Astrocytomas

Brain tumors that exhibit purely astrocytic differentiation can be separated into two major categories: diffuse and circumscribed. Complete surgical resection is rarely attained with diffuse astrocytoma because of the inherently infiltrative nature of the neoplastic cells, which extend well beyond the apparent gross margin of the tumor.

Diffuse Astrocytomas

Diffuse astrocytoma (WHO grade II) is a mildly hypercellular infiltrative neoplasm composed of well-differentiated, spindle- to stellate-shaped astrocytes with minimal nuclear atypia and separated by a loosely fibrillary (and sometimes microcystic) background. Nuclei are characteristically irregular, angulated, and hyperchromatic. Mitotic figures are either absent or rare, and there is no vascular proliferation or necrosis. Glial fibrillary acidic protein (GFAP) may be highly or weakly expressed. Two morphologic subtypes are recognized: protoplasmic and gemistocytic. Protoplasmic astrocytomas are composed of small tumor cells with scant GFAP expression and are frequently associated with a myxoid or microcystic background. Gemistocytic astrocytomas consist of a predominant population of large rounded neoplastic astrocytes with a copious amount of glassy eosinophilic cytoplasm that is strongly GFAP-positive and has an eccentrically located nucleus. Despite their benign morphologic appearance, diffuse astrocytomas have an intrinsic tendency to recur, spread extensively, and undergo anaplastic progression to a higher grade. The latter propensity is especially true of the gemistocytic variant. The time to recurrence and progression after initial clinical evaluation varies from case to case but ranges from months to several years.

Anaplastic astrocytoma (WHO grade III) is a hypercellular glioma composed of poorly differentiated astrocytes consisting of a mixture of pleomorphic fibrillary and gemistocytic cells with significant nuclear atypia and prominent mitotic activity. These malignant tumors may develop as a result of anaplastic progression from a preexisting, low-grade diffuse astrocytoma or may arise de novo. The mean age of patients with anaplastic astrocytoma at initial diagnosis is approximately 41 years, which falls between the age means for patients with low-grade diffuse astrocytoma and glioblastoma. Anaplastic astrocytomas typically show anaplastic progression to glioblastoma after an average of 2 years.

Glioblastoma multiforme (GBM; WHO grade IV) is unfortunately both the most common glioma and the most malignant primary brain tumor arising in adults. Most commonly, GBMs are solitary tumors of the cerebral hemispheres but may develop at almost any site within the neuraxis, including the cerebellum and the spinal cord. In many cases they infiltrate across the corpus callosum or arise directly within it, with bilateral extension (butterfly tumor). Multifocal tumors are observed in about 2% of patients and are often mistaken for metastatic disease on preoperative neuroimaging studies. The necrotic tumor mass may be partially delineated on gross examination, but infiltrating glioma cells can easily be identified microscopically well beyond the apparent gross tumor boundaries. The cellular morphology of GBM cells is highly variable, with the spectrum ranging from small, tightly packed, round or elongated cells to giant bizarre and multinucleated forms, all of which are frequently encountered within a single tumor. Mitotic figures are typically readily identified, and corresponding proliferation marker indices, such as the Ki-67 antigen, show elevated levels. Positive immunostaining for GFAP is characteristic but highly variable and can be absent in some instances. Microvascular proliferation and foci of necrosis are histologic hallmarks of GBM (Fig. 96-1). The presence of necrosis is not required for a diagnosis of GBM; vascular proliferation, in conjunction with pleomorphism and increased mitotic activity, is sufficient according to WHO 2007 criteria.

FIGURE 96-1 Glioblastoma. The most malignant form of diffuse glioma, glioblastoma is also the most common primary brain tumor. Diagnostic histopathologic features, as seen here, include tumor necrosis with surrounding pseudopalisading tumor cells (referred to as “pseudopalisading necrosis”) and hyperplasia of adjacent blood vessels (vascular proliferation) in response to the hypoxic conditions. Based on clinical, morphologic, and molecular characteristics, glioblastomas can be further subclassified into a number of subtypes with prognostic significance (see text for details).

The typical peripheral, ring-like zone of contrast enhancement seen on computed tomography (CT) and magnetic resonance imaging (MRI) corresponds to the highly vascularized peripheral area of the neoplasm. Vascular proliferation is defined as the presence of blood vessels with multilayered vessel walls (more than two cell layers thick). So-called glomeruloid vascular proliferation constitutes the most obvious and characteristic example of the florid microvascular proliferation seen in GBM.

Two subsets of GBM, primary and secondary, have been described based on clinical and genetic data. Primary GBM arises de novo (i.e., without evidence of a preexisting lower grade astrocytoma), typically in patients in the sixth decade of life and beyond. Epidermal growth factor receptor (EGFR) gene amplification occurs in about 40% of primary GBMs. In contrast, secondary GBM tends to develop in younger adults (<45 years old) by malignant progression from a diffuse astrocytoma of WHO grade II or III. The genetic hallmark of secondary GBM is TP53 mutation. Large areas of necrosis are typical of GBMs, which also frequently exhibit multiple small serpiginous zones of necrosis surrounded by densely crowded tumor cells in a pseudopalisading pattern. The hypoxic perinecrotic apoptotic cells strongly express vascular endothelial growth factor (VEGF), which in turn induces the characteristically prominent vascular proliferation.

Gliomatosis cerebri (WHO grade III) has historically been considered to be a unique glial tumor entity sui generis, but mounting evidence over the last decade, including support from molecular studies, favors conceptualization of gliomatosis cerebri as a pattern of exceptionally diffuse involvement of the central nervous system (CNS) that can be seen with any of the diffuse glioma subtypes, including oligodendroglioma.

Oligodendroglial and Oligoastrocytic Glial Tumors

Oligodendroglioma (WHO grade II) is a well-differentiated, diffusely infiltrating tumor composed of cells resembling normal oligodendroglia. Most oligodendrogliomas arise in adults in the fourth and fifth decades. Their preferential location is the white matter of the cerebral hemispheres, from which tumor cells typically infiltrate the overlying cortex. As viewed macroscopically and on neuroimaging studies, oligodendrogliomas often appear somewhat more circumscribed than astrocytomas. They are composed of uniform round cells with cleared cytoplasm surrounding a central spherical nucleus (fried egg appearance). The perinuclear halo is a diagnostically useful fixation artifact present only in formalin-fixed, paraffin-embedded tumor tissue (Fig. 96-2). Mitotic activity is inconspicuous. A branching network of small delicate blood vessels (chicken wire pattern) is a classic histologic feature of many oligodendrogliomas. Microcalcifications are also common. Subpial tumor infiltration, perineuronal satellitosis, and perivascular satellitosis of tumor cells (secondary structures of Scherer) are characteristically seen in oligodendrogliomas that infiltrate gray matter. No oligodendroglioma-specific immunohistochemical markers are currently available. Oligodendrogliomas generally recur locally and ultimately undergo anaplastic progression.

FIGURE 96-2 Oligodendroglioma. The hallmark morphologic features of oligodendroglioma that separate this diffuse glioma from the astrocytic series are the uniformly round nuclei with surrounding cytoplasmic clearing (“perinuclear halos”). The classic oligodendroglial morphology seen here on hematoxylin and eosin–stained tissue sections correlates highly with the combined deletion of chromosomal arms 1p and 19q and predicts a favorable response to therapy.

Anaplastic oligodendroglioma (WHO grade III) is an oligodendroglioma in which high-grade features, such as increased mitotic activity, microvascular proliferation, or necrosis (or any combination of such features), are present. Some tumors show florid vascular proliferation and necrosis that mimic what is seen in GBM. Varying numbers of cells with eosinophilic GFAP-positive cytoplasm that resemble miniature gemistocytes (minigemistocytes) or astrocytes (gliofibrillary oligodendrocytes) may be present. The hallmark genetic signature of oligodendroglioma (low grade and anaplastic) is combined whole-arm deletion of chromosomes 1p and 19q, which arises secondary to an initial translocation event and constitutes an independent prognostic marker, with 1p or 19q loss being associated with improved outcome regardless of the specific therapeutic regimen.

Oligoastrocytoma (WHO grade II) and anaplastic oligoastrocytoma (WHO grade III) are currently regarded as mixed diffuse gliomas with astrocytic and oligodendroglial components. There is no consensus on the minimal percentage of each component required for diagnosis of a mixed glioma. By WHO 2007 criteria, the diagnosis is based entirely on morphologic features, as assessed on hematoxylin and eosin–stained tissue sections, without consideration of molecular genetic characteristics, and is very subjective with high interobserver variability. In general, anaplastic oligoastrocytoma exhibits high-grade features such as increased mitotic activity and often microvascular proliferation, but otherwise it has the same subjective diagnostic criteria as oligoastrocytoma. According to WHO 2007 criteria, the presence of tumor necrosis in anaplastic oligoastrocytoma mandates upgrading, and such lesions have been given the designation GBM with an oligodendroglioma component (WHO grade IV). Anaplastic oligoastrocytomas that exhibit deletion of both 1p and 19q are considered to have a favorable genetic signature, whereas those with intact 1p/19q status and p53 immunopositivity are considered genetically closer to astrocytomas.

Ependymal Tumors

Ependymoma (WHO grade II) is a slowly growing neoplasm of children and young adults that originates from the ependymal lining of the cerebral ventricles. An infratentorial location is the most frequent in children, whereas in adults most of these tumors are supratentorial. Ependymomas may occur outside the ventricular system in the brain parenchyma and also in the spinal cord. Ependymomas are grossly characterized by a sharply demarcated edge. As seen histologically, classic ependymomas are moderately cellular tumors composed of oval cells with monomorphic nuclei and tapering eosinophilic cytoplasm. Some ependymomas have a more glial appearance, whereas others are more epithelioid. Some ependymoma variants (cellular, tanycytic) mimic other primary tumors, although others (papillary, clear cell) may mimic secondary tumors. The histologic hallmarks of ependymoma are the perivascular pseudorosette (perivascular collars of radiating tumor cell cytoplasmic processes) and, more elegantly but less frequent, the true ependymal rosette (tumor cells surrounding a central lumen) (Fig. 96-3). GFAP and epithelial membrane antigen (EMA) immunopositivity is a frequent finding in ependymoma. GFAP reactivity is often strongest in the perivascular pseudorosettes, and EMA positivity takes the form of cytoplasmic dot-like and ring-like staining. Electron microscopy may be required in some cases to identify the ultrastructural features associated with ependymal cell differentiation (intercellular lumina filled with microvilli and sometimes cilia and prominent intercellular junctional complexes).

FIGURE 96-3 Ependymoma. As opposed to the diffuse gliomas of astrocytic or oligodendroglial differentiation, ependymoma exhibits a significantly less infiltrative growth pattern that predisposes to surgical resection. Thus, accurate intraoperative histopathologic diagnosis is of great importance. The most characteristic architectural feature of ependymoma, as illustrated here, is perivascular pseudorosettes (cuffs of finely fibrillar cytoplasmic processes that the tumor cells extend to blood vessel walls).

Anaplastic ependymoma (WHO grade III) typically shows increased mitotic activity and microvascular proliferation.

Myxopapillary ependymoma (WHO grade I) is a distinct low-grade variant of ependymoma that arises almost exclusively from the caudal portion of the spinal cord of adults in the conus medullaris/filum terminale region. The tumor is usually well circumscribed and covered by an outer layer of investing leptomeninges (capsule). Layers of cuboidal or spindled tumor cells surround myxoid microcysts. Collars of myxoid material also surround blood vessels. Surgical resection of intact tumors can be curative in some cases; however, the presence of micrometastases, which are not visible to the unaided eye, or frank capsular breaching by the tumor can lead to diffuse dissemination among the nerve roots of the cauda equina and ultimately result in significant morbidity.

Subependymoma (WHO grade I) is an indolent intraventricular glioma of adults (rare cases arise in the spinal cord). Asymptomatic lesions are often discovered only as incidental findings at autopsy, but subependymomas occasionally produce ventricular obstruction of the lateral or fourth ventricles. Surgical resection is curative. As seen microscopically, the tumor is composed of clusters of small, uniform, benign-appearing tumor cell nuclei separated by extensive cell-free areas of finely fibrillary matrix. Lateral ventricular examples are prone to prominent microcystic change that can obscure the characteristic multinodular architecture. Cases of mixed subependymoma and classic ependymoma are rare but well documented; the clinical course of such tumors is similar to that of WHO grade II ependymoma.

Choroid Plexus Tumors