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Brain Tumors
Clinical Vignette
A 47-year-old self-employed father presented to the emergency department having difficulty discriminating coins in his pocket. He had been skiing that day and was concerned enough to seek medical attention on his way home. His general health was excellent. The only abnormality on his neurologic examination was confined to his right hand. Here he demonstrated loss of two-point discrimination in his fingers as well as an inability to identify numbers traced on his right palm and to identify common objects such as a safety pin, paper clip, or various coins with these fingers. All of these maneuvers were normal for his left hand.
Magnetic resonance imaging (MRI) demonstrated a 4- by 6-cm heterogeneously gadolinium-enhancing, vascular tumor with a large amount of peritumor edema high in his left parietal lobe. Stereotactic needle biopsy demonstrated a glioblastoma (GBM). Radiation and chemotherapy were given. He ultimately died as a result of local tumor recurrence that did not respond to treatment 15 months after presentation.
Brain tumors are a relatively common neurologic disorder particularly when one combines primary central nervous system (CNS) lesions and those metastatic to the brain and its leptomeninges. Taken together, these tumors are among the most common cerebral disorders in adults, second only to Alzheimer disease, stroke, and multiple sclerosis. With the exception of leukemia in children, primary brain tumors are the most common malignancy. GBM arising from within the glial cell matrix occurs in all age groups but is most prevalent after age 65 years. A higher age at onset is the most significant predictor of poor outcome. GBM is the most devastating of CNS malignancies; there are very few 2-year survivors. Glial cell tumors comprise more than two-thirds of all primary brain tumors.
Although one might think that the temporal profile of a patient's illness may sometimes suggest either a benign or malignant process, one cannot depend on this history to make a differential diagnosis. Brain tumors typically present with one of four clinical scenarios: (1) focal cerebral or cranial nerve (CN) deficits that are gradually progressive over a few weeks to many months, (2) seizures, (3) headache and signs of increased intracranial pressure primarily demonstrating papilledema and sixth-nerve palsies, or (4) stroke mimic―that is, involving an apocalyptic onset. Personality changes, evolving language dysfunction, focal loss of sensory discrimination, or motor limitation such as a clumsy hand, and ataxic gait are focal signs that usually define the site of the tumor accurately. However, there are certain false localizing signs that may lead to initial confusion.
When a slowly enlarging, previously asymptomatic cerebral tumor decompensates, certain false localizing signs may cause diagnostic confusion. Transtentorial uncal-parahippocampal herniation occurs, with the offending hemisphere herniating medially through the tentorium cerebri, compressing the contralateral corticospinal tract carrying motor fibers. These fibers originating in the opposite motor cortex control movement on the same side of the body as the site of the tumor. For example, a very large right-sided tumor affects the left corticospinal tract carrying right-sided motor fibers, leading paradoxically to a hemiparesis ipsilateral to the tumor. Another false localizing sign occurs when a large herniating tumor compresses the opposite third nerve, thus leading to pupillary dilation contralateral to the side of the lesion. Today these clinically confusing signs are less likely to occur with earlier MRI diagnosis of these tumors before they reach a critical mass that could cause these herniation syndromes.
The occurrence of a new-onset seizure in an adult must always lead to diagnostic consideration of a brain tumor. It is estimated that 30% of brain tumors present in this fashion. The tumor types and their locations are essential determinants significantly influencing seizure characteristics. Brain tumors with a high risk for epilepsy include diffuse gliomas, brain metastases, and various developmental tumors.
The availability of MRI makes the differentiation relatively simple for those occasional brain tumors that present so acutely that they mimic a stroke. MRI primarily provides morphologic and functional information, including tumor localization, vascular permeability, cell density, and tumor perfusion. The concurrent employment of positron emission tomography (PET) enables the assessment of molecular processes, such as glucose consumption, expression of nucleoside and amino acid transporters, as well as alterations of DNA and protein synthesis. Perhaps multimodal diagnostic imaging will eventually allow one to differentiate a “tumefactive” demyelinating lesion from the much more common glioma. At present, however it is necessary to establish a tissue diagnosis to determine an appropriate therapeutic plan.
Despite tremendous advances in both the understanding of the biology of malignant gliomas and new neuro-oncologic therapies, the prognosis remains very poor. However, antiangiogenic agents, immune therapies, and checkpoint inhibitors are demonstrating some therapeutic promise for malignant gliomas.
Malignant Brain Tumors
When considering a new brain tumor diagnosis, it is important to determine whether the lesion has arisen from within the brain itself (primary), or whether it has spread to the brain from a cancer elsewhere in the body (metastatic). Primary brain tumors are commonly solitary and frequently have irregular margins. They may arise from glial, ependymal, or lymphoid cells. Gliomas are the most common tumors of glial origin; however, both astrocytes and oligodendrocytes can also form tumors. In contradistinction, primary neuronal tumors are very rare, particularly in adults. Metastatic tumors are often multiple, with gadolinium enhancement on MRI and sharply defined borders. The most common systemic cancers that metastasize to the brain are lung, breast, melanoma, and kidney.
Traditionally microscopic features have been the primary means of glial cell tumor classification. However, an emerging understanding of the molecular events responsible for the genesis of gliomas is having an impact not only on the diagnostic classification of these tumors but also on treatment selection as well as survival for specific glioma types. Small-molecule inhibitors and monoclonal antibodies may eventually provide targeted therapies that selectively block newly appreciated aberrant growth-signaling pathways within gliomas.
Gliomas
Epidemiology
The chance of developing a primary malignant brain tumor in the United States is small relative to the chance of developing a tumor of the lung, breast, colon, or prostate. The majority of these primary malignant brain tumors are gliomas. Data collected by the Central Brain Tumor Registry of the United States (CBTRUS) and Surveillance, Epidemiology, and End Results consortia demonstrate an adult incidence of 5.1 gliomas per 100,000 person-years; almost 50% of these are glioblastomas. Brain cancer incidence rises with age, peaking at 65–70 years. For glioblastoma the highest incidence is at age 62 years. Men are significantly more likely to develop a glioma (M : F = 1.8). Brain cancer incidence also varies regionally; the incidence in Hawaii is roughly half that in New England, and globally the incidence of brain tumors in Israel is roughly eight times that in Japan. Although some studies suggest that Caucasians are more predisposed to gliomas than African or Asian populations, variable access to healthcare and diagnostic imaging across regions and cultures may be the primary mechanism explaining this discrepancy rather than genetic susceptibility differences. Gliomas, like most cancers, are usually a random event and rarely have a familial predisposition. However, having a first-degree relative with a glioma doubles a patient's risk. Rarely, gliomas occur as part of an inherited disorder such as neurofibromatosis types 1 or 2 or tuberous sclerosis. There are no well-defined environmental risk factors with the exception of previous brain irradiation that predispose patients to glioma.
Pathology
Gliomas typically exhibit features of astrocytes, oligodendrocytes, or both (mixed glioma) ( Fig. 49.1 ). Microscopically, gliomas appear as diffusely infiltrating cancers of three types: astrocytic, oligodendroglial, and oligoastrocytic (combining the morphologic features of both oligodendroglioma and astrocytoma).
The World Health Organization (WHO) uses a three-tiered classification system based on histologic criteria that divide gliomas into infiltrating (WHO grade II), anaplastic (WHO grade III), and GBM (WHO grade IV). WHO grade II tumors may contain a high proportion of cells that appear histologically normal. Here the percentage of cells that are dividing (as determined by mib-1 or KI-67 staining) is often 2% or less. Anaplastic gliomas exhibit more atypical cells, with pleomorphic nuclei having growth rates in the range of 5%–10% but no evidence of necrosis. High growth rates (>10% mitotic figures) and necrosis are characteristic for GBM. Pilocytic astrocytomas (WHO grade I) are a separate category of glioma that are histologically characterized by Rosenthal fibers; they usually occur in children and often have a good prognosis if surgical resection can be achieved.
Gliomas are not staged as other cancers are because they rarely metastasize outside the CNS. Analysis of tumor samples for genetic abnormalities can help to predict response to therapy and will likely lead to a better classification system for gliomas. This classification is valuable prognostically; diffuse glioma (WHO grade II) has a median survival of 5–15 years; anaplastic glioma 2–5 years; and GBM 12–18 months.
Glioblastoma
These malignant tumors frequently present with seizures, aphasia, or other focal symptomatology, pointing to the specific areas of pathologic origin. Very infrequently, a glioma may manifest itself more globally, as gliomatosis cerebri, wherein there is widespread dissemination of neoplastic cells globally through a hemisphere or even the entire brain. These relatively rare patients may present with cognitive or personality changes. On other occasions, even though the patient presents relatively acutely with focal findings, the clinician is surprised to find a diffusely invasive malignant tumor despite a clinical presentation compatible with an acute focal brain pathology. This is the very common, most aggressive, and least likely of the gliomas to respond to therapy. The historical descriptor multiforme refers to the tumor's heterogeneous gross pathologic appearance. Often areas of necrosis, hemorrhage, and fleshy tumor exist within the same tumor focus.
Two types of GBM (WHO grade IV astrocytomas) are distinguished by molecular features. Primary GBM arises without evolving from a lower grade tumor with a median age at diagnosis of 62. Characteristically, primary GBMs have an amplification and overexpression of the epidermal growth factor receptor (EGFR) and ligand (EGF). Primary GBM is characterized by the presence of the wild-type isocitrate dehydrogenase 1 (IDH-1) gene and is associated with a shorter overall survival (15 months). Secondary GBM arises from a low-grade astrocytoma in a younger adult (median age at diagnosis mid-40’s). It is characterized by the presence of IDH-1 mutation and more commonly harbors a p53 mutation. As it undergoes anaplastic transformation, the secondary GBM accumulates other genetic derangements, most notably, mutation of the Rb gene, deletion of the tumor suppressor gene p16/ cyclin-dependent kinase inhibitor 2A (CDKN2A) , and amplification of cyclin-dependent kinase 4 (CDK4).
When the clinical behavior and genetic abnormalities of GBM tumors are reviewed, a developmental dichotomy emerges. Younger patients with GBM sometimes have a longer history of symptoms or a history of a lower-grade glioma, suggesting that the tumor developed from a lower-grade precursor, whereas older patients with GBM tend to have relatively sudden symptom onset, suggesting that the malignancy did not evolve from a less aggressive tumor. Genetic analysis of GBM samples from older patients frequently reveals overexpression of the EGFR and loss of 10q. Tumor samples from younger patients are more likely to show mutations in p53 and RB, overexpression of the platelet-derived growth factor receptor, and loss of 19q—changes often seen in lower-grade gliomas.
Diagnosis, Treatment, and Prognosis
MRI is the most specific diagnostic modality ( Fig. 49.2 ). On most occasions, one sees focal heterogeneous and irregularly margined cystic mass lesions with perilesion edema, gadolinium rim enhancement. In contrast, occasional patients with gliomatosis cerebri have a characteristic diffusely abnormal MRI picture characterized by multiple areas of subtle white matter enhancement with extension into the cortical mantle, extending far beyond what their clinical presentation usually dictates ( Fig. 49.3 ).
Even with early diagnosis, the prognosis for individuals with glioblastoma remains grim and most patients will fail therapy within 12 months of diagnosis. The first treatment step is to perform as wide a surgical resection as is functionally tolerable. Younger patients with a normal examination who have had a gross total resection have the best prognosis. Postoperative radiation therapy (RT) clearly benefits many patients, as those GBM patients who receive RT have a median survival twice that of those who did not.
Combining RT with concomitant and adjuvant chemotherapy is now the standard of care for patients with GBM. RT plus temozolomide leads to a modest benefit in overall survival (14.6 vs. 12.1 months). However, more importantly, there is a significant increase in the percentage of those surviving 2 or more years (26.5% vs. 10.4%). Bevacizumab, an antagonist of vascular endothelial growth factor, has been approved by the US Food and Drug Administration for patients with recurrent GBM.
With the limited efficacy of standard treatments, there is an imperative to develop better therapies through translational science and clinical trials. Molecular research is defining a number of potential glioma cell targets. These are mostly second messenger molecules involved in pathways that enhance cell proliferation or inhibit programmed cell death. The goal is to treat a selected group of patients whose tumors overexpress the specific target of the treatment drug.
Diffuse Astrocytic and Oligodendroglial Glioma
Clinical Vignette
A 34-year-old right-handed woman presented with generalized seizures. Several months earlier, she had noted episodes of an unusual smell, but these did not cause her immediate concern. Brain MRI demonstrated a right temporal lobe lesion, bright on T2 and fluid-attenuated inversion recovery (FLAIR) imaging but hypointense on T1, with no evidence of enhancement after gadolinium ( Fig. 49.4 ). The patient was treated with oxcarbazepine and admitted to the hospital. Open biopsy was nondiagnostic but subsequent temporal lobectomy revealed an oligodendroglioma with a Ki-67 index of 3.8%. Postoperatively, the patient was treated with monthly temozolomide for 1 year. She is now receiving no treatment and has been clinically and radiographically stable for 2 years.
Clinical Presentation/Pathology
Diffuse gliomas are slow-growing tumors with a symptom history that can extend from months to years. Although easily defined by MRI (see Fig. 49.4 ), diffuse gliomas often do not enhance with gadolinium. Their course is usually relatively stable for several years before eventually progressing. At the time of diagnosis, diffuse glioma has a more favorable overall survival than glioblastoma. However, eventually some diffuse gliomas may progress to become GBM, with its inherently poor prognosis. Histologically, diffuse gliomas may be described as infiltrating astrocytoma, oligodendroglioma, or oligoastrocytoma (mixed glioma). A low mitotic index, younger patient age, and a supratentorial non-elegant locus (i.e., not affecting language function) that is amenable to resection predict a longer progression-free survival.
Treatment and Prognosis
The choice of therapeutic modalities is always an issue. Retrospective studies suggest that gross total resection for gliomas that can be safely removed provides longer progression-free survival. However, the surgeon can never remove all tumor tissue when dealing with infiltrative gliomas. These lesions harbor an innate, almost serpiginous invasion of what appears to be grossly normal brain tissue to the surgeon's eye. At the time of resection, these characteristics prevent appreciation of the full microscopic extent of the entire tumor mass. Therefore gliomas will eventually demonstrate progression even after what appears initially to be a gross “total resection.” In this setting, so-called disabling resections in patients with astrocytomas or oligodendrogliomas are neither wise nor helpful. This is especially true when dealing with tumors in eloquent cerebrocortical areas―including language, memory, and function―as well as those portions essential to the use of extremities, particularly motor structures within the dominant hemisphere, where preservation of functional mobility is particularly important.
Subtotal resection is indicated for most gliomas remediable by decompression without leaving a significant disability (such as aphasia) and especially when the tumor's mass effect is causing disability. In patients with pilocytic astrocytoma, surgical indications differ slightly; a complete resection may provide a cure; therefore a more aggressive surgical approach may be appropriate.
The next therapeutic decision is whether to recommend external beam RT. Although RT does not prolong overall survival, there is a significant increase in progression-free survival in the treated group. Unfortunately this benefit may be offset by a higher incidence of long-term cognitive impairment in the RT-treated group. Survival is not the only factor when RT is being considered, since some clinical predictors suggest which patients will benefit from RT. If more than two answers to the five following questions are yes, the patient is likely to benefit from RT: (1) Is the patient older than age 40 years? (2) Is the tumor symptomatic (other than seizures)? (3) Does the tumor cross the midline? (4) Is the tumor an astrocytoma (as opposed to an oligodendroglioma)? (5) Is the tumor larger than 5 cm?
The dose of RT for diffuse glioma is usually 54 Gy given in 30 fractions. Higher doses have not shown a clear benefit and should not be used.
Until recently chemotherapy has not been employed for the treatment of diffuse glioma. However, the recent widespread use of temozolomide, an oral alkylating agent for GBM, raises the question of whether there are a selected group of patients with diffuse glioma who potentially may also benefit from this therapy. Temozolomide is currently used in patients who do not meet the criteria for RT, as listed earlier, but whose tumors have a mitotic index of greater than 3%. Although patients with low-grade tumors have a much better prognosis than those with anaplastic glioma and GBM, diffuse glioma is still usually fatal. The median survival is 5–7 years for astrocytoma and 7–10 years for oligodendroglioma.
Anaplastic Glioma
Clinical Vignette
A 49-year-old right-handed man presented with 5 weeks of numbness and weakness in the left leg. Examination revealed decreased strength and slowed rapid movements of his left foot. There was extinction to touch and loss of joint position sense. Brain MRI revealed a 3-by-4-cm cystic mass centered in the medial aspect of the right parietal lobe and heterogeneous enhancement with gadolinium ( Fig. 49.5 ).
Lesion resection revealed an anaplastic astrocytoma (AA) (see Fig. 49.5 ). Postoperatively, the patient was treated with a combination of RT and concomitant temozolomide. He is neurologically intact and radiographically stable 3 years after diagnosis.
Pathology
Anaplastic gliomas are WHO grade III tumors with a higher mitotic index than diffuse gliomas but lack the necrosis and endothelial proliferation of glioblastomas. They commonly affect patients in the age range of 35–50 years who often present with symptoms dating back just a few weeks or months. As in diffuse glioma, anaplastic gliomas can be composed of astrocytes (AAs), oligodendrocytes (anaplastic oligodendroglioma [AO]), or a mixture of the two (anaplastic oligoastrocytoma [AOA]). The presence of an oligodendroglial component and especially co-deletion of chromosome 1p and 19q confers a better prognosis.
Treatment and Prognosis
Theoretically, complete surgical resection is the best initial intervention; however, a heroic but neurologically disabling procedure is not indicated, as noted in the section on diffuse astrocytic and oligodendroglial tumors. Most patients with anaplastic gliomas should be treated with radiation. It is not clear whether adding a chemotherapy drug such as temozolomide at the time of diagnosis is beneficial. Previous studies have shown a high rate of response to temozolomide in patients with recurrent AAs. AA has a median survival of approximately 3 years.
Anaplastic Oligodendrogliomas
These are a special subset of tumors where the optimal treatment remains controversial. They frequently (70%) respond to procarbazine, lomustine, and vincristine (PCV) chemotherapy. Genetic analysis demonstrates that the vast majority of the responders have a specific genetic profile (loss of 1p and 19q). This group has a median survival of 10 years; in contrast, other AO patients lacking this profile have a median survival much closer to the 3 years of AA patients. The addition of alkylating chemotherapy to radiation improves long-term survival in co-deleted anaplastic oligodendroglioma. Aggressive chemotherapy (with bone marrow transplant), even in patients with AO, has not significantly prolonged survival.
Primary Central Nervous System Lymphoma
Previously a relatively rare tumor, primary CNS lymphoma (PCNSL) has risen dramatically in incidence over the past 30 years. There are two clinical subtypes of this disease. In immunocompetent patients, PCNSL occurs in an older population. This is similar to other non-Hodgkin lymphomas. Pathologic evaluation typically demonstrates monoclonal B cells. Patients with human immunodeficiency virus, organ transplantation, or other intrinsic or medication-induced immunosuppression are much more likely to develop PCNSL than non-immunosuppressed individuals. Histologically, this is a polyclonal B-cell tumor that is associated with the activation of Epstein-Barr virus.
MRI in PCNSL patients usually demonstrates a homogeneously enhancing lesion or lesions often adjacent to a ventricle ( Fig. 49.6 ). A positive cerebrospinal fluid (CSF) cytology is found in 25%–50% of these individuals. Biopsy is essential to make the diagnosis. A large resection is usually not indicated, as most of these tumors respond well to chemotherapy and/or RT. In some immunocompetent patients these enhancing brain lesions can disappear either spontaneously or with corticosteroid therapy. For this reason, if PCNSL is suspected, biopsy should be performed prior to treatment with corticosteroids.
PCNSL is markedly sensitive to therapy in immunocompetent patients; median survival is often in excess of 3 years. There are two approaches to treatment. The first involves high-dose intravenous (IV) methotrexate as a single agent or in combination with rituximab and temozolomide. The second combines a lower dose of IV methotrexate with ara-C, intrathecal methotrexate, and whole-brain RT. This approach is well tolerated in younger patients; however, significant cognitive toxicity occurs in patients older than age 60 years. Immunosuppressed patients are less likely to benefit from chemotherapy and treatment with RT alone. If possible, consideration should be given to reversing the immunosuppression.
Other Primary Brain Tumors
Ependymoma
These are unusual tumors of glial origin that can arise anywhere within the neuraxis. The floor of the fourth ventricle is the most common intracranial site for an ependymoma to develop. Histologically, ependymomas often have a cellular appearance characterized by a pseudo-rosette perivascular pattern. There is also a more malignant version with an anaplastic appearance; although unlike the case in gliomas, anaplasia may not confer poor prognosis. Myxopapillary ependymoma is a variant that occurs within the filum terminale at the end of the spinal cord.
MRI is the study of choice ( Fig. 49.7 ). Surgical resection is the primary treatment; however, tumor location determines whether a complete resection is achievable. The extent of tumor resection is the most important indicator of the eventual clinical course. Surgical resection of a myxopapillary ependymoma frequently results in a cure. Indicators of poor prognosis include incomplete resection and CSF spread. Such patients require either local or craniospinal RT. Chemotherapy is seldom used at the time of diagnosis.
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