42

Epidemiology
The oropharynx is the posterior continuation of the oral cavity and connects with the nasopharynx (above) and laryngopharynx (below). It is located between the soft palate superiorly, and the hyoid bone inferiorly. The main sites of the oropharynx consist of the posterior and lateral pharyngeal wall, faucial arches, tonsillar fossa (TF), soft palate (SP), and the base of tongue (BOT). These structures play a crucial role in swallowing and speech. By obstructing the “air space” or by infiltrating muscles or nerves, locally advanced oropharyngeal tumors can significantly impede these functions. The same holds for intensive treatment regimen: it can cause deformities and/or impairment of particular functional (sub) units, resulting eventually in severe (late) side effects. It has long been known that patients with a history of smoking or excessive consumption of alcohol are believed to be at increased risk for developing cancer in the oropharynx (31,37). Overall these cancers comprise less than 0.5% of all cancers in men in the United States, which amounts to approximately 5000 new cases each year (319). According to the Surveillance, Epidemiology, and End Results report of the National Cancer Institute, in 2001 the age-adjusted incidence was 1.5 per 100,000 white men and 3.2 per 100,000 black men (271). These cancers more often afflict men (4:1); they are diagnosed most frequently in the sixth and seventh decades of life. Oropharyngeal cancers are readily accessible to clinical examination and staging. Historically, in the early stage and in the moderately advanced tumors, radiation therapy (RT) has been the preferred therapy mode because of its organ function-preservation properties (300,321). Most (±95%) oropharyngeal cancers are squamous cell carcinomas (SCC). Although reports can be found of other histologic subtypes (1,14,72,93,158), such as minor salivary gland tumors, lymphoepitheliomas, malignant lymphomas, mesenchymal tumors, or metastases from other extracranial tumor sites, these will not be discussed in great detail as they are considered beyond the scope of the present chapter.
Anatomy
The SP, anterior faucial pillar, and the retromolar trigone are embryologically connected to the oral cavity. However, because of their clinical behavior, tumors of these structures are preferably classified with oropharyngeal malignancies. The inferior part of the TF is referred to as the glossopalatine sulcus (Fig. 42.1). The lateral border of the retromolar trigone extends upward into the buccal mucosa, medially it blends with the anterior tonsillar pillar. Its base is formed by the last lower molar and the adjacent gingivolingual surface. The lateral walls of the oropharynx are limited posteriorly by the TF proper and the posterior tonsillar pillar. The anterior and posterior tonsillar pillars are the folds of mucous membrane that cover the underlying glossopalatine and pharyngopalatine muscles, respectively. Deep to the lateral wall of the TF are major vessels (Figs. 42.2 and 42.3) and muscular components such as the superior constrictor muscle, the upper fibers of the middle constrictor muscle, the pharyngeus and stylopharyngeus muscles, and the glossopalatine and pharyngopalatine muscles. Stratified squamous epithelium covers all of these structures. The tonsil has a heavy lymphoid network. The pharyngeal wall is related to the second and third cervical vertebrae. Nerve supply is from the cranial nerves IX and X. The BOT lies posterior and inferior to the palatoglossal arch. It is bounded anteriorly by the circumvallate papillae, laterally by the glossopharyngeal sulci and oropharyngeal walls, and inferiorly by the valleculae and the pharyngoepiglottic fold. Embryologically, its epithelium is derived from the entoderm, unlike that from the oral tongue (ectoderm). The body of the BOT is formed by thick muscles, the genioglossus, styloglossus, palatoglossus, and hypoglossus muscles. The muscles originate from the margins of the mandible and are attached to the hyoid bone. The blood supply and the innervation are by the lingual arteries and hypoglossal nerve, respectively.
Natural History
In general, tumors of the anterior tonsillar pillar and soft palate are better differentiated and biologically less aggressive than those of the TF. For example, 50% to 60% of patients with primary tumors in the anterior tonsillar pillar, retromolar trigone, and SP had necks with clinically negative findings, in contrast to only 24% of those with TF primaries (149). Lesions of the TF (231), retromolar trigone (39), and BOT tend to grow more extensively. Perez et al. (234) observed that the primary tumor was confined to the TF in only 5.4%. Byers et al. (171) described 14% mandibular invasion in carcinomas of the retromolar trigone. At diagnosis, 75% of BOT cancers have invaded adjacent structures, including the glossopharyngeal sulcus, pharyngeal wall, larynx, and/or faucial arches. The most common complaint at presentation of tumors in the oropharynx is pain; this pain is either attributed to (severe) mucositis, deep infiltration of the tumor or is referred (Fig. 42.4). However, patients with primary tumors of the oropharynx can also be asymptomatic or have only vague discomfort at presentation. BOT tumors, for example, typically grow insidiously. Because the BOT is devoid of pain fibers, they are mostly asymptomatic until they have progressed significantly. With local advancement and/or with infiltration of the pterygoid muscles, patients can experience trismus and, ultimately, bleeding or swallowing problems, or can have difficulty with speech.
Diagnosis is typically established by clinical examination in the outpatient clinic and/or examination under general anesthesia, including morphologic confirmation (biopsy) of the lesion and tattooing of the clinical target volume (CTV). In the Erasmus Medical Center—Daniel den Hoed, Rotterdam (Erasmus MC), at the time of diagnosis/staging, with the patient still under general anesthesia, the lesion is frequently marked with marker seeds. This enables the extensions of the lesion to be visualized on x-ray films. From a series of patients implanted with platinum markers, we found, for example, that the TF significantly moves during swallowing and even in rest (because of respiration). Maximum excursions in rest were found to be 3.6 mm. This type of information contributes to a more
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accurate determination of the planning target volume (PTV) margin (Figs. 42.5 and 42.6). Conventionally, platinum (Pt) or gold (Au) marker seeds were used, particularly for those patients to be boosted by brachytherapy (BT) (175). Because of significant scattering properties on computed tomography (CT), nonmetallic seeds are being tested. Panendoscopy can reveal synchronous second primaries. Ultrasound fine-needle aspiration biopsy has become an indispensable tool for pro diagnosis and for staging, especially where it concerns the lymph nodes. Multislice CT and magnetic resonance imaging (MRI) scans are now obligatory imaging tools. CT scanning with contrast enhancement using 2-mm slices is better for detecting lymph nodes and for bone detail. MRI is preferred for the evaluation of the parapharyngeal space. Axial slices are usually sufficient; sagittal MRI is helpful for detecting early pre-epiglottic space infiltration. CT combined with positron emission tomography scanning seems an extremely promising, powerful tool for diagnostic and simulation purposes, but is not yet available in every institution. Several textbooks contain helpful overviews (8,59,123,171,208,232).
Tumors are staged according to the American Joint Committee on Cancer classification system (Table 42.1) (6). Dentulous patients are at increased risk for caries and osteoradionecrosis from the reduction and qualitative change of salivary flow, change in pH, and proliferation of bacteria believed to be responsible for caries. Panorex x-ray films, identification of nonrestorable teeth for pretreatment extraction, dental trays for fluoride rinse, protection against scatter radiation, as well as education about long-term oral hygiene, should be engaged before RT and/or chemotherapy (CHT) is applied. In fact, the quite common development of osteoradionecrosis in the past (17) should be prevented by adequate measures. Finally, given the complexity of head and neck tumors, all patients should be
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formally discussed in a head and neck tumor board, with or without the patient being present, before the initiation of any treatment.

perez_02_01

Injury to DNA is the primary mechanism by which ionizing radiation kills cells (4,83). Most DNA damage is repaired, but lethal double-strand breaks are thought to persist in the form of locally multiply damaged sites (300) of about 15 to 20 nucleotides in size that cause micronuclei formation, chromosome aberrations, and cell death through loss of the reproductive integrity of the cell's genome (38,66,112,158,235,236). However, many biologic factors affect the relationship between the amount of physical energy deposited, the extent of DNA damage that is caused, the number of cells that are killed, and the severity of the tissue response.
The energy initially deposited by ionizing radiation is largely converted into the generation of free radicals. Since cells are made up largely of water (about 85%), most of the damage to biologic molecules caused by x-rays (perhaps 65% or more) is mediated through free radicals formed by activated water, and in particular, hydroxyl radicals, and most DNA damage is therefore indirect. A chain of physicochemical reactions is initiated that is heavily influenced by the intracellular milieu, which influences the persistence of free radicals and the other chemical species that are formed, and the damage that results. Perhaps the most important molecular presence is that of oxygen (5), although other electron-affinic molecules will also play a role. Oxygen can participate in the free radical-generation chain, fix free radical damage, and limit chemical repair. Conversely, sulfhydryl molecules, which vary in natural abundance, scavenge free radicals and may limit the extent of damage.
In contrast to sparsely ionizing x-rays, densely ionizing high linear energy transfer (LET) radiations (e.g., neutrons, α-particles) deposit their energy so intensely along their tracks that lethality relies more on direct ionization to cause damage in DNA and other molecules than on indirect action through ionization of water. The outcome of the interaction of the physicochemical events initiated by ionizing radiation with the biologic system therefore varies with the nature of the radiation and the intracellular milieu, in addition to obvious factors such as dose and dose rate.
Further complexities are that cells sense and respond to radiation damage and this mechanism varies, depending on their biochemical and genetic make-up. Several molecules have been identified by which cells sense damage to DNA (the DNA damage response), and to other intracellular structures and molecules, including mitochondria, membrane lipids, and certain growth factor receptors. Recognition of damage leads to activation of signal transduction pathways aimed at making a coherent and appropriate response to injury. The internal molecular signaling network that exists within a cell as well as the external signals they are receiving (e.g., from hypoxia, cytokines, cell-cell contact, and the extracellular matrix) influence the nature of the response. The resultant radiation-induced pathways can promote cell death or survival, cell cycle arrest or progression, and DNA repair or instability. In other words, the way the cell “perceives” radiation damage plays an important role in determining the final response. Since tumorigenesis requires mutations in molecular pathways that govern cell death, cell cycle, and DNA repair, it follows that genetic alterations associated with cancer frequently affect the response to radiation therapy. It should be noted that similar pathways are often activated in response to stresses other than radiation, including chemotherapy, hyperthermia, oxidative agents, and inflammation. However, radiation differs from these in that it causes a relatively large number of large lesions in DNA that are not only frequently lethal but drive a predominance of pathways triggered by DNA double-strand break formation.
Finally, in addition to molecular and cellular factors that determine intrinsic cellular radiosensitivity, tissue-related and clinical features of radiation exposure add several additional layers of complexity. For example, the number of cells in a tissue capable of regenerating function will be important, as will the way the regenerative potential is distributed as functional subunits within the tissue. Tissue responses may not relate directly to radiation's cytotoxic effects. For example, in tumors, although local control requires elimination of tumor clonogens, in some circumstances vascular damage could be important, especially when irradiation is combined with biologics or chemotherapeutic drugs. Also, irradiation modifies the tumor-host relationship, including interactions with infiltrating cells, such as macrophages and lymphocytes, which have been shown to be able to both promote and inhibit tumor growth. Effects have been described, mainly in vitro, in which the irradiated cell affects the viability or mutability of surrounding “bystander” cells. Such bystander effects may involve more than one mechanism but are presumably, in vivo in normal tissues, a “danger” signaling mechanism for responses to irradiation aimed at tissue healing. Further, some side effects of radiation therapy on
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normal tissues (13) may result from the release of cytokines and other biologic factors or may be associated with remodeling of the normal tissues, rather than cell death per se. For example, late radiation-induced normal tissue fibrosis depends to an extent on cell depletion by radiation, but is more an attempt at a healing response that can be modified by numerous factors, including health status, presence of infection, surgery, injury, and so on.
So, while the initial deposition of energy and subsequent radiochemical events are complete within thousandths of a second following irradiation, a chain of biologic events is initiated that induce programmed cell death or survival, tissue repair and remodeling, all of which depend on the intercellular signaling network, all of which are influenced by systemic and local physiologic conditions. Given the complexity of the biologic condition, it is impossible to predict biologic or clinical outcomes from the amount of physical energy deposited. In other words, biological dose differs from physical dose.
Remarkably, while cells and tissues may respond differently to the same physical dose of radiation, any given tissue appears to respond in a fairly predictable way. The reason for this apparent constancy is that tissue responses are governed largely by cell turnover and the regenerative reserve in the tissue that is generally similar between individuals. Therefore, normal mucosal reactions occur at the same time interval after the start of irradiation and have similar dose-response relationships in most patients. While tumor responses may be more variable than those in normal tissues, certain histologic types of tumors are regarded as more curable by irradiation, and others are not. Reproducible differences in biologic response between tissues are, in fact, exploited for therapeutic benefit. A good example is the use of standard dose fractionation in conventional radiation therapy. This protocol was derived empirically but actually exploits differences in the biologic response between tumor and normal tissues to the same physical dose of radiation. The radiobiologic rationale for the use of dose fractionation in standard radiation therapy has been encapsulated in the 4 “Rs” (reoxygenation, redistribution, repair, and repopulation) (311). This chapter aims to explain how radiobiologic concepts derived from studies dealing with responses within and between normal tissues and tumors are relevant in clinical radiotherapy.

43_02_01

SECTION 43.2
Neoplasms of the Central Nervous System
VICTOR A. LEVIN
STEVEN A. LEIBEL
PHILIP H. GUTIN
Incidence and Classification
Genetic, Molecular, Environmental, Viral, and Other Factors Associated with Central Nervous System Neoplasia
Anatomic and Clinical Considerations
Intracranial Tumors
Spinal Axis
Neurodiagnostic Tests
Neuroimaging
Tangent Screen, Perimetry, Audiometry, and Electroencephalography
Tumor and Cerebrospinal Fluid Markers
Indications for and Interpretation of Cerebrospinal Fluid Examination
Factors That May Produce Clinical Deterioration
Glucocorticoid Use
Surgery
General Considerations
Surgical Planning
Preoperative and Anesthetic Management
Craniotomy for Supratentorial Tumors
Craniotomy for Posterior Fossa Tumors
Stereotactic Tumor Biopsy
Radiation Therapy
General Considerations
Tolerance of the Brain
Tolerance of the Spinal Cord
Central Nervous System Radiotherapy Toxicity Scoring Systems
Tumor Target Volume and Treatment Techniques
Chemotherapy
General Pharmacologic Considerations
Regional Drug Delivery Considerations
Cerebral Astrocytomas
Pathology Classification
Rationale for Surgery
Surgical Principles for Cerebral Astrocytomas
Reoperation for Cerebral Astrocytomas
Radiation Therapy
Chemotherapy
Brain Stem Gliomas
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Chemotherapy
Cerebellar Astrocytomas
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Chemotherapy
Optic, Chiasmal, and Hypothalamic Gliomas
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Chemotherapy
Oligodendrogliomas
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Chemotherapy
Ependymoma
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Chemotherapy
Meningiomas
Clinical and Pathologic Considerations
Surgery
Chemotherapy
Primitive Neuroepithelial Tumors
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Chemotherapy
Medulloblastoma
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Chemotherapy
Pineal Region Tumors
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Chemotherapy
Pituitary Adenomas
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Craniopharyngiomas
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Cerebellopontine Vestibular Schwannomas
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Glomus Jugulare Tumors
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Chordomas
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Hemangioblastomas and Hemangiomas
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Choroid Plexus Papilloma and Carcinoma
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Chemotherapy
Spinal Axis Tumors
Clinical and Pathologic Considerations
Surgery
Radiation Therapy
Chemotherapy
Chapter References
INCIDENCE AND CLASSIFICATION
Available registry data from Surveillance, Epidemiology, and End Results for 1973 to 1990 indicate that the combined incidence of all recorded primary intracranial
and spinal axis tumors is between 2 and 19 in 100,000 per year, depending on age. 1 There is an early peak (3.1 in 100,000) between 0 and 4 years, a trough (1.8 in
100,000) between 15 and 24 years, and then a steady rise in incidence that reaches a plateau (17.9 to 18.7 in 100,000) between 65 and 79 years of age. In general,
the incidence of primary brain tumors is more common in whites than blacks and the mortality is higher in male than female subjects.
The diversity in primary intracranial and spinal axis tumors partly results from the diversity of phenotypically distinct cells capable of transformation into tumors. Table
43.2-1 shows the hypothetical 15 cell types that can give rise to these tumors. Because of changes in classification and reporting of these tumors, the tumor registry
data are not completely accurate. The relative frequency of 15 families of intracranial tumors is given in Table 43.2-2, and the distribution of spinal tumors is shown in
Table 43.2-3.2,3 The most common tumors are those that are derived from glial precursors (astrocytes, ependymocytes, and oligodendrocytes). The existence of
histologically mixed astrocytoma-oligodendroglioma and the extremely uncommon astrocytoma-ependymoma implies that astrocytomas, oligodendrogliomas, and
ependymomas may arise from common stem or progenitor cells. The facts that these tumors arise in different locales within the cranium and the spinal axis and that
various types predominate at different ages suggest that differing molecular and genetic mechanisms may underlie tumorigenesis at different times in the life span.
TABLE 43.2-1. Classification of Primary Intracranial Tumors by Cell of Origin
TABLE 43.2-2. Frequency of Primary Intracranial Central Nervous System (CNS) Tumors
TABLE 43.2-3. Distribution of Primary Spinal Tumorsa
Central nervous system (CNS) tumors are the most prevalent solid neoplasms of childhood, the second leading cancer-related cause of death in children younger
than 15 years of age, and the third leading cancer-related cause of death in adolescents and adults between the ages of 15 and 34 years. However, most intracranial
tumors occur in people older than 45 years. Glioblastoma rarely occurs in people younger than 15 years, but dramatically increases after the age of 45. The incidence
of most glial tumors, other than glioblastoma multiforme, actually decreases with increasing age. There is some concern that the incidence of glioblastoma multiforme
is increasing in the elderly population, 4 although incorrect ascertainment preceding the widespread availability of computed tomography (CT) scans in the late 1970s
and magnetic resonance imaging (MRI) in the 1980s may account for some of the presumed increase in incidence. 5,6 A similar age-related increase in prevalence
occurs with differentiated or benign meningiomas that increase from 0.2% of all primary intracranial tumors in patients younger than 24 years of age to 39% of tumors
in patients older than 65 years.
The overall incidence of primary spinal cord tumors is approximately 15% of that of brain tumors. For gliomas, the age-adjusted incidence is 0.11% to 0.14%; for
meningiomas, 0.08% to 0.28%, depending on sex (female higher than male subjects); and for nerve sheath tumors, 0.07% to 0.13%. 3 As shown in Table 43.2-3, the
frequency of specific spinal cord tumors is strikingly different from that of the brain tumors. Gliomas constitute 46% of primary intracranial tumors while only 23% of
spinal tumors. Unlike brain gliomas, most spinal cord gliomas are ependymomas with a predilection for the cauda equina. Schwannomas and meningiomas account
for approximately 60% of spinal tumors, with schwannomas being slightly more frequent; both types occur most often in adult life. Other less common spinal tumors
are the lipomas, dermoids, and hemangioblastomas.
GENETIC, MOLECULAR, ENVIRONMENTAL, VIRAL, AND OTHER FACTORS ASSOCIATED WITH CENTRAL NERVOUS SYSTEM
NEOPLASIA
In Chapter 43.1, the contribution of genetics and molecular biology to the understanding of CNS tumorigenesis is covered in detail. Less important associations of
CNS neoplasia are those associated with viruses, chemicals, and physical forces.
The epidemiology of primary CNS tumors has provided hints but few definitive observations with respect to environmental or occupational causes. Although brain
tumors can be experimentally induced in a high proportion of rodents by the use of certain chemicals, the association of chemical exposure and brain tumors is limited
to a few occupations. A higher than expected increase in the incidence of brain tumors has been observed as a result of purported exposure to pesticides, herbicides,
and fertilizers, 7 various petrochemical industries,8 and health professions.9 Whether these statistical observations are credible is difficult to determine. Aside from a
known association between vinyl chloride and gliomas, there are no common chemical or environmental threads among these observations. 8 There has also been
concern that electromagnetic fields could account for some glial tumors, although the majority of studies do not support such a conjecture. 10,11 and 12
Viruses have been implicated directly in the development of gliomas only in rats, dogs, and monkeys. In all cases, direct CNS injection of the virus is required. In rats,
the avian sarcoma virus produces glial tumors13; in dogs, Rous sarcoma virus leads to gliosarcomas 14; in owl monkeys, a human polyoma virus (JC virus) produces
glial neoplasms15; and in hamsters, JC virus produces medulloblastomas.16 Although a direct association between virus exposure and CNS tumors has not been
established in humans, patients with primary CNS lymphoma have been observed to have a high incidence of infection with Epstein-Barr virus and evidence of
Epstein-Barr virus in their tumor tissue.17 Common viral exposure could explain the occasional glioma cluster observed in schools and communities. However, it is
extremely difficult to pinpoint mutations due to a virus to validate this hypothesis.
CNS neoplasia, like most cancers, appears to be unassociated with prior trauma. It has been suggested that the incidence of meningiomas is higher in patients with a
prior history of head trauma, but this hypothesis was not supported by a prospective study. 18 Trauma could be a progression event; however, this theory would be
difficult to prove.
The incidence of CNS tumors after treatment for a prior malignancy is small. The literature contains examples of astrocytomas occurring 3 to 7 years after craniospinal
axis irradiation and chemotherapy for acute lymphocytic leukemia and craniopharyngioma 19,20 and 21 unfortunately, none of the reports contains sufficient information to
determine risk assessment. In non-Hodgkin's lymphoma, 2% of 44 second malignancies were an astrocytoma.22 As in the cases discussed previously, no measure of
risk assessment is possible, although such infrequent reporting would suggest that these are uncommon or rare events. Meningiomas have been reported in
association with scalp irradiation for tinea capitis, the risk for meningiomas being as high as 21% in one study. 23,24
For unknown reasons, transplant recipients and patients with acquired immunodeficiency syndrome have substantially increased risks for primary CNS lymphoma but
not gliomas.
ANATOMIC AND CLINICAL CONSIDERATIONS
The clinical presentation of the various tumors is best appreciated by considering the relation of signs and symptoms to anatomy. 25
INTRACRANIAL TUMORS
Intracranial tumors produce symptoms primarily by two mechanisms: mass effect (and increased intracranial pressure), due entirely to the tumor or to the tumor and
surrounding edema, or infiltration and destruction of normal tissue.
General Signs and Symptoms
Typical infiltrative intracerebral tumors, such as the various grades of astrocytoma and oligodendroglioma and some of the more primitive neuroectodermal tumors,
can produce headache, gastrointestinal upset such as nausea and vomiting, personality changes, and slowing of psychomotor function. These may be the only
clinical indications of tumor.
Because headache is a common presenting symptom in patients with intracranial tumor, clinical patterns and their localizing value must be appreciated. Brain
parenchyma does not have pain-sensitive structures, and tumor pain (headache) has been attributed to local swelling and distortion of pain-sensitive nerve endings
associated with blood vessels, primarily in the meninges. Tumors grow at different rates and, therefore, achieve variable size before signs and symptoms occur. But
once a tumor has achieved a critical volume causing compression and displacement of brain, the onset and demise of headache seem to correlate with changes in
intracranial pressure.
Headaches can vary in severity and quality; they often occur in the early morning hours or on first awakening. Patients sometimes complain of an uncomfortable
feeling in the head rather than headache. Although there is not an exact relation between the location of tumor headache and the location of the tumor, some rules
are worth remembering. More often than not, frontal and temporal tumors produce headache in frontal, retroorbital, or temporal regions, whereas infratentorial tumors
tend to produce occipital and retroauricular headache. Occasionally, however, retroorbital headaches are observed with infratentorial tumors.
Gastrointestinal symptoms are common. Patients complain of loss of appetite, queasiness, nausea, and, occasionally, vomiting. Vomiting appears more commonly in
children and in patients harboring infratentorial rather than supratentorial tumors. Although textbooks discuss projectile vomiting as an infrequent generalized
symptom of brain tumors, in these authors' experience, it is common in children but rare in adults. From reports in the literature and discussions with experienced
neurosurgeons, it seems as though there is a lower incidence of vomiting currently compared with past years; this may reflect the fact that patients are diagnosed
earlier than in previous years and receive glucocorticoids that can modify dramatically many of the generalized signs and symptoms of brain tumors.
Sometimes the only presenting symptoms are changes in personality, mood, mental capacity, and concentration. Occasionally, merely a slowing of psychomotor
activity is the antecedent symptom of intracranial tumor. Patients with brain tumors tend to sleep longer at night and nap during the day. These changes in function
and activity often are apparent to the family and the examiner but not to the patient; in other instances, only the patient recognizes the changes in mental function.
None of these symptoms are unique to brain tumors; they could easily be confused with depression, neurasthenia, or other psychological problems.
Focal Cerebral Syndromes
Although fewer than 10% of patients presenting with seizures have a brain tumor as the cause of the seizure, seizures are a presenting symptom in approximately
20% of patients with supratentorial brain tumors. With rapidly growing infiltrative malignant gliomas, they are likely to take the form of focal motor or sensory seizures,
although generalized seizures are also common. In patients with slowly growing astrocytomas, oligodendrogliomas, or meningiomas, generalized seizures may
antedate the clinical diagnosis by months to years. The value of the focal seizure as a means of tumor localization is high, sufficiently so that tumor should be
considered causative until proven otherwise.
The distribution of infiltrative parenchymal tumors in the brain is directly related to the mass of the lobe or region. Frontal tumors occur more commonly than parietal
tumors, which, in turn, occur more often than temporal lobe tumors, and so forth. Anatomic or regional involvement by tumors, although not completely stereotypic as
it is with CNS vascular disease, nonetheless has certain features that distinguish them and help the clinician localize the tumor or, at least, to consider the diagnosis.
The frontal lobe syndrome varies markedly from patient to patient. It can range from personality change to headache and mild slowing of contralateral hand
movements and to contralateral spastic hemiplegia, marked elevation in mood, or loss of initiative and dysphasia (if it is the dominant lobe). Assuming the normal
pattern of left hemisphere dominance, unilateral tumors affecting the right frontal lobe can cause left hemiplegia, slight elevation in mood, difficulty in adapting to new
situations, loss of initiative, and even occasional primitive grasp and sucking reflexes. Left frontal lobe tumors can cause right hemiplegia and nonfluent dysphasia
with or without some apraxia of lip, tongue, or hand movements.
Bifrontal disease, a condition usually associated with infiltrative gliomas and primary CNS lymphomas, can cause varying degrees of bilateral hemiplegia, spastic
bulbar palsy, severe impairment of intellect, lability of mood, dementia, and prominent primitive grasp, suck, and snout reflexes.
Temporal lobe syndromes, like frontal lobe syndromes, can range from symptoms that are detectable only on careful testing of perception and spatial judgment to
severe impairment of recent memory. Homonymous quadrantanopsia, auditory hallucinations, and even aggressive behavior can occur as a result of tumors of either
temporal lobe. Involvement of the nondominant temporal lobe can also result in minor perceptual problems and spatial disorientation. Dominant temporal lobe
involvement can lead to dysnomia, impaired perception of verbal commands, and even a full-blown, fluent Wernicke-like aphasia. Bilateral disease, involving both
temporal lobes, is rare in comparison with the bilaterality of frontal lobe tumors that readily cross through the corpus callosum. This is fortunate, because bitemporal
tumor involvement is devastating. It produces impairment of memory, especially recent memory, and can lead to dementia.
Parietal lobe syndromes affect sensory and perceptual functions more than motor modalities, although mild hemiparesis is sometimes seen with extensive parietal
lobe tumors. Tumors impinging on either parietal lobe can produce a decrease in the perception of cortical sensory stimuli that may vary from mild sensory extinction,
observable only by testing, to a more severe sensory loss with deep tumors that leads to hemianesthesia or other hemisensory abnormalities. Homonymous
hemianopsia or visual inattention also may occur. In addition, involvement of the nondominant parietal lobe can lead to perceptual abnormalities and, in severe cases,
to anosognosia and apraxia for self-dressing. Unilateral dominant parietal lobe tumors lead to alexia, dysgraphia, and certain types of apraxia.
Occipital lobe tumors can produce contralateral homonymous hemianopsia or visual aberrations that take the form of imperception of color, object size, or object
location. Bilateral occipital disease can produce cortical blindness.
The classic disconnection syndromes associated with corpus callosum lesions are seen rarely in patients with brain tumors. Even though infiltrative gliomas often
cross the corpus callosum in the region of the genu or the splenium, the involvement of additional structures complicates neurologic interpretation, obscuring classic
disconnection syndromes. With respect to partial lesions, interruption of association fibers in the anterior part of the corpus callosum usually causes a failure of the
left hand to carry out spoken commands. Lesions in the splenium of the corpus callosum interrupt visual fibers connecting the right occipital lobe and left angular
gyrus, resulting in an inability of patients to read or name colors.
Symptoms related to thalamic tumors vary as a function of tumor size and whether the tumor produces secondary blockage of cerebrospinal fluid (CSF) flow and
hydrocephalus. Occasionally, tumors in the thalamus and, less commonly, in the basal ganglia, can reach 3 to 4 cm in diameter before the patient has symptoms
severe enough to seek medical attention. Patients typically present with headaches resulting from hydrocephalus and increased intracranial pressure secondary to
trapping of the lateral horn of one of the ventricles. In addition or independently, patients can present with a mild sensory abnormality on the contralateral side, which
is detected only by testing of sensory extinction or, rarely, severe neuropathic pain syndrome. Patients may complain of intermittent paresthesias on the contralateral
side; because they are episodic and seizure-like, anticonvulsant drugs are used sometimes and actually may be beneficial. With more involvement of the basal
ganglia, contralateral intention tremor and hemiballistic-like movement disorders can be observed. Thalamic tumors usually do not present in a manner typical of
thalamic strokes, unless bleeding into the tumor has occurred.
Focal Infratentorial Syndromes
The brain stem, composed of the medulla oblongata and the pons, has both nuclear groups and traversing axons. Tumors invading or compressing the brain stem can
produce dire consequences; even a small increase in size (e.g., 1 to 2 mm) may lead to death or devastating signs and symptoms. Tumors can be primarily intrinsic or
intrinsic with exophytic components in the fourth ventricle, peripontine cisterns, or in both locations. Cranial nerve involvement, therefore, can be at the nuclear level
or of the cranial nerve as it leaves the brain stem.
The most common tumor of the brain stem is an astrocytoma (glioma), the initial clinical manifestations of which are palsies involving cranial nerves VI and VII on one
side in 90% of patients. These usually are followed by involvement of long tracts resulting in hemiplegia, unilateral limb ataxia, ataxia of gait, paraplegia, hemisensory
syndromes, gaze disorders, and, occasionally, hiccups. Less commonly, long tract signs precede the cranial nerve abnormalities; this is more likely with confined
intrinsic brain stem lesions.
The midbrain, juxtaposed between the pons and the cerebral hemispheres, encompasses the tectum, the cerebral peduncles, and the cerebral aqueduct. If the
midbrain is involved, obstructive hydrocephalus can occur, producing vomiting, drowsiness, and cerebellar signs. Patients with medullary tumors have a more rapidly
progressive course and are more likely to have deficits in cranial nerves VI (usually late), VII, IX, and X, and dysarthria, personality change, and head tilt. Unlike the
expansive posterior fossa tumors, headache, vomiting, and papilledema occur late. Fourth ventricular tumors, because of their location, tend to produce obstructive
hydrocephalus early in their development. This produces profound headache and vomiting and associated disturbances of gait and balance. With rapidly progressing
lesions, cerebellar herniation may develop.
Tumors of the cerebellum have valuable localizing signs and symptoms. In slowly growing tumors, the initial symptoms may be headache and nausea, which are
caused by increased intracranial pressure, and mild imbalance in gait or ataxia of a limb. In more rapidly growing cerebellar tumors, there may be prominent morning
headache; vomiting; a stumbling gait with frequent falling, nystagmus, and dizziness; and visual symptoms caused by papilledema. Abnormal posturing of the head is
seen often in children but not in adults. In children, the head is tilted back and away from the side of the tumor. Posturing of the head is curious in that it indicates
unilateral cerebellum-foramen magnum herniation. Bilateral sixth cranial nerve palsies are uncommon. Midline lesions in and around the cerebellar vermis lead to
truncal and gait ataxia, whereas lesions in a cerebellar hemisphere lead to unilateral appendicular ataxia, most readily observed in upper extremity movements.
Tumors of the base of the skull, although not particularly common, nevertheless are important because many are curable by surgery. Table 43.2-426 summarizes the
salient clinical features of seven of the more common clinical syndromes.
TABLE 43.2-4. Differential Diagnosis of Tumors at the Base of the Skull
A classic base of skull tumor presentation is that associated with vestibular schwannomas, the most frequent cause of the cerebellopontine angle syndrome. Almost
all such patients have involvement of the auditory or vestibular portions of cranial nerve VIII; fortunately, most patients have little morbidity from surgery. Potential
postoperative complications depend on size of tumor and surgical approach used. The morbidity of surgery can be facial weakness, hypoesthesia of cornea,
disturbance of taste, sensory loss of the face, ataxia of gait, and unilateral appendicular ataxia. Deafness and vestibular dysfunction due to damage to the auditory
and vestibular nerve branches are characteristic of these tumors. Finally, these tumors can attain an extremely large size before they are discovered.
Another group of tumors that present with distinct signs and symptoms is that which occurs in or near the sella turcica. Table 43.2-5 summarizes the location, tumors,
and some of the salient features of sellar and parasellar tumors. 27
TABLE 43.2-5. Clinical Syndromes Associated with Tumors of Sellar Region
Many patients present with defects of the visual field, less commonly with blindness and optic atrophy. The visual field abnormality is usually a partial or complete
bitemporal hemianopsia associated with intrasellar tumors such as pituitary adenomas. With lesions that expand from below the optic chiasm, the upper temporal
quadrants are affected first. Patients can also present with scotomata in either eye. With long-standing, slowly progressive disease, unilateral or bilateral optic atrophy
can be observed. Expansion of tumor may involve the hypothalamus and compression of the third ventricle, leading to obstructive hydrocephalus and signs of
increased intracranial pressure, such as headache and nausea and vomiting.
Some of the pituitary tumors produce secondary signs and symptoms, because they elaborate hormones that create various syndromes of endocrine hyperactivity
(Table 43.2-6). A few pituitary tumors produce no detectable hormones or produce hormones in quantities that assume no clinical significance. Currently, it is
uncommon for patients with endocrine-active tumors to present with large tumors; it is more common for patients with endocrine-inactive tumors to seek medical
attention because of optic chiasmal compression hypopituitarism as a consequence of a large mass. Compression leads to detectable hyposecretion of specific cells,
with production of growth hormone being the most sensitive, followed closely by gonadotropins. Cells producing thyroid-stimulating hormone and corticotrophin are
much more resistant, and their function is impaired only at a later stage of growth.
TABLE 43.2-6. Clinical Syndromes Produced by Endocrine-Activity Pituitary Adenomas
Table 43.2-7 summarizes the differential diagnosis of tumors by location in children and adults. 28
TABLE 43.2-7. Differential Diagnosis of Tumors by Location and Age at Onset of Symptoms
Acute and Life-Threatening Syndromes Caused by Intracranial Tumors
Because the brain and the spinal cord are surrounded by a rigid skull and dural membranes, expanding lesions within or abutting the brain or spinal cord can cause
displacement of vital structures. This can lead, in the brain, to respiratory arrest and death and, in the spinal cord, to paraplegia or quadriplegia.
To understand the sequence of events leading to temporal lobe-tentorial (uncal) herniation and cerebellar-foramen magnum herniation, a visual image of intracranial
anatomy is needed. The tentorium cerebelli forms a rigid tissue partition between the cerebral hemispheres above and the cerebellum and brain stem below. Through
this opening passes the midbrain centrally and cranial nerve III anterolaterally. Immediately lateral to cranial nerve III lies the medial portion of the temporal lobe
called the uncus. An expanding mass lesion situated above the tentorium may displace the uncus medially and inferiorly beneath the tentorium. Table 43.2-8
summarizes the neurologic findings and pathologic causes for the events that constitute the temporal lobe-tentorial herniation syndrome. 29
TABLE 43.2-8. Temporal Lobe-Tentorial (Uncal) Herniation
A rapid increase in the volume of the supratentorial compartment leading to herniation can be caused by many different factors. A rapidly growing glioblastoma can
present in this manner, although it is more usual for it to occur as a terminal or near terminal event after ineffective therapy for the tumor. It can also occur when there
is a dramatic increase in the amount of edema associated with metastasis to the brain or with hyponatremia and hypoosmolar syndromes. The injudicious use of
parenteral hypoosmolar 5% dextrose in water often is sufficient to produce an abrupt increase in brain edema and temporal lobe herniation. The authors of this
chapter also have seen temporal lobe herniation follow a group of shortly spaced seizures. Presumably, the seizures, which are associated with hypoventilation,
produce local hypoxia around the tumor with a resultant increase in brain edema.
Mass lesions in the infratentorial compartment can displace brain tissue upward through the tentorium, but more commonly force brain tissue downward through the
foramen magnum. In this situation, the cerebellar tonsils move caudally through the foramen magnum, and in doing so, wedge against the medulla, causing the
findings summarized in Table 43.2-9.29
TABLE 43.2-9. Cerebellar Foramen Magnum Herniation
Cerebellar-foramen magnum herniation frequently results from, or is contributed to by, obstructive hydrocephalus. In such instances, emergency removal of fluid from
the more cephalad ventricular system may relieve symptoms and be life saving. Surgical intervention is indicated only if the reason for the herniation is treatable. In
the instance of cerebellar-foramen magnum herniation aggravated by acute obstructive hydrocephalus, ventriculoperitoneal shunting is often necessary. Care must be
taken, however, because too rapid a change in the CSF dynamics can lead to a rapid and damaging movement of the brain, which can lead to occlusion of posterior
cerebral arteries and brain stem injury.
These two herniation syndromes lead to death, unless there is prompt intervention. The immediate intravenous administration of hyperosmotic agents, such as
mannitol or urea, and large doses of synthetic glucocorticoids, such as dexamethasone or methylprednisolone, should be given promptly to reduce intracranial
pressure and to avert impending death.
Hemorrhage into a tumor is not as common as might be expected, although the incidence of intratumor hemorrhage may increase because of iatrogenic
thrombocytopenia associated with the current use of chemotherapy in the treatment of brain tumors. Primary tumors that most commonly bleed de novo are
glioblastoma and oligodendrogliomas; of the metastatic tumors, those from the lung, melanoma, hypernephroma, and choriocarcinoma are most likely to be
associated with intratumoral hemorrhage. Signs and symptoms of intratumoral hemorrhage may be temporized by the use of osmotic agents and glucocorticoids, but if
extensive and life-threatening, operation and decompression are indicated. Under no circumstances should a lumbar puncture be performed in any of the acute
herniation syndromes. In fact, lumbar puncture should never be done indiscriminately. The indications for lumbar puncture are discussed in another section of this
chapter (see Neurodiagnostic Tests, later in this chapter).
SPINAL AXIS
To understand the clinical presentation of tumors of the spinal axis, the local anatomy ( Fig. 43.2-1) and how tumors might present with respect to anatomy must be
appreciated. The cranial dura is firmly adherent to the skull (with the exception of dural duplications of the falx and tentorium), and no extradural space normally exists
between dura and skull. An entirely different anatomic relation in the spinal canal accounts for a well-defined extradural space containing epidural fat and blood
vessels. By way of the intervertebral foramina, this extradural space communicates with adjacent extraspinal compartments (e.g., the mediastinum and the
retroperitoneal space). With rare exceptions, extradural tumors are metastatic, reaching the extradural space through intervertebral foramina.
FIGURE 43.2-1. Cross-section of thoracic spinal cord shows relation of spinal nerves to intraspinal tracts.
Tumors arising inside of the dural tube (intradural tumors) may originate within the spinal cord (intramedullary), or they may take origin outside the spinal cord
(extramedullary). The two common extramedullary intradural tumors, neurilemmoma (schwannoma) and meningioma, are attached, respectively, to sensory nerve
roots and to dura and involve the spinal cord by compression.
Neurology of Spinal Cord Tumors
A spinal tumor produces two effects: local (focal) and distal (remote). Local effects indicate the tumor's location along the spinal axis, and distal effects reflect
involvement of motor and sensory long tracts within the spinal cord. Table 43.2-10 summarizes the clinical findings useful in localizing a spinal cord tumor.
TABLE 43.2-10. Clinical Manifestations of Spinal Cord Tumors
Distal effects are common to all spinal tumors sooner or later, and symptoms and signs are confined to structures innervated below the spinal cord level of
involvement. Although neurologic manifestations commonly begin unilaterally, a full-blown Brown-Séquard syndrome of cord hemisection can occur but is rare. More
characteristic are motor changes: weakness and spasticity, if the tumor lies above the conus medullaris, or weakness and flaccidity, if at or below the conus. Typically,
sensory impairment begins distally in the feet. Impairment of bladder function occurs later in tumors above the conus, but may be an early manifestation of tumors in
or below the conus. The upper level of impaired long tract function usually is several segments below the actual site of tumor involvement.
Local manifestations may reflect involvement of bone, with pain constituting the cardinal symptom of metastatic tumors. Involvement of spinal roots produces pain,
sensory impairment, and weakness with atrophy in the appropriate radicular distribution. Less often, involvement of spinal gray matter produced by extensive pressure
from extramedullary tumors or direct damage by intramedullary tumors causes segmental sensory and motor changes.
Historically, tumors at or near the foramen magnum have been diagnosed incorrectly more often than have spinal tumors at any other site, because foramen magnum
tumors can mimic such diverse conditions as multiple sclerosis, amyotrophic lateral sclerosis, and cervical disk disease. The frequency of delayed diagnoses of these
tumors justifies the dictum that MRI is indicated as a diagnostic measure in any neurologic disease that can be accounted for by a lesion at or below the foramen
magnum.
Occasionally, a cervical intramedullary tumor mimics syringomyelia, with dissociated sensory loss, weakness, and wasting in the arms and hands and variable long
tract involvement. In most instances, the clinical presentation of a spinal tumor does not indicate if it is extradural or intradural.
The rate at which symptoms develop can be helpful in distinguishing extradural from intradural tumor, with a history of days to a few weeks characterizing metastatic
extradural tumors, and a longer course, often many months, reflecting the slower growth of intradural tumors. A history of previously diagnosed cancer or other system
involvement also is helpful.