Astrocytic Tumors

Astrocytic tumors constitute the largest group of intracranial tumors in both adults and children. Their locations, gross and histologic features, biologic behavior, and genetic alterations vary greatly. The WHO distinguishes four grades of astrocytic tumors based on their histologic characteristics (Table 11.5).

Astrocytic Tumors (Grades 2, 3, and 4) Diffuse astrocytoma grade 2, anaplastic astrocytoma grade 3, and glioblastoma grade 4 constitute the largest group of primary intracranial tumors affecting individuals from early adulthood to late midlife. These tumors are apt to progress malignantly: Diffuse astrocytomas can progress to anaplastic astrocytomas and glioblasto-mas, and anaplastic astrocytomas to glioblastomas. A significant number of tumors are associated with specific molecular abnormalities. Common genetic alterations are mutations of tumor suppressor gene p53 and loss of chromosome 17q; and overexpression of several oncogenes and their receptors, such as EGFR, PDGF, fibroblast growth factors (FGFs), and vascular endothelial growth factor (VEGF) receptors. In an appreciable number of astrocytomas, the progression from a low grade to a higher grade is associated with the inactiva-tion of specific tumor suppressor genes and losses of specific chromosomes.

Diffuse Astrocytoma (Grade 2)

This tumor typically occurs in the cerebral hemispheres of young adults, less often in the brainstem, cerebellum. and cerebral hemispheres of children and adolescents. The tumor grows slowly and diffusely infiltrates the local structures, gradually enlarging and deforming them. Clin

Regional Distribution of Common Neuroepithelial Tumors

Optic Nerve/Chiasma

Cerebral

Hypothalamus

Hemispheres

Cerebellum

Brainstem

Ventricles

Astrocytoma Glioblastoma Oligodendroglioma Ependymoma

Astrocytoma Medulloblastoma

Choroid plexus papilloma

Astrocytoma

ically, it often presents with seizures for months or years before focal neurologic deficits and raised ICP develop. Postsurgical survival is variable, averaging 5 years.

Diffuse astrocytoma is characterized grossly by poor demarcation from the adjacent healthy tissue and histologically by the low cellularity of well-differentiated neoplastic astrocytes displaying minimal pleomorphism and few or no mitosis. Vascular supply is sparse, and necrosis is absent.

Genetic alterations are mutations in the p53 gene, loss of chromosome 17, and overexpression of the PDGF system. The inactivation of the cell-cycle regulatory table 1 1.5.

Astrocytic Tumors

Diffuse astrocytoma (grade 2) Fibrillary Protoplasmic Gemistocytic Anaplastic astrocytoma (grade 3) Glioblastoma (grade 4) Pilocytic astrocytoma (grade 1) Subependymal giant cell astrocytoma (grade 1) Desmoplastic infantile astrocytoma/ganglioma (grade 1) Pleomorphic xanthoastrocytoma (grade 2)

system is implicated in the progression of a diffuse astrocytoma to an anaplastic astrocytoma.

The three subtypes of diffuse astrocytomas are (a) protoplasmic, (b) fibrillary, and (c) gemistocytic.

A protoplasmic astrocytoma has a homogenous, translucent, gelatinous appearance. It is composed of neoplastic astrocytes with small, round to oval nuclei, which are moderately rich in chromatin and are surrounded by scanty cytoplasm with few processes. GFAP expression is sparse. Microcytic and mucoid degenerations are common (Fig. 11.2).

The fibrillary astrocytoma grossly is firm—in places rubbery—and the cut surfaces are whitish-gray. The tumor is composed of small stellate and elongated neo-plastic astrocytes with fine fibrillary processes forming a loose meshwork and bundles, leaving the pre-existing tissue relatively preserved. GFAP expression is variable. Entrapped neurons are easily detected between the tumor cells. In the white matter, the astrocytic bundles run along the fiber tracts. Microcystic degenerations may be present (Fig. 11.3).

The gemistocytic astrocytoma is soft and homogenous. It is composed of large, plump neoplastic astrocytes with abundant glassy eosinophilic cytoplasms and peripherally displaced nuclei (Fig. 11.4). GFAP expression is common.

figure 11.1

Diffuse protoplasmic astrocytoma. A well adjusted lively and sociable woman had her first tonic-clonic seizure at 33 years of age. One year later, she was evaluated for headaches and, around the same time, her behavior gradually changed: She became withdrawn, uncommunicative, spent the days in bed, neglected her appointments with her psychiatrist, and obstetrician. Following delivery of a healthy child, her condition rapidly deteriorated, she appeared catatonic, and died a few weeks later. A. The convolutional pattern of the left frontal lobe is effaced by a soft homogenous grayish mass lesion. B. The white matter of both frontal lobes, the corpus callosum, and the caudate are diffusely enlarged by a poorly demarcated, soft, gelatinous, pinkish-gray tumor that contains tiny cystic cavities. C. The tumor is moderately cellular, composed of neoplastic protoplasmic astrocytes showing mild nuclear pleomorphism (HE). Blood vessels are sparse; mitoses and necrosis are absent

figure 11.1

Diffuse protoplasmic astrocytoma. A well adjusted lively and sociable woman had her first tonic-clonic seizure at 33 years of age. One year later, she was evaluated for headaches and, around the same time, her behavior gradually changed: She became withdrawn, uncommunicative, spent the days in bed, neglected her appointments with her psychiatrist, and obstetrician. Following delivery of a healthy child, her condition rapidly deteriorated, she appeared catatonic, and died a few weeks later. A. The convolutional pattern of the left frontal lobe is effaced by a soft homogenous grayish mass lesion. B. The white matter of both frontal lobes, the corpus callosum, and the caudate are diffusely enlarged by a poorly demarcated, soft, gelatinous, pinkish-gray tumor that contains tiny cystic cavities. C. The tumor is moderately cellular, composed of neoplastic protoplasmic astrocytes showing mild nuclear pleomorphism (HE). Blood vessels are sparse; mitoses and necrosis are absent

Protoplasmic Astrocytoma

figure 1 1.2

Microcystic degeneration in a protoplasmic astrocytoma.

figure 1 1.2

Microcystic degeneration in a protoplasmic astrocytoma.

Anaplastic Astrocytoma (Grade 3) This tumor affects chiefly adults, and occurs in the cerebral hemispheres. Grossly, it is somewhat better demarcated, soft, and grayish-pink. Histologically, cel-lularity is high, and pleomorphism conspicuous. Hyper-chromatic nuclei vary from small to large to multinucleated giant cells. Mitoses are frequent. Vascular proliferation usually is not prominent, and necrosis is absent (Figs. 11.5, 11.6, and 11.7). It may disseminate along the subarachnoid space (Fig. 11.8).

The genetic alteration is inactivation of the cell-cycle regulatory system, which includes the p16, cyclin-dependent kinase 4 (cdk4), cyclin D1 and retinoblastoma (Rb) proteins. Loss of the putative tumor suppressor gene on chromosome 19, amplification of the EGFR gene, and expression of VEGF gene are implicated in the progression to a glioblastoma.

Diffuse Fibrillary Astrocytoma Grade

figure 1 1.3

Fibrillary astrocytoma in an 11-year-old girl. A and B. A poorly demarcated, firm grayish tumor diffusely enlarges the right basal ganglia, both thalami, and upper brainstem and (C) extends extraparenchymally above the midbrain tectum. D. The tumor is composed of neoplastic astrocytes showing a mild nuclear pleomorphism and dense, elongated fibrillary processes which fill the intercellular spaces. The neuronal pattern of the infiltrated gray structures is generally preserved (HE).

figure 1 1.3

Fibrillary astrocytoma in an 11-year-old girl. A and B. A poorly demarcated, firm grayish tumor diffusely enlarges the right basal ganglia, both thalami, and upper brainstem and (C) extends extraparenchymally above the midbrain tectum. D. The tumor is composed of neoplastic astrocytes showing a mild nuclear pleomorphism and dense, elongated fibrillary processes which fill the intercellular spaces. The neuronal pattern of the infiltrated gray structures is generally preserved (HE).

figure 1 1.4

Gemistocytic astrocytoma in the wall of the third ventricle. A. It consists of large, plump, neoplastic astrocytes with glassy pink cytoplasm and eccentrically placed nucleus (HE). B. The cells strongly react for GFAP (immunostain).

figure 1 1.4

Gemistocytic astrocytoma in the wall of the third ventricle. A. It consists of large, plump, neoplastic astrocytes with glassy pink cytoplasm and eccentrically placed nucleus (HE). B. The cells strongly react for GFAP (immunostain).

Hepatic Stellate Gfap

figure 1 1.5

Anaplastic astrocytoma. A 35-year-old man, about 3 weeks prior to his death, developed severe, persistent headaches and gradually became confused and disoriented. Bilateral papilledema was the only significant neurologic finding. A. A large hemor-rhagic tumor fills the anterior horns, destroys the septum and fornices, and extends into the walls of the third ventricle. B. It is highly cellular. The neoplastic cells have large hyperchromatic nuclei and variable amounts of cytoplasm. Bizarrely-shaped multinucleated cells are occasionally seen (HE).

figure 1 1.5

Anaplastic astrocytoma. A 35-year-old man, about 3 weeks prior to his death, developed severe, persistent headaches and gradually became confused and disoriented. Bilateral papilledema was the only significant neurologic finding. A. A large hemor-rhagic tumor fills the anterior horns, destroys the septum and fornices, and extends into the walls of the third ventricle. B. It is highly cellular. The neoplastic cells have large hyperchromatic nuclei and variable amounts of cytoplasm. Bizarrely-shaped multinucleated cells are occasionally seen (HE).

EBBHHfl [lfl?1

figure 1 1.6

Anaplastic astrocytoma. A 7-year-old girl had a 3-week history of headaches, vomiting, right extremity weakness, and somnolence. Examination revealed bilateral papilledema, right hemiparesis, impaired touch and pain sensations, and asterognosis in the right hand, which was in an athetoid-like posture. A. A large, soft, grayish tumor diffusely enlarges the left thalamus. B. The tumor is highly cellular, with moderately large pleomorphic astrocytes. C. Intermixed are larger multinucleated cells (HE).

Glioblastoma (Grade 4)

Gliablastoma (GB), the most malignant fast-growing glioma, constitutes 50% to 60% of astrocytic tumors and 12% to 15% of all intracranial tumors. It occurs in mid and late midlife, the peak incidence being between 40 and 70 years of age. The average clinical course is 12 to 18 months (Fig. 11.9).

Glioblastoma arises either de novo from remnants of embryonal glial cells (primary GB) or from the malignant transformation of a low-grade or an anaplastic

figure 1 1.7

Anaplastic pontine astrocytoma in a 48-year-old woman. The tumor diffusely enlarges the pons and the tegmentum. It is grayish, soft, in places hemorrhagic.

figure 1 1.7

Anaplastic pontine astrocytoma in a 48-year-old woman. The tumor diffusely enlarges the pons and the tegmentum. It is grayish, soft, in places hemorrhagic.

astrocytoma (secondary GB). These two subtypes of glioblastomas differ in their genetic alterations and clinical presentations. Primary glioblastoma chiefly affects older adults and presents with a short history of a few weeks to a few months. It rarely displays mutations in p53 tumor suppressor gene, but frequently displays the overexpression or amplification of the EGFR gene. Conversely, secondary glioblastoma affects younger adults and presents with a longer history of several months to years. It frequently displays mutations in p53 tumor suppressor gene and rarely overexpression of EGFR gene.

Grossly, glioblastoma is commonly situated in the cerebral hemispheres, preferentially in the frontal and temporal lobes. It appears circumscribed, but the borders are ill-defined. Some tumors tend to grow along the corpus callosum, into the opposite hemisphere in a butterfly pattern. Rarely, they are multifocal. Cut surfaces have a multicolored appearance; they contain pinkish-gray viable tissue, yellow necrosis, cystic degenerations, and rusty and reddish areas marking old and fresh hemorrhages. Being a fast-growing tumor, extensive edema and mass effects are prominent (Figs. 11.10, 11.11, 11.12, and 11.13).

Histologically, they are characterized by:

• High cellularity with a great degree of anaplasia and pleomorphism. Some cells are small, round to oval;

figure 1 1.8

Anaplastic astrocytoma with subarachnoid dissemination. A 25 year-old man, following a one and a half year history of right-sided headaches and partial complex seizures with uncinate fits underwent a craniotomy for removal of a large right temporal lobe tumor diagnosed histologically as anaplastic astrocytoma. The surgery was followed by radiation and chemotherapy. One year later, he developed weakness in his legs and urinary retention. A myelogram showed diffuse obstruction of the subarachnoid space in the thoracolumbar region. Despite chemotherapy, he progressively deteriorated and died a few months later. A. Transverse section of the brain at thalamus level shows tumorous infiltration in the wall of a large residual cavity that communicates with the temporal horn. B. Ventricular wall shows a hypercellular and pleomorphic astrocytic tumor (HE). C. Massive tumorous infiltrations around the medulla and spinal cord, extending deeply into the parenchyma (HE).

c figure 1 1.8

Anaplastic astrocytoma with subarachnoid dissemination. A 25 year-old man, following a one and a half year history of right-sided headaches and partial complex seizures with uncinate fits underwent a craniotomy for removal of a large right temporal lobe tumor diagnosed histologically as anaplastic astrocytoma. The surgery was followed by radiation and chemotherapy. One year later, he developed weakness in his legs and urinary retention. A myelogram showed diffuse obstruction of the subarachnoid space in the thoracolumbar region. Despite chemotherapy, he progressively deteriorated and died a few months later. A. Transverse section of the brain at thalamus level shows tumorous infiltration in the wall of a large residual cavity that communicates with the temporal horn. B. Ventricular wall shows a hypercellular and pleomorphic astrocytic tumor (HE). C. Massive tumorous infiltrations around the medulla and spinal cord, extending deeply into the parenchyma (HE).

figure 1 1.9

Glioblastoma, clinical presentation. A 57-year-old right-handed man experienced three episodes of incoherent speech for several hours within 1 month prior to hospitalization. His past medical history was significant for old head injuries. A. Contrast-enhanced T1-weighted MRI shows a left temporal tumor surrounded by massive edema. The tumor was resected and histologically diagnosed as glio-blastoma. The surgery was followed by radiation therapy. B. A postoperative CT scan shows total resection of the tumor and resolution of the edema. C. Nonetheless, one year later, a CT scan shows recurrence of the tumor with massive edema. A few months later, he died. D. An extensive necrotic tumor occupies the left temporo-occipital region.

others are elongated, slender, or spindle-shaped; and still others are large, with one or multiple hyperchro-matic nuclei. Giant monstrous cells are not uncommon. More mature astrocytes are sometimes present and express variably GFAP-immunoreactivity.

• High mitotic activity, often with bizarre mitotic figures.

• A rich vascular supply; the blood vessels display endo-thelial and adventitial proliferations and thrombotic occlusion. A glomeruloid appearance of proliferated capillaries is typical.

• Necroses are common and extensive. Smaller ones are surrounded by tumor cells in a pseudopalisading pattern (Figs. 11.14, 11.15, and 11.16)

Glioblastoma, when it reaches the subarachnoid space or the ventricles, may disseminate along the CSF pathways, forming small nodules or diffuse infiltrates. It seldom metastasizes outside the nervous system to the lymph nodes, lung, liver, and bone marrow.

Genetic alterations include loss of chromosome 10, amplification of EGFR oncogene and inactivation of the cell-cycle control system, and the expression of the VEGF receptor gene.

Variants of glioblastomas. Giant cell glioblastoma consists mostly of large bizarre-shaped glial cells. Gliosar-coma has a dense mesenchymal component.

figure 11.10

Glioblastoma. A large, left, poorly demarcated frontal tumor shows pinkish viable tumor, small cysts, areas of necrosis, and fresh hemorrhages. The left hemisphere is swollen, and the ipsilateral ventricle is compressed.

figure 11.10

Glioblastoma. A large, left, poorly demarcated frontal tumor shows pinkish viable tumor, small cysts, areas of necrosis, and fresh hemorrhages. The left hemisphere is swollen, and the ipsilateral ventricle is compressed.

figure 11.11

Glioblastoma. A 52-year-old man began to complain at times of smelling an acid-like odor or tasting something peculiar (uncinate fits). At other times, he complained of a floating sensation (vertiginous spells). His steadily deteriorating memory made him unable to function as a salesman. During this time, he received psychiatric treatment intermittently for depression. Examination prior to his sudden death at age 57 showed left hemiparesis, increased deep tendon reflexes, and Babinski sign. The right temporal lobe, including the uncus and the hippocampus, is tumorously enlarged. It contains grayish viable tumor, necrosis, and rusty areas from old hemorrhages.

figure 11.11

Glioblastoma. A 52-year-old man began to complain at times of smelling an acid-like odor or tasting something peculiar (uncinate fits). At other times, he complained of a floating sensation (vertiginous spells). His steadily deteriorating memory made him unable to function as a salesman. During this time, he received psychiatric treatment intermittently for depression. Examination prior to his sudden death at age 57 showed left hemiparesis, increased deep tendon reflexes, and Babinski sign. The right temporal lobe, including the uncus and the hippocampus, is tumorously enlarged. It contains grayish viable tumor, necrosis, and rusty areas from old hemorrhages.

Astrocytic Tumors (Grades 1 and 2)

Pilocytic Astrocytoma (Grade 1)

This slowly growing tumor affects chiefly children and adolescents. It occurs commonly in the cerebellum, optic nerves/chiasma, and hypothalamus/third ventricle and, less often, in the cerebral hemispheres. When situated in

Hypothalamus Third Ventricle

figure 11.12

Glioblastoma. A 53-year-old woman with no previous psychiatric history was taken to a mental hospital following her knife attack on her husband. She had recently become more and more bizarre, complaining of severe headaches and inability to retain food. She had accused family members of trying to poison her. She also believed that her sister was turning her into a dog. During her examination, she was confused and incoherent. Her behavior rapidly changed from unresponsive to excitable and bizarre. During the third week of hospitaliza-tion, she was found stuporous. The following day, she died. A large glioblastoma is situated in the left posterior temporal lobe, extending into the right temporal lobe across the sple-nium in a butterfly pattern. It consists of grayish viable tumor and extensive yellow necrotic areas intermixed with old and recent hemorrhages.

the optic nerves and chiasma, it may be associated with neurofibromatosis type 1 (NF1). Grossly, the tumor is fairly well circumscribed, soft, gray; it may adjoin a cyst or form a mural nodule within the cyst (Fig. 11.17). Histologically, the tumor is composed of elongated, mono- or bipolar pilocytes (hair cells), which form fascicles or a loose fibrillary matrix, and of small stellate cells with fine cytoplasmic processes. Microcysts, Rosenthal fibers, and eosinophilic bodies are characteristic features. The vascular supply is rich, and a variable degree of hyalinization and proliferation are present; these features do not necessarily predict a poor prognosis. Mitosis is uncommon. The tumor is apt to extend to the perivascular and sub-arachnoid spaces. Genetically, a gain on chromosome 6 to 10 is frequent; NF1-associated tumors may show a loss of chromosome 17q.

Subependymal Giant Cell Astrocytoma (Grade 1) Subependymal giant cell astrocytoma (grade 1) is a slowly growing, well-demarcated tumor within the

Subependymal Giant Cell Astrocytoma

figure 11.13

Glioblastoma. A. A grayish, firm, relatively circumscribed tumorous infiltration obscures the temporal convolutions. B. On transverse section, the tumor contains fresh hemorrhages and viable tumor in the cortex.

figure 11.13

Glioblastoma. A. A grayish, firm, relatively circumscribed tumorous infiltration obscures the temporal convolutions. B. On transverse section, the tumor contains fresh hemorrhages and viable tumor in the cortex.

Cell Bizarre Cytological Feature

figure 11.14

Glioblastoma, cytological features. A. Densely populated area of small, poorly differentiated glial cells (HE). B. Fusiform cells forming loose bundles displaying large atypical glial cells (HE). C. Giant mononucleated and multinucleated glial cells (HE). D. Some tumor cells express GFAP (immunostain). E. Atypical mitotic figure (HE).

figure 11.14

Glioblastoma, cytological features. A. Densely populated area of small, poorly differentiated glial cells (HE). B. Fusiform cells forming loose bundles displaying large atypical glial cells (HE). C. Giant mononucleated and multinucleated glial cells (HE). D. Some tumor cells express GFAP (immunostain). E. Atypical mitotic figure (HE).

lateral ventricles, often at the foramen Mono. It affects young children, and occurs commonly in the tuberose sclerosis syndrome (see Chapter 13). Histologically, the tumor cells vary in appearance: Some are large and globoid with abundant eosinophilic cytoplasm; others are small and fibrillated. Calcifications are common.

Pleomorphic Xanthoastrocytoma (Grade 2) Pleomorphic xanthoastrocytoma affects children and young adults, and occurs in the cerebral hemispheres, rarely in the cerebellum. Grossly, the tumor is attached to the leptomeninges. It may contain a large cyst or form a mural nodule in a cyst wall. The histology is characterized by cellular pleomorphism with spindle cells and

L MjaSf'1

IHlIRBSiB

figure 11.15

Glioblastoma, vascular features. A. Endothelial capillary hyperplasia. B. Glomeruloid capillary proliferation.

figure 11.16

Glioblastoma, necrosis. Serpiginous areas of necrosis are surrounded by pseudopalisading tumor cells.

figure 11.16

Glioblastoma, necrosis. Serpiginous areas of necrosis are surrounded by pseudopalisading tumor cells.

Infantile Spasm Gross Pathology

figure 11.17

Pilocytic astrocytoma. A 2.5-year-old boy with unremarkable history developed infantile spasms and began to mentally deteriorate. At age 7, a large right temporoparietal mass lesion was diagnosed and parts of it—60 g—were resected. He received no radiation therapy. Following a temporary improvement, he developed seizures and slowly deteriorated. At age 13.5, following an 11-year clinical course, he died. A. A huge, fairly well-demarcated tumor occupies the temporal lobe and greater part of the hemisphere. B. Anteriorly it contains a large cyst. C. Astrocytes with uni- and bipolar processes form a fibrillary matrix around a capillary. D. Rosenthal fibers are abundant in some areas.

figure 11.17

Pilocytic astrocytoma. A 2.5-year-old boy with unremarkable history developed infantile spasms and began to mentally deteriorate. At age 7, a large right temporoparietal mass lesion was diagnosed and parts of it—60 g—were resected. He received no radiation therapy. Following a temporary improvement, he developed seizures and slowly deteriorated. At age 13.5, following an 11-year clinical course, he died. A. A huge, fairly well-demarcated tumor occupies the temporal lobe and greater part of the hemisphere. B. Anteriorly it contains a large cyst. C. Astrocytes with uni- and bipolar processes form a fibrillary matrix around a capillary. D. Rosenthal fibers are abundant in some areas.

large mono- and multinucleated cells. Numerous cells contain lipid droplets, and a rich reticulin network separates the cells into small clusters.

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