Primary Intracranial Neoplasm

Anatomy

Meninges:

  • Dura mater (also known as the pachymeninges)
    • Tough layer
    • Most external
  • Pia mater
    • Innermost layer
    • Folds into the sulci, indentations, and irregularities of the CNS surface
  • Arachnoid Mater (webbed structure)
    • Between pia and dura mater
    • These two layers (pia-arachnoid)
  • Leptomeninges= Arachnoid+pia mater ( lepto=thin )
  • Falx Cerebri:
    • Dural folds separate the two hemispheres of the cerebrum
  • Tentorium
    • Dural folds that separate the cerebrum from the cerebellum and brainstem

Brain:

  • Size of the brain : 16x14x12 cm
  • Brain volume : 1,300 cm3
  • Weight : 1,300 g ( 800 - 2,000 g)
  • Average thickness of the cerebral cortex : 2.5 mm

The CNS:

  • White matter (60%)
  • Gray matter (40%)

The Sulcus:

  • Central Sulcus
    • Separates the frontal and parietal lobes
    • Ant and Post to Central Sulcus = Rolandic Cortex
      • In front of Central Sulcus
        • Motor Area
        • Control body and face motor
          • This area called HOMONUCLUS
            • Laterally : Face
            • Mesially : Body
      • Posterior to Central Sulcus
        • Sensory Area
  • Sylvian fissure
    • Separates the frontal and temporal lobes
  • Calcarine Sulcus
    • Separates the parietal and occipital lobes

Cerebrum:

** Sensory and Motor:**

  • Start to locate central gyri ( that should be easy )
  • Then think about pre-central gyri area and post-
    • pre-
      • Sensory
    • post-
      • Motor
    • Lateral —> Face
    • Mesial —> Legs

Speech and language:

  • Two regions:
    • Frontal
      • dominant side
        • Motor speeach = Broca
      • just above sylvian fissure
    • Temporal
      • Sensory, or receptive (Wernicke's)
      • Dominant superior temporal gyrus
        • posterior end of sylvian fissure
      • Mesial part of the temporal lobe —> Hippocampus & fornix
        • Associated with short-term memory
  • Primary visual cortex —> medial and inferior surface at the occipital pole

Anatomic Location and Clinical Considerations

~Major symptom categories:
Increase ICP
Neurologic Defecit specific to locatoin
Higher order neurocognitive defecit
Endocrinologic dysfunction
  • Increase ICP
    • Headache
      • Irritation of dura
      • irritation of intracranial vessels ( tumour bulk, edema )
      • obstruction of CSF
        • Obstructive hydrocephalus
      • Cavernous sinus —> pain fibers
    • Nausea, Vomiting
    • Gait and imbalance alteration
    • personality changes
    • somnolence
    • slow psychomotor
    • High ICP get worse during sleep:
      • Recumbency
      • Hypoventilation
  • Neurologic defecit specific to location
    • Seizure
  • Higher order neurocognitive defecit
  • Endocrinologic dysfunction
Symptoms%20and%20Signs.bmp

Frontal tumors

  • Changes in personality
  • Loss of initiative
  • Abulia (loss of ability to make independent decisions)
  • Posterior frontal tumors
    • Contralateral weakness <— affecting the motor cortex
    • Expressive aphasia
      • if dominant (usually left) frontal lobe.
  • Bifrontal disease
    • Butterfly gliomas
    • Lymphomas
    • Memory impairment
    • Labile mood
    • Urinary incontinence.

Temporal tumors

  • Perception and spatial judgment impairment
  • Memory
  • Homonymous superior quadrantanopsia
  • Auditory hallucinations
  • Abnormal behavior
  • Seizure
  • Nondominant temporal tumors
    • Minor perceptual problems & spatial disorientation
  • Dominant temporal lobe tumors
    • Dysnomia
    • Impaired perception of verbal commands
    • Fluent (Wernicke’s-like) aphasia.

Parietal tumors

  • Sensory disorders
    • Stereognosis
    • Hemianesthesia
      • + poor proprioception
      • —> gait instability
  • Homonymous inferior quadrantanopsia
  • Incongruent hemianopsia
  • Visual inattention
  • Nondominant parietal tumors
    • Contralateral neglect
    • Anosognosia
    • Apraxia
  • Dominant parietal tumors
    • Alexia
    • Dysgraphia
    • Apraxia

Occipital tumors

  • Contralateral homonymous hemianopsia
    • Or complex visual aberrations
  • Perception of color, size, or location affected
  • Bilateral occipital tumors
    • Cortical blindness.

Corpus callosum

  • Infiltrative tumour cross the genu or the splenium
    • Classic corpus callosum disconnection syndromes
    • Rare
    • Interruption of the anterior corpus callosum
      • Failure of the left hand to carry out spoken commands
    • Lesions in the posterior corpus callosum
      • Interruption in visual fibers that connect the right occipital lobe to the left angular gyrus
        • Inability to read or name colors

Thalamus tumors

  • Obstructive hydrocephalus
    • Headache
  • Trapping of one lateral ventricular horn
  • Sensory
  • Motor
    • From basal ganglia involvement
  • Aphasia ( if on dominant side )
  • Thalamic pain disorders

Brainstem

  • Pontine glioma is the most common
  • Cranial nerve VI & VII palsies
  • Long tract signs
    • Hemiplegia
    • Unilateral limb ataxia
    • Gait ataxia
    • Paraplegia
    • Hemisensory syndromes
    • Gaze disorders
    • Hiccups!

Midbrain

  • Between the pons and the cerebral hemispheres
  • Eencompasses:
    • Tectum
      • Tectal involvement ==> Parinaud syndrome
        • Also a Pineal region mass make Parinaud Syndrome
    • Cerebral peduncles
      • Contralateral motor impairment
    • Cerebral aqueduct
      • Hydrocephalus.

Parinaud Syndrome

  • Cluster of abnormalities of eye movement and pupil dysfunction
    • Deficiency in upward-gaze
    • Pupillary light-near dissociation (pupils respond to near stimuli but not light)
    • Convergence-retraction nystagmus

Medulla

  • Dysphagia
  • Dysarthria
  • CN IX, X, XII
  • If medullary cardiac and respiratory centers —> fatal
  • Gait and imbalance
  • Cerebellar herniation

Cerebellar tumors

  • Midline, around vermis
    • Truncal and gait ataxia
  • Lateral hemispheric
    • Unilateral appendicular ataxia, usually worst in the arm
  • Abnormal head position, with the head tilting back and away from the side of the tumor, is seen often in children but rarely in adults. * * Bilateral sixth cranial nerve palsies are uncommon and reflect hydrocephalus.

Mass lesions within or abutting the brain or spinal cord can cause displacement of vital neurologic structures. This can lead, in the brain, to herniation syndromes with respiratory arrest and death and, in the spine, to paraplegia or quadriplegia. Subfalcine herniation, usually from a unilateral frontal tumor, is often asymptomatic. In transtentorial (temporal lobe) herniation, the medial temporal lobe shifts into the tentorial notch, compressing cranial nerve III and the ipsilateral cerebral peduncle, resulting in pupillary dilation and lack of response to light. Coma usually follows. In tonsillar herniation, increasing posterior fossa mass effect displaces one or both cerebellar tonsils into the foramen magnum, causing posturing, coma, and respiratory arrest. Both tonsillar and transtentorial herniation are rapidly fatal without prompt intervention.

Hemorrhage into a tumor can also cause acute neurologic deterioration. This is often associated with iatrogenic coagulopathies such as thrombocytopenia due to chemotherapy or anticoagulation therapy for deep venous thrombosis. Primary tumors that most often bleed de novo are glioblastoma and oligodendrogliomas; of the metastatic tumors, lung cancer, melanoma, renal cell cancer, thyroid cancer, and choriocarcinoma most often show hemorrhage.

Lumbar puncture should not be performed in any of the acute herniation syndromes or when herniation is imminent. In fact, lumbar puncture should be avoided in the setting of significantly elevated ICP associated with a brain tumor.

Spinal Axis Tumors
For the clinical presentation of tumors of the spinal axis to be understood, the local anatomy must be appreciated (Fig. 121.2). Intracranially, the dura is adherent to the skull, and there is normally no extradural space. In the spinal canal, the extradural space contains fat and blood vessels. Through the intervertebral foramina, the extradural space communicates with the mediastinum and the retroperitoneum. Nearly all extradural tumors are metastases or locally invasive non-CNS neoplasms (e.g., carcinomas, sarcomas), with direct extension from adjacent vertebral bodies or through the foramina.

Intradural spinal tumors arise from the spinal cord (intramedullary) or from surrounding structures (extramedullary). The two common extramedullary intradural tumors, schwannoma and meningioma, arise from nerve roots and from the dura, respectively. A spinal tumor can produce local (focal) and distal (remote) symptoms, or both. Local effects indicate the tumor’s location along the spinal axis, and distal effects reflect involvement of motor and sensory long tracts within the cord. Table 121.4 summarizes the clinical findings useful in localizing a spinal cord tumor.
Distal symptoms and signs are confined to structures innervated below the level of the tumor. Neurologic manifestations often begin unilaterally, with weakness and spasticity, if the tumor lies above the conus medullaris, or weakness and flaccidity if the tumor is at or below the conus. Impairment of sphincter and sexual function occurs later unless the tumor is in the conus. The upper level of impaired long-tract function usually is several segments below the tumor’s actual site. Local manifestations may reflect involvement of bone (with axial pain) or spinal roots, with radicular pain and loss of motor and sensory functions of the root or roots.

Epidemiology
In 2005 there were an estimated 20,000 new cases of primary CNS tumors in the United States and 13,000 deaths (34), for an incidence of approximately 7.4 per 100,000 persons. The incidence of brain tumors increases with age to reach 50 per 100,000 at ages >75 years (34).
The majority of CNS tumors in adults arise in the supratentorial compartment. Most arise in the parenchyma and the majority of these are high-grade gliomas (34). There is a male preponderance for most brain tumor types except neurinomas and meningiomas; for the latter, the female to male ratio is approximately 2:1 (34). During the 1990s, an increase in tumors among older patients was noted, independent of the increasing percentage of older individuals in our society. This may have been partly due to better detection after the introduction of magnetic resonance imaging (MRI). An increase in incidence of primary CNS lymphoma is most likely due to the increasing numbers of immunosuppressed patients in the setting of human immunodeficiency virus (HIV) and posttransplant use of immunosuppressants (47).
P.719

FIGURE 32.2. The supratentorial parts of the central nervous system (CNS) include the telencephalon (cerebral hemispheres with frontal, parietal, occipital, and temporal lobes) and the diencephalon, with the dominant thalamus nucleus, the hypothalamus, the pituitary stalk, and the neurohypophysis inferoanteriorly and the pineal body posteriorly, which represent the midline central structures of the supratentorial CNS. (From Sobotta/Figge atlas of human anatomy, Vol. 2, 9th ed. Munich: Urban & Schwartzenberg, 1977, with permission.)

FIGURE 32.3. Section through telencephalon and brainstem parallel with the cerebral peduncles. View of the posterior surface of the plane of sectioning. On the right side of the figure, the section reaches back to approximately the middle of the cerebral peduncle (oblique section). I to III indicate thalamic nuclei: I, medial nucleus; II, anterior nucleus; III, lateral nucleus. (From Sobotta/Figge atlas of human anatomy, Vol. 2, 9th ed. Munich: Urban & Schwartzenberg, 1977, with permission.)
P.720

Occupational and environmental exposures have been associated with the development of CNS tumors. Farmers and petrochemical workers have been shown to have a higher incidence of primary brain tumors. A variety of chemical exposures have been linked, as reviewed by Ohgaki and Kleihues (165). The use of cellular phones has been questioned as a contributing factor to the development of brain tumors. Although two studies showed no increased incidence in cellular phone users (99,106), a more recent study found the overall odds ratio highest among individuals with the greatest cumulative lifetime cell phone use (>2,000 hours) (95).
Primary CNS lymphoma has been shown to be associated with Epstein-Barr virus. The majority of primary CNS lymphomas are B-cell large immunoblastic types, and Epstein-Barr virus DNA is identifiable in nearly all cases (100).
Prior exposure to ionizing radiation is a known risk factor for development of primary CNS tumors, particularly meningiomas, but also astrocytomas, sarcomas, and other tumor types (137). There is a 2.3% incidence of primary brain tumors in long-term survivors among children given prophylactic cranial irradiation for acute leukemia; this is a 22-fold increase over the expected incidence (5,157).
Development of intracranial malignancy is also associated with several hereditary diseases such as neurofibromatosis type 1 (characterized by cutaneous neurofibromas, cafรฉ au lait spots, bone abnormalities, and CNS tumors) and neurofibromatosis type 2 (less common, characterized by bilateral seventh nerve acoustic neuromas as well as gliomas, meningiomas, and neurofibromas). Other neurocutaneous syndromes include von Hippel-Lindau disease and tuberous sclerosis. Other hereditary associations are with retinoblastoma and Li-Fraumeni syndrome.
Although the exact nature of the carcinogenic events leading to brain tumor induction is not known, experimental evidence suggests an accumulation of genetic alterations that lead to the acquisition of a malignant phenotype through activation of cellular oncogenes and loss of cellular tumor suppressor genes (164,165).
Natural History
The natural history of a primary brain neoplasm is determined by its histology, grade, and location. The majority of adult gliomas spread invasively without forming a natural capsule. They frequently cause edema in surrounding tissue. This edema may be vasogenic, ischemic, or cytotoxic. It is commonly seen on T2-weighted MRI and is responsible for at least some of the clinical symptoms and signs. The edema is considered to be a consequence of altered bloodโ€“brain barrier (BBB) permeability. Different tumors cause varying amounts of edema (in descending order: metastases, astrocytomas, meningiomas, and oligodendrogliomas).
Some high-grade neoplasms metastasize by โ€œseedingโ€ into the subarachnoid and ventricular spaces and, by gravity or flow, cause metastatic deposits in the spinal canal. Tumors that have a propensity for CSF spread include medulloblastomas, primitive neuroectodermal tumors (PNET), and CNS lymphoma. The exact frequency of CSF spread among other histologies (e.g., germ cell tumors, ependymomas) is debated in the literature. Extracranial metastases from primary brain tumors are rare but can occur with medulloblastomas, germinomas, and high-grade astrocytomas. Peritoneal metastases have occasionally been noted in patients who have had a ventriculoperitoneal shunt placed to relieve obstructive hydrocephalus. The incidence is low and does not preclude shunting patients with obstruction.
Clinical Presentation
The presenting symptoms of a primary brain tumor are typically classified as generalized or focal. Headache is more prevalent in patients with faster growing, high-grade tumors. Seizures are a more common presenting feature in lower grade tumors. Focal neurologic deficits such as weakness, language dysfunction, or sensory loss are seen with low-grade tumors, a consequence of their slower rate of growth. Acute events such as hemorrhage markedly alter the tempo of symptom onset regardless of tumor grade. Table 32.1 summarizes common clinical presentations of the more common CNS tumors.
Because brain parenchyma is anesthetic, headaches associated with brain tumors may be due to increased intracranial pressure or to local pressure on sensitive intracranial structures (mainly dura and vessels). Characteristically headaches associated with increased intracranial pressure occur in the morning. Associated findings may include focal neurologic deficits, motor deficits, behavioral changes, and papilledema. Cushing's triad is classically associated with increased intracranial pressure, but the full triad (hypertension, bradycardia, respiratory irregularity) is seen in only one third of the cases of increased intracranial pressure. Long-standing increases in intracranial pressure may lead to optic atrophy and blindness because of transmission of the pressure to the optic nerves.
Seizures are common in patients with brain tumors, especially those with low-grade neoplasms. Seizure foci most likely originate from the brain adjacent to the tumor nidus. Seizures may be partial (simple, complex, or secondarily generalized) or generalized (tonic clonic, absence).
CSF dissemination of tumor cells should be suspected in patients with neurologic deficits that cannot be attributed to the primary tumor. Lumbar back pain or bowel or bladder dysfunction, for example, may suggest CSF metastasis in the lumbar cistern with involvement of the cauda equina.
Diagnostic Work-Up
The initial work-up of patients with brain tumors must include a complete history and general physical examination. Information obtained from relatives and friends is helpful because many tumors cause mental changes not appreciated by the patient. Inherited diseases associated with brain tumors and history of infections may be indicators of etiology and in the case of hereditary syndromes increase vigilance in surveying for other cancers.
Neurologic examination includes assessment of mental condition (behavior, mood, sensorium, intelligence, thought content, language, insight into own disease), coordination (walking, balance, alternating movement), sensation (pain, touch, vibration, position sense, stereognosis, point discrimination), reflexes (deep, superficial, clonus), motor (strength, tonus, resistance to passive movement), and cranial nerves. Ophthalmoscopy is performed to check for papilledema as a sign of increased intracranial pressure.
In patients with symptoms, signs, or imaging suggestive of systemic involvement, biopsy confirmation of at least one of the metastatic sites is recommended. Solitary brain lesions in adult patients with systemic cancer are far more likely to be a cerebral metastasis than a primary CNS tumor, although this is not always the case.
Imaging Studies
The imaging modality of choice for most CNS tumors is MRI, which can demonstrate neuroanatomy and local pathologic
P.721

processes in exquisite detail. Computed tomography (CT) is generally reserved for those unable (implanted pacemaker, metal fragment, paramagnetic surgical clips) or unwilling because of claustrophobia to undergo MRI.
Table 32.1 Symptoms, Signs, and Diagnostic Characteristics of Various Intracranial Tumors
Tumor Common Symptoms Common Signs Imaging Characteristics
Glioblastoma multiforme Headache, seizure, unilateral weakness, mental changes Focal presentation related to tumor location Enhancing MRI or CT lesion, hypodense interior, often with associated edema
Meningioma Localized headache Focal presentation related to tumor location Enhancing MRI or CT lesion associated with dura
Astrocytoma Headache, seizure, unilateral weakness, mental changes Focal presentation related to tumor location May not enhance on CT or MRI
Cerebral Headache, seizure, unilateral weakness, mental changes Focal presentation related to tumor location
Cerebellar Occipital headache Increased intracranial pressure (i.e., papilledema), abducens and oculomotor nerve deficits; coordination
Brainstem or thalamus Nausea, vomiting, ataxia Increased intracranial pressure (i.e., papilledema), abducens and oculomotor nerve deficits; ataxia May be seen only on MRI
Optic nerve Ocular changes Ocular changes Uniform enhancement on MRI or CT scan
Medulloblastoma Morning headaches, nausea, vomiting Coordination, increased intracranial pressure (i.e., papilledema), abducens and oculomotor nerve deficits Heterogeneously enhancing on MRI or CT, typical lateral location in adults
Ependymoma Morning headaches, nausea, vomiting Coordination, increased intracranial pressure (i.e., papilledema), abducens and oculomotor nerve deficits Heterogeneous enhancement on MRI or CT with or without calcification
Neurilemoma, schwannoma, neurinomas Unilateral deafness, vertigo Ipsilateral acoustic and facial or trigeminal nerve deficits Homogenous enhancing mass on MRI or CT, arising from cranial nerve
Oligodendroglioma Insidious headache, mental changes Focal presentation related to tumor location Heterogeneous lesion that may or may not enhance on MRI or CT, frequently with calcification, cystic regions, or hemorrhage
Lymphoma Focal presentation related to tumor location Focal presentation related to tumor location Homogeneous, intense enhancement on MRI, may have a diffuse or โ€œcotton woolโ€ appearance
Craniopharyngioma Headache, mental changes, hemiplegia, seizure, vomiting, visual impairment Cranial nerve deficits (IIโ€“VII) Mixed cystic, calcified lesion on MRI and CT, arising from suprasellar region
CT, computed tomography; MRI, magnetic resonance imaging
Magnetic Resonance Imaging
The most useful imaging studies are T1-weighted sagittal images, gadolinium (Gd)-enhanced and unenhanced T1 axial images, and T2-weighted axial images. As with CT contrast, the gadolinium leaks into parenchyma in areas with BBB breakdown, and the paramagnetic properties of gadolinium generate increased signal on T1 scans. T1 images usually are better at demonstrating anatomy and areas of contrast enhancement. T2 and FLAIR (fluid-attenuated inversion recovery) images are more sensitive for detecting edema.
Tumor appearance on T1-weighted MRI is similar to that on CT, as are the contrast enhancement patterns. The anatomic definition and image resolution are much better with MRI, however, and tumor volumes are better delineated than with CT, particularly with low-grade neoplasms that do not enhance with the administration of contrast material (Fig. 32.4). Tumor and edema demonstrate increased signal on T2-weighted MRI. The area of increased T2 signal on MRI usually includes the hypodense area on CT, but the MRI typically identifies a larger edema volume than the corresponding CT scan. Although both edema and tumor can be seen to extend along white matter tracts, T2 signal tracking across the corpus callosum is more commonly due to tumor involvement than edema.
Neuraxis Imaging
For neoplasms at high risk of spread to the CSF, staging of the neuraxis is essential. Gd-enhanced MRI of the spine has replaced myelography as the imaging modality of choice. Ideally, neuraxis imaging should be performed before surgery. In the immediate postoperative period, spinal MRI scans may be difficult to interpret because arachnoiditis and blood products in the CSF can mimic leptomeningeal metastasis. Delayed spinal MRI (>3 weeks after surgery), combined with an increased dose of intravenous gadolinium, is a sensitive imaging study for leptomeningeal disease.
Newer Imaging Modalities
Improved MRI technology permits extremely rapid acquisition of sequential MRIs, allowing detailed imaging of tumor perfusion and cerebral blood flow to help clarify tumor architecture. Functional mapping of the cerebral cortex may be possible through measurements of local changes in oxygen consumption with specific tasks. This anatomic identification of functionally eloquent regions of brain parenchyma permits more extensive surgical resection while avoiding injury to these critical areas. Positron emission tomography (PET) also can give information on metabolic and BBB function (Fig. 32.5). MR-spectroscopy
P.722

may better delineate infiltrating tumor from peritumoral edema in the nonenhancing region surrounding the tumor mass. In the future, incorporation of three-dimensional (3D) MRI reconstructions, functional imaging, and metabolic maps may allow a comprehensive assessment of tumor volume and its relationship to the functional normal brain. Such information should facilitate surgical resection and radiotherapy planning. Integration of metabolic scans into posttreatment follow-up may help distinguish between tumor recurrence and treatment-related changes, although most modalities have a relatively high false negative rate (i.e., scan suggests treatment-related changes, but active tumor is actually present).

FIGURE 32.4. Magnetic resonance image of brain showing (A) glioblastoma, demonstrating a contrast-enhancing lesion with central necrosis and vasogenic edema; and (B) low-grade glioma, illustrating a nonenhancing lesion difficult to delineate from normal parenchyma.

FIGURE 32.5. Oligodendroglioma imaged using an anatomical imaging technique, contrast enhanced 3D-SPGR T1-w MRI (top image panel), and a functional imaging technique, FDG PET (bottom image panel). The red contour delineates the extent of increased metabolic activity seen using functional imaging. Looking at the top panel, one can appreciate the fact that if the anatomical image set alone would be used for target definition it would yield a gross underestimation of the target volume as compared with the functional imaging technique.
Histologic Confirmation of Diagnosis
Tissue diagnosis is required for most brain tumors. The morbidity of biopsy has decreased significantly with improvements in operative technique and anesthesia, as well as the availability of stereotactic biopsy techniques. Exception might be made in selected patients, for example, patients with known active systemic cancer and multiple lesions that are radiographically consistent with brain metastases, patients with typical clinical and MRI findings of a brainstem glioma or optic nerve meningioma, or HIV-positive patients with CT or MRI findings consistent with primary CNS lymphoma.
P.723

Table 32.2 Differential Diagnosis of Space-Occupying Lesions on Computed Tomography or Magnetic Resonance Imaging
Pathology Features on CT or MRI
Neoplasm
Primary Solitary, no prior cancer, thick nodular CE
Metastatic Multiple, prior cancer, ++edema, located at gray/white junction
Infectious
Abscess Fever, acutely ill, ยฑsystemic infection, cyst cavity with smooth thin walls and CE
Cerebritis Fever, acutely ill, ยฑsystemic infection, diffuse T2 change, no CE mass
Meningitis Diffuse enhancement of meninges on T1-weighted imaging (may simulate leptomeningeal metastases)
Vascular
Infarct Gray and white matter involvement, wedgelike vascular distribution
Bleeding Homogenous, clears quickly, residual hemosiderin ring
Treatment-related necrosis Central hypodensity, ring CE, edema, >6 mo after radiation therapy or chemotherapy, metabolic scan shows low activity
CE, contrast enhancement; CT, computed tomography; MRI, magnetic resonance imaging
Cerebrospinal Fluid Cytology
CSF cytology is essential for staging tumors with a propensity for CSF spread (e.g., medulloblastoma, PNET, germ cell tumors, CNS lymphoma). Sampling of the CSF in the immediate postoperative period may lead to false-positive results, however, and is best done before surgery or more than 3 weeks after surgery, as long as there is no uncontrolled raised intracranial pressure.
CSF spread of tumor may be associated with several abnormal findings by CSF examination. These include CSF pressure above 150 mm H2O at the lumbar level in a laterally positioned patient, elevated protein level, typically >40 mg/dL, a reduced glucose level (below 50 mg/mL), and the finding of tumor cells by cytologic examination. Tumor markers in the CSF may help in making the diagnosis.
Differential Diagnosis
Most adults with new or persistent neurologic findings (focal deficit, increased intracranial pressure, seizures, altered mentation) are investigated using CT or MRI. Thus, the differential diagnosis of brain tumors usually is reduced to the differential diagnosis of space-occupying lesions (Table 32.2).
Pathology
Primary intracranial tumors are of ectodermal and mesodermal origin and arise from the brain, cranial nerves, meninges, pituitary, pineal, and vascular elements. The nomenclature of brain tumors has changed over time. The most widely used classification system at the present time is that of the World Health Organization (WHO). The WHO classification of primary CNS tumors lists approximately 100 distinct pathologic subtypes of CNS malignancies in 12 broad categories (Table 32.3) (117). Guidelines for assigning grade of malignancy are provided, where applicable.
Molecular Genetics
Gliomagenesis, or the genetic alterations that characterize the malignant transformation of normal glial cells (astrocytes or oligodendroglial cells) into tumor cells, is an area of active investigation. Although still incompletely understood, most of the efforts have focused on astrocytic tumors. These studies demonstrate that astrocytes undergo transformation with the loss of tumor suppressor genes critical for cell growth, differentiation, and function. These genes are TP53, the retinoblastoma (RB) gene, the INK4a (inhibitor of cyclin-dependent kinase 4) gene, and the PTEN gene. In low-grade astrocytomas TP53 is rendered inactive by gene mutation or gene deletion. This critical step in transformation is found in approximately 60% of low-grade gliomas. The progression into anaplastic astrocytoma and glioblastoma multiforme (GBM), here secondary GBM, is accompanied by RB and PTEN mutations with cell aneuploidy and overexpression of cyclin-dependent kinase 4 (CDK4). Most series report that 40% of GBM are secondary GBM and that the average patient age is younger. Some studies report a favorable prognosis for patients with secondary GBM, although this may be related to the impact of younger age and better performance
P.724

status of this group compared with patients with de novo (primary) GBM. Emerging data suggest that promoter methylation of the PTEN gene in low-grade gliomas may be causally linked to secondary malignant transformation to GBM.
In de novo (primary) GBM, the sequence of genetic changes is different, although the phenotype by routine histopathology is indistinguishable. In addition, recent studies suggest that there are major differences in gene expression profiles between primary and secondary GBM with the former demonstrating a mesenchymal or stromal pattern, whereas the secondary genotype is characterized by abnormalities in cell cycle components (250). Primary GBM often (60%) show amplification of the epidermal growth factor receptor (EGFR) with or without expression of the EGFR deletion mutant variant III, deletions in the INK4a gene with loss of p14 and p16, and diploid cells. In addition, PTEN mutation is far more common in primary GBM compared with secondary GBM, approximately 25% versus 4% (164). The loss of heterozygosity in chromosome 10q causes inactivation of PTEN, a gene downstream of focal adhesion kinase (Fak) that controls cell migration and invasiveness. This effect is mediated by activating Akt, a serine/threonine (ser/thr) kinase involved in cell proliferation and survival (138,238). The loss of heterozygosity of chromosome 10 has been shown in several studies to have a highly significant and independent impact on prognosis (164,235,244).
The protein encoded by the RB gene (pRb) regulates the cell cycle by inhibiting progression beyond the G1/S restriction point. Mitogenic signals activate a molecular cascade known as Ras-mitogen activated protein kinase (Ras/MAPK). MAPK inhibits pRb, activates the transcriptional factor E2 F, and cells enter the S phase. The INK4a gene converges on the Rb pathway by activating three cyclin kinase inhibitors (CKIs): p15, p16, and p19. These CKIs inhibit a family of kinases known as cyclin-dependent kinases (CDKs) 2, 4, and 6, triggering cell cycle progression by inhibiting pRb. Thus, although mutation or deletion of the Rb gene is uncommon, alterations in the control of the Rb pathway play a major role in the phenotype of anaplastic astrocytoma and GBM. Similarly, primary mutations in Ras are less common or absent in glial tumors compared with other cancers. However, there is overexpression or constitutive activation of other receptor tyrosine kinases (RTKs) as well as autocrine loops that in turn activate Ras, spawning interest in the modulation of Ras signal transduction cascade as a therapeutic approach (12,59).
Similar cascades exist for other signal transduction molecules. Many factors such as the epidermal growth factor (EGF) and the vascular endothelial growth factor (VEGF) bind to specific tyrosine kinase receptors with downstream effects, resulting in typical final tumor behavior or proliferation, invasion, and angiogenesis. The enhancement in signal transduction pathways can result from overexpression of growth factors, their receptors, or mutations in downstream signaling proteins, leading to constitutive activation or inactivation of negative regulators of the pathway.
General Management
The medical management of patients with brain tumors includes control of increased intracranial pressure, treatment and/or prevention of seizures, and identification and treatment of venous thromboembolic disease.
Cerebral Edema
Glucocorticoids are used before and after surgery and during the early weeks of radiotherapy to control neurologic signs and symptoms due to cerebral edema. Lower doses of steroids (e.g., 2 to 4 mg dexamethasone) twice daily have been shown to be as effective as higher doses. Prolonged steroid use is associated with a number of significant medical problems, such that this medication should be tapered to the lowest dose necessary to control symptoms and discontinued if possible. Dexamethasone is the most common corticosteroid used because of lesser mineral-corticoid effects. As with all corticosteroids, a slow taper is mandatory to prevent a rebound in cerebral edema. The taper may require several weeks, and adrenal function tests may be necessary to determine if physiologic steroid replacement is required.
Seizures
Patients with seizures due to tumor or to treatment-associated necrosis or gliosis require treatment with anticonvulsants. Since first-generation anticonvulsants such as carbamazepine, phenobarbital, and valproate have been shown to induce hepatic cytochrome P450 isoenzymes, markedly increasing the metabolism and clearance of several cancer chemotherapy agents such as paclitaxel and irinotecan (68,78), newer generation anticonvulsants, such as levetiracetam, lamotrigine, and pregabalin that do not affect cytochrome P450 activity are now preferred.
Prophylactic anticonvulsant use remains controversial, although the American Academy of Neurology has concluded that data supporting the use of prophylactic anticonvulsant use do not exist (80).
Surgery
In general terms, surgical procedures can be summarized as biopsy for diagnosis only, surgical resection for cure, surgical debulking for management of mass effect related symptoms, or CSF diversion procedures to relieve acute symptoms caused by increased intracranial pressure or hydrocephalus. Complete resection of tumor is associated with a survival advantage for most tumor types (123,258). However, for some radio- and/or chemosensitive malignancies such as primary CNS lymphoma, aggressive resection is unnecessary, and the surgeon's role is limited to providing diagnostic material.
Operative Technique
CT- and MRI-guidance systems provide surgeons with intraoperative navigation based upon preoperative and/or intraoperative imaging studies. In general, these systems consist of a computer workstation operated by the surgeon into which the relevant imaging studies have been loaded, together with infrared or ultrasound detectors that recognize the 3D orientation and position in space of various tools. Once the patient is registered, the tumor's margins are โ€œvisualizedโ€ below the scalp so that the surgeon can plan the smallest and safest, approach. Resection is assisted by use of the intraoperative microscope and guided by the appearance and consistency of tumor tissue compared with surrounding normal brain. Intraoperative CT, MRI, or ultrasonography can be used to evaluate the completeness of tumor resection. In the case of lesions that are in or near suspected functional cortex, cortical mapping can be performed to localize areas that are critical for motor or speech function. Endoscopy can be used to minimize access for resection of intraventricular lesions or pituitary tumors, as well as for re-establishing pathways of CSF flow, for example, in cases of tumors that have obstructed the cerebral aqueduct, thereby avoiding the need for a CSF shunt.
Stereotactic biopsy is performed by applying the same general principles. With either a stereotactic frame or surface applied scalp fiducials in place, a CT or MRI is performed and the imaging data loaded into an image guidance system. A target
P.725

and entry points are selected and the trajectory is visualized on the computer workstation. The entry point is located on the patient's scalp and a small burr hole or twist drill hole is made. The biopsy needle is oriented using the image guidance system, passed to the appropriate depth, and tissue samples are obtained. Multiple tissue samples may be obtained along the needle tract, until the pathologist can provide intraoperative frozen-section confirmation that adequate tissue has been obtained. The volume of tissue removed during stereotactic biopsy is insufficient to relieve mass effect, and patients who are symptomatic due to mass effect are better treated by craniotomy and resection.
Radiotherapy
Radiobiological Considerations Underlying Tissue Injury
The process of radiation injury in the brain is highly complex and dependent on a variety of factors including dose, volume, fraction size, and the specific target cell population, as well as secondary mechanisms of expression of injury such as vascular leak causing edema, vascular endothelial loss resulting in hypoxic injury, and reactive gliosis. Some structures (e.g., the hypothalamus) appear to be substantially more sensitive to radiation than others (151). Even focal lesions may result in widespread radiographic and/or functional perturbations. The time course for the manifestation of injury can be highly variable and the clinical picture easily confounded with tumor progression. The effect on endothelial cells often becomes manifest as an early T2 signal abnormality on MRI, possibly due to disruption of the BBB and edema formation. Metabolic perturbations observed with PET may reflect demyelination of oligodendroglial cells. Further vascular perturbation and regeneration in response to injury results in an enhancing lesion on imaging. Delayed effects include white matter necrosis and vascular obliteration. The time course can be shortened from several months to a few weeks by increasing the volume of brain irradiated or increasing the fraction size or total dose.
Historically, late injury from radiotherapy has been reported as the โ€œtoleranceโ€ dose at either the 5% or 50% risk level at 5 years (TD 5/5 or TD 50/5). The values for whole-brain fractionated radiotherapy at 2 Gy per fraction are 60 Gy and 70 Gy, respectively. With partial brain irradiation, the corresponding values are 70 Gy and 80 Gy, respectively. Recent studies that have modeled the effect of increasing fraction size on cell survival in late-responding normal tissues suggest that when only a small volume of normal tissue is included in high isodose lines (as in high precision small field radiotherapy), the use of a hypofractionated regimen may be biologically sound, given the advantage of larger fraction sizes in terms of tumor cell kill.
Treatment Delivery
Conventional External-Beam Radiotherapy
Conventional external-beam radiotherapy commonly is started 2 to 4 weeks after surgery to allow for wound healing. Typically a dose of 45 to 60 Gy is delivered in 25 to 30 fractions over a period of 5 to 6 weeks. Fraction sizes >2 Gy generally are avoided because of the higher risk of late CNS toxicity.
The volume of normal brain irradiated to high doses must be minimized. For a small lesion, multiple noncoplanar treatment fields that have unique entrance and exit pathways can be used. The use of intensity-modulated radiotherapy (IMRT) may yield even more conformal dose distributions and better avoidance of organs at risk (226). For larger lesions a vertex field in combination with two wedged lateral fields or a wedge pair to stay off the contralateral hemisphere typically is employed. Patient immobilization devices that limit inter- and intrafraction patient motion as well as daily online imaging, using orthogonal x-ray imaging systems, cone beam CT, or megavoltage CT, all permit use of smaller margins and thereby contribute to limiting the amount of normal brain irradiated (249). Radiotherapy techniques are described in detail below.
Stereotactic Radiosurgery
Stereotactic radiosurgery (SRS) requires a team comprised at a minimum of a neurosurgeon, radiation oncologist, and radiation oncology physicist. SRS can be delivered using a linear accelerator (LINAC) system or a Gamma Knife (Elekta Corp, Stockholm). In LINAC radiosurgery circular collimators ranging from 4 to 40 mm are used to collimate the treatment beam into a circular pencil beam, and treatment is delivered using multiple noncoplanar arcs that intersect at a single point to treat an approximately spherical target of <4 cm in diameter. Newer miniaturized multileaf collimators allow beam shaping. The Gamma Knife is a fixed beam multisource radiation unit containing 201 cobalt-60 (60Co) sources that are collimated using a helmet with circular apertures ranging from 4 to 18 mm that are focused onto a single target point. For irregularly shaped lesions, treatments delivered using either noncoplanar arcs delivered through a single circular collimator or a single collimator helmet lead to the inclusion of a large amount of normal brain and yield inferior conformality. In these cases it is advantageous to use multiple circular collimators or collimator helmets placed on different target points.
Radiation Therapy Oncology Group (RTOG) study 90-05 established the maximum tolerated dose of single faction SRS to be 24 Gy, 18 Gy, and 15 Gy for tumors โ‰ค20 mm, 21โ€“30 mm, and 31โ€“40 mm in maximum diameter, respectively (213).
Fractionated Stereotactic Radiotherapy
For lesions larger than 4 cm and/or located in critical regions, the delivery of a single large fraction treatment as in SRS is not desirable because of a high risk of CNS toxicity. Fractionated stereotactic radiotherapy (FSRT) is a hybrid between conventionally fractionated radiotherapy and SRS that combines fractionation with stereotactic localization and targeting techniques. Various systems for FSRT have been developed, with a reported accuracy between 1 and 3 mm (16,146,269). As for SRS, the use of multiple arcs and circular collimators for irregularly shaped lesions leads to the inclusion of a large amount of normal tissue, and the use of multiple noncoplanar fixed fields each having a unique entrance and exit pathway will be preferable because of better conformality (248,249).
Heavy Charged Particles
Heavy charged particle beams deposit their dose at a depth that depends on their energy over a distance of few millimeters when the heavy charged particles come to rest, the so-called Bragg peak. In order to cover a larger volume, the particle beam can be modulated, in effect adding up multiple Bragg peaks. The very sharp dose gradient at the distal edge permits the use of high-dose radiotherapy for tumors in critical locations, such as at the clivus and base of skull, and provides better normal tissue sparing in other situations, especially, for example, in craniospinal irradiation (116).
Brachytherapy and Radiocolloid Solutions
Selection criteria for brachytherapy include tumor confined to one hemisphere, no transcallosal or subependymal spread,
P.726

small size (<5 to 6 cm), well circumscribed on CT or MRI, and accessible location for the implant. A balloon-based system placed into the cavity at the time of surgery has been employed in the treatment of recurrent malignant gliomas whose largest spatial dimension is <4 cm and are roughly spherical (240). After treatment planning the balloon is filled with a liquid that contains organically bound iodine-125 (125I) and treatment is completed within 3 to 7 days. Direct infusion of radioimmunoglobulins has been used in primary and recurrent brain gliomas (199).
Radiotherapy Techniques
The radiotherapy techniques most commonly employed in the management of CNS tumors are craniospinal irradiation (CSI), whole brain radiotherapy (WBRT), and partial brain irradiation. The indications for each of these techniques are discussed under the sections on the individual tumor types. CSI is a complex technique that requires considerable expertise. It is more frequently used in management of pediatric CNS tumors and is discussed in detail in Chapter 82. Partial brain irradiation is the technique most commonly used for the treatment of adult CNS tumors.
General Concepts
Pertinent Anatomic Landmarks
The skull contains radiographic and surface topographic reference points for appreciation of beam-to-head projection geometry. The external auditory meatus participate in the definition of anatomic reference planes in the head (e.g., Reid's baseline and the Frankfort horizontal plane, connecting points in the two external auditory meatus and one anterior infraorbital edge). Unless marked at simulation, the external auditory meatus may be difficult to see on lateral projections because of the overlying temporal bone structures. The two lateral parts of the anterior cranial fossa, the two anterior parts of the middle cranial fossa floors, and the two mandibular angle points, with their lateral locations, represent appropriate reference points.
In a lateral radiograph, the sella turcica is centrally located and marks the lower border of the median telencephalon and diencephalon. The hypothalamic structures are located an additional 1 cm superior to the sellar floor, and the optic canal runs at most 1 cm superior and 1 cm anterior to that point. The pineal body (or the tentorial notch) usually sits approximately 1 cm posterior and 3 cm superior to the external auditory meatus.
The cribriform plate is the most inferior part of the anterior cranial fossa; it is an important reference point for the inferior border of whole-brain irradiation fields. In most patients, little distance is found between the lateral projections of the lens and the most inferior part of the cribriform plate.
The temporal lobes are situated in the middle cranial fossae, the floor of which is easily identified on lateral radiographs. Individualized blocks should always be used to delineate the field inferior border for WBRT.
On an anteroposterior radiograph with a Frankfort horizontal plane (ear markers and one inferior orbital edge in a horizontal plane), the temporal bones (pyramids) project in the orbits. This implies that the ethmoid sinuses and the sphenoid sinus will project between the orbits, the sella just above these air cavities, and the foramen magnum just below the connection line between the inferior orbital edges. The frontal and occipital lobes therefore project above the orbits, and the temporal lobes and cerebellum in and somewhat below the orbits.
Treatment Setup
The head should be positioned so that its major axes are parallel with and perpendicular to the central axis incident beam and the treatment table. It may be preferable to fully flex or extend the neck in some patients depending on tumor location and choice of beams, although the use of noncoplanar fields and IMRT techniques makes this less necessary.
Reproducibility of head positioning is achieved by using a fixation device. Many commercial and home-built devices are available for this purpose, with a precision ranging from 1 to 5 mm. With the advent of image-guided radiation therapy (IGRT) and intrafraction motion detection, unprecedented accuracy can be achieved in delivering radiotherapy. This permits substantial reduction in margins for setup variability (249).
Target Volume Definition
Two major factors drive margin selection: the inaccuracy of estimating the clinical target volume (CTV) and the specific dosimetric and setup variability components that are institution-specific and determine the planning target volume (PTV). In general, for benign tumors such as meningioma, the gross target volume (GTV) estimate relatively accurately reflects the CTV, and only a minor margin expansion of a few millimeters is necessary, with particular attention to the region referred to as the โ€œtail,โ€ where the distinction between tumor and vasculature can be difficult. For nonenhancing glial neoplasms, WHO grade II and III tumors, the use of FLAIR or T2 abnormality plus a 1 to 2 cm margin is commonly employed for CTV definition. For enhancing high-grade gliomas, a shrinking field approach is utilized: the initial CTV includes the enhancing tumor plus FLAIR or T2 abnormality plus approximately 2 cm, and the boost field the enhancing tumor only plus 2 cm.
Common sense and practice dictates that these CTV expansion margins should not traverse anatomically discontiguous structures or include areas unlikely to be infiltrated by tumor. Inclusion of the bony skull is unnecessary unless direct tumor extension is suspected. With some exceptions, โ€œcompartmental crossingโ€ to the contralateral hemisphere or, for example, into the posterior fossa or the brainstem for a supratentorial cortical tumor, is not necessary.
Ten Haken et al. (243) compared volumetric reconstructions of target volumes with CT or MRI data for 3D treatment planning and concluded that MRI defined larger volumes; on average, increases in block margin were approximately 0.5 cm. Interobserver variation in volume definition was on the order of magnitude of the differences between the CT and MRI. The CT scan defined abnormalities were not always perceptible on the MRI studies, confirming the need for integration of MRI and CT scan data for optimal 3D treatment planning for CNS tumors.
Treatment Techniques
Partial Brain Irradiation
Precise immobilization, employing a mask or other fixation system, is routine. Treatment planning CT scans are used for dose-calculation purposes, but since the majority of CNS tumors are best visualized using MRI, CT-MRI coregistration is performed to enable contouring using the MRI data sets. Most modern treatment planning software allows for CT-MRI coregistration, but physics expertise is required to ensure that the MRI studies are obtained in a controlled and reproducible environment so as not to degrade the anatomic fidelity of the images. The 3D contrast-enhanced STEALTH (Medtronic, Louisville, Co) sequence acquisitions that are commonly employed for intraoperative planning serve well for radiotherapy planning as well. For
P.727

nonenhancing tumors, especially glial neoplasms, the FLAIR sequence and T2 sequences are best for the definition of tumor extent. Such sequences are also helpful for patients with GBM treated with partial brain irradiation since they best demonstrate the extent of any so-called edema. MRI-based planning also permits more accurate identification and contouring of normal dose-sensitive structures, which can be avoided using IMRT or conformal avoidance techniques. The unique and irregular tumor shapes and surrounding normal structures preclude the use of โ€œprescriptive fields.โ€ Multiple field arrangements, using 3D planning sometimes including noncoplanar beam arrangements and IMRT, are recommended.
Three-dimensional conformal therapy is increasingly used in the treatment of both primary and metastatic brain tumors. Significant sparing of normal brain can be achieved using conformal irradiation rather than conventional treatment (246). In the University of Michigan study, a 3D treatment plan reduced the volume encompassed by the 95% isodose by over 50% compared with conventional lateral opposed partial-brain fields. A small series of patients with conformally planned fields to doses of more than 70 Gy have been treated without significant increase in morbidity (132).
The RTOG has recently completed a large trial (RTOG 9803) employing 3D techniques for GBM. Patients (n = 104) were treated with 3D conformal radiotherapy to an initial clinical target volume defined by the resection cavity, residual gross tumor and a margin of 1.5 cm, and 0.3 cm for setup error. The resection cavity, residual gross tumor volume plus 0.3 cm was boosted to a total of 66 or 72 Gy. Grade 3 or greater late radiotherapy toxicity was seen in only three patients: two developed grade 3 brain toxicity after 66 Gy and one had grade 4 brain toxicity after 72 Gy. The 78-Gy dose level is currently being analyzed.
Multiple planar and noncoplanar fields (minimum five to six) encompassing the tumor and surrounding edema with an appropriate margin (PTV), sometimes with the use of static or dynamic wedges and multileaf collimation, can be used to deliver 60 to 64.8 Gy in 1.8-Gy fractions (Fig. 32.6A,B). Marks et al. (140) described some of these techniques and suggested that noncoplanar beams were preferable to coplanar beams when the target was located in the central regions of the head. Soisson et al. (226) analyzed coplanar IMRT versus noncoplanar beams, further validating the value of noncoplanarity for skull base tumors. Three-dimensional and IMRT techniques are especially helpful for cochlear sparing (21).
Whole Brain Irradiation
WBRT is used most often for patients with brain metastases, but also for patients with primary CNS lymphomas and glioblastomatosis cerebrii, and as a component of CSI.
Whole-brain irradiation is administered through parallel-opposed lateral portals. The inferior field border should be inferior to the cribriform plate, the middle cranial fossa, and the foramen magnum, all of which should be distinguishable on simulation or portal localization radiographs (Fig. 32.7). The safety margin depends on penumbra width, head fixation, and anatomic factors, but should be at least 1 cm, even under optimal conditions. A special problem arises anteriorly because sparing of the ocular lenses may require blocking with <5-mm margins at the cribriform plate.
The anterior border of the field must be approximately 3 cm posterior to the ipsilateral eyelid for the diverging beam to exclude the contralateral lens. However, this results in only approximately 40% of the prescribed dose to the posterior eye. A better alternative is to angle the beam approximately 3 degrees or more (100- or 80-cm source-to-axis distance midline, but also field size dependent) against the frontal plane so that the anterior beam border traverses posterior to the lenses (approximately 2 cm posterior to eyelid markers). Placing a radiopaque marker on both lateral canthi and aligning the markers permits individualization in terms of the couch angle. This arrangement provides full dose to the posterior eyes. However, the eyelid-to-lens and -retina topography is individually more constant than the canthus, and lateral beam eye shielding is better individualized with the aid of CT or MRI scans (112). When in doubt about tumor coverage or lens sparing for tumors in a subfrontal or middle cranial fossa location, CT-based contouring and planning should be considered.
With attention to the margin below the cribriform plate, the middle cranial fossa, and the posterior fossa and blocking the eyes, no substantial clinical problems with cataract development, lacrimal gland injury, or isolated relapses at the cribriform plate or in the posterior fossa have been reported.
Craniospinal Irradiation
Traditional CSI techniques utilize opposed lateral cranial fields and one or more posterior spinal fields depending on patient size. The junctioning of noncoplanar fields in the cervical region is potentially hazardous because of the risk of overlap resulting in radiation myelitis. Consequently, great attention needs to be paid to precise immobilization, and a variety of immobilization devices are available for this purpose. Image guidance during radiotherapy can help in ensuring day-to-day reproducibility. The prone position permits direct visualization of the light field from the linear accelerator on the patient thereby allowing daily adjustments of the junctions. However, if anesthesia or sedation are required as may be the case with young children, a supine setup may be considered safer (245). To avoid the risk of dose overlap, two techniques (with numerous variations) are used. In the first, a gap is employed between abutting fields such that the beam edges intersect deep to the spinal cord. This gap could result in a cold spot in a small segment of the spinal cord. If the beam intersection point were raised dorsally, a hot spot would result. The second technique attempts to avoid this problem by using a half-beam technique in which the caudal edge of the brain is matched precisely with the cephalad edge of the abutting spine field without cold or hot spots. This requires collimator angulation and sometimes a couch rotation as well. For both techniques, the use of moving junctions (known as โ€œfeatheringโ€) smooths out any dose inhomogeneity (115). Several studies have demonstrated that adequate coverage of the subfrontal region, posterior fossa, and depth assessment of the cord requires CT-based planning. Given the complexity of CSI, we recommend that it be delivered at centers with adequate staff, experience, and expertise.
With sophisticated techniques such as tomotherapy, it is possible to treat the entire neuraxis in a single setup (7). In recent years, protons as well as IMRT techniques have been used for CSI.
Chemotherapy and Targeted Agents
Conventional Chemotherapy
Many conventional chemotherapy agents do not adequately penetrate brain, while some drugs, despite having a molecular weight and chemical structure that make them appear capable of crossing the BBB, are p-glycoprotein substrates that are actively prevented from crossing into brain parenchyma. Even when drug delivery is adequate, most CNS tumors have proven to be quite resistant to most chemotherapeutic agents. Alkylating agents have been most widely studied, beginning with
P.728

P.729

early clinical trials that used the nitrosoureas, BCNU (carmustine) and CCNU (lomustine). These drugs cross the BBB, but prolonged use is difficult because of cumulative myelotoxicity and the dose-related risk of pulmonary fibrosis. Despite response in 15% to 40% of patients, the impact on survival has been modest at best. Procarbazine has similar efficacy but is better tolerated. Cisplatin and carboplatin have been used as either single agents or in combination regimens. Response rates have been modest and, as with other alkylating agents, their impact on survival is unclear. Topoisomerase I (CPT-11, irinotecan) and topoisomerase II inhibitors (etoposide) have shown only modest activity. Taxanes, such as paclitaxel, have not demonstrated activity as single agents. Temozolomide is a recent addition that is administered orally with excellent bioavailability and a good toxicity profile and has been shown to provide a survival benefit for some glial tumors.

FIGURE 32.6. A: Intensity-modulated radiotherapy treatment (IMRT) plan of a right-sided residual oligodendroglioma (orange) demonstrating tight target coverage and excellent conformal avoidance of critical structures, optic chiasm (red), and pituitary (purple), as evidenced by the dose volume histogram. B: IMRT beam arrangement employed in the IMRT plan shown in (A). Surface renderings of the right-sided residual oligodendroglioma (orange), the optic chiasm (red), the pituitary (purple), and the eyes are shown. The beam arrangement clearly illustrates the principles of geometric avoidance of critical structures.

FIGURE 32.7. Lateral portal localization film of whole brain illustrating adequate inclusion of the cribriform plate and the anterior and middle cranial fossae.
Combination regimens, such as BCNU and temozolomide, have not been shown to be more efficacious (190). This disappointing result is likely the consequence of needing to reduce the dose of each agent because of overlapping myelotoxicity.
Convection-Enhanced Delivery
Methods for circumventing the BBB include intrathecal injection of chemotherapy agents into the CSF space, implantation of slow-release chemotherapy wafers into a tumor resection cavity (22,268), chemotherapy along with pharmacologic or osmotic BBB disruption (60,121), and convection enhanced drug delivery (CED). CED involves the use of intracerebrally implanted catheters to deliver a drug of interest into the brain parenchyma or tumor, at a slow but continuous rate of flow. Unlike diffusion, in which a drug distributes along an exponentially decaying concentration gradient and which is highly dependent upon the size of the drug molecules, drug distribution by CED is less size dependent, occurs over a much larger volume of brain tissue, and results in a more uniform drug concentration (87). Drugs and agents that do not normally cross the BBB are not substrates for the active transporters that constitute the BBB. These are large and/or hydrophilic and are ideal candidates for delivery via CED. Examples of drugs and agents that have been studied for CED include viruses (92), paclitaxel (133), topotecan (110), and a variety of toxins. These toxins are engineered to include a targeting ligand (e.g., interleukin-4 [IL-4], IL-13, tumor growth factor-ฮฑ [TGF-ฮฑ], transferrin) and a genetically altered bacterial toxin that is effective only when internalized by a cell that expresses the target of the ligand (113,202,265,266). Combinations of these agents with chemotherapy and radiotherapy are in early stages of investigation.
Polymer Delivery
BCNU impregnated in a polymer and made into a wafer has been used for local delivery, placed on the walls of the resection cavity at the time of surgery. The wafer slowly undergoes biodegradation, releasing the active drug. This local delivery system has the advantages of minimal systemic toxicity, no limitation posed by the BBB, and delivery of very high local concentrations of chemotherapy. Initial studies in GBM have been promising (22,268).
Targeted Agents
The molecular changes seen in gliomas offer opportunities for targeted therapies. Signal transduction pathways, for example, are often markedly enhanced and may contribute to the cancer phenotypic and biologic changes, and new molecules that block signal transduction pathways are undergoing extensive investigation (197). These include drugs that block angiogenesis (vascular endothelial growth factor receptor [VEGFR]); proliferation, tumor cell invasion, and survival (EGFR); cell survival (platelet-derived growth factor receptor [PDGFR]); as well as inhibitors of downstream signaling molecules such as AKT, Ras, Raf kinase, and mTOR. To date, single agent strategies have shown minimal efficacy, and, since in the molecularly complex situation that characterizes high-grade glioma modulation of a single pathway it is unlikely to result in meaningful or durable tumor responses, clinical trials are now focusing on combination regimens (197).
Follow-Up
The follow-up schedule for the patient with a brain tumor must be frequent enough to check on side effects and to taper steroids shortly after completion of treatment. Periodic CT scans or MRIs are used to detect early evidence of tumor recurrence at a stage when further therapy may be contemplated. Assessment of intellectual functioning and quality of life is important, and patients must be monitored for neuroendocrine and ophthalmologic side effects.
Sequelae of Treatment
Surgery
With appropriate patient selection, diligent surgical technique and use of surgical adjuncts such as speech and/or motor mapping, the rate of complications can be minimized. Even in the best of hands new temporary neurological deficits can be seen in 15% or more of patients, although the rate of permanent new deficits is typically now <5% (242). The incidence and types of deficits seen following surgery depend upon the location of the tumor and the deficits present preoperatively. The most common complications associated with surgery are bleeding and infection, particular in the case of reoperation in a patient who has received prior radiotherapy and/or chemotherapy or when chemotherapy wafers are placed into a resection cavity (142). It has been suggested that the use of linear incisions (as opposed to U-shaped flaps) can help reduce the incidence of incision-related complications, such as infection (42). Posterior fossa resections, particularly in children with medulloblastoma, may
P.730

be associated with posterior fossa syndrome (mutism plus bulbar symptoms). Transient perioperative edema, within about 48 hours of surgery, may be responsible for early postoperative neurologic worsening and can often be mitigated with the use of a short course of high-dose steroid therapy.
Patients with postoperative neurologic deterioration require careful clinical assessment, and in most cases a CT or MRI is required to determine the cause of the deterioration. MRI diffusion weighted sequences can be used to detect the presence of a new infarct. A high index of suspicion should be maintained for postoperative infection because symptoms may be masked by perioperative steroid use, and the headache and fever associated with craniotomy may obscure the classic signs of meningitis.
Radiotherapy
The response of intracranial tissues to radiation has been classically divided into three phases based on the timing of onset of symptoms: acute, subacute, and late.
Acute Toxicity
Transient worsening of pretreatment deficits may develop during the course of treatment, and further acute toxicities may manifest up to 6 weeks following completion of irradiation. These symptoms are believed to be the consequence of a transient peritumoral edema and usually respond to a short-term increase or the institution of corticosteroids. Persistent or refractory symptoms may be caused by tumor progression, and repeat imaging while under treatment may be indicated if the clinical condition worsens despite steroids.
General symptoms such as fatigue, headache, and drowsiness may be seen, especially in individuals treated with large brain fields or with CSI. A mild dermatitis that develops in irradiated areas may be treated with topical agents if necessary. Alopecia within the irradiated areas is common and may be permanent with higher total doses. Nausea and vomiting independent of changes in intracranial pressure may occur, particularly with posterior fossa or brainstem irradiation. Otitis externa can be seen if the ear is included in the irradiation fields, and serous otitis media also may occur. Patients treated with CSI with photons are at risk for mucositis and esophagitis because of the exit dose from the spinal fields through the oropharynx and mediastinum. Hematologic toxicity may also be seen in these patients due to irradiation of the vertebral bodies, a major depot of bone marrow in adults.
Subacute Toxicity
Subacute or โ€œearly delayedโ€ toxicity that develops during the 6-week to 6-month period following irradiation is attributed to changes in capillary permeability as well as transient demyelination due to damage to oligodendroglial cells. Symptoms, which include headache, somnolence, fatigability, and deterioration of pre-existing deficits, usually respond to steroids. The main challenge is to distinguish the clinical and imaging findings from tumor recurrence.
Late Sequelae
Late sequelae of radiotherapy appear from 6 months to many years following treatment and are usually irreversible and progressive. They are thought to be due to white matter damage from vascular injury, demyelination, and necrosis. The pathophysiology of radiation induced neurocognitive damage is complex and involves inter- and intracellular interactions between vasculature and parenchymal cells, particularly oligodendrocytes, which are important for myelination. Oligodendrocyte death occurs either due to direct p53 dependent radiation apoptosis or due to exposure to radiation induced TNF-ฮฑ (29,43). Postradiation injury to the vasculature involves damage to the endothelium leading to platelet aggregation and thrombus formation, followed by abnormal endothelial proliferation and intraluminal collagen deposition (49).
The most serious late reaction to radiotherapy is radiation necrosis, which has a peak incidence at 3 years. Radiation necrosis can mimic recurrent tumor clinically by the reappearance and worsening of initial symptoms and neurologic deficits and radiographically with the development of a progressive, irreversible, enhancing mass with associated edema on imaging. PET, MR-spectroscopy, and nuclear and dynamic CT scanning procedures may aid in the differentiation of radiation necrosis from recurrent tumor. The best treatment for symptomatic necrosis is control of symptoms with steroids followed by surgical debulking, although even after resection necrosis may progress. Other measures include use of corticosteroids with anticoagulation or hyperbaric oxygen, although randomized trials have not shown these to be useful. Although focal necrosis is usually due to radiotherapy alone, diffuse leukoencephalopathy is more commonly associated with the combination of radiotherapy and chemotherapy, particularly methotrexate.
Inclusion of the middle ear may result in high-tone hearing loss and vestibular damage, especially in patients who receive cisplatin. Retinopathy or cataract formation may be seen if the eye is in the radiation field. Optic chiasm and nerve injury may manifest as a decrease in visual acuity, visual field changes, or blindness at doses >54 to 60 Gy. Onset of hormone insufficiency from irradiation of the hypothalamicโ€“pituitary axis is variable but may be seen with doses as low as 20 Gy.
Cranial irradiation can produce neuropsychological changes and neurocognitive impairment; other factors such as tumor-related morbidity, as well as the effects of surgery and chemotherapy, may also contribute (49,127). These changes are thought to be due to interactions between the vasculature and parenchymal cells. Hippocampal-dependent functions of new learning, memory, and spatial information processing appear to be most affected (151). Doses as low as 2 Gy can induce apoptosis in the proliferating cells in the hippocampus (173). Agents such as methylphenidate and memantine may improve neurocognitive function (148).

High-Grade Glioma

Low-Grade Glioma

Ependymoma

Gliomatosis Cerebri
Gliomatosis cerebri is a rare condition with diffuse involvement of multiple parts of the brain (greater than two lobes), sparing neurons and normal structures. On MRI, there is typically diffuse increased signal on T2-weighted and FLAIR images and low or absent signal in the affected areas on T1-weighted images. Treatment remains undefined. Perkins et al. (175) reviewed the treatment outcomes of 30 patients with gliomatosis cerebri treated with radiotherapy at M.D. Anderson Hospital. Transient radiographic improvement or disease stabilization was achieved in 87% of patients with clinical improvement observed in 70%. Patients younger than 40 and those with nonglioblastoma histology had significantly improved overall survival.
In a French trial, 63 patients with gliomatosis cerebri were treated initially with PCV or temozolomide (204). Objective responses were observed in 33% of patients and radiologic responses in 26% with no significant difference between the two regimens. Median progression-free survival and overall survival were 16 and 29 months, respectively. Regardless of regimen, patients with an oligodendroglial component had significantly better outcomes in terms of progression-free and overall survival.
A retrospective review of 296 patients with gliomatosis cerebri from the literature (n = 206) and the Association des Neuro-Oncologues d'Expression Francaise (ANOCEF) network (n = 90) was recently published (237). Median survival was 14.5 months. Patients younger than 42, with better KPS, low-grade histology, or oligodendroglial subtype, had better outcomes. The impact on survival of radiotherapy remained unclear.
Evidence-Based Treatment Summary
Maximal surgical resection is not an achievable goal.
Radiotherapy is considered the standard, but no trials have validated its role.
The role of chemotherapy remains ill defined.
Adult Brainstem Glioma
Brainstem gliomas account for 15% of all pediatric brain tumors (225) but are rare in adults. They can be divided into several distinct types. The diffuse intrinsic pontine tumors are generally high-grade astrocytomas, either anaplastic astrocytomas or GBM, while focal, dorsally exophytic or cervicomedullary are usually low grade and have a much better prognosis. Although rare, other aggressive tumors such as PNETs and atypical teratoid-rhabdoid tumors also occur in the brainstem (26,271). Nonneoplastic processes that may be confused with a primary brainstem tumor include neurofibromatosis, demyelinating diseases, arteriovenous malformations, abscess, and encephalitis.
Diffuse intrinsic pontine glioma remains one of the most challenging brain tumors. Even biopsy is restricted because of the substantial risk of morbidity and mortality. This appears to be as true in the adult population as in children (154). The diagnosis is usually based on a short history of rapidly developing neurologic findings of multiple cranial nerve palsies (most commonly VI and VII), hemiparesis, and ataxia, in combination with the classic MRI finding of diffuse enlargement of the pons with poorly marginated T2 signal involving 50% or greater of the pons (57). Most are nonenhancing. Enhancement, particularly in a focal lesion, may suggest a juvenile pilocytic astrocytoma rather than a high-grade glioma; these lesions should be biopsied.
Treatment
Corticosteroids may be necessary to manage neurologic symptoms until treatment is instituted. Patients with hydrocephalus may require placement of a ventriculoperitoneal shunt. The approach to treatment should be based on the type of brainstem glioma as determined by both the clinical presentation and radiographic findings. Surgery is the treatment of choice for operable lesions (i.e., accessible focal tumors, dorsally exophytic and cervicomedullary tumors). For low-grade tumors amenable to surgical resection, as in other low-grade gliomas, the role of postoperative radiotherapy is controversial and many would advocate close observation. For unresectable low-grade tumors radiotherapy should be delivered using volumes and doses as for low-grade gliomas in other locations.
Involved field radiotherapy is the primary treatment for infiltrating pontine gliomas. The GTV is usually best defined using T2-weighted or FLAIR MRI. A margin of 1 to 1.5 cm is added to create a CTV and further expanded by 0.3 to 0.5 cm to create a PTV. Margins may not need to be uniform in all directions, particularly where bone limits tumor extension. These lesions should be treated with doses on the order of 55.8 to 60 Gy using daily fractions of 1.8 to 2.0 Gy per day. Although radiotherapy provides short-term benefits, long-term results remain dismal. There is no advantage to the use of higher doses given using hyperfractionation. Chemotherapy has no established role. Chapter 82 provides more details as most data on intrinsic pontine gliomas come from pediatric trials.
Fewer data exist with respect to brainstem glioma in adults, but there is some evidence that these tumors may be less aggressive in adults, with overall survival that ranges from 45% to 66% at 2 to 5 years (Table 32.6), perhaps because of a greater frequency of more favorable tumor types (211). In the series from ANOCEF, 48 adult patients with brainstem gliomas were grouped on the basis of their clinical, radiological, and histologic features (89). Nearly half had nonenhancing diffusely infiltrative tumors and had symptoms that were present for more than 3 months. Eleven of these 22 patients underwent biopsy, and nine had low-grade histology. Nearly all underwent radiotherapy and had a median survival of 7.3 years. A second group of 15 patients who had presented with rapid progression of symptoms and had contrast enhancement on MRI were described. Fourteen of these patients underwent biopsy and anaplasia was identified in all 14 specimens. Despite radiotherapy, the median survival in this group was 11.2 months, which approximates the survival in pediatric series.
Evidence-Based Treatment Summary
Surgical resection is indicated for patients with favorable tumor types but is not an achievable goal in patients with intrinsic pontine gliomas.
For intrinsic pontine tumors, radiotherapy is considered the standard. Dose-escalation strategies have been ineffective.
P.740

Table 32.6. Adult Brainstem Glioma Treated with Radiotherapy
Authors (Reference) Adult Patients (Total Patients) RT Dose (Gy) RT Dose per Fraction Overall Survival
Shrieve et al. (222) 19 (60) 66โ€“78 1 Gy b.i. d. 53% (2 y)
Guiney et al. (90) 21 (53) 44โ€“55 1.67โ€“2.25 Gy daily 49% (3 y)
Linstadt et al. (135) 14 66โ€“78 1 Gy b.i. d. 59% (3 y)
Landolfi et al. (124) 19 59.4โ€“72 1.8 daily or 1 Gy b.i. d. 45% (5 y)
Guillamo et al. (89) 48 52โ€“68 (mean dose) 1.8โ€“2.0 Gy daily or 1โ€“1.2 Gy b.i. d. 66% (2 y)
RT, radiotherapy; b.i.d., twice daily
Medulloblastoma
Medulloblastoma is a relatively rare tumor in adults with an incidence of 0.5 per 100,000 (31,34). The majority arise in the 20- to 40-year age group. Adult medulloblastomas are more frequently located laterally than those in childhood (50% vs. 10%), and are more frequently desmoplastic (189). Medulloblastoma is a densely cellular tumor with small, darkly staining ovoid cells with hyperchromatic nuclei and frequent mitoses. Homer-Wright rosettes (clustered cells surrounding a central eosinophilic core) are characteristic. CSF dissemination may manifest as positive cytology or macroscopic seeding of the subarachnoid space and is not uncommon. Systemic spread is seen in approximately 5% of patients, mostly to bone and bone marrow. Shunt procedures have been suggested as a cause, although modern series dispute this (9).
P.741

In children, adverse prognostic factors include male gender and age <3 years (169). Patients with total or near-total resections fare better than those with subtotal resection or biopsy only, and residual tumor >1.5 cm2 on postoperative scans is an adverse prognostic factor. Patients with CSF spread have a worse prognosis. Patients are classified as โ€œaverage riskโ€ if there is <1.5 cm2 residual tumor and no dissemination; patients with >1.5 cm2 residual and/or dissemination are considered โ€œhigh risk.โ€
Treatment
All patients with nondisseminated medulloblastoma should undergo complete resection if feasible. In some cases, extension into the brainstem precludes complete resection without significant morbidity.
Although it is not clear if the biology of adult medulloblastoma is different from pediatric medulloblastoma, long-term survival seems comparable, and in general the treatment guidelines for pediatric medulloblastoma detailed in Chapter 82 should probably be followed. Postoperative radiotherapy should begin within 28 to 30 days following surgical resection whenever possible. Radiotherapy is delivered to the entire craniospinal axis. This is followed by a boost to the entire posterior fossa using parallel-opposed portals or more commonly now posterior oblique fields or other multifield techniques to spare the cochlea. Although there may be less concern over long-term toxicity of full-dose CSI in adults as compared with children, adults treated for medulloblastoma with a mean dose to the whole brain of 35 Gy have been shown to have long-term cognitive deficits (119). It may be reasonable to extrapolate from the pediatric experience and to treat healthy young adults with average risk disease with reduced dose CSI (23.4 Gy) as long as appropriate chemotherapy is administered. The total dose to the posterior fossa should be 54 to 55.8 Gy. However, a note of caution is advised. Many adult patients, particularly those who are โ€œolderโ€ or who have comorbidities, may not tolerate the postradiation chemotherapy as well as their pediatric counterparts, and the long-term outcome in adults treated with reduced-dose craniospinal irradiation and chemotherapy is not known. Full-dose CSI (36 Gy) should be delivered in the setting of high-risk disease. This is then followed by a boost to the posterior fossa as for average-risk disease. Intracranial and spinal metastases should be boosted as well to total doses on the order of 45 to 50 Gy for spinal metastases and 50 to 54 Gy for intracranial metastases. Treatment is usually delivered at 1.8 Gy per day.
The role of adjuvant chemotherapy in children with medulloblastoma is well established but remains unclear in adults. A series of 32 adults with medulloblastoma from Germany has shown a nonsignificant trend to prolonged survival with adjuvant chemotherapy (101). In general treatment in adults should probably parallel that in children, even though as noted treatment may be compromised by poorer tolerance to chemotherapy.
Results of Treatment
The group from University of Californiaโ€“San Francisco reported their experience of adult patients with medulloblastoma between 1975 and 1991 (189). Twenty patients had complete resection, 23 had subtotal resection, and four had biopsy alone. Thirteen patients had dissemination of disease. All patients received CSI and 32 received chemotherapy. The 5-year overall survival rate was 60%. Survival was significantly associated with extent of disease: it was 81% for patients with average-risk disease and 54% for those with high-risk disease. Male patients and those who required a shunt fared worst; longer survival was associated with the use of adjuvant chemotherapy. The majority of relapses, 16/28, had a posterior fossa component.
Frost et al. (75) reviewed 48 patients over the age of 16 years (36 men and 12 women). Complete macroscopic removal was achieved in 22 patients, subtotal removal in 23, and biopsy only in three; 46 patients received CSI and two were treated with local irradiation only. The 5- and 10-year overall survival rates were 62% and 41%, respectively. Significant factors for disease-free survival were stage, functional status at the time of radiotherapy, and absence or presence of hydrocephalus before surgery. Recurrent disease developed in 24 patients, 14 of whom relapsed first in the posterior fossa. Subtotal tumor removal was the only factor predictive of posterior fossa relapse.
Giordana et al. (79) reported on 44 patients older than 18 years of age with medulloblastoma. The overall 5- and 10-year survival rates were 40% and 35.6%, respectively. Factors that predicted a longer survival were age younger than 37 years, decade of diagnosis (1977 to 1990), radiotherapy (50 to 55 Gy to the posterior fossa and 30 to 35 Gy to the spinal canal), and nuclear isomorphism.
A retrospective review of 32 patients 16 years of age or older was reported from Harvard (38). The tumors were located laterally in 19 patients and in the midline in 13. Eight patients had evidence of CSF dissemination. All patients received CSI with a median dose of 36 Gy to the craniospinal axis and 55 Gy to the posterior fossa. Additionally, 24 patients received chemotherapy. The disease-free survival at 5 years was 57%, but importantly, nearly 30% all relapses occurred more than 5 years after treatment. Another interesting finding in this series was the unusual pattern of bone as the only site of relapse in three of eight average risk patients who had received radiotherapy alone. This mirrors an experience from Memorial Sloan-Kettering Cancer Center in which nine recurrences in 45 adults with medulloblastoma involved extraneural sites (177).
The largest series to date of adult medulloblastoma is a retrospective review of 253 patients over the age of 18 treated at thirteen different French institutions between 1975 and 2004. The median follow-up in this series was seven years. On multivariate analysis, brainstem involvement, fourth ventricular floor involvement, and posterior fossa radiation dose <50 Gy were negative prognostic factors. Overall survival was 72 at 5 years and 55 at 10 years. One hundred and twenty-four patients were classified as having average risk disease, and 67 of these received chemotherapy along with CSI. Overall survival was not different between patients treated with full-dose CSI alone and patients treated with CSI doses <34 Gy in combination with chemotherapy. However, it should be noted that this was a heterogenous group of patients, and only 12 of these patients received a spinal dose โ‰ค29 Gy. Thus, long-term outcome of adults treated with reduced-dose CSI to 23.4 Gy and chemotherapy is still unknown (169a).
Evidence-Based Treatment Summary
There are no prospective randomized trials evaluating major therapeutic issues in this disease in adults.
Maximal surgical resection should be performed, where feasible.
Standard treatment consists of postoperative radiotherapy to the craniospinal axis followed by a boost to the posterior fossa.
The use of chemotherapy generally follows the pediatric indications and guidelines.
Primary Central Nervous System Lymphoma
CNS lymphomas comprise <3% of primary intracranial malignancies. Immunodeficiency, either congenital or acquired (organ transplant or HIV disease), is the only known risk factor for the development of primary CNS lymphoma. Nonimmunosuppressed patients present typically in the sixth and seventh decades of life, whereas immunosuppressed individuals more
P.742

commonly present in the third and fourth decades of life. Since the early 1990s, there has been a large increase in the incidence of primary CNS lymphoma, primarily due to patients with acquired immunodeficiency syndrome (AIDS). In patients with a diagnosis of HIV infection surviving longer than 4 years, the frequency may be as high as 10% to 20%, although with the introduction of effective antiviral regimens the incidence of primary CNS lymphoma is decreasing.
The majority of primary CNS lymphomas are B-cell lymphomas of intermediate or high grade. The diagnosis is made after no systemic involvement has found. They typically develop as solitary or multiple periventricular masses in the cerebral hemispheres, although they can also arise in the meninges or the vitreous/retina. They are intensely enhancing on MRI and may have a diffuse or โ€œcotton woolโ€ appearance on imaging. Although on CT or MRI they appear focal, diffuse involvement of the parenchyma is invariably present. Primary CNS lymphomas frequently seed the CSF space either at presentation (16% to 47% reported) or at relapse. Involvement of the vitreous and retina is seen in 15% to 20% of patients. Primary intraocular lymphoma is associated with the subsequent development of CNS lymphoma in up to 80% of patients.
The symptoms and signs of CNS lymphoma are those of any intracranial mass lesions, and the CT or MRI appearance usually suggests the diagnosis. Tissue diagnosis with open or stereotactic biopsy is necessary to rule out other primary or metastatic tumors. Immunohistochemical analysis should be performed to confirm monoclonality and B- versus T-cell type. Staging investigations should include an ophthalmologic assessment to rule out ocular involvement, CSF cytology, complete blood count, Epstein-Barr virus, and HIV serology. Systemic staging (CT of chest and abdomen, bone marrow biopsy) is rarely positive in patients with typical findings of CNS lymphoma, but should be performed if systemic symptoms are present (weight loss, night sweats, fever).
Treatment
The role of surgery is limited to establishing the tissue diagnosis. This is best achieved by stereotactic biopsy; extensive tumor resection offers no survival benefit. Since primary CNS lymphoma often responds dramatically to corticosteroid therapy, corticosteroids should be avoided if possible until after tissue is obtained.
The optimal treatment for primary CNS lymphoma remains controversial. Early reports focused on radiotherapy and given the widespread involvement, whole-brain radiotherapy is required. Median survival with radiotherapy is approximately 18 months (219). RTOG 83-15 reported a local control rate of only 39% with whole-brain irradiation to 40 Gy plus a 20-Gy boost to primary tumor site (46). Unlike non-CNS lymphoma there appears to be a dose response with a threshold between 30 and 50 Gy, with a median of 40 Gy. A study by Bessell et al. (11) comparing two different radiotherapy schedules in patients who had complete response to chemotherapy with CHOD/BVAM (cyclophosphamide, doxorubicin, vincristine, and dexamethasone/BCNU, vincristine, methotrexate, and cytarabine) showed a higher relapse rate and reduced survival rate in patients who received 30.6 versus 45 Gy. This was significant for patients younger than 60.
The combination of radiation and chemotherapy may be superior to radiation alone; 5-year survival rates are 22% to 40% compared with 3% to 26% with radiotherapy alone. Systemic high-dose methotrexate seems to be the most effective agent, with a response rate (partial and complete) of >50% and a 2-year survival rate when combined with radiotherapy of 43% to 73% (184). High-dose methotrexate regimens produce adequate levels of drug in the CSF so that direct instillation of chemotherapy (e.g., using an Ommaya reservoir) into the CSF is not necessary (81).
The commonly used schedule for primary CNS lymphoma in nonimmunosuppressed patients is 40 to 45 Gy to the whole brain. The posterior orbits should be included in the whole-brain fields. In patients with ocular involvement, the whole eye should be treated to 30 to 40 Gy, with shielding of the anterior chamber and lacrimal apparatus after this dose. The frequent association of ocular lymphoma with synchronous or metachronous CNS lymphoma has led to the recommendation of prophylactic brain irradiation in all patients by some investigators. Others recommend only ocular irradiation in the absence of demonstrable CNS disease. CSI has been advocated for patients with documented CSF involvement. However, intrathecal chemotherapy may be equally efficacious and less toxic, with less impact on bone marrow reserve.
For immunosuppressed patients with primary CNS lymphoma, modification of the irradiation dose and schedule may be necessary. Patients with poor prognostic features (low KPS, CD4 counts <200, advanced AIDS) may be treated with an abbreviated course of radiotherapy (e.g., 36 to 40 Gy).
Results of Treatment
Corticosteroids and radiotherapy produce clinical improvement in most patients, but there are few long-term survivors. In a prospective RTOG study in which patients were treated with 40 Gy to the whole brain with a local boost to 60 Gy (161), local control and survival were not significantly improved over previous reports of whole-brain doses of 45 to 50 Gy, suggesting a plateau in radiation response. As in the earlier study, the pattern of failure was predominantly local (60%), with isolated spinal relapse being very uncommon (<5%). Younger age (<60 years vs. >60 years) and higher pretreatment performance status (KPS โ‰ฅ70 vs. KPS <70) were associated with longer survivals (20 to 24 months vs. 4 to 6 months). Overall median survival was 11.6 months, with a 2-year survival rate of 28%.
Long-term results with intravenous and intrathecal methotrexate, cranial radiotherapy, and intravenous cytarabine are encouraging, especially in patients younger than 50 years (5-year survival rate of 60%). In older patients (>50 years), results are poor (5-year survival of rate of <10%) and toxicity is greater with dementia and ataxia in a substantial proportion of patients (67).
Chemotherapy has also been used without radiotherapy or as a means of delaying radiotherapy particularly in patients over age 60 because of the substantial risk of neurologic toxicity associated with the use of combined modality treatment in this patient population (13). Complete responses are typically seen in over 50% of patients. Single agent methotrexate using a dose of 8 g/m2 had a high response rate, but responses were of a relatively short duration with a median progression-free survival of approximately 1 year (6). An intensive combination regimen using methotrexate, cytarabine, a vinca alkaloid and cyclophosphamide, and ifosfamide together with intrathecal chemotherapy resulted in complete response in approximately 60% of patients and median progression-free survival of 21 months. There was a 9% treatment-related death rate (174). High-dose chemotherapy with stem cell rescue has also been tested in patients with newly diagnosed primary CNS lymphoma. An initial report describes 14 patients who responded to initial induction chemotherapy then received intensive chemotherapy with stem cell rescue (1). Progression-free survival was only 9 months.
In patients with immunosuppression and primary CNS lymphoma, results are discouraging, although selected patients (non-HIV immunosuppression, favorable-prognosis patients with AIDS) may have survival comparable with that of nonimmunosuppressed populations when treated in a standard fashion (52).
P.743

Evidence-Based Treatment Summary
Surgical resection is not necessary.
For most patients, whole-brain radiotherapy is considered the standard to a volume that includes the posterior orbits.
High-dose methotrexate-based regimens, generally used in preradiotherapy, have become widely accepted in patients fit enough to tolerate them and appear to be associated with improved survival.
Chemotherapy alone with deferred radiotherapy may be preferred in elderly patients because of substantial risk of neurotoxicity associated with combined chemotherapy-radiotherapy regimens.

Meningioma

Vestibular Schwannoma and Neurofibroma

Hamangioblastoma - Hemangiopericytoma

Oligodendroglioma

Craniopharyngioma