Whenever possible, the evaluation of a brain tumor patient begins with a detailed history focusing on the most common symptoms observed in patients bearing intracranial mass lesions. Headaches are the most common symptom in brain tumor patients, occurring in at least 50% of patients at some point. Classically, brain tumor patients present with headaches that are worse upon waking in the morning and may often be severe enough to wake a patient from sleep. This type of headache is thought to occur as a result of temporary increases in intracranial pressure caused by physiologic elevations in PCO2 common during sleep. Normally, transient increases in PCO2 that occur during sleep do not result in headache. However, in the brain tumor patient, during sleep, the combination of elevated intracranial pressure due to mass effect from the presence of the tumor and cerebral vasodilation due to increased PCO2, causes an additive increases in intracranial pressure, ultimately resulting in headache. Headaches related to elevated intracranial pressure can also occur throughout the day as a result of maneuvers that raise intracranial pressure, such as straining, coughing, or bending over.
More commonly, headaches seen in brain tumor patients are not related to elevations in intracranial pressure. Headaches typically caused by brain tumors occur as the neoplastic process involves intracranial structures containing pain fibers. Unlike the brain parenchyma, the dura is richly innervated with pain fibers and is likely the most common source of headaches in brain tumor patients. Dural irritation is also involved in the pathogenesis of other types of headaches. This pathophysiologic overlap may explain the clinical observation that brain tumor-associated headaches may lack any distinguishing characteristics. Brain tumor patients often describe their headaches as deep and aching but these features are highly variable. These may have been previously misdiagnosed as sinus, tension, or migraine headaches. Headaches in brain tumor patients may also be due to visual difficulties in the setting of direct or indirect (through elevated intracranial pressure) tumor effects on the optic pathways and oculomotor nerves.
A number of attributes of the headaches associated with brain tumors can provide useful diagnostic information. First, brain tumors in patients who present with headaches are more likely to be found in noneloquent or functionally silent areas of the central nervous system. Second, headaches occur more frequently in patients with rapidly growing brain tumors. Rapidly growing brain tumors commonly cause severe headaches from meningeal irritation, hemorrhage within the tumor, and/or obstructive hydrocephalus. Obstructive hydrocephalus is a neurosurgical emergency that must be considered in any brain tumor patient presenting with the acute onset of severe headache. In addition, the location of headaches in brain tumor patients commonly provides localizing information. Brain tumors are usually located ipsilateral to the most severe pain.
Seizures are another common presenting finding in patients with brain tumors. Interestingly, seizures are more common with low-grade gliomas than high-grade gliomas. The incidence of seizures in patients with low-grade glioma is estimated as high as 85%. Seizures are the initial presenting symptom in 9% of patients with metastatic brain tumors and 18% of patients with high-grade glioma. Moreover, 25%-50% of all patients with brain tumors experience seizures at some point in their disease course. While seizures associated with brain tumors can be disabling, they can also lead to early diagnosis, and, therefore early treatment.
The nature of seizure activity may hold diagnostic significance. Subcortical and cortical tumors are more likely to cause seizures than those of deeper structures. Focal seizures with primarily motor phenomena, such as tonic-clonic seizures, often occur as a result of involvement of tumor with the primary motor cortex within the frontal lobe. Temporal tumors resulting in temporal lobe seizures typically have variable manifestations that may make localization difficult. Focal seizures due to parietal lesions may present with language disturbance, somatosensory abnormalities, or vestibular symptoms. Focal seizures caused by brain tumors may be secondarily generalized and may ultimately affect multiple cortical regions, causing variable symptomatology. Status epilepticus also can occur as a presentation of brain tumors.
Syncope, another common presentation of brain tumor, must be distinguished from seizure. There are multiple pathophysiologic mechanisms underlying syncope in brain tumor patients. In patients with tumor burden resulting in chronically elevated intracranial pressure and decreased brain compliance, a sudden additional rise in intracranial pressure may compromise cerebral blood flow, resulting in syncope. Transient increases in intracranial pressure that may result from sneezing, coughing, vomiting, or straining are tolerated in patients with normal physiology but may cause syncope in brain tumor patients. Syncope caused by transient increases in intracranial pressure may represent impending herniation and requires urgent neurosurgical attention.
In addition, there are a number of symptoms that commonly present in association with headache, seizure, or syncope. Nausea and vomiting are present at the initial encounter with at least 40% of patients with brain tumors. Nausea and vomiting may be caused by elevations in intracranial pressure and/or direct tumor involvement of the area postrema in the dorsal surface of the fourth ventricle.
Cognitive decline is common especially in the elderly patient and is often misdiagnosed as Alzheimer’s disease. Cognitive decline may easily be confused with depression and is thought to result from generalized fatigue, loss of appetite, and interest in everyday activities. Frontal tumors frontal masses are commonly associated with cognitive decline. Frontal masses, especially those affecting both frontal lobes may also result in apraxia and urinary retention.
A key component of the interview of the brain tumor patient the past medical and family history. The incidence of central nervous system metastases is increasing due to improved survival in patients with the most common types of solid organ cancers. A family history of brain tumors may suggest a familial cancer syndrome. Among the most common familial syndromes predisposing to brain tumor occurrence include von Hippel–Lindau syndrome, tuberous sclerosis, neurofibromatosis 1 and 2, Turcot syndrome (familial adenomatous polyposis), and Lynch syndrome (hereditary nonpolyposis colorectal cancer).
Physical findings are highly variable depending on tumor location and extent of disease. Nonspecific physical findings can occur with elevated intracranial pressure including papilledema (edema of the head of the optic nerve associated with engorgement of retinal veins) and oculomotor palsy (due to uncal herniation). However, the most helpful physical findings are those that assist in localizing the lesion (Table 36–5). Focal neurologic signs such as muscle weakness are common and when caused by peritumoral edema may be rapidly reversible with the administration of steroids.
Aphasia suggests involvement with cortical language centers located in the dominant frontal or parietal lobe. Aphasic patients may be misdiagnosed with dementia or psychiatric disorders. The diagnosis of brain tumor should be considered in, patients without psychiatric history who develop a psychiatric disorder.
Table 36–5.Brain tumor-localizing signs and symptoms. ||Download (.pdf) Table 36–5. Brain tumor-localizing signs and symptoms.
|Location ||Sign(s) |
|Frontal lobea ||Impaired intellectual function |
| ||Language impairment,b specifically abulia |
| ||Impaired gait |
| ||Personality changes |
| ||Hemiparesisc |
|Dominant temporal lobe ||Aphasia |
| ||Impaired auditory discrimination |
| ||Memory loss |
| ||Contralateral superior quadrantanopia |
|Nondominant temporal lobe ||Seizures |
| ||Visual, auditory, olfactory hallucinations |
| ||Contralateral superior quadrantanopia |
|Uncus ||CN III palsy |
|Parietal lobe ||Impaired sensory perception |
| ||Contralateral inferior quadrantanopia |
| ||Aphasia |
| ||Anosoagnosiad |
|Occipital lobe ||Visual deficits |
|Posterior fossa ||Posterior hcadahcc |
| ||Neck stiffness |
| ||Opisthotonos |
|Brainstem ||Cranial nerve palsies |
| ||Long-tract signs |
|Cerebellopontine angle ||Unilateral hearing loss |
| ||Tinnitus |
| ||Vertigo |
| ||Facial palsy |
| ||Facial anesthesia |
| ||Cerebellar signs |
|Sellar region ||Endocrine abnormalities |
| ||Bitemporal hemianopsia |
| ||CN III palsy |
|Pineal region ||Parinaud syndrome: |
| ||Upgaze palsy |
| ||Ptosis |
| ||Loss of pupillary light reflex |
| ||Retraction-convergence nystagmus |
|Meningeal infiltration ||Cranial nerve palsies |
| ||Diffuse headache |
| ||Meningeal reaction |
Radiographic imaging is performed to confirm the clinical diagnosis of brain tumor. Imaging provides information regarding localization, tumor type and the effect of a lesion on surrounding structures. Due to its wide availability, speed, and affordability, noncontrast CT is commonly the initial screening test for patients with brain tumors. CT is also the test of choice for evaluating the extent of tumor invasion into adjacent bony structures. CT angiography can be helpful in evaluating blood supply to tumors or in evaluating the relationship of blood vessels to the tumor.
Whenever possible MRI of the brain with and without gadolinium-based contrast is performed in the brain tumor patient. Traditional morphologic MRI is performed to assess tumor location, size, cellularity, associated cystic components, associated edema or hemorrhage, necrosis, margins, and invasion into surrounding structures, vascularity, and enhancement. Morphologic data can be used to estimate the WHO grade and suggest the tissue diagnosis of a lesion. However, the gold standard for brain tumor diagnosis remains tissue histology. High-quality contrast MRI images are vital for defining the relationship of tumor tissue to eloquent cortical areas and, consequently an operative plan. In addition, MRI images can be reconstructed to create three-dimensional models that can be used during surgery.
Metabolic MRI or magnetic resonance spectroscopy (MRS) can be used to supplement information obtained from traditional morphologic MRI. MRS is used to compare the small molecule content of tumor tissue and normal surrounding brain tissue. MRS improves the accuracy of brain tumor diagnosis by differentiating brain tumors from lesions that appear similar on routine MRI such as abscesses. In addition MRS detects subtle changes in small molecule content that correlate with tumor grade. In treated brain tumors, MRS enables differentiation between radiation necrosis and residual tumor.
A number of alternative magnetic resonance techniques have clinical application in the imaging of brain tumors. These can enable clinicians to make more accurate preoperative diagnoses and provide information about interaction of tumor tissue with adjacent functional cortical structures. Diffusion MRI characterizes brain tumors based on measurement of molecular mobility and is useful in differentiating tumors from similar-appearing lesions, estimating cellularity, and measuring response to treatment. Perfusion MRI is useful for evaluating tumor angiogenesis, endothelial permeability, and response to treatment. Functional MRI maps functional cortical areas and can be used to create an operative corridor or plan for resection that minimizes risk to eloquent surrounding structures. Similarly diffusion tensor imaging defines the integrity of white matter tracts surrounding a tumor and is commonly used in the planning of both surgical and radiation therapy.
Traditional catheter-based cerebral angiography has both historical and contemporary significance in brain tumor imaging. Cerebral angiography was once used to infer tumor location and morphology by measuring displacement of blood vessels by a tumor. Currently, angiography is used in the context of highly vascular lesions, including some meningiomas and hemangiomas, for preoperative embolization. Embolization of vascular tumors diminishes operative risk and difficulty.
Fifty percent of newly diagnosed brain tumors are primary tumors of glial origin (astrocytes and oligodendrocytes). Glial tumors are stratified in a scale of increasing aggressiveness. Grades one and two are classified as low-grade gliomas whereas, grades three and four are high grade. High-grade gliomas are faster growing and consequently carry a worse prognosis than low-grade gliomas.
Low-Grade Gliomas: Astrocytes, Oligodendrogliomas, and Mixed Gliomas
—Approximately 26% of newly diagnosed glial tumors are astrocytomas and 2% are oligodendrogliomas. Between 1500 and 1800 new low-grade gliomas are diagnosed in the United States each year. WHO grade 1 gliomas are reserved for pilocytic tumors. Pilocytic astrocytomas represent 5.2% of all primary intracranial tumors in adults and 20% of all brain tumors in children younger than 15 years. WHO grade 2 lesions are diagnosed based on their infiltration and tendency to progress to higher grade lesions over time. The most common subtypes of low-grade gliomas include juvenile astrocytomas, diffuse astrocytomas, oligodendrogliomas (representing 6.5%), and mixed gliomas.
The etiology of low-grade gliomas is unknown. Genetic studies suggest that mutation or deletion of the tumor suppressor gene TP53 plays a role in the tumorigenesis of low-grade gliomas. Known oncogenic signaling pathways have consequences on tumor metabolism promoting a cellular switch to aerobic glycolysis. Isocitrate dehydrogenase 1 and 2 (IDH 1 and 2) catalyze the decarboxyation of isocitrate into alpha ketoglutarate. IDH1 and IDH2 mutations are found in 40% glioma (70% of low grade, 50% of grade III, and 5%-10% of primary glioblastoma). The impact of these mutations on low-grade diffuse gliomas remains unclear; however, they offer a robust and independent survival benefit in all tumor grades.
Low-grade astrocytomas occur with peak incidence in the young adult population (most commonly in 20-40s). They originate in white matter regions within the CNS, grow slowly and distort surrounding brain structures. Histologically, there is a modest increase in cellularity, disruption of the normal orderly pattern of glial cells, and elongated nuclei. There is no endothelial proliferation or tissue necrosis. Three histologic subtypes of low-grade astrocytomas include fibrillary, gemistocytic, and protoplasmic.
Oligodendrogliomas occur predominantly within the gray matter of the cerebral hemispheres, are well-circumscribed, calcified, and have a slight predominance for the frontal lobes. Like astrocytomas, they occur predominantly in younger patients with most frequent diagnosis in the third decade of life. Histologically, oligodendrogliomas are characterized by uniform cell density and round nuclei with perinuclear halos appearing as a classic “fried egg” appearance. Oligodendrogliomas rarely show a mutation in TP53. In 1994 a codeletion in the long arm of chromosome 1p36 and the short arm of chromosome 19q13 was shown to predict chemosensitivity and better prognosis.
Radiographically, low-grade gliomas are iso- or hypodense to brain on CT scan and do not enhance with contrast. Calcification is common in oligodendrogliomas. On MRI, low-grade glioma are iso- to hypointense on T1-weighted imaging (T1WI) and typically hyperintense on T2-weighted imaging (T2WI) and are not contrast-enhancing.
The term malignant glioma includes anaplastic astrocytoma (AA), glioblastoma multiforme (GBM), gliosarcoma, and malignant oligodendroglioma (Figure 36–13). There is wide difference in the prognosis, aggressiveness, and response to therapy between the different tumors in this group.
Magnetic resonance imaging of a deep right temporal mass proven to be a high-grade glioma. (A) FLAIR imaging demonstrating a mass with significant surrounding white matter edema. (B) T1-weighted contrast enchanced image demonstrating smaller enhancing portion of the mass.
Malignant astrocytoma, the most common type of adult brain tumor, makes up 15% of all intracranial tumors and 50%-60% of primary brain tumors. While relatively rare, malignant astrocytoma is the fourth most common cause of cancer-related deaths. The incidence of AAs and GBM increases with increasing age. There is little difference in incidence from nation to nation, however, in the United States these tumors are less common among Africans and African Americans.
The majority of malignant gliomas occur sporadically. However, patients with the autosomal recessively inherited, Turcot syndrome have a high rate of malignant glioma (usually medulloblastomas and astrocytomas) in combination with familial adenomatous polyposis. Similarly, patients with tuberous sclerosis and neurofibromatosis type 1 and 2 often develop brain tumors including gliomas.
The most significantly mutated genes in glioblastoma include TP53 (seen in 42% of patients), PTEN (seen in 33%), neurofibromatosis 1 (NF1) (21%), EGFR (18%), PIK3R1 (10%), and PIK3CA (7%). Mutations of TP53 have been identified in the autosomally dominantly inherited Li–Fraumeni syndrome, which results in malignant gliomas in addition to tumors involving breast, blood, bone, and the adrenal cortex. It has recently been suggested that a subpopulation of cells with stem-like properties (cancer stem cells) are present in glioblastoma offering resistance to chemotherapy and radiation.
A hallmark of malignant gliomas is the propensity to invade and migrate along white matter tracts. Invasion increases with increased grade and growth factors such as epidermal growth factor increase this invasion. Autopsy studies show that malignant glioma cells spread through the CSF and extend into and beyond areas on MRI with T2 signal change. Histologically, grade 3 gliomas show mitotic activity and nuclear atypia but no necrosis, while grade 4 tumors have nuclear atypia, mitoses, endothelial proliferation, and areas of necrosis. The radiologic hallmarks of GBM are ring enhancement and areas of central necrosis detected on CT and MRI.
Gangliogliomas are rare tumors found most commonly in patients between the ages of 15 and 20 with a history of seizures. They represent 1% of CNS neoplasms in adults, 7.6% in children. They can be found in any region of the central nervous system, but seem to occur predominantly in the temporal lobes. Gangliogliomas are distinguished histologically from pure gliomas by their mixture of neuronal and glial elements. Calcification is common. Macroscopically, they may appear solid or cystic. They are generally well-circumscribed, cystic tumors that may display a mural nodule projecting into the cyst cavity. Imaging characteristics vary in their enhancement and signal qualities on MRI. Lesions can exhibit cystic or solid components or a combination of both. Tumor calcification is a common imaging feature. Gangliogliomas are typically benign WHO I or II tumors with indolent behavior offering a 93%-98% 5-year survival. Five percent of gangliogliomas, however, are aggressive anaplastic or malignant gangliogliomas WHO grade III-IV based on the presence of increased cellularity, microvascular proliferation, and areas of necrosis.
Brainstem gliomas represent 10%-20% of all CNS tumors in children. Brainstem gliomas are a heterogeneous group with diverse clinical presentations, prognoses, and patterns of growth. They are described as focal, diffuse, cervicomedullary, and dorsally exophytic. Focal tumors are less than 2 cm in size with a well-circumscribed appearance on MRI and no surrounding edema. They are most prevalent in the midbrain and medulla, but can occur at any level in the brainstem. These children typically present with focal cranial nerve deficits and contralateral hemiparesis. Diffuse tumors (diffuse intrinsic pontine gliomas) account for the majority of brainstem gliomas (80%) and commonly arise in the pons. These patients typically present with bilateral cranial nerve deficits, ataxia, and long tract signs. Cervicomedullary brainstem gliomas take their origin from the upper cervical cord and extend rostrally into the cervicomedullary junction and often present with lower cranial nerve deficits and long tract signs. Dorsal exophytic tumors account for 20% of brainstem gliomas and arise from the floor of the fourth ventricle. They are typically sharply delineated from surrounding structures. These patients present with cranial nerve deficits, elevated intracranial pressure, and failure to thrive.
MRI scan has allowed for the recognition of the four classes of brainstem glioma. Even though MRI contrast signal poorly correlates with histologic grade, MRI provides adequate anatomic visualization. Focal tumors are classically well circumscribed and small without infiltration or a significant amount of surrounding edema. Dorsal exophytic tumors arise in the floor of the fourth ventricle and are typically hyopintense on T1-weighted imaging, hyperintense on T2-weighted imaging, and homogenously enhance with gadalinium contrast. Diffuse brainstem tumors are hypointense on T1-weighted images and hyperintense on T2 sequences. Because MRI characteristics for diffuse tumors are highly specific an accurate diagnosis can be made in the majority of cases. Recent literature has shown that the mortality associated with biopsy of brainstem tumors may have been modestly exaggerated. Biopsy is therefore considered in cases of abnormal clinical presentation or imaging.
B. Primitive Neuroectodermal Tumors
Primitive neuroectodermal tumors (PNET) are thought to originate in cells from primitive neural crest. PNET includes medulloblastomas, pinealoblastomas, ependymoblastomas, esthesioneuroblastomas, and neuroblastomas. PNET are more common in children than adults. Medulloblastomas are PNETs within the posterior fossa and account for 20% of childhood brain tumors and 1% of all adult tumors. Medulloblastomas are the most common primary central nervous system tumor in children younger than 18 years old.
Several syndromes result in an increased incidence of medulloblastomas, including tuberous sclerosis, neurofibromatosis, Gorlin syndrome, and Turcot syndrome. Loss of portions of chromosome 17 either through deletions or unbalanced translocation is associated with over 50% of medulloblastomas. Over the past decade, transcriptional profiling of medulloblastomas revealed the existence of 4 distinct subgroups; WNT, SHH, Group 3, and Group 4. WNT medulloblastomas have a classic histology, WNT gene expression signature, and the best prognosis with more than 95% in 5 years. These patients tend to be the least common (10% of cases) and are rarely metastatic. SHH-driven medulloblastomas exhibit a desmoplastic histology (although occasionally large cell or anaplastic are seen). Patients SHH tumors represent an intermediate prognosis with survival ranging from 60% to 80%. Group 3 medulloblastoma have the worst prognosis with 50% metastatic at the time of diagnosis. These tumors exhibit aberrant MYC expression with focal high-level amplifications. Group 4 medulloblastomas account for 40% of cases with an intermediate prognosis similar to the SHH subgroup. Group 4 tumors are driven by the oncogenes MYCN and CDK6 (cyclin-dependent kinase 6). Unlike other subgroups group 4 medulloblastoma predominately affect men and metastases are seen in 30% of cases. These subgroups have reestablished what was previously considered a single tumor entity but are now requiring different therapeutic approaches.
Grossly, medulloblastomas typically occur within the cerebellar vermis and are poorly demarcated, purplish, soft, and friable. Histologically, these tumors are highly cellular, composed of homogenous fields of small, round, blue-cell tumors with hyperchromatic nuclei, minimal cytoplasm, and occasional calcification. Other histologic characteristics of these tumors include varying degrees of neuronal and glial differentiation, Homer Wright rosettes (nuclei surround a clear central area of cell processes indicative of neuroblastic differentiation) are often present and mitotic figures are numerous.
Meduloblastomas are PNET within the posterior fossa. Histologically similar tumors within the pineal gland are pinealoblastomas, and within the supratentorial space are neuroblastomas. Retinoblastomas are histologically similar tumors within the eye, PNET originating from olfactory epithelium are termed esthesioneuroblastomas, and intraventricular PNET are ependymoblastomas.
On CT, medulloblastomas are typically hyperdense, homogenously enhancing, and occasionally cystic. Small areas of calcification can be appreciated on CT. Scattered areas of hemorrhage, necrosis, and calcification can occur. On MRI, medullolastomas are isointense or hyopintense to brain on T1WI, hyperintense to brain on T2WI and intensely contrast enhancing. If medulloblastoma is suspected, MRI of the spine is obtained to rule out metastases. Lumbar puncture should be performed with extreme caution because the majority of children have associated obstructive hydrocephalus.
The pineal gland is bounded ventrally by the quadrigeminal plate and midbrain tectum, dorsally by the splenium of corpus callosum, rostrally by the posterior aspect of the third ventricle, and caudally by the cerebellar vermis. Tumors in this region are usually found incidentally on MRI and are most common in children, making up 3%-8% of pediatric brain tumors. The pineal region has several diverse cell types including glial cells, arachnoid cells, pineal glandular tissue, ependymal lining, sympathetic nerves, germ cells, and remnants of ectoderm. Tumors within this area can therefore be grouped into 4 categories: germ cell tumors, pineal parenchymal cell tumors, glial cell tumors, and other miscellaneous tumors and cysts. In the pediatric population germinomas and astrocytomas are the most common tumor type. Germ cell tumors and pineal cell tumors occur primarily during childhood. In the adult population, pineal tumors are more commonly gliomas and meningiomas.
Germ cell tumors, ependymomas, and pineal cell tumors can metastasize through the CSF causing myelopathic or radiculopathic symptoms. Pineal tumors typically present with symptoms of increased intracranial pressure from obstructive hydrocephalus, direct brainstem and cerebellar compression and endocrine dysfunction. In addition, Parinaud syndrome (upgaze paralysis, convergence-retraction nystagmus, pseudo-Argyll Robertson pupils, eyelid retraction, and conjugate downgaze in the primary position) is associated with pineal tumors.
MRI is the primary diagnostic imaging modality for pineal tumors, but it does not reliably predict tumor histology. In contrast, tumor markers may be useful in the diagnostic process, to determine response to treatment, or as an indicator of early recurrence. Elevation of serum or CSF alpha-fetoprotein (AFP) or human chorionic gonadotropin (HCG) suggests a germ cell tumor. Mildly elevated AFP suggests the presence of a fetal yolk sac tumor. Marked elevation of AFP suggests endodermal sinus tumors while smaller elevations are suggestive of embryonal cell carcinoma or immature teratoma. HCG is often markedly elevated with choriocarcinomas.
Ependymomas were previously thought to arise from the ependymal cells lining the ventricles and central canal of the spinal cord; however, they have recently been shown that radial glial cells are the cells of origin. They occur in both children and adults and 65% occur within the posterior fossa (most commonly in children). Ependymomas are quite rare representing only 6% of all gliomas in adults. However, they are the third most common brain tumor in children (behind pilocytic astrocytomas and medulloblastomas). Three cases per 100,000 children younger than 15 are diagnosed each year with this tumor type.
The etiology of posterior fossa ependymomas is unknown however significant advancements have been made over the past decade on their biological profile allowing the identification of different molecular subgroups. Group A patients have laterally located tumors and younger patients with more than 50% recurrence rate (independent of extent of surgical resection). Group B patients have a slightly more favorable prognosis and older age at diagnosis. Familial cases have also been identified. As with several other primary CNS tumors, these tumors often have loss of heterozygosity of chromosome 22q, which contains the neurofibromatosis 2 (NF2) gene. Patients with neurofibromatosis have an increased incidence of gliomas including ependymomas.
A histologic grading system that correlates with tumor aggressiveness is used to classify ependymomas. Histologically, ependymomas are often characterized by, epithelium-like cells in a rosette pattern, formed by a ring of polygonal cells surrounding a central cavity. Tumors may also exhibit perivascular pseudorosettes, intranuclear inclusions, calcifications, and papillary clusters.
The imaging characteristics of ependymomas are variable, but they are typically isodense to cerebral cortex on noncontrast head CT. Calcifications and cystic components within the tumor are frequent. On MRI the solid portion is typically isointense to gray matter on T1WI and isointense to hyperintense on T2WI.
Cerebral lymphoma involving the brain, spinal cord, or ocular structures can occur either primarily or as a metastasis. The source of premalignant lymphocytes is controversial because the CNS lacks lymphoid tissue. CNS lymphoma occurs most commonly in severely immunocompromised patients where it is commonly associated with Epstein–Barr virus infections. CNS lymphoma represents 1% of intracranial tumors with a steady increase in prevalence over the past 20 years. The increase in CNS lymphoma is likely secondary to the increased number and longer lifespan of patients with acquired immunodeficiency syndrome (AIDS) and immunosuppression after organ transplantation. Interestingly, the incidence of CNS lymphoma has steadily increased in immunocompetant patients with an increase from 2.5 to 30 cases per 10 million. Deletions of DKN2A are frequently reported in CNS lymphoma.
Macroscopically, primary CNS lymphomas occur within the parenchyma, subependyma, or meninges and can be either circumscribed or irregular. Microscopically, they exhibit diffuse perivascular distribution and infiltrate the walls of blood vessels (perivascular cuffing). The tumor cells are similar in histology to systemic non-Hodgkins lymphoma cells. Primary CNS lymphomas are monoclonal B-cell lymphomas of diffuse large cell or large cell immunoblastic variant. Anti-CD45 antibody staining differentiates CNS lymphoma from other tumor types.
On CT, CNS lymphomas are typically hyper- or isodense to brain with strong contrast enhancement. On MRI, these tumors are usually isointense or hypointense on T1WI, hyperintense on T2WI and display varying degrees of gadalinium enhancement. Low-volume lumbar puncture performed during the workup of CNS lymphoma may reveal high protein, low glucose pleocytosis. While CSF cytology may be diagnostic, stereotactic brain biopsy is often needed for definitive diagnosis.
The most common tumors of the choroid plexus include choroid plexus papillomas. Choroid plexus carcinomas are rare. Choroid plexus papillomas are most prevalent in patients less then 2 years old and account for less than 1% of all intracranial tumors. Presenting symptoms result from elevated intracranial pressure due to hydrocephalus, and mass effect from tumor growth.
Meningiomas are typically benign, slow growing extra-axial tumors arising from the arachnoid cap cells of the meninges (Figure 36–14). They can originate wherever arachnoid is present. They are characterized by either their location, or histopathology, and are commonly located along the falx, cortical convexity, and sphenoid bone.
Sagittal MRI image demonstrating a contrast enhancing dural-based lesion (arrow) proven to be a meningioma at time of resection.
Menigniomas account for 15%-19% of primary brain tumors and as many as 3% of the population older than 60 years have an intracranial meningioma on autopsy. Their incidence increases with age and peaks by 45 years of age. There is a female-to-male ratio of 2:1.
Inactivation of the NF2 gene found on the long arm of chromosome 22 (22q12.3) is the main genetic event associated with the development of meningiomas. Loss of one copy, truncated, or mutations toward the 5′ end of the NF2 gene occurs in up to 80% of sporadic meningiomas and all patients with neurofibromatosis type 2. Consequently, NF2 patients are more likely to develop intracranial meningioma of varying types. Chromosome 22q contains the NF2 tumor suppressor gene, Merlin.
There are multiple histologic subtypes of meningioma, but they are typically characterized by the presence of densely packed sheets of cells (similar to appearance of normal arachnoid cells), psammoma bodies (whorls of calcium and collagen), intranuclear cytoplasmic pseudoinclusions, and Orphan Annie nuclei (nuclei with central clearing from peripheral migration of chromatin). Radiographically, meningiomas are hyperdense to brain and a broad dural attachment can often be identified. On T2-weighted MRI, most meningiomas are hyperintense and are typically contrast enhancing on both CT and MRI.
H. Nerve Sheath Tumors and Acoustic Neuromas
Nerve sheath tumors are benign tumors of Schwann cell origin that involve predominantly the fifth, seventh, eighth, and tenth cranial nerves. The most common, vestibular schwannomas (aka acoustic neuromas, AN) originate in the internal auditory canal from the inferior or superior portion of the vestibular nerve at the junction of the central and peripheral myelin. The three most common presenting symptoms include insidious hearing loss, high-pitched tinnitus, and disequilibrium.
AN account for 8%-10% of all intracranial tumors in adults. Most ANs are unilateral, however, patient with neurofibromatosis type 2 commonly have bilateral AN. AN is believed to result from the loss of a tumor suppressor gene located on the long arm of chromosome of 22.
Macroscopically, ANs are lobular, encapsulated, and solid with grayish colored material. Surrounding cranial nerves are often stretched over the capsule of the tumor. Microscopically, these tumors are identical to peripheral schwannomas. They are comprised of Antoni A and Antoni B fibers. Antoni A fibers are dense, narrow, elongated bipolar cells with numerous nuclei and firm cytoplasm. Antoni B fibers are a loose reticulated semi-palisading arrangement of Schwann cells.
CT is useful for distinguishing tumor extension into the bony internal auditory canal. On MRI, ANs are isointense on T1WI without contrast. With gadalinium enhancement they are often homogenously enhancing. The lack of a dural tail, differentiates AN from cerebellopontine angle meningiomas.
Pituitary adenomas are benign tumors originating from the anterior pituitary gland and represent 10% of intracranial tumors diagnosed. They are most commonly diagnosed between 40 and 50 years of age. They are classified according to their endocrine function or histological staining. Secreting tumors release supraphysiologic levels of hormones that result in distinct clinical syndromes. Hypersecretion of prolactin causes amenorrhea-galactorrhea syndrome in women and impotence in men. Hypersecretion of adrenocorticotropic hormone (ACTH) causes Cushings disease. Hypersecretion of growth hormone causes acromegaly in adults and gigantism in children. Pituitary adenomas can hypersecrete thyrotropin (producing hyperthyroidism) or gonadotropins (leutinizing hormone and follicle stimulating hormone).
Pituitary tumors may exert mass effect on adjacent structures. Optic chiasm compression results in bitemporal hemianopsia. Compression of the pituitary gland itself results in varying degrees of hypopituitarism. Compression upon the cavernous sinus causes ptosis, facial pain, and diplopia from pressure upon cranial nerves III, IV, V1, V2, and VI. Occlusion of the cavernous sinus may cause proptosis and chemosis.
J. Metastatic Brain Tumors
Metastatic brain tumors originate in from malignancies outside of the CNS that have spread to the brain or spinal cord (Figure 36–15). They are most common brain tumor with a yearly incidence of 100,000-200,000 cases per year in the United States. Autopsy studies show that 20%-25% of patients with cancer have brain metastasis. Metastases occur more frequently in adults in their fifth to seventh decades of life. The most common primary tumors in adults giving rise to CNS metastases are lung, breast, skin, renal, and colon cancers. In children, leukemia and lymphoma, osteogenic sarcoma, and rhabdomyosarcoma are the most common primary tumors that spread to the CNS.
Sagittal MRI image demonstrating multiple contrast enhancing lesions (arrows) in the infra- and supratentorial spaces. Biopsy demonstrated metastatic adenocarcinoma.
Histopathology of metastases mirrors that of the primary tumor. MRI is more sensitive than CT in detecting metastases. Metastases are typically seen at the gray-white junction and show varying degrees of contrast enhancement.
The differential diagnosis of intracranial masses is narrowed through a detailed history and physical exam. Important considerations include patient demographics, chronology of symptoms, past medical history, and specific neurologic deficits. Once imaging is obtained, the list of possible diagnoses can be further refined, as the location of a lesion can suggest its nature. For example, the three most common posterior fossa tumors of childhood include astrocytoma, medulloblastoma, and ependymoma. The most common tumors of the cerebellopontine angle include meningioma, acoustic neuroma, and epidermoid cyst. In addition the pattern of contrast enhancement and whether the lesion appears to arise from within the brain parenchyma or meninges are important considerations in generating an accurate differential diagnosis.
A. Preoperative Medical Management
With few exceptions, surgery is the backbone of the current treatment of brain tumors. The success of surgical intervention depends on adequate preoperative medical management and surgical planning. Steroids are commonly used preoperatively to reduce the symptoms of mass effect and edema caused by the tumor. The timing and dose of steroids varies based on surgeon preference. A common regimen for adults is dexamethasone 6 mg IV or PO every six hours. If mass effect is profound, doses as high as 20 mg every four hours may be considered. Some surgeons believe that it is easier to resect a tumor when peritumoral edema is minimized by preoperative decadron administration.
The use of anticonvulsants in brain tumor patients at presentation, preoperatively, and postoperatively is somewhat controversial. Without question, patients presenting with seizures attributed to a brain tumor should be initiated on an anticonvulsant. However, with few exceptions, there is no data to suggest prophylactic use of anticonvulsants reduces the risk of new onset seizures in brain tumor patients. Among the exceptions are: (1) tumor involvement in highly epileptogenic areas such as the motor cortex, (2) low-grade gliomas, which carry a high risk of seizures, (3) patients with metastatic lesions that commonly invade the cortex, and (4) patients with both metastases and leptomeningeal spread.
Because of a favorable toxicity profile and cost, phenytoin is the first line antiepileptic agent. Phenytoin may cause GI upset and should be administered with a H2 blocker or proton-pump inhibitor. Phenytoin levels must be monitored to ensure a therapeutic serum drug concentration. Leviteracetam is an alternative used for patients if there is potential for drug interactions related to induction of the P450 system by phenytoin. In contrast to phenytoin, levels of leviteracetam need not be monitored.
B. Surgical Considerations
The surgeon must decide whether the goal of intervention is obtaining biopsy only, subtotal resection, or attempting gross total resection. With few exceptions, gross total resection offers the best chance of survival and is the preferred treatment. Tumor resection requires careful consideration of a number of key factors including: (1) tumor size, (2) location, (3) gross, radiographic, and pathologic characteristics, (4) sensitivity to radiation, and importantly, (5) the medical and neurologic status of the patient.
The timing of surgery is important in preoperative planning. Patients who present with rapid deterioration due to elevated intracranial pressure typically require prompt intervention. Tumor growth can be brisk in patients with large, high-grade tumors and small increases in tumor volume can cause a profound increase in intracranial pressure. Rapid intervention may also be necessary in the setting of obstructive hydrocephalus. Cerebrospinal fluid diversion (typically via ventriculostomy) is an alternative to urgent tumor resection in patients with obstructive hydrocephalus secondary to tumor growth. In cases where tumor burden is not causing profound neurologic deficit or elevated intracranial pressure, resection can be arranged as a semi-elective procedure.
Once in the operating room for brain tumor resection, a number of important principles of positioning are vital to a successful resection. Most tumor resections require immobilization of patient’s head in a Mayfield head holder. The position should be selected create the most direct access to the lesion while avoiding risk to other bodily structures. Positioning should promote venous drainage from the lesion and the cranial compartment by ensuring the jugular veins are not compressed and that the head is elevated. In most cases, surgeons prefer to position the patient with the operative corridor perpendicular to the floor. This approach generally minimizes brain retraction and is the most ergonomic for the surgeon. Pressure points of the remainder of the patient should be padded especially thoroughly given the lengthy nature of some tumor resections.
The shape of the skin incision and bone flap is dependent on the desired approach, size of the lesion, and surgeon preference. Small tumors can be adequately exposed and resected via linear or curvilnear incisions with a small bone flap. Resection of deep lesions, especially those involving the skull base, often require creation of a sizable scalp flap and removal of a large window of bone. Whenever possible, incisions should be planned behind the hairline, minimizing the amount of hair removal in deference to cosmetic concerns. The placement of the incision is largely determined by the location of the lesion. Frameless stereotaxy, a technology that relies on a three-dimensional rendering of the patient’s preoperative MRI, can enable accurate tumor localization based on preoperative imaging and can be helpful in minimizing the size of the incision. Standard approaches to intracranial lesions minimize the morbidity of exposure by limiting the risk to key neural and vascular structures.
The central goal of brain tumor surgery is maximizing the removal of neoplastic tissue while minimizing collateral damage to surrounding normal brain and vascular structures. Standards for achieving this goal vary based on tumor type. For example, the goal of the resection of a high-grade glioma is to remove all enhancing portions of the tumor, in contrast to the goal for the resection of a low-grade glioma to remove the tissue that appears abnormal on T2-weighted MRI. Several large retrospective studies published in the last decade suggest that duration of survival is directly related to extent of resection or the proportion of tumor removed at the time of surgery. The goal for resection of meningioma is to remove both the tumor and its dural origin. Metastatic tumors are typically well demarcated and often encapsulated and the goal is to remove the entire tumor.
One of the central challenges in brain tumor surgery is that neoplastic tissue that is easily detected on MRI is often virtually indistinguishable from normal brain. Several studies evaluating the extent of brain tumor resection highlight the fact that in many cases, especially in diffusely invasive brain tumors, a significant amount of residual tumor remains even after gross total resection. Moreover, surgeons have a limited ability to predict when all resectable tumor has indeed been removed. Consequently, a variety of technologies have been developed to improve surgical outcomes. Stereotactic navigation is utilized to improve extent of resection but there is little evidence that it can improve extent of resection. Retrospective analyses suggest that intraoperative MRI, an approach in which brain tumor resection is performed in a highly specialized surgical suite containing an MRI machine, improves extent of resection. Fluorescent and visible dyes have been proposed as a means of identifying tumor margins intraoperatively for more than 60 years. Recently a phase III clinical trial has demonstrated that the fluorescent dye 5-ALA may improve the extent of resection and six-month progression-free survival in glioblastoma patients. A number of efforts are underway to use dye-based and label-free intraoperative microscopy to improve the surgeon’s ability to distinguish tumor-infiltrated brain from noninfiltrated tissue.
Intraoperative electrophysiologic monitoring of brain activity is often used in tumors within eloquent cortex to determine a safe route for exposure of tumor and the safe limits for extent of resection. Electrophysiologic motor mapping can be performed with the patient under general anesthesia or awake. In asleep motor mapping, specific regions of the motor cortex or corticospinal tract are stimulated with electrical current while the electromyographic response in target muscles is recorded. In awake motor mapping direct electrical stimulation of motor cortex or corticospinal tracts is performed while a patient is asked to perform specific tasks. An arrest of motor activity with direct electrical stimulation suggests that the portion of brain being stimulated is involved in motor function. Similarly, in awake language mapping specific regions of the brain, commonly the dominant frontal and temporal lobes are stimulated to look for speech arrest. Awake language mapping of brain tumor patients has broadened our understanding of the organization of the human language cortex and circuits.
Following resection, meticulous attention is paid to achieving hemostasis in the operative corridor to minimize the risk of postoperative hemorrhage. Whenever possible, to diminish the risk of cerebrospinal fluid leak, a watertight dural closure is performed. The bone flap is replaced and the galea is reapproximated. Scalp closure that omits closure of the galea provides little strength and raises the risk of dehiscence.
C. Postoperative Management
Following resection patients are observed closely in an ICU setting, typically for overnight, where serial neurological examinations are carried out. Depending on the extent of resection, steroids may be tapered over the days following surgery. Anticonvulsants are continued in patients who have a history of seizures and, when there has been extensive brain dissection, they may be continued for 1-4 weeks following surgery. Given the prognostic significance of extent of resection for glioma patients and the difficulty in detecting residual tumor during surgery, it is becoming standard practice for surgeons to obtain postoperative MRI imaging with contrast to evaluate for residual tumor within 24 hours of resection. When there is a low suspicion of residual tumor or when further surgery is not possible, postoperative imaging may be deferred.
Surgical resection is cornerstone of brain tumor therapy but it is rarely capable of eradicating all tumor cells. Furthermore, resection may not be favored when eloquent structures are likely to be damaged. Adjuvant radiation and chemotherapy regimens have been developed to address the inability of current surgical techniques to reliably eradicate residual or unresectable tumor.
Radiation kills tumor cells by directly damaging cellular structures, inducing lethal mutations in cellular DNA and by activating pathways for programmed cell death. Radiation can be delivered to brain tumors in a fractionated manner, which allows normal tissue repair between treatments and increases the toxicity of the radiation to tumor tissue.
Regimens for radiation therapy of brain tumors vary with tumor type. The optimal dose and timing of adjuvant radiation therapy for low-grade glioma is controversial. Typically, radiation is reserved in low-grade glioma until there is evidence of tumor progression or neurologic deterioration. Early radiation therapy is suggested in elderly patients, for tumors that have crossed the midline and in the setting of intractable seizures. Because of the cognitive consequences of radiation therapy, it may be delayed in younger patients until there is suspicion of recurrence
For high-grade glioma, the findings of a study conducted by the Brain Tumor Cooperative Group (BTCG) demonstrated an increase in survival in HGG patient undergoing radiation therapy plus surgery compared to surgery alone from 14 to 31 weeks. A landmark study on the use of radiation in conjunction with temozolomide has defined the current standard for radiation therapy in glioblastoma patients: 2 Gy given 5 days per week for 6 weeks, totaling 60Gy.
Two important clinical trials have established the standard therapy for metastatic lesions. Currently, acceptable care of patients with brain metastases consists of resection followed by whole brain radiation therapy, or stereotactic radiosurgery (SRS), in which a high dose of radiation is administered to the tumor bed, in addition to whole brain radiation therapy. The use of radiation therapy has been extensively investigated. Currently, radiation therapy is indicated as an adjunct to surgery in the setting of recurrent meningioma or subtotal resection. Occasionally in a poor surgical candidate or if a meningioma is in a location carrying high surgical risk, radiation therapy may be used in isolation.
Clinical trials of chemotherapy for low-grade glioma have been limited and the use of chemotherapy for this remains experimental. The one exception is low-grade gliomas, typically those with 1p deletion and oligodendroglial lineage, which are particularly sensitive to PCV (procarbizine, carmustine, and vincristine) or temozolomide. In contrast, a recent clinical trial in patients with proven GBM comparing radiation alone to radiation in combination with the oral alkylating agent temozolomide demonstrated a modest but significant increase in survival from 12.1 to 14.6 months. The current standard of care for patients with GBM combines radiation therapy with oral temozolomide. Chemotherapy has not shown any benefit in the treatment of brain metastases and meningiomas. Future efforts in the development of novel chemotherapeutic agents are focused on developing novel inhibitors of signaling pathways that are active only in brain tumor cells. Developing novel methods for the delivery of traditional chemotherapeutic agents is also an area of active research.
Patients with primary and metastatic brain tumors are at risk of developing postoperative medical as well as surgical complications. Sawaya proposed the most common classification scheme for complications associated with brain tumor surgery in 1998. In a case series of 400 craniotomies for treatment of brain tumors, complications were classified as neurological, regional, and systemic. Neurologic complications are outcomes that produce visual field, motor, sensory, or language deficits. Neurologic complications are the result of injury to normal brain structures, cerebral edema, hematoma, or vascular injury. In most series, the risk of a new neurologic deficit after craniotomy for resection of an intrinsic brain tumor ranges from 10% to 25%. The risk factors for adverse neurologic outcomes include older age (greater than 60 years), deep tumor location, tumor proximity to eloquent regions, and low functional performance score (Karnofsky score less than 60%). Neurologic complications can be minimized by individualizing the surgical approach for each patient, cortical mapping techniques, minimizing excessive brain retraction, meticulous hemostasis, and early identification of major venous structures.
Regional complications are those related to the surgical wound or brain parenchyma, without neurologic deficit. They occur in 1%-5% of patients undergoing craniotomy for resection of an intrinsic brain tumor. Regional complications include wound infections, pneumocephalus, Cerebrospinal fluid fistula, hydrocephalus, seizure, brain abscess/cerebritis, meningitis, and pseudomeningocele. These complications occur more readily in the elderly. Posterior fossa location and reoperations are associated with a higher rate of pseudomeningocele, CSF fistula, hydrocephalus, and wound infections. Postoperative wound infections and cellulitis occur in 1%-2% of patients after supratentorial craniotomy. They typically result from skin bacterial contamination (Staphylococcus aureus and Staphylococcus epidermidis). The risk of postoperative seizures following supratentorial craniotomy is 0.5%-5%. Prophylactic antiepileptic drugs can be routinely used in the postoperative period; however, their dose and duration is an area of controversy.
Systemic complications include all generalized adverse events, including deep vein thrombosis (DVT), pulmonary embolus, pneumonia, urinary tract infections, myocardial infarction, and sepsis. These medical complications occur in 5%-10% of patients undergoing craniotomy for removal of an intrinsic brain tumor and are more prevalent in older patients (greater than 60 years) and neurologically impaired patients (Karnofsky score less than 60%). DVT is the most common complication occurring in 1%-10% of patients within the first month after a craniotomy. Patients with systemic cancer, glioblastoma multiforme, meningiomas, lower extremity paralysis, bed rest, and prolonged surgery are at particularly increased risk of developing a DVT or pulmonary embolus. Early postoperative mobilization, intermittent compression devices, and postoperative anticoagulation with low-molecular-weight heparin have decreased the incidence of postoperative DVT.
Craniotomy for resection of brain tumor can be performed safely and most complications can be prevented with careful preoperative planning, meticulous surgical technique, and attentive postoperative care.
The prognosis of brain tumor patients varies based on a number of factors, including, but not limited to, general functional status at the time of diagnosis, tumor type, location, and age.
The prognosis of glioma patients is determined by tumor grade, age, extent of resection, Karnofsky performance status, and treatment response. Improvement in survival when radiographically complete resection is achieved is greatest for those with low-grade lesions. While more modest, high-grade glioma patients with radiographically complete resection also have survival improvement compared to incomplete resection. Achieving gross total resection improves survival by lowering the risk of recurrence and reducing tumor cell burden to levels that can be eradicated or controlled with adjuvant therapy.
In general, the prognosis of meningioma patients is more favorable than that of glioma patients. The prognosis of meningioma patients is determined by the extent of resection and tumor grade. The Simpson classification system stratifies meningioma patients into outcome groups based on extent of resection. Patient age, extent of surrounding structure invasion, male gender, genetic factors, and tumor grade are among the factors that are linked to prognosis. Recurrence has been estimated to occur in approximately 20% of patients with benign meningiomas but is much more common in higher grade lesions.
The survival of patients with untreated brain metastasis is quite poor (1-2 months), but survival can be prolonged by 4 or more months with optimal surgical and radiation therapies. Extent of extracranial disease is a key prognostic factor in patients with brain metastases. Age and Karnofsky performance status have an important bearing on overall survival.
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