Neuro-Oncology

Clinical Presentations of Brain Tumors

Brain tumors commonly present with symptoms of elevated intracranial pressure or focal neurologic dysfunction. Elevated intracranial pressure can directly result from an enlarging mass or can be secondary to the development of hydrocephalus stemming from obstruction of the ventricular system and cerebrospinal fluid (CSF) flow by the tumor. The specific neurologic dysfunction depends on the local mass effect of the tumor.

Clinical Manifestations. Traditionally, headaches, nausea and vomiting, and papilledema constitute the clinical triad of increased intracranial pressure. Headaches resulting from elevated intracranial pressure are generalized in location and usually are worst upon awakening, occasionally even waking a patient from sleep. The vomiting is ascribed to pressure in the region of the fourth ventricle. Papilledema, or blurring of the optic disc margin due to swelling of the optic nerve (cranial nerve II) from the increased intracranial pressure, can be detected by ophthalmoscopic examination.

Local mass effect can result in a variety of neurologic symptoms, depending on what structures are affected. Symptoms may stem from local neural tissue invasion or compression of adjacent structures. Often, these focal signs and symptoms will manifest before the tumor enlarges to the point of causing increased intracranial pressure. Clinical presentations depend on the function of the affected tissue. In addition, headaches may also result from local mass effect. Typically, these headaches localize to the side of the tumor. They are usually dull and constant in character. Occasionally they may be severe. The combination of headaches associated with new neurologic abnormalities or changes in headache suggesting increased intracranial pressure should warrant consideration of an underlying neoplasm.

Seizures are another common sign that occur in association with an underlying malignancy. They can be either generalized or focal, with the focal seizures representative of the underlying location of the tumor. For example, distinct motor or sensory symptoms , such as weakness or numbness, relate to the functions of the cortical areas affected by the tumor. Cognitive changes may herald an underlying intracranial malignancy, especially if they are frontal in location. Often these changes are subtle, with patients experiencing fatigue, memory difficulties, personality changes, or apathy . Difficulties with balance or disequilibrium often occur when tumors arise in the posterior fossa. Visual field defects, such as a homonymous hemianopsia, may result from damage to the optic tracts, and bitemporal hemianopsia is often seen with compression of the optic chiasm by pituitary tumors. Occasionally, patients will be asymptomatic, but the physical examination may reveal subtle neurologic abnormalities, such as a drift of an upper extremity, asymmetric reflexes, or a positive Babinski sign.

Diagnostic Studies. Once suspicion is raised of an intracranial malignancy, neuroimaging is warranted. Gadolinium-enhanced magnetic resonance imaging (MRI) is the diagnostic modality of choice because it allows visualization of the tumor in relation to the surrounding brain parenchyma, especially in the posterior fossa. Computer tomography (CT) is still used in patients for whom magnetic resonance imaging (MRI) is contraindicated or in emergent situations where time is of essence. In addition, it is superior to MRI in the detection of bony involvement, particularly in the region of the skull base. Other imaging modalities include magnetic resonance spectroscopy (MRS), which analyzes the chemical composition of the area of interest in an effort to differentiate tumor from other abnormalities, and positron emission tomography (PET) with fluorodeoxyglucose (FDG), which detects metabolically active tumors. Finally, perfusion MRI has emerged as a potentially useful technique because it identifies areas of increased vascularity, which can be useful for planning of surgical removal.

Gliomas

Gliomas represent tumors arising from glial cells that comprise the supporting tissue in the brain. In general, gliomas can be classified as “low grade” or “high grade” depending on the degree of aggressiveness. Low-grade gliomas (LGG) are slower-growing tumors, whereas high-grade gliomas (HGG) are more aggressive. They are further subdivided based on their histopathologic appearance. For example, astrocytomas represent tumors arising from astrocytes, whereas oligodendrogliomas have features consistent with oligodendrocytes. Other tumors falling under the category of gliomas include ependymomas, glioblastomas, and rarer tumors, such as gangliogliomas.

LGG are less common than HGG and tend to affect younger patients. LGG include those tumors designated as World Health Organization (WHO) grade I or II. The most common LGG are diffuse astrocytomas, oligodendrogliomas, and pilocytic astrocytomas, which is discussed in the pediatric section. Rarer tumors include ganglioglioma and pleomorphic xanthoastrocytoma. Although ependymomas are considered gliomas and labeled as WHO grade II, they are traditionally considered separate from the other LGG. HGG include those tumors comprising WHO grade III or higher. Anaplastic astrocytomas, anaplastic oligodendrogliomas, and anaplastic oligoastrocytomas are WHO grade III tumors, while the more common glioblastoma is WHO grade IV.

Clinical Manifestations. The neurologic presentation depends on the location and size of the tumor and its rate of growth. Very slow–growing tumors can become impressively large without causing significant symptoms. More rapidly growing small tumors located near sensitive areas, such as the cerebral cortex, may cause seizures, or difficulties with language or vision. Tumors located deep within the frontal lobe may reach significantly larger size before producing focal neurologic symptoms, even if they grow rapidly. Headache and cognitive dysfunction with memory loss and apathy may develop as early symptoms of these deep tumors, especially if the corpus callosum is involved. Tumors within the brainstem produce symptoms such as double vision, facial weakness, or difficulty swallowing related to local involvement of the brainstem nuclei. Gangliogliomas, which commonly arise in the temporal lobe, are notable for causing seizures.

Diagnostic Studies. On magnetic resonance imaging (MRI), LGG often present as an enhancing lesion. Pilocytic astrocytomas may have a large cystic component with an enhancing mural nodule (see Pediatric Brain Tumors later). Calcifications are sometimes present, most commonly seen with oligodendrogliomas of all grades. Anaplastic gliomas may resemble glioblastomas on MRI, highlighting the necessity of obtaining tissue through tumor removal or by biopsy for a definitive neuropathologic diagnosis. Ependymomas usually strongly enhance, with cystic and calcification components commonly seen. Often, the presence of calcifications in a fourth ventricle tumor is suggestive, although nondiagnostic, of an ependymoma. Because 10% of ependymomas will have disseminated upon presentation, it is necessary to image the entire brain and spine by MRI and examine the cerebrospinal fluid for the presence of malignant cells.

Treatment. The treatment of gliomas is highly variable and depends on the histopathologic subtype. For pilocytic astrocytomas and gangliogliomas, complete surgical resection is potentially curative. For LGG with significant residual disease after resection, the treatment consists of radiation or chemotherapy alone or in combination. In general, anaplastic gliomas are treated very similarly to glioblastomas, using a combination of radiation and chemotherapy. One exception is oligodendrogliomas with deletions of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q). These tumors are responsive to treatment with chemotherapy alone, and they have a favorable prognosis.

Glioblastoma

Glioblastomas are the most frequently occurring subtype of glioma and the most aggressive. As World Health Organization (WHO) grade IV tumors, their histopathologic features include nuclear atypia, hypercellularity, mitoses, microvascular proliferation, and necrosis. Middle-aged adults are most commonly affected, with a peak incidence in the fifth to eighth decade. Glioblastomas are preferentially localized to the cerebral hemispheres; very rarely, they occur in the brainstem, meninges, or the spinal cord. For “primary” or “de novo” glioblastomas that arise with no preexisting lesion, the natural history is usually short, with a median survival of 15 to 18 months. Glioblastomas that develop through progression from lower-grade gliomas are labeled “secondary.” These are much less frequent, typically occur in younger patients, and are associated with longer survival than primary tumors. Comparisons of the molecular profiles of primary and secondary glioblastomas indicate that they represent distinct entities with evolution through different genetic abnormalities and through activation of different molecular signaling pathways.

Clinical Manifestations. As discussed above, signs and symptoms of underlying glioblastomas reflect the location of the tumor and its rate of growth. Because of the rapid rate of growth, symptoms tend to be of shorter duration before diagnosis. The most frequent presenting symptoms are headache and seizures.

Diagnostic Studies. On MRI, glioblastomas commonly present with heterogeneous or ring-like enhancement admixed with central areas of necrosis. Fluid attenuated inversion recovery (FLAIR) and T2-weighted MRI images illustrate infiltrative tumor and surrounding edema, which is often significant. If MRI is contraindicated, CT with and without contrast is acceptable, although the anatomy is less defined.

Treatment. Treatment of glioblastomas is multimodal, involving surgery, radiation, and chemotherapy. Initial neurosurgical resection allows for definitive diagnosis, alleviation of neurologic symptoms, and debulking, which can improve outcome. After surgery, patients undergo radiation in combination with chemotherapy. External beam radiation has been shown to be the single most effective treatment for glioblastomas and other high-grade gliomas. The addition of temozolomide, a chemotherapy agent, has been shown to significantly extend survival. Despite combined therapy, the tumors almost inevitably recur and progress. Prognostic factors associated with increased survival include younger age, higher performance status, greater extent of resection, as well as some genetic factors, such as the presence of the deoxyribonucleic acid (DNA) repair enzyme O6-methylguanine–DNA-methyltransferase or isocitrate dehydrogenase (IDH1) mutation. Experimental therapies targeting angiogenesis (the formation of new blood vessels from preexisting adjacent vessels) have emerged as novel anticancer agents. For example, bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor (VEGF) was granted accelerated approval by the Food and Drug Administration (FDA); however, its effect on survival remains modest. Much current research has focused on the development and use of small molecule inhibitors to target molecular signaling pathways implicated in tumorigenesis.

In addition to treatment of tumor growth, symptomatic treatment is equally as important. Corticosteroids are often used to relieve the surrounding edema. Antiepileptic agents are only necessary when patients suffer from seizures.

Pediatric Brain Tumors

Brain tumors are the second most common type of cancer in children and the most common type of solid tumor. These tumors often occur in the posterior fossa; the most common types include pilocytic astrocytomas, brainstem gliomas, and medulloblastomas.

Pilocytic astrocytomas are World Health Organization (WHO) grade I tumors. They can occur in any region of the central nervous system, but frequently arise in the cerebellum of children. The tumors often have both cystic and solid components. In some cases, the cystic component may be quite large, with the associated solid tumor mass appearing as a smaller “mural” nodule in the cyst wall.

Brainstem gliomas encompass a number of tumor subtypes, each with its own pathologic and clinical characteristics. Although they can be seen in adult patients, they are far more common in children. There are four types: dorsal exophytic gliomas, tectal gliomas, cervicomedullary gliomas, and diffuse infiltrating pontine gliomas. Dorsal exophytic gliomas are slow-growing low-grade astrocytomas arising from the floor of the fourth ventricle. Intrinsic midbrain tectal gliomas tend to be low-grade astrocytomas, occurring next to the third ventricle and aqueduct of Sylvius. Cervicomedullary tumors typically are low-grade astrocytomas of the upper spinal cord and lower brainstem, although other tumor types can be seen. The most aggressive type is the diffuse infiltrating pontine glioma,. These tumors are WHO grade III or IV and have a very poor prognosis, with median survival of only 9 months despite maximal treatment with radiation and chemotherapy.

Medulloblastomas are WHO grade IV embryonal brain tumors that arise in the cerebellum and tend to disseminate through cerebrospinal fluid (CSF) pathways throughout the brain and spine. They are highly cellular tumors with highly variable prognosis that is not predicted by histologic features. Analysis of their molecular profiles has revealed that this heterogeneity arises because they consist of multiple subclasses associated with distinct demographics, genetics, clinical presentation, and outcome. The large majority of tumors are diagnosed in childhood or adolescence.

Clinical Manifestations. In general, brainstem gliomas produce symptoms reflecting the exact location of the tumor in the brainstem, rate of growth, and presence of CSF flow obstruction. Patients with tectal gliomas often display signs and symptoms of isolated hydrocephalus. Dorsal exophytic brainstem tumors may manifest with headaches due to hydrocephalus combined with ataxia from cerebellar dysfunction. Diffuse pontine gliomas often present with double vision and facial weakness due to cranial nerve VI and VII palsies, accompanied by motor and cerebellar dysfunction of the contralateral limbs. Medulloblastomas can present with ataxia from cerebellar dysfunction, cranial nerve deficits, headache and vomiting from hydrocephalus, or occasionally, signs and symptoms attributable to spinal cord or nerve root compression from extensive tumor dissemination.

Diagnostic Studies. With the advent of MRIs, the ability to diagnose brainstem tumors has improved tremendously. Tectal gliomas and diffuse intrinsic pontine gliomas frequently are diagnosed based on MRI appearance alone without biopsy. This is especially important given the high risk of neurologic injury from the biopsy procedure. Dorsal exophytic brainstem tumors tend to have sharp borders and are relatively homogeneous.

Medulloblastomas are generally well-defined midline cerebellar lesions with regions of mineralization, intratumoral cysts and blood vessels and heterogeneous enhancement. Because of the propensity for medulloblastomas to disseminate, the entire neuroaxis must be imaged. In addition, the CSF should be analyzed for the presence of tumor cells as the tumor tends to spread along the CSF pathways.

Treatment. Dorsal exophytic brainstem tumors and cervicomedullary tumors are amenable to surgical resection, followed by chemotherapy or radiation for progressive or symptomatic tumors that cannot be completely removed. Tectal gliomas are generally managed by addressing the hydrocephalus, although larger or progressive tumors may need further treatment. Diffuse infiltrating pontine lesions are treated with a combination of fractionated radiotherapy and chemotherapy.

Initial treatment of medulloblastomas consists of surgical resection, with the extent of surgical resection a significant prognostic factor. Subsequent treatment depends on whether patients fall into “average risk” (older than 3 years, with near or total resection of the tumor and no evidence of disseminated disease) or “high risk” (younger than 3 years, less than near-total resection and evidence of disseminated disease) categories. Average-risk patients are treated with lower doses of radiation and less chemotherapy.