Chapter 65. The Central Nervous System: IV. Neoplasms

Intracranial and spinal neoplasms may be primary or metastatic; in most autopsy series, metastatic tumors are more common. Primary intracranial neoplasms number about 13,000 new cases per year in the United States and represent about 2% of deaths from malignant neoplasms. They are the second most common group of neoplasms in children, after leukemia and lymphoma if considered as one group. Taken overall, 65% of primary intracranial neoplasms are of glial origin (gliomas), 10% meningiomas, 10% acoustic schwannomas, 5% medulloblastomas, and 10% others. Primary malignant lymphomas of the central nervous system have recently increased in frequency because they are common in patients with acquired immunodeficiency disease (AIDS). Tumors of neurons per se are extremely uncommon except in childhood (eg, medulloblastoma).

Classification

Histogenetic Classification

Classification on a histogenetic basis has great theoretical value and provides a means of logically remembering all the different kinds of intracranial neoplasms (Table 65-1).

Topographic Classification

When a patient presents with an intracranial neoplasm, its location can usually be ascertained by clinical examination and radiologic studies. According to their location, intracranial neoplasms may be classified as supratentorial or infratentorial. Further subdivisions in these main compartments are recognized (Table 65-2), leading to a topographic classification. When the location of the neoplasm is combined with the patient's age, a clinically useful differential diagnosis of the histologic type of the neoplasm can be derived. For example, if a child presents with a neoplasm in a cerebellar hemisphere, it is most likely a juvenile pilocytic astrocytoma (Table 65-2).

Classification According to Biologic Potential

The criteria used to determine malignancy in neoplasms are somewhat different from those used elsewhere in the body:

1. Even highly malignant intracranial neoplasms generally do not metastasize outside the craniospinal axis (Fig 65-1). Metastasis within the craniospinal axis via the cerebrospinal fluid does occur, most commonly with medulloblastoma, pineoblastoma, malignant ependymoma, pineal germinoma, and glioblastoma multiforme.

2. Destructive infiltration of the brain is the major criterion of malignancy for intracranial neoplasms, and infiltration of brain substance usually prevents complete removal at surgery. All glial neoplasms invade brain, and all must be considered malignant. Neurologic deficits resulting from destructive invasion by malignant neoplasms are irreversible. Benign neoplasms, on the other hand, cause neurologic deficits due to compression; these often reverse when the neoplasm is removed.

3. The rate of growth of neoplasms also correlates well with malignant behavior. Rapidly growing neoplasms such as glioblastoma multiforme and medulloblastoma are highly malignant. Low-grade malignant neoplasms such as well-differentiated astrocytoma and oligodendroglioma grow slowly. Benign neoplasms usually grow very slowly, enlarging over several years.

4. Recurrence after treatment is almost invariable with malignant intracranial neoplasms. Recurrence also occurs with many benign neoplasms such as meningioma and craniopharyngioma, and therefore recurrence of itself is not a criterion of malignancy.

5. The term benign for any intracranial neoplasm is probably inappropriate. Benign intracranial neoplasms frequently produce extremely serious clinical disease and may cause severe neurologic deficits and death unless treated. The term thus does not mean that these neoplasms are harmless but implies rather that they are slow growing and do not infiltrate the brain substance.

Pathology & Clinical Features

(Figure 65-1)

The specific clinicopathologic features of intracranial neoplasms will be considered with the individual neoplasms. In general, intracranial neoplasms cause the following clinical and pathologic changes:

Compression

Compression of adjacent neural tissues occurs with all expanding neoplasms. When the rate of growth is slow, compression leads to atrophy, which may cause symptoms of dysfunction—eg, atrophy of the motor cortex adjacent to a meningioma causes upper motor neuron paralysis; compression of a cranial nerve may cause cranial nerve palsy. In general, relief of compression is followed by significant recovery of function. With long-standing compression, there may be a permanent deficit.

Destruction

Destruction of neural tissues by direct infiltration with a malignant neoplasm produces an irreversible deficit.

Cerebral Edema

Cerebral edema is commonly present around infiltrative neoplasms and may be severe. It is believed to result from the neovascularization that accompanies malignant neoplasms. The new vessels have a poorly developed blood–brain barrier that permits exit of proteins and fluids more easily than from normal vessels. Cerebral edema tends to be most marked in highly malignant neoplasms. Cerebral edema causes elevation of intracranial pressure that is additive to the mass effect of the tumor.

Irritative Effects

Irritation of neural tissues may occur with both compressing and infiltrating neoplasms. Abnormal stimulation is usually manifested as either simple or complex partial focal epilepsy. A neoplasm near the motor cortex may generate an abnormal electrical potential that causes motor stimulation of the entire contralateral half of the body (jacksonian epilepsy). Up to 5% of individuals with intracranial neoplasms experience one or more seizures. Note that although only a minority of cases of epilepsy are due to tumors, seizures should be fully investigated for cause due to tumor or other treatable disease, particularly when the onset is in adult life or when the seizure is focal rather than generalized (see Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases).

Hydrocephalus

Neoplasms in the region of the third ventricle or in the posterior fossa may cause obstructive hydrocephalus. This causes marked elevation of intracranial pressure.

Increased Intracranial Pressure

Intracranial neoplasms cause increased intracranial pressure due to (1) the mass effect of the neoplasm itself, (2) cerebral edema, or (3) hydrocephalus. Many patients with intracranial neoplasms present with the effects of increased intracranial pressure—headache, vomiting, papilledema, and false localizing signs due to displacement of the brain and to herniations (see Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases). Shift of structures can often be detected radiographically and provides a clue to the site of intracranial neoplasms.

Diagnosis

Clinical examination and radiologic imaging provide excellent localization of mass lesions of the nervous system. Specific diagnosis, however, is based on microscopic examination of a sample from the tumor. Stereotactic biopsy and open resection are the methods available for obtaining tissue samples. Examination of cerebrospinal fluid is rarely useful because (1) lumbar puncture is not usually performed in the presence of mass lesions, and (2) the yield of neoplastic cells in cerebrospinal fluid is low even with highly malignant neoplasms.

Cerebral Hemisphereastrocytoma

Astrocytoma in the cerebral hemisphere is the most common primary neoplasm of the brain and occurs chiefly in adults (Table 65-2).

Well-Differentiated (Grade I) Astrocytomas

Well-differentiated (grade I) astrocytomas are infiltrative, slowly growing neoplasms that form firm, white, ill-defined masses (Figure 65-2). Microscopically, they show slightly increased cellularity and astrocytes with cytologic features that deviate very slightly from normal. Neurofibrillary processes are present and, often, abundant (fibrillary astrocytoma). Well-differentiated astrocytomas, although low-grade malignant neoplasms, are practically impossible to excise surgically because of irregular extension beyond the apparent margin. They progress slowly to cause death approximately 5–10 years after presentation.

Anaplastic (Grade II & Grade III) Astrocytomas

Anaplastic astrocytoma is a more rapidly growing neoplasm that forms a white infiltrative mass in the cerebral hemisphere. Microscopically, it is composed of astrocytes that show greater cellularity, more pleomorphism, neovascularization with proliferation of endothelial cells, and an increased mitotic rate. Anaplastic astrocytomas show a higher rate of cell proliferation than well-differentiated astrocytoma. The proliferative rate may be measured by (1) the percentage of cells in the S phase of the cell cycle and (2) the percentage of cells expressing proliferation-associated antigens such as Ki67. They commonly cause death after 1–5 years.

Glioblastoma Multiforme (Grade IV Astrocytoma)

Glioblastoma multiforme is the most common type of astrocytoma. It is also one of the most malignant and rapidly growing neoplasms of the brain. Grossly, glioblastomas appear as large infiltrative masses that typically extend across the midline as the so-called “butterfly” tumor. The cut surface commonly shows hemorrhage and necrosis (Figure 65-3). Microscopically, they are composed of highly pleomorphic astrocytic cells with frequent mitotic figures. Necrosis is an important indicator of aggressive behavior (Figure 65-4). Prominent neovascularization is common. Glioblastoma multiforme is highly malignant, with a median survival of 1 year after diagnosis.

Juvenile Pilocytic Astrocytoma

Juvenile pilocytic astrocytoma is a neoplasm of children and adolescents found most commonly in the cerebellar hemispheres. It accounts for 25% of intracranial neoplasms in children under age 10 years. Grossly, it is well circumscribed and often cystic. Microscopically, it shows hypercellularity and is composed of cytologically uniform fibrillary astrocytes. Microcystic change and the presence of enlarged astrocytic fibers (Rosenthal fibers) are characteristic features.

Juvenile cerebellar pilocytic astrocytoma is a very slowly growing tumor that is extremely well circumscribed. It is almost benign in its biologic behavior. Surgical removal results in permanent cure in most cases.

Juvenile pilocytic astrocytoma may also occur in the region of the hypothalamus. Though slowly growing and circumscribed, it is rarely possible to completely remove a hypothalamic pilocytic astrocytoma, and it frequently causes death.

Brain Stem & Spinal Cord Astrocytoma

Astrocytomas also occur in the brain stem and spinal cord and are analagous to the different types occurring in the cerebral hemispheres.

Oligodendroglioma occurs in the cerebral hemisphere in adults 30–50 years of age. It is uncommon in pure form but more often is part of a mixed glial neoplasm with astrocytic and oligodendroglial components.

Grossly, oligodendrogliomas are well-circumscribed solid neoplasms. Seventy-five percent of oligodendrogliomas have speckled calcification that is visible on x-ray. Microscopically, the neoplasm is composed of numerous small uniform oligodendroglial cells. Mitotic activity is scarce.

Clinically, oligodendroglioma is a slowly growing neoplasm. The prognosis after surgical removal is good, although recurrence is common.

Ependymoma

Ependymoma is an uncommon neoplasm that occurs at all ages but is relatively more common in children. It accounts for 60% of intramedullary spinal cord neoplasms; in the brain, 60% occur in the fourth ventricle.

Grossly, ependymomas form well-circumscribed, reddish-brown nodular masses that occur in relation to the ventricular system. They grow slowly but have the ability to spread via the cerebrospinal fluid and should be considered as low-grade malignant neoplasms. Microscopically, ependymomas are highly cellular, with small polygonal cells that form ependymal tubules and perivascular pseudorosettes. Well-differentiated ependymomas tend to grow slowly and may be cured by complete surgical removal. Less differentiated ependymomas infiltrate, grow rapidly, and have a poor prognosis.

A specific type of ependymoma called myxopapillary ependymoma occurs in the filum terminale and presents as a cauda equina tumor in young adults.

Choroid Plexus Papilloma

Choroid plexus papilloma is a rare neoplasm that tends to occur in the ventricles of young children. Grossly, it is characterized by a highly vascular papillary mass growing into the ventricle. Microscopically, the papillary processes have vascular cores and are lined by uniform columnar cells. Calcification may be present. Rarely, infiltration of brain, cytologic atypia, and increased mitotic activity justify a diagnosis of choroid plexus carcinoma.

Choroid plexus papillomas may sometimes secrete increased amounts of cerebrospinal fluid and give rise to communicating hydrocephalus.

Colloid Cyst of the Third Ventricle

Colloid cysts are believed to have an ependymal origin. They occur in the anterior third ventricle and are unilocular cysts lined by cuboidal epithelium and containing thick gelatinous fluid. As they enlarge, colloid cysts may block the foramen of Monro, producing acute obstructive hydrocephalus.

Medulloblastoma is derived from primitive neuroectodermal cells. It occurs mainly in children, accounting for 25% of all intracranial neoplasms in children under age 10 years. Its most common location is the midline cerebellar vermis in the posterior fossa.

Grossly, medulloblastoma appears as a grayish-white fleshy mass with infiltrative margins. Microscopically, the tumor is highly cellular and composed of sheets of small primitive cells with hyperchromatic nuclei and scant cytoplasm. Mitotic figures are frequently present.

Medulloblastoma is highly malignant and frequently seeds the cerebrospinal fluid to produce metastases around the spinal cord. The prognosis is poor, but recent aggressive chemotherapeutic regimens have improved the outlook somewhat.

The pineal gland is situated in the midline, dorsal to the midbrain and the posterior part of the third ventricle. It is composed of pinealocytes, which are modified neuroectodermal cells.

Pinealocyte Neoplasms

Pineocytoma is a benign or low-grade malignant neoplasm composed of well-differentiated pinealocytes. It occurs mainly in adults.

Pineoblastoma resembles medulloblastoma. It occurs in childhood and is highly malignant.

Germ Cell Neoplasms

Neoplasms arising from primitive germ cells in the nervous system occur most commonly in the pineal region. Germinoma, which resembles the testicular seminoma microscopically, is most common and typically forms a well-circumscribed mass that compresses the midbrain, causing abnormalities in ocular movement and hydrocephalus. Germinomas are malignant and tend to spread along cerebrospinal fluid (CSF) pathways. Germinomas are extremely radiosensitive neoplasms, and cures have been recorded following radiation therapy.

Other germ cell neoplasms occurring in the region of the pineal gland include teratoma, embryonal carcinoma, yolk sac carcinoma, and choriocarcinoma. All are very uncommon.

Meningioma can occur at any age but is rare in childhood. Meningiomas occur most frequently in middle-aged women—the predominance in women is probably related to the presence of progesterone receptors on the tumor cells.

Pathology

Meningiomas usually arise outside of the brain substance and have an attachment to the dura. They present grossly as a firm encapsulated mass that compresses adjacent neural structures (Figure 65-5). Infiltration of the dura is usual and does not indicate malignancy. Meningiomas are frequently associated with hypertrophy of the overlying bone (hyperostosis); this may be so pronounced as to cause a palpable mass in the skull. Meningiomas may also infiltrate bone and extend into the scalp, a locally aggressive behavior pattern that still does not necessarily indicate malignancy. The term malignant meningioma is used only when the neoplasm infiltrates the underlying brain.

Microscopically, meningioma is composed of sheets or whorls of meningothelial cells, which are plump spindle cells with oval nuclei and scant cytoplasm (syncytial or meningothelial meningioma). In some cases, the meningothelial cells are more elongated, resembling fibroblasts (fibroblastic meningioma). Psammoma bodies (round, laminated calcifications) occur in many meningiomas. Mitoses are rare. When there is necrosis, cellular pleomorphism, or a high mitotic rate, the term atypical meningioma may be used.

Biologic Behavior

Meningioma is a benign neoplasm. However, because of infiltration of dura and bone, complete surgical removal may be difficult in some cases, and there is a 10% recurrence rate. The recurrence rate increases in (1) atypical meningiomas (20–30% recurrence rate) and (2) malignant meningiomas (90% without radiotherapy).

Clinical Features

Meningiomas occur throughout the craniospinal axis, producing specific clinical features that depend on their location (Figure 65-6). Sites of predilection are (1) the parasagittal region and falx cerebri, giving rise to motor deficits; (2) the surface of the cerebral hemispheres, causing focal epilepsy and cortical dysfunction depending on exact location; (3) the olfactory bulb, compressing the optic nerve and causing blindness; (4) the sphenoidal ridge, compressing the cranial nerves passing into the orbit; (5) the posterior fossa, with features of a cerebellopontine angle tumor; and (6) the spinal cord, causing spinal compression.

Neoplasms arising in the nerve sheaths—schwannoma and neurofibroma—will be considered in the section on soft tissue neoplasms (Chapter 66: The Peripheral Nerves & Skeletal Muscle). Nerve sheath neoplasms occur in relation to cranial and spinal nerve roots, particularly the sensory nerve roots.

The most common intracranial example is the acoustic schwannoma (neuroma), which arises in the eighth cranial nerve and presents as a cerebellopontine angle mass. In this location, it compresses adjacent cranial nerves and cerebellum. Schwannoma less frequently arises from the fifth cranial nerve.

Neurofibromas are the most common neoplasms occurring in the intradural but extramedullary compartment of the spinal column. They cause progressive spinal cord compression.

Cerebellar hemangioblastoma is a benign neoplasm that occurs either sporadically or as part of von Hippel-Lindau disease (Chapter 62: The Central Nervous System: I. Structure & Function; Congenital Diseases). It appears grossly as a well-circumscribed mass with cystic and solid components (Figure 65-7). Microscopically, numerous endothelium-lined vascular spaces are separated by trabeculae of cells with lipid-laden cytoplasm.

Clinically, presentation is with cerebellar dysfunction, hydrocephalus, or polycythemia (the tumor produces erythropoietin). Surgical removal is usually curative.

Primary malignant lymphoma of the brain is very uncommon in otherwise healthy individuals. Its incidence is greatly increased in immunocompromised patients, such as those with AIDS and persons who have received organ transplants.

Intracranial lymphoma most commonly occurs in the deep cerebral hemispheres and is frequently multifocal. The commonest types are high-grade B cell lymphomas, most commonly B-immunoblastic lymphoma. Treatment with chemotherapy is of limited efficacy, and the prognosis is poor.

Craniopharyngioma

Craniopharyngioma is believed to be derived from Rathke's pouch, the epithelial remnant of the foregut that contributes to the origin of the pituitary gland. It occurs mainly in childhood in the suprasellar region adjacent to the pituitary stalk.

Typically, craniopharyngioma is encapsulated and has cystic and solid components. In some cases, local infiltration makes complete surgical removal difficult. Microscopically, the cystic spaces are lined by stratified squamous epithelium and contain an oily fluid in which cholesterol crystals can be identified. The solid areas are composed of stroma and squamous epithelium that resembles tooth-forming ameloblastic epithelium. Calcification is usually present.

Craniopharyngiomas present with compression and destruction of (1) the pituitary, causing hypopituitarism—in children, growth retardation is a common finding; (2) the optic chiasm, causing visual field defects; and (3) the third ventricle, causing hydrocephalus. Treatment is surgical, often followed by radiation therapy in cases where complete surgical removal is not possible. The recurrence rate is high.

Epidermoid Cyst

Epidermoid cysts are derived from rare embryonic epidermal remnants. The most common locations are the cerebellopontine angle, the suprasellar region, and the lumbar region of the spinal cord in relation to spina bifida.

Epidermoid cysts are benign cystic structures lined by stratified squamous epithelium and filled with keratin. Surgical removal is curative.

Chordoma

Chordoma is a neoplasm derived from notochordal remnants found in the base of the skull and the dorsal aspect of the vertebral bodies. Chordoma occurs most commonly at either end of the notochord in the following locations: (1) in the sacrococcygeal region, where it causes compression of the cauda equina; (2) at the clivus, from which it extends into the posterior fossa, compressing the brain stem; and (3) in the suprasellar region, where it compresses the pituitary stalk and third ventricle.

Grossly, chordoma appears as a lobulated nodular mass that arises in bone and protrudes inward into the cranial cavity and spinal canal. It has a gelatinous appearance on cut section and histologically resembles the notochord, being composed of large cells with abundant bubbly cytoplasm (physaliphorous cells).

Chordomas are malignant neoplasms that grow slowly but inexorably. Complete surgical removal is rarely possible. Most patients die of their tumor, usually after several years.

Neoplasms metastatic to the brain are common and may be derived from melanomas or from primary tumors in almost any organ, most commonly the lung, breast, kidney, stomach, and colon. The brain metastasis may be the first manifestation of a previously occult malignant neoplasm, in which case differentiation from a primary intracranial neoplasm is difficult without biopsy. More frequently, metastasis to the brain occurs during the terminal phase in a patient with disseminated cancer (Fig 65-8).

Meningeal involvement by metastatic neoplasms occurs frequently in patients with acute leukemia. This presents a problem because the blood–brain barrier prevents chemotherapeutic agents from reaching the meningeal leukemic cells. The diagnosis of meningeal involvement can be made by identifying leukemic cells in cerebrospinal fluid. These patients can then be treated either with intrathecal chemotherapy or craniospinal irradiation.