surgical excision. In addition, grade I tumors do not share the inherent tendencies of other gliomas to progress to tumors of higher grade. Within the diffuse astrocytomas, the specific criteria differentiate between the less biologically aggressive forms (grades II and III) and GBM (grade IV). Regardless of their grade at the time of diagnosis, all diffuse astrocytomas tend to progress to GBM (synonymous with grade IV). Criteria used to distinguish grade IV lesions include marked neovascularity, variable mitotic activity, increased cellularity, nuclear pleomorphism, and microscopic evidence of necrosis. One common and distinctive histopathologic feature of GBM is pseudopalisading (Figure 1), in which areas of viable neoplastic cells form an irregular border surrounding areas of necrotic debris. This feature is indicative of the uncontrolled growth within the tumor.
An important concept in understanding the pathologic characteristics of high-grade astrocytomas is that a single infiltrative astrocytoma (ie, grades II-IV) frequently contains multiple areas of variable histologic features. This concept is important for several reasons. First, a sampling error in a limited biopsy may mean that the degree of malignancy seen by the neuropathologist may not reflect the degree of malignancy present elsewhere in the tumor. Such sampling error may result in significant undergrading of some lesions. Overgrading, however, cannot be caused by sampling error, because the true grade of the tumor is based on its most malignant component. For this reason, the imaging appearance of the tumor is an essential adjunct to the pathologic information. For example, if the imaging findings strongly suggest the presence of a GBM, with such features as necrosis or hemorrhage, and the pathologic analysis of the biopsy specimen indicates a grade II fibrillary astrocytoma, strong consideration should be given to repeating the biopsy.
Another important consequence of the histologic variations seen within infiltrative astrocytomas is the lack of correlation between the radiologic or even the gross pathologic margin of the tumor and the true margins of the area of neoplastic infiltration. An astrocytoma is seen on radiologic images because it produces significant mass effect, edema, necrosis, or hemorrhage. These imaging features correlate well with the histopathologic changes seen in higher-grade tumors, such as rapid cell growth leading to hypercellularity and neovascularity. Studies of tumor angiogenesis, which is another area of active research, have shown that the tumor cells secrete various substances, including vascular endothelial growth factor (33,34) and renin (35), which induce the rapid growth of new blood vessels. These new tumor-induced vascular channels are structurally abnormal and to varying degrees lack the normal blood-brain barrier. This characteristic leads to transudation of fluids and protein into the extracellular space that may be detected radiologically as vasogenic edema. MR imaging in particular is exquisitely sensitive to abnormal or disproportionate amounts of tissue water, both intra- or extracellular (Figure 2). Neither edema nor enhancement, however, truly demarcate the histologic margins of these tumors. Immediately adjacent to radiologically abnormal areas, there may be areas of low-grade astrocytoma and zones of infiltration by small numbers of high-grade tumor cells that do not cause significant mass effect and do not have abnormal vessels that can cause edema and thus are not detectable on MR images. Thus, even when all radiologically visible portions of the tumor have been excised, the surgical margins may not be "clean," and further neoplastic growth can (and usually does) occur in the adjacent brain, leading from microscopic residual to gross recurrence (36).
Several distinct histologic variants within the grade IV astrocytomas or GBMs have been described, including the giant cell GBM, previously called the monstrocellular sarcoma, and the small cell GBM, which is relatively less common (Figure 3). Some GBMs contain a high proportion of malignant mesenchymal cells and are termed gliosarcomas or Feigin tumors. Certain histologic features of these tumors, such as the tendency for these sarcomatous areas to be perivascular, have given rise to the theory that the sarcoma component arises within areas of endothelial proliferation in the malignant glioma, perhaps directly from the walls of tumor vessels. Rarely, an intraaxial tumor is seen that consists almost entirely of these sarcomatous elements and is called a fibrosarcoma of the central nervous system. Although the histogenesis has not been proved, fibrosarcoma of the central nervous system may represent an unusual outcome of gliosarcomatous degeneration. In addition, GBM may exhibit areas of chondroid or osseous metaplasia. Despite histologic variations, the prognosis and response to various treatment modalities are virtually the same for all grade IV tumors; therefore, these latter histologic features do not alter prognosis and are primarily for descriptive purposes. Whether these variations will come to be considered as distinct subtypes or possibly even distinct entities unto themselves remains to be seen.
Pathologic Characteristics