Diffuse astrocytomas

Diffusely infiltrating astrocytic tumors are the most common primary neoplasms in adults and constitute more than 60% of all brain tumors. The incidence of astrocytomas differs somewhat regionally, but recent estimates suggest an incidence rate of 0.4 per 100,000 people for grade II astrocytomas and an incidence rate of 3.2 per 100,000 people for glioblastoma. The histologic grade shows a direct correlation with the age at presentation, whereby WHO grade II tumors present in younger adults in their fourth or fifth decades, whereas glioblastomas (WHO grade IV) peak in the elderly (mean age at diagnosis 61 years). Men seem more affected than women with a male-to-female ratio of 1.5:1.0 for all astrocytic tumors (except pilocytic astrocytoma).

WHO grade II diffuse astrocytomas are morphologically heterogeneous and characterized by a high degree of cellular differentiation, slow growth, low mitotic activity, and diffuse infiltration and spread into adjacent brain structures ( Fig. 1 ). Tumor cells express glial fibrillary acidic protein (GFAP), a protein typically found in astrocytomas. WHO grade II diffuse astrocytomas can be found at any site in the CNS but preferentially in the cerebral hemispheres, particularly in the subcortical and deep white matter of frontotemporal lobes. Although these lesions are rare in children, the main site in pediatric patients is the brainstem (so-called brainstem glioma). Three major variants of WHO grade II diffuse astrocytomas can be distinguished morphologically, and these comprise the fibrillary, gemistocytic, and protoplasmic variants. These subtypes, however, often coexist and a clear subclassification is not possible.

Histologic features of diffuse astrocytomas (hematoxylin-eosin–stained sections). ( A ) WHO grade II diffuse astrocytoma with low cellularity and mild nuclear pleomorphism; ( B ) anaplastic sstrocytoma, WHO grade III, shows hypercellularity and anaplastic nuclei; ( C ) glioblastoma, WHO grade IV, shows tumor cells with pleomorphic cells and pseudopalisading necrosis.

Anaplastic astrocytomas (WHO grade III) are defined as diffuse astrocytomas with focal or dispersed anaplasia. They may arise from low-grade astrocytomas but are also frequently diagnosed at first biopsy, without indication of a less malignant precursor lesion. These tumors are grossly more discernible because they are more cellular and form a more readily identifiable tumor mass. The infiltrative nature tends to create an overall increase of tissue volume without inducing a destructive effect. In comparison to low-grade tumors, these neoplasms are microscopically remarkable for increased cellularity and enlarged, irregular hyperchromatic nuclei (see Fig. 1 ). Capillaries are lined by a single layer of endothelium, and frank vascular proliferation and necrosis are not present. Immunoreactivity for GFAP is less consistent than for grade II lesions. In contrast to low-grade astrocytomas, these lesions display increased mitotic activity with a proliferative fraction (Ki-67/MIB-1 labeling) of 5% to 10%.

Glioblastomas (WHO grade IV) are the most malignant tumors within the spectrum of diffuse astrocytoma and account for approximately 12% to 15% of all intracranial neoplasms and up to 60% of all astrocytic tumors. They affect mainly adults with a peak incidence between 40 and 70 years. Fewer than 10% of glioblastomas arise from a lesion of lower malignancy grade (secondary glioblastoma) and manifest in younger patients (mean age of 45 years). Most are found de novo (primary glioblastoma) after a short clinical history and are seen in older individuals (mean age 62 years). The majority of tumors are located within the cerebral hemispheres; they often infiltrate deep nuclei and spread along white matter tracts to the contralateral hemisphere. Brainstem involvement is rare and mainly present in children. Other sites, such as spinal cord or cerebellum, are infrequently involved. Microscopically, glioblastomas are heterogeneous. They show a high degree of cellularity, pleomorphism, and mitotic activity in addition to microvascular proliferation and necrosis (see Fig. 1 ). The latter two features are the cardinal diagnostic features of glioblastomas and help distinguish them from grade III astrocytomas. Three distinct glioblastoma variants have been described, which are gliosarcoma, giant cell glioblastoma, and small cell glioblastoma.

Gliosarcomas are defined as glioblastoma intermixed with a sarcomatous component and represent approximately 2% of all glioblastomas. The clinical features are similar to those of classic glioblastomas. Critical diagnostic parameters are a biphasic growth pattern with areas of glial and mesenchymal differentiation. Molecular changes are variable but similar to those occurring in glioblastoma; however, tumor histogenesis is controversial.

Giant cell glioblastomas are remarkable for the presence and predominance of markedly bizarre, multinucleated giant cells, within an abundant stromal reticulin network. In spite of their unusual appearance, the consistent expression of GFAP in conjunction with genetic profiling confirmed its astrocytic nature.

Small cell glioblastoma is characterized by a predominance of small, anaplastic cells that resemble those in a primitive neuroectodermal tumor (PNET). The distinction is made via immunohistochemistry, because these tumors lack expression of synaptophysin that is typical of PNET. The small cell phenotype seems to correlate with the presence of EGFR amplification. Although typical glioblastoma features are not present, overall survival times are less than 1 year.

Circumscribed astrocytic lesions

Pilocytic astrocytomas are slowly growing, well circumscribed glial tumors with preferential growth in midline CNS structures. More than 75% of these tumors are seen in children and adolescents within the ages of 8 to 13 years. These tumors represent approximately 6% of all intracranial tumors and occur at an incidence of less than 1 case per 100,000 individuals per year. In infancy it is one of the most frequent brain tumors. The cerebellum is the most commonly affected site, with preferential involvement of the cerebellar hemispheres. The optic nerve and chiasm are second in frequency, followed by the cerebral cortical hemispheres, brainstem, infundibulum, hypothalamus, and spinal cord. In the brainstem, these lesions tend to occur mainly in the dorsal regions and pontomedullary junction, contrasting diffusely infiltrative astrocytomas, which grow typically in the ventral pons. The histopathology can show a variety of patterns and pose great diagnostic challenges. PAs typically demonstrate a biphasic pattern in which fibrillated, compact areas are intermingled with loosely structured, microcystic, and mucinous regions within the tumor tissue. The predominant cell type is an elongated, unipolar or bipolar cell with thin hair-like (Greek pilos [hair]) processes, which is immunoreactive for GFAP. The histogenetic origin of these tumors is still enigmatic. Characteristic of PAs is the presence of Rosenthal fibers and eosinophilic granular bodies. These are bright eosinophilic, either carrot-shaped or round structures, and considered amorphous degradation products associated with intermediate filaments. Mitoses are in general absent or infrequent, and the proliferative index (Ki-67/Mib-1) is less than 1%, although it can be focally slightly elevated. PAs have a tendency to invade leptomeninges or subarachnoid space. In contrast to diffusely infiltrating astrocytomas, PAs do not have an intrinsic tendency to progress to a higher grade and are considered a benign glial tumor. The survival rates range from close to 100% at 5 years to approximately 95% at 10 years with recurrence-free intervals of up to 20 years. The WHO assigned grade I to PAs, whereby the grading scheme developed for diffusely infiltrating astrocytomas does not apply. Rarely, these lesions show more aggressive biologic behavior characterized by significant proliferative activity; they are then considered WHO III tumors, equivalent to anaplastic astrocytomas.

Pilomyxoid astrocytoma is considered a variant of pilocytic astrocytoma and typically found in the hypothalamic/chiasmatic region. Histologically, pilomyxoid astrocytoma is composed of monomorphic, bipolar cells with angiocentric arrangements and a striking mucinous background. In contrast to pilocytic astrocytomas, these tumors do not display a biphasic cytoarchitecture; furthermore, they lack Rosenthal fibers or eosinophilic granular bodies and show a high mitotic rate. Infants and children (median age 10 months) are the main affected groups, and prognosis seems less favorable than for PAs. Local recurrences and spread through cerebrospinal fluid do occur more readily than with pilocytic astrocytomas; thus, the WHO assigned grade II to these tumors.

Pleomorphic xanthoastrocytomas are rare tumors, which account for fewer than 1% of glial neoplasms and typically manifest in children and young adults, in whom they are associated with a longstanding history of seizures. The majority of these tumors are found in a superficial location, particularly in the temporal lobe, and there is a tendency to involve the overlying subarachnoid space. Characteristic histologic features are multinucleated and lipidized giant cells with bizarre nuclei, which tend to express GFAP, an astrocytic marker. A reticulin rich stromal background is a hallmark feature. These tumors show low proliferative activity. Macroscopically, they are well demarcated and only small portions seem to invade adjacent brain and perivascular spaces. These tumors have been assigned WHO grade II. Many pleomorphic xanthoastrocytomas show a benign clinical course, usually with long-term survival after tumor resection. Only few tumors undergo malignant transformation.

Subependymal giant cell astrocytomas are benign neuroepithelial tumors, which tend to develop in the context of tuberous sclerosis. These tumors typically manifest before age 30 years and are located within the walls of the lateral ventricles. Histologically, they are composed of large ganglioid cells with both astrocytic and neuronal differentiation. Their histogenesis, however, is largely unknown. It is hypothesized that they are related to and/or derived from hamartomatous lesions typically seen in tuberous sclerosis. Subependymal giant cell astrocytomas are designated WHO grade I. Symptomatic lesions are treated with resection and many studies have shown that these tumors have an almost uniformly favorable prognosis.