Cell-specific markers

Data derived from references [24-26]

Abbreviations: GFAP — glial fibrillary acidic protein; GH — growth hormone; PRL — prolactin; ACTH — adrenocorticotrophic hormone; FSH — follicle stimulating hormone; LH — leuteinizing hormone; TSH — thyroid stimulating hormone.

Data derived from references [24-26]

Abbreviations: GFAP — glial fibrillary acidic protein; GH — growth hormone; PRL — prolactin; ACTH — adrenocorticotrophic hormone; FSH — follicle stimulating hormone; LH — leuteinizing hormone; TSH — thyroid stimulating hormone.

TABLE 1.4 WHO Classification: Tumors of Neuroepithelial Tissue

Astrocytic tumors

Oligodendroglial tumors

Ependymal tumors

Mixed gliomas

Choroid plexus tumors

Neuronal and mixed neuronal-glial tumors

Pineal parenchymal tumors

Neuroepithelial tumors of uncertain origin

Embryonal tumors

TABLE 1.5 WHO Classification: Astrocytic Tumors

Diffuse Astrocytomas

Astrocytoma (WHO grade II) Fibrillary Protoplasmic Gemistocytic Anaplastic astrocytoma (WHO grade III) Glioblastoma multiforme (WHO grade IV) Giant cell glioblastoma Gliosarcoma Localized Astrocytomas (WHO grade I) Pilocytic astrocytoma Pleomorphic xanthoastrocytoma Subependymal giant cell astrocytoma degenerate into the most aggressive form of glioma, the GBM.

Diffuse Astrocytomas. The current WHO classification divides astrocytomas into diffuse and localized varieties (see Table 1.5) [24,25,30]. The diffuse astro-cytomas are intrinsically invasive and often travel along white matter tracts deep into normal brain. There are three groups of diffuse astrocytic neoplasms: astrocytoma (WHO grade II; peak age of 30-39 years), AA (WHO grade III; peak age of 40-49 years), and GBM (WHO grade IV; peak age of 50-69 years), including the GBM variants giant cell glio-blastoma and gliosarcoma (both WHO grade IV). Diffuse astrocytic tumors can be divided into fibril-lary, protoplasmic, and gemistocytic forms, with the fibrillary form being most common. The presence of gemistocytic and protoplasmic cellular variations are most often visualized in WHO grade II tumors. WHO grade II astrocytomas are considered low-grade tumors and usually occur in the cerebral white matter. These tumors are characterized by a relatively uniform population of proliferating neoplastic astro-cytes in a fibrillary matrix, with minimal cellular and nuclear pleomorphism or atypia (see Fig. 1.1). Grade II tumors may display diffuse and intense staining with GFAP. Tumor margins are poorly delineated and suggest significant infiltration into surrounding brain. Within infiltrated regions of brain, ''secondary structures of Scherer'' may be noted, with the presence of tumor cells around cortical neurons (i.e., perineuronal satellitosis), along white matter tracts, and around blood vessels. Mitotic figures are absent and there is

FIGURE 1.1 WHO grade II fibrillary astrocytoma (1A and 1B). Note the neoplastic astrocytes in a fibrillary matrix, with mildly increased cellularity and pleomorphism. No mitoses or hypervascularity is present. H&E @ 200x. See Plate 1.1 in Color Plate Section.
FIGURE 1.2 WHO grade II gemistocytic astrocytoma. Low-grade astrocytic tumor demonstrating numerous, plump gemistocytic astrocytes, with eosinophilic cytoplasm and short cellular processes. H&E @ 200x. See Plate 1.2 in Color Plate Section.
FIGURE 1.3 WHO grade III fibrillary astrocytoma (AA). The tumor is more densely cellular than grade II, with significant cellular and nuclear pleomorphism and atypia. Mitotic figures are evident. H&E @ 200x. See Plate 1.3 in Color Plate Section.

no evidence for vascular hyperplasia. Microcystic change is commonly noted in all variants of grade II astrocytoma. The fibrillary variant is characterized by tumor cells with mild to moderately pleomorphic astrocyte-appearing nuclei and cellular processes that form a fibrillary background. Gemistocytic cells (i.e., plump astrocytes with eosinophilic cytoplasm and short cellular processes) may be present in fibrillary tumors, but as a minor cell population. If the tumor has gemistocytes representing greater than 20 per cent of neoplastic cells, then the histological designation is changed to a gemistocytic astrocytoma (see Fig. 1.2) [31]. Gemistocytic astrocytomas tend to behave in a more aggressive fashion than other grade II tumors, with a high propensity (approximately 80 per cent) for degeneration into AA and GBM. The gemistocytic cells appear to be resistant to apoptosis and express high levels of mutant p53 and bcl-2 [32]. Fibrillary tumors with a high percentage of gemistocytes (i.e., 5-19 per cent) appear to be biologically affected by the presence of these cells, since there is a significant negative correlation with progression to higher grades of astrocytoma [33]. Protoplasmic astrocytomas are rare and have features of inconspicuous cytoplasm and cellular processes. The Ki-67 labeling index of WHO grade II astrocytomas is typically less than 4 per cent, with a mean of approximately 2.0-2.5 per cent.

Higher grade diffuse astrocytomas include AA (WHO grade III) and GBM (WHO grade IV), as well as the GBM variants giant cell glioblastoma and gliosarcoma (WHO grade IV) (see Table 1.5) [24,25, 30,34]. Anaplastic astrocytomas are similar to grade II tumors, except for the presence of more prominent cellular and nuclear pleomorphism and atypia, and mitotic activity (see Fig. 1.3). In addition, grade III and IV tumors usually do not stain as intensely or as homogeneously with GFAP. According to WHO criterion, the critical feature that upgrades a grade II tumor to an AA is the presence of mitotic activity, with anaplastic tumors having Ki-67 indices in the range of 5-10 per cent in most cases. Other features of anaplasia can be present, such as multinucleated tumor cells and abnormal mitotic figures. Regions of vascular proliferation and necrosis are absent in grade III astrocytomas.

Glioblastoma multiforme is classified as a WHO grade IV tumor and has similar histological features to AA, but with more pronounced anaplasia (see Fig. 1.4) [24,25,30,34]. The presence of microvascular proliferation and/or necrosis in an otherwise malignant astrocytoma upgrades the tumor to a GBM. Vascular proliferation is defined as blood vessels with ''piling up'' of endothelial cells, including the formation of glomeruloid vessels. The glomeruloid vessels can form undulating garlands that surround necrotic zones in some cases. Necrosis can be noted in large amorphous areas, which appear ischemic in nature, or can appear as more serpiginous regions with surrounding palisading tumor cells (i.e., perinecrotic pseudopalisading). Necrosis with nuclear pseudo-palisading is essentially pathognomonic for GBM. Other features of GBM that are typically prominent include marked cellular and nuclear pleomorphism and atypia, mitotic figures and multinucleated giant cells, and pronounced infiltrative capacity into surrounding brain, with extensive production of ''secondary structures'' within the cerebral cortex. In addition to giant cells, other cell types that may be a a b sßiai

figure 1.4 WHO grade IV fibrillary astrocytoma (GBM). A highly cellular tumor with marked cellular and nuclear pleomorph-ism, numerous mitoses, giant cells (4A; H&E @ 400x), regions of necrosis with pseudopallisading tumor nuclei (4B; H&E @ 100x), and dense vascular proliferation (4C; H&E @ 200x). See Plate 1.4 in Color Plate Section.

b sßiai figure 1.4 WHO grade IV fibrillary astrocytoma (GBM). A highly cellular tumor with marked cellular and nuclear pleomorph-ism, numerous mitoses, giant cells (4A; H&E @ 400x), regions of necrosis with pseudopallisading tumor nuclei (4B; H&E @ 100x), and dense vascular proliferation (4C; H&E @ 200x). See Plate 1.4 in Color Plate Section.

noted include ''small cells'', gemistocytes, granular cells, lipidized cells, perivascular lymphocytes, and regions of metaplasia. Labeling indices with Ki-67 are usually in the range of 15-20 per cent, but can be much higher in some tumors.

figure 1.5 WHO grade IV gliosarcoma. The biphasic nature of the tumor is demonstrated, with high-grade astrocytoma consistent with GBM in the left hemifield and sarcomatous, spindle-shaped cells with pleomorphic nuclei in the right hemifield. H&E @ 200x. See Plate 1.5 in Color Plate Section.

Recent molecular biological studies would suggest that GBM can be further classified based on the spectrum of amplified oncogenes and mutations or deletions of tumor suppressor genes [34-37]. GBM can be designated as a secondary tumor when derived from a lower grade neoplasm (e.g., WHO grade II or III), or as a primary GBM when it arises de novo from normal astrocytes without any intervening stages. Secondary GBM (mean age of onset 38-42 years) typically have mutations of p53 (60-70 per cent), activation of the ras pathways, mutation or inactiva-tion of the retinoblastoma gene (43 per cent), inacti-vation of p14ARF and p16 (35-60 per cent), and amplification of the platelet-derived growth factor (PDGF) gene. In contrast, primary GBM (mean age of onset 54 to 56 years) have amplification of the epidermal growth factor receptor (EGFR) gene (40 per cent), mutation of the PTEN tumor suppressor gene (32 per cent), and other genetic abnormalities such as loss of the p16 tumor suppressor gene (35 per cent).

Variants of GBM that are also classified as WHO grade IV tumors include the giant cell glioblastoma and gliosarcoma [24,25,30]. Giant cell glioblastoma (also known as monstrocellular sarcoma) is a rare histological variant of GBM that has a predominance of multinucleated giant cells within a more prominent reticulin network [38]. The giant cells may measure more than 500 microns in diameter and have up to 20 nuclei. Giant cell glioblastomas consistently stain with GFAP and are usually more circumscribed than GBM. Molecular analysis demonstrates a high rate (75-90 per cent) of p53 mutations. Gliosarcomas are a GBM variant that display a biphasic histological pattern, with alternating areas of glial and mesenchymal differentiation (see Fig. 1.5) [39]. The gliomatous regions are similar in appearance to typical GBM, with dense cellularity and nuclear atypia, necrosis, and a variable degree of GFAP expression. The sarcomatous regions are often well demarcated from the glial regions by a reticulin network, which may be very dense in some tumors. Spindle cells within the sarcomatous portion of the tumor also have anaplastic features, such as nuclear atypia and mitotic activity. Regions of necrosis may also be noted in sarcomatous regions of tumor. Gliosarcomas have a similar molecular phenotype to GBM, with frequent mutation and/or deletion of p53, PTEN, and p16, as well as amplification of mdm2. However, in contrast, the frequency of amplification of the EGFR is quite low.

Localized Astrocytomas. In the WHO classification, the localized astrocytomas include the pilocytic astrocytoma (WHO grade I), pleomorphic xantho-astrocytoma (PXA; WHO grade II), and the subepen-dymal giant cell astrocytoma (WHO grade I) [24,25,30]. Pilocytic astrocytomas are slow growing, relatively circumscribed tumors that usually occur in children (peak age 10-12 years) and young adults (peak age 20-24 years). These tumors can arise anywhere in the brain, but have a predilection for the cerebellum, optic nerves and optic pathways, and hypothalamus. Pilocytic astrocytomas can present as a homogeneous, well-demarcated mass, with a gliotic surrounding margin, or as an enhancing mural nodule associated with a large cyst [40]. The distinctive histological feature is the presence of cells with slender, elongated nuclei and thin, hair-like (i.e., piloid), GFAP-positive, bipolar processes (see Fig. 1.6). These cells are found in a biphasic background, which consists of dense fibrillary regions alternating with loose, microcystic areas. Also frequently noted are Rosenthal fibers, which are eosinophilic, refractile, corkscrew-shaped deposits. The presence of Rosenthal fibers is highly suggestive of a pilocytic astrocytoma. Another characteristic feature is the eosinophilic granular body, which is a circular profile of granular, amorphous material. In some cases, pilocytic astrocytomas can demonstrate mild degrees of cellular and nuclear pleomorphism, mitotic activity, vascular proliferation, regions of necrosis, and invasion of the subarachnoid space. However, in these tumors, it does not denote a poor prognosis, as in higher grade, diffuse astrocytomas. Labeling index studies with Ki-67 report values of 0.5-1.5 per cent in most tumors.

The PXA is a supratentorial tumor with a predilection for the superficial temporal lobes that usually occurs in younger patients (mean age 15-18 years) with a longstanding history of seizure activity [24,25,30]. On histological examination, PXA demonstrates significant pleomorphism, with numerous atypical giant cells and astrocytes with prominent nucleoli (see Fig. 1.7) [41]. Also present are large foamy (xanthomatous) cells with lipidized cytoplasm that express GFAP. Regions of focal lymphocytic and plasma cell infiltration can occur, along with a reticulin-positive stroma that delineates fascicles of cells. Typical PXA do not have mitotic activity, necrosis, or vascular pleomorphism and are classified

FIGURE 1.6 WHO grade I pilocytic astrocytoma. The tumor demonstrates ''piloid'' neoplastic astrocytes, with minimal cellular-ity, pleomorphism, cells with delicate hair-like processes, and the presence of numerous Rosenthal fibers. H&E @ 200x. See Plate 1.6 in Color Plate Section.
FIGURE 1.7 Pleomorphic xanthoastrocytoma (PXA). Note the presence of mild cellular and nuclear pleomorphism, with numerous atypical giant cells and large astrocytes with foamy (xanthomatous) cytoplasm. H&E @ 200x. See Plate 1.7 in Color Plate Section.

as WHO grade II. However, a sub-group of PXA can have anaplastic features, including increased mitotic activity (> 5 mitoses per high power field), necrosis, and endothelial proliferation. By WHO criteria, these tumors should be classified as ''PXA with anaplastic features''. The term ''anaplastic PXA'' (grade III) is not recommended at this time.

Subependymal giant cell astrocytoma is a benign, slow-growing tumor that typically arises in the walls of the lateral ventricles and is almost invariably associated with tuberous sclerosis [24,25,30]. The tumor is composed of cells with extensive glassy, eosinophilic cytoplasm. Some cells may have a neuronal appearance, with vesicular nuclei and large nucleoli. Subependymal giant cell astrocytomas are classified as WHO grade I.

Oligodendrogliomas and Oligoastrocytomas. Oligodendrogliomas are a form of diffuse glioma that can be of pure or mixed histology and are classified as WHO grade II or III [24,25,30]. They typically occur in young to middle-aged adults (peak age 35-45 years) with a history of seizures, within the white matter of the frontal and temporal lobes. Pure low-grade oligodendroglial tumors (WHO grade II) are characterized histologically by a moderately cellular, monotonous pattern of cells with round nuclei and perinuclear halos (the classic ''fried egg'' appearance; see Fig. 1.8) [42]. The perinuclear halos are an artifact of the formalin fixation process of the tumor tissue. Foci of calcification are frequent, and can be quite dense in some cases. Delicately branching blood vessels are prominent (i.e., ''chicken-wire'' vasculature), but do not display endothelial proliferation. GFAP staining is limited in the majority of oligodendrogliomas, except for the variant that has a significant component of mini-gemistocytes (small cells with round nuclei and eosinophilic cytoplasm), which strongly express GFAP. Oligodendrogliomas have a pronounced invasive capacity and are known to invade the gray and white matter diffusely, with a strong tendency to form secondary structures of Scherer, in particular perineuronal satellitosis. Mitoses are absent or rare and necrosis is not present. Labeling studies with Ki-67 usually demonstrate indices less than 5 per cent, with a mean of approximately 2 per cent. The diagnosis of an anaplastic oligodendroglioma (WHO grade III) requires the presence of additional histologic features, including a higher degree of cellularity and mitotic activity, vascular endothelial hyperplasia, nuclear pleo-morphism, and regions of necrosis (see Fig. 1.9). These tumors behave in a more aggressive fashion, with a higher proliferative rate (Ki-67 labeling index > 5 per cent) and capacity for invasion of

FIGURE 1.8 WHO grade II oligodendroglioma. Demonstrates the classic features of typical oligodendroglioma, with moderate cellularity and numerous round cells with the ''fried egg'' pattern of perinuclear halos, and delicate ''chicken wire'' vasculature. H&E @ 400x. See Plate 1.8 in Color Plate Section.

FIGURE 1.8 WHO grade II oligodendroglioma. Demonstrates the classic features of typical oligodendroglioma, with moderate cellularity and numerous round cells with the ''fried egg'' pattern of perinuclear halos, and delicate ''chicken wire'' vasculature. H&E @ 400x. See Plate 1.8 in Color Plate Section.

surrounding brain. In some cases, anaplastic oligo-dendrogliomas can develop further malignant features and degenerate into a tumor similar to GBM. By WHO criteria, an oligodendroglioma with predominant astrocytic areas that look like GBM should be classified as an oligoastrocytoma grade III, rather than a GBM.

Advances in molecular neuropathology have begun to clarify the biological underpinnings of variability in response to treatment of oligodendro-gliomas [42-44]. The majority of tumors demonstrate genetic losses on chromosome 1p (40 to 92 per cent) and/or 19q (50-80 per cent). There is a strong predilection for deletions of 1p and 19q to occur together, but in some tumors they can be singular events. Loss of 1p and/or 19q are mutually exclusive to certain other molecular abnormalities, such as mutation of p53, amplification of EGFR, or mutations of the PTEN tumor suppressor gene. Patients with oligodendrogliomas that contain deletions of 1p and 19q are consistently more responsive to irradiation and chemotherapy, and have an overall median survival of 8-10 years. In contrast, patients with tumors that do not have deletion of 1p and 19q are more resistant to all forms of therapy, and have an overall median survival of only 3-4 years.

Mixed oligoastrocytomas can be classified as WHO grade II or III tumors [24,25,30]. Distinct populations of neoplastic oligodendroglial cells and astrocytes can be identified within the mass that have similar features to pure versions of the tumor (see Fig. 1.10) [45]. The percentage of each cell population can be quite variable, with an even mixture of cell types or

FIGURE 1.9 WHO grade III oligodendroglioma. A more densely cellular tumor with prominent cellular and nuclear pleomorphism, mitotic activity (9A), and increased vascularity (9B). H&E @ 400x. See Plate 1.9 in Color Plate Section.
FIGURE 1.10 Mixed oligoastrocytoma. The tumor demonstrates cellular regions of neoplastic astrocytic cells and adjacent, less cellular areas more consistent with low-grade oligodendroglioma, with the presence of some ''fried egg'' cells. H&E @ 200x. See Plate 1.10 in Color Plate Section.

with one cell type predominating. The astrocytic and oligodendroglial populations can be totally separate within the tumor (biphasic pattern) or more intermingled (diffuse). Tumors with WHO grade II features will have mild to moderate cellularity, absent or low mitotic activity, minimal cellular and nuclear pleomorphism, and lack vascular proliferation and necrosis. Grade III tumors demonstrate more pronounced cellularity and anaplasia of cells and nuclei, a high mitotic rate, vascular endothelial proliferation, and necrosis. At the molecular level, oligoastrocytomas are often heterogeneous, with the

TABLE 1.6 WHO Classification: Ependymal Tumors

Ependymoma (WHO grade II) Cellular Papillary Clear cell Tanycytic

Anaplastic ependymoma (WHO grade III) Myxopapillary ependymoma (WHO grade I) Subependymoma (WHO grade I)

astrocytic portion having the typical genotype of low-grade diffuse astrocytomas, with p53 mutations and loss of chromosome 17p. Allelic loss of 1p and/or 19q is commonly present in the oligodendroglial component (30-70 per cent), but may also occur in astrocytic tumor cells.

Ependymomas. Ependymomas are slow-growing tumors derived from the ependymal lining cells of the ventricular system and are classified by the WHO as grades I, II, and III (see Table 1.6) [24,25,30]. These tumors are most common in children and young adults and typically grow as intraventricular masses, often from the floor of the fourth ventricle. They are commonly divided into typical ependymoma (grade II) and anaplastic ependymoma (grade III). In addition, the WHO recognizes four histological variants of ependymoma, including the cellular, papillary, clear cell, and tanycytic subtypes, as well as two low-grade (grade I) forms, myxopapillary ependymoma and subependymoma. On histological examination, WHO grade II ependymomas are densely cellular and

FIGURE 1.11 WHO grades II and III ependymoma. The typical low-grade tumor is densely cellular and composed of oval to carrot-shaped cells, with dense speckled nuclei and tapering eosinophilic cytoplasm (11A; H&E @ 200x). Note the ependymal perivascular psuedorosette in the center of the field. The anaplastic ependymoma is more pleomorphic and demonstrates mitotic activity (11B; H&E @ 400x). See Plate 1.11 in Color Plate Section.

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