Glial and Glioneuronal Tumors

Pathologic Features

Grossly, low-grade and anaplastic tumors are ill defined and subtly discolored with secondary mass effects identical to those seen radiographically. As described earlier, there are typically foci of microscopic disease beyond the grossly suspected borders that are invisible to the naked eye. Glioblastomas are classically variegated with foci of necrosis and hemorrhage ( Fig. 9.2A ).

Diffuse astrocytomas may have a wide morphologic spectrum ( Table 9.1 ), although the fibrillary pattern is the prototype—composed of elongated, irregular hyperchromatic nuclei, often with no discernible cytoplasm embedded in a dense fibrillary matrix ( Fig. 9.3A ) with thickened eosinophilic cytoplasmic processes. Other morphologic patterns include gemistocytic (eccentric bellies of cytoplasm) (see Fig. 9.3C ), protoplasmic (wispy cobweb-like processes), giant cell (large mononucleated and multinucleated cells with abundant cytoplasm) ( Fig. 9.4A ), small cell (monomorphic oval nuclei with minimal cytoplasm) (see Fig. 9.4E ), epithelioid (cells with discrete cell membranes) (see Fig. 9.4G ), and granular (large cells with granular, periodic acid-Schiff [PAS]–positive cytoplasm) (see Fig. 9.4H ). Diffuse astrocytomas are characterized by invasive growth such that nonneoplastic cells are often intermixed and may even predominate in some areas. Secondary structures of Scherer include subpial condensation, perineuronal satellitosis, and perivascular aggregation (see Fig. 9.3B ). At their extreme, they may involve multiple lobes of the brain and extend into the brainstem and/or cerebellum (formerly called gliomatosis cerebri). A number of grading schemes have been applied, although the WHO scheme is the standard. Grade 2 astrocytomas have atypia only. Grade 3 astrocytomas additionally have significant mitotic activity, and grade 4 astrocytomas have microvascular proliferation or necrosis, often both. The number of mitotic figures necessary for grade 3 astrocytoma has been debated, but one may be enough in a small biopsy (e.g., stereotactic needle) specimen, whereas more are needed in resection specimens. Microvascular proliferation is defined by multilayering of endothelium/myofibroblasts/pericytes or glomeruloid vessels (i.e., multiple lumina) (see Fig. 9.3I ). The necrosis may be bland and infarct-like, but it is most commonly serpentine with associated nuclear pseudopalisading (i.e., lining up of tumor nuclei at the periphery of the acellular necrotic area) (see Fig. 9.3J ).

By immunohistochemistry, most astrocytomas are positive for glial fibrillary acidic protein (GFAP), although the degree of cytoplasmic positivity is highly variable. It may be difficult to distinguish reactive astrocytes in the background from neoplastic cells. S-100 protein is a less specific glial marker but is positive in most gliomas. Neurofilament may be useful for highlighting entrapped axons, thus calling attention to the infiltrative growth pattern. Diffuse astrocytomas may show p53 overexpression. A subset show evidence of IDH1 (R132H) immunoreactivity, a feature also shared by many oligodendrogliomas but not seen with nonneoplastic lesions. A subset of tumors also demonstrate evidence of an ATRX mutation (loss of immunostaining). Finally, MIB-1 (Ki-67) is useful for estimating the proliferative index, which is roughly proportional to the histologic grade (see Fig. 9.3E ).

Differential Diagnosis

The most common and morphologically challenging diagnostic consideration in diffuse astrocytoma is oligodendroglioma. There is considerable morphologic overlap between low-grade astrocytoma and oligodendroglioma, and perinuclear halos may not be notable in a previously frozen or rapidly fixed specimen. Therefore molecular classification is necessary to look for IDH mutation and ATRX loss (see Figs. 9.3F–H and 9.5 ). In poorly differentiated cases, metastatic carcinoma (GFAP negative, cytokeratin positive) and melanoma (HMB-45, MelanA positive) enter the differential diagnosis. One caveat to keep in mind is that keratin cocktails, such as AE1/AE3, often cross-react with GFAP intermediate filaments and may lead to false-positive results with astrocytomas. In general, low-molecular-weight keratins such as CAM5.2 do not suffer this problem and are thus preferable in this differential. Neurofilament may be helpful for highlighting the infiltrative nature of astrocytomas as opposed to metastases, as the latter tend to push axon-rich parenchyma to the side rather than infiltrate. CNS lymphomas are similarly infiltrative but are characterized by angiocentricity and immunoreactivity for lymphocytic (CD45) and B-cell (CD20, CD79A, PAX5) markers. In post-treated astrocytomas, a common differential diagnosis is that of tumor recurrence or progression versus radiation necrosis. Histologically there is often a combination of each with some suggestion that the prognosis is improved when radiation necrosis predominates. Although it is not always possible to distinguish radiation necrosis from tumor necrosis, the former is typified by large geographic zones of infarct-like necrosis unassociated with nuclear pseudopalisading, with or without dystrophic calcification. Other radiation effects consist of parenchymal rarefaction and vascular changes, including telangiectasia, hyalinization, and fibrinoid necrosis of vessel walls (see Fig. 9.8 ) . In patients with low-grade astrocytomas with low cellularity and minimal atypia, distinction from reactive gliosis may be difficult. Findings supportive of neoplasia include radiographic features of diffuse glioma, nuclear enlargement/hyperchromasia, nuclear clustering, IDH mutation, increased MIB-1 proliferative index, and p53 overexpression.

Prognosis and Therapy

The biologic behavior of diffuse astrocytic neoplasms is highly variable, although all are considered malignant. Pre-IDH era, the two most powerful prognostic variables were patient age and histologic grade, and average survival times by grade were 5 to 10 years, 2 to 3 years, and 1 year for grades 2, 3, and 4, respectively. As more studies emerge, histologic grading criteria may not stratify risk for patients with IDH-mutant astrocytomas in the WHO grade 2 and 3 categories. IDH1/2 mutations are associated with better outcomes than IDH wildtype. Other molecular features can be integrated with morphology for further prognostic classification (see Fig. 9.5 ). IDH-wildtype (de novo) glioblastomas have the worst prognosis with median overall survival (OS) of 9.9 months following surgery and radiation and 15 months following surgery, radiation, and chemotherapy. Astrocytoma, IDH mutant, grade 4 tends to fair better with 24-month OS following surgery and radiation and 31-month OS following surgery, radiation, and chemotherapy. H3.3 G34-mutant high-grade gliomas have better survival than IDH-wildtype glioblastoma and H3 K27M-altered diffuse midline glioma but worse than that of IDH-mutant astrocytoma grade 4. Methylation of the O6-methylguanine DNA methyltransferase (MGMT) promoter is a prognostic factor associated with an improved response to chemotherapy with temozolomide and longer overall survival in glioblastoma. Less powerful prognostic variables include Karnofsky performance status (degree of neurologic impairment) and extent of surgical resection.

Pathologic Features

Pilocytic astrocytomas typically appear well demarcated grossly, although there is nearly always some microscopic evidence of infiltration, usually at the edges. Cystic degeneration is common.

Microscopically, the classic pilocytic astrocytoma has a biphasic appearance with alternating dense and loose/microcystic components ( Fig. 9.8A ). In some cases, only one of the two patterns is encountered. The dense regions often resemble fibrillary astrocytoma, except that the cytoplasmic processes are particularly long and hairlike (i.e., piloid, as indicated by the tumor’s name). The latter is best appreciated on cytologic specimens such as intraoperative smears. They also differ from fibrillary astrocytoma by a typically more solid growth pattern (e.g., lack of neurofilament-positive entrapped axons) and, in most cases, the presence of corkscrew-shaped brightly eosinophilic Rosenthal fibers (see Fig. 9.8B and C ). The loose component sometimes looks remarkably similar to oligodendroglioma, although the long, thin cellular processes are often highlighted with a GFAP immunostain. In addition, this component frequently harbors mulberry-shaped eosinophilic granular bodies (EGBs), which may be numerous or rare (see Fig. 9.8D ). In the latter scenario, staining with PAS and diastase may help draw attention to these structures. The nuclei of pilocytic astrocytomas are typically oval with bland chromatin, but significant atypia (perhaps degenerative in nature) may occasionally be seen and is generally unassociated with increased mitotic/proliferative activity. Multinucleated forms may also be visualized. Glomeruloid vessels with multiple lumina are also typical and should not be mistaken for the multilayered endothelial hyperplasia of diffuse gliomas. Nevertheless, the latter may be encountered in pilocytic astrocytomas as well and does not have the ominous significance that it does in diffuse gliomas. Bland infarctlike necrosis is encountered in roughly 5 % of pilocytic astrocytomas and similarly has no clinical significance. Likewise, extension into the subarachnoid space is quite common and does not alter the prognosis. In contrast, pseudopalisading necrosis and foci of hypercellularity with increased proliferative activity should prompt consideration of an alternative diagnosis or malignant transformation, an exceptionally rare complication in pilocytic astrocytomas with most examples being encountered after radiation therapy.

Prognosis and Therapy

Pilocytic astrocytomas are benign (WHO grade 1) neoplasms treated primarily with surgery, with overall 5- and 10-year survival rates of greater than 95 %. However, depending on patient age and location, they occasionally produce significant morbidity and mortality. Therefore subtotally resected cases may undergo radiotherapy and/or chemotherapy for enhanced local control. The pilomyxoid astrocytoma has variable behavior, but most are more aggressive than a pilocytic astrocytoma and more prone to local recurrence and cerebrospinal spread.

Pathologic and Gross Findings

Grossly, SEGA is a solid, well-demarcated mass, often with zones of dense calcification. Candle gutterings are smaller versions that are more widely distributed along the ventricular surface. They are otherwise identical microscopically.

Histologically, SEGA is a noninfiltrative mass composed of spindled and epithelioid cells arranged in sweeping fascicles or even perivascular pseudorosettes, such as those encountered in ependymomas ( Fig. 9.10A ) . The cells often have a mixed glioneuronal appearance with brightly eosinophilic cytoplasm resembling that of astrocytes, along with large vesicular nuclei and prominent nucleoli similar to those of ganglion cells (see Fig. 9.10B ). Mitoses and necrosis are uncommon and do not have a negative impact on prognosis. Immunostains reveal GFAP positivity in a subset of tumor cells. Neuronal marker immunoreactivity may also be seen in some cells, sometimes in the same cells that are GFAP positive. Other cells are negative for both. Because of the mixed glioneuronal features, some prefer the term subependymal giant cell tumor rather than SEGA.

Prognosis and Therapy

SEGAs are benign tumors (WHO grade 1) and probably represent hamartomatous rather than neoplastic proliferations. Rare examples recur but do not undergo malignant progression. Despite its benign nature, SEGA has significant prognostic implications for patients and their families because of this tumor’s nearly universal association with tuberous sclerosis.

Pathologic Features

Grossly, PXAs appear well demarcated and firm. Cystic components are seen in some. Histologically they are characterized by foci of pleomorphic astrocytes and spindled mesenchymal-like cells arranged in fascicles or a storiform pattern ( Fig. 9.12 ). Multinucleated cells are common. Lipidized astrocytes (xanthoastrocytes) are seen in roughly one-fourth of cases (see Fig. 9.12A ). Despite the pleomorphism, the mitotic/proliferative index is low in most cases (see Fig. 9.12B ). EGBs are typical (see Fig. 9.12C ), and Rosenthal fibers may also be seen, particularly at the edges of the tumor. Unlike diffuse astrocytomas, there is increased intercellular reticulin deposition, either diffusely or in a patchy fashion (see Fig. 9.12D ). The latter corresponds to basal lamina ultrastructurally, which is why PXA has been speculated to arise from a specialized subpial astrocyte with basal lamina production. Occasional cases are mixed with classic ganglioglioma, intratumoral ganglion cells, or lesser forms of neuronal differentiation, such as synaptophysin or neurofilament positivity, in otherwise astrocytic-looking cells. Subsets of tumor cells are GFAP positive, but the fraction is highly variable. The definition of anaplasia is controversial, although ironically there is less pleomorphism with an overall resemblance to high-grade diffuse astrocytomas, including frequent mitoses, endothelial hyperplasia, pseudopalisading necrosis, or any combination of these findings.

Prognosis and Therapy

PXA generally has a favorable prognosis, with many cases curable by surgery alone (5-year overall survival 90 %). Nevertheless, it is recognized that a minority undergo malignant progression, which, along with a somewhat less predictable behavior than that of pilocytic astrocytoma and ganglioglioma, accounts for the WHO grade 2 designation. Anaplastic PXA, WHO grade 3, is associated with aggressive behavior and shortened survival.

Pathologic Features

Grossly, astroblastomas appear well demarcated and may be cystic. Histologically, they have mixed astrocytoma-like and ependymoma-like features (see Fig. 9.13 ). Like ependymomas, they grow in a relatively circumscribed fashion and have perivascular pseudorosettes. However, the cells are more epithelioid or cuboidal with broader perivascular processes (see Fig. 9.13B–D ). Characteristically, abundant vascular hyalinization is evident (see Fig. 9.13A ). Papillary foci are common, and the tumor cells are usually strongly GFAP positive (see Fig. 9.13C and D ).

Prognosis and Therapy

Because of the rarity of this tumor type, little clinical experience has accrued. Surgery is the treatment of choice. Currently they are divided into well-differentiated and anaplastic (proliferative index >5 %) types, the latter more likely to recur or lead to patient death.