Primary and Metastatic Brain Tumors: Page 2 of 5
Primary and Metastatic Brain Tumors: Page 2 of 5
Screening for Metastatic Brain Tumors
Screening for brain metastases is performed in only a few clinical situations.
Lung Cancer
Approximately 10% to 15% of patients with small-cell lung cancer have brain metastases at diagnosis, and such metastases develop in more than 45% of patients during their illness. Therefore, cranial CT or MRI is performed as part of the initial evaluation for extent of disease.
Occasionally, patients with non–small-cell lung cancer (NSCLC) undergo routine cranial CT or MRI before definitive thoracotomy, because the presence of brain metastases may influence the choice of thoracic surgical procedure. This approach is particularly valuable in patients with suspected stage IIB or III disease for whom thoracotomy is considered following neoadjuvant therapy.
Diagnosis
Radiographic Appearance of Primary Lesions
MRI
The diagnosis of a brain tumor is best made by cranial MRI. This should be the first test obtained in a patient with signs or symptoms suggestive of an intracranial mass. MRI is superior to CT and should always be obtained with and without contrast material such as gadolinium.
High-grade or malignant primary brain tumors appear as contrast-enhancing mass lesions that arise in white matter and are surrounded by edema (Figure 1). Multifocal malignant gliomas are seen in ~5% of patients.
Low-grade gliomas typically are nonenhancing lesions that diffusely infiltrate and tend to involve a large region of the brain. Low-grade gliomas are usually best appreciated on T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI scans (Figure 2). As many as 40% of nonenhancing tumors may harbor foci of high-grade glioma.
CT
A contrast-enhanced CT scan may be used if MRI is unavailable or if the patient cannot undergo MRI. It is important to note that a pacemaker is not always a contraindication to MRI, and some centers will have pacemaker protocols wherein patients without high-degree heart block may, with the approval of their cardiologist, undergo imaging with resetting of their pacemaker afterward. CT is adequate for excluding brain metastases in most patients, but it can miss low-grade tumors or small lesions located in the posterior fossa. Tumor calcification is often better appreciated on CT than on MRI.
PET
Body positron emission tomography (PET) scans performed for staging of systemic malignancies have a sensitivity of only 75% and a specificity of 83% for identification of cerebral metastases. Therefore, in this setting they are less accurate than MRI, which remains the gold standard.
Radiographic appearance of metastatic lesions
On CT or MRI, most brain metastases are enhancing lesions surrounded by edema, which extends into the white matter (Figure 3). Unlike primary brain tumors, metastatic lesions rarely involve the corpus callosum or cross the midline.
The radiographic appearance of brain metastases is nonspecific and may mimic other processes, such as infection. Therefore, the CT or MRI scan must always be interpreted within the context of the clinical picture of the individual patient, because cancer patients are particularly vulnerable to opportunistic CNS infections or may develop second primaries, which can include primary brain tumors.
Other imaging tools
Magnetic resonance spectroscopy (MRS) and perfusion imaging can help differentiate low-grade from high-grade brain tumors but cannot distinguish different tumor types of the same grade.
Pathology
Glial tumors arise from astrocytes, oligodendrocytes, or their precursors and exist along a spectrum of malignancy. The astrocytic tumors are graded, using the four-tier WHO system. Grade I tumors are localized tumors such as pilocytic astrocytomas or gangliogliomas, which are usually found in children and younger adults. Grade II tumors are low-grade diffuse astrocytomas. Grade III (anaplastic astrocytoma) and IV (glioblastoma) tumors are high-grade malignant neoplasms. Grading is based on pathologic features, such as endothelial proliferation, cellular pleomorphism, mitoses, nuclear atypia, and necrosis. The oligodendroglial neoplasms are classified as either low-grade oligodendroglioma (grade II) or anaplastic oligodendroglioma (grade III).
Low-grade glial tumors (such as astrocytoma and oligodendroglioma) and mixed neuronal-glial tumors (such as ganglioglioma) grow slowly but have a propensity to transform into malignant neoplasms over time. Transformation is usually associated with progressive neurologic symptoms and the appearance of enhancement on MRI.
The high-grade gliomas include glioblastoma, gliosarcoma, anaplastic astrocytoma, and anaplastic oligodendroglioma. These tumors are extremely invasive, with tumor cells often found up to 4 cm away, and even on the contralateral side of the brain from the primary tumor.
Ependymoma
Intracranial ependymomas are relatively rare, accounting for less than 2% of all brain tumors. They are most frequently seen in the posterior fossa or spinal cord, although they may also arise in the supratentorial compartment. Ependymomas are typically low grade histologically, but their high rate of recurrence indicates malignant behavior.
Medulloblastoma
Medulloblastomas are uncommon in adults but are one of the two most common primary brain tumors in children (the other being cerebellar astrocytomas). Medulloblastomas arise in the cerebellum and are always high-grade neoplasms.
Two studies developed distinct molecular classifications of medulloblastoma seen in both children and adults. Northcott and colleagues used integrative genomics to identify the following four specific molecular variants of medulloblastoma: WNT, SHH, group C, and group D. These four types had distinct subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. SHH tumors were seen in infants and adults, whereas WNT and group D tumors were seen among all ages. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (group C), and KCNA1 (group D) could appropriately classify medulloblastomas in approximately 98% of patients. Group C tumors peaked in childhood, were not seen in adults, and conferred the poorest prognosis, independent of metastatic status. Remke and colleagues used gene expression profiling to reveal three distinct molecular variants of adult medulloblastoma, with distinct demographics, genetics, transcriptome, and prognostic implications: SHH, WNT, and subtype D. Both overall survival and progression-free survival were superior for WNT-driven tumors and intermediate for SHH-driven tumors, while subtype D tumors trended toward shorter survival. In a nonrandomized phase II trial, 70 patients 70 years and older with a Karnofsky Performance Status (KPS) score of less than 70 were given temozolomide alone (150 to 200 mg/m2 daily for 5 days every 4 weeks) until progression. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 13% and 14% of patients, respectively. Median progression-free survival time was 16 weeks and median overall survival was 25 weeks; compared with historical controls, these outcomes were significantly greater than those associated with supportive care alone. Eighteen patients (26%) increased their KPS score to 70 or greater.
Primitive Neuroectodermal Tumors
Primitive neuroectodermal tumors (PNETs) are high-grade, aggressive tumors that usually occur in children. They include pineoblastoma and neuroblastoma. Histologically, they are identical to medulloblastomas, but their prognosis is usually worse than that of medulloblastomas. Thus, their biology is different, even though they may be similar pathologically.
Extra-Axial Tumors
The most common extra-axial tumor is the meningioma. Meningiomas are usually benign tumors that arise from residual mesenchymal cells in the meninges. They produce neurologic symptoms by compressing the underlying brain. Meningiomas rarely are malignant or invade brain tissue (Figure 4).
Other common extra-axial tumors include pituitary adenoma, epidermoid or dermoid tumors, and acoustic neuroma (vestibular schwannoma). Most extra-axial tumors have a benign histology but can be locally invasive. Many extra-axial benign tumors are incidentally identified on MRI performed for nonspecific symptoms, such as headache. Most of these tumors do not require therapy and do not enlarge. Many benign extra-axial tumors identified in this way can be observed with serial imaging studies alone.
Metastatic Brain Tumors
The pathology of metastatic brain lesions recapitulates the pathology of the underlying primary neoplasm. This feature often enables the pathologist to suggest the primary source in patients whose systemic cancer presents as brain metastasis. However, even after a complete systemic evaluation, the site of the primary tumor remains unknown in 10% to 15% of patients with brain metastases.
Staging and Prognosis
Staging
Staging is not applicable to most primary brain tumors because they are locally invasive and do not spread to regional lymph nodes or distant organs. Staging with an enhanced complete spinal MRI and cerebrospinal fluid (CSF) evaluation is important for a few primary tumor types, such as medulloblastoma, ependymoma, and PNET, because they can disseminate via the CSF. All systemic cancers are stage IV when they present with a brain metastasis.
Prognostic Factors
For most patients with primary brain tumors, prognosis is inversely related to pathologic grade and patient age, and is directly related to the overall clinical condition at diagnosis. Several molecular markers that correlate well with prognosis have been identified, such as mutations of the IDH1 gene in the majority of low-grade gliomas and loss of heterozygosity on chromosomes 1p and 19q, which is characteristic of oligodendroglioma.
Several studies have identified glioblastoma subtypes on the basis of gene expression profiles: proneural, neural, classic, and mesenchymal. Proneural tumors are more likely to carry mutations of IDH1 and p53 and are associated with improved overall survival. Classic tumors frequently (95% of the time) demonstrate EGFR amplification, while mesenchymal tumors are most likely to have mutations or deletions of NF1, often combined with inactivation of PTEN. Classic tumors also have a higher activity of mesenchymal and astrocytic markers CD44 and MERTK, as well as high expression of CHI3L and MET, and are associated with the shortest overall survival time.
The Cancer Genome Atlas (TCGA) presented its most recent update on the landscape of somatic mutations in glioblastoma in 2013. Several recurrently mutated genes were identified, as well as complex rearrangements of genes for signature receptors including EGFR and alpha-type platelet-derived growth factor receptor (PDGFRA). Telomerase reverse transcriptase (TERT) promoter mutations correlated with elevated mRNA expression, supporting a role in telomerase reactivation. Additionally, survival advantage of the proneural subtype was conferred by the glioma CpG island methylator phenotype (G-CIMP). Finally, DNA methylation of the O-6-methylguanine-DNA methyltransferase (MGMT) gene may be a predictive biomarker for chemotherapeutic treatment response.
The importance of the mutation in IDH1 at arginine 132 (IDH1R132MUT) has now been well established. Glioblastomas arising with and without the IDH1 mutation appear to be distinct entities arising from separate cells of origin. It is thought that EGFR amplification or PTEN loss leads to IDH1 wild-type glioblastoma, while a non–stem cell neural precursor in the frontal lobe that undergoes IDH1 mutation and the CpG island methylator phenotype (CIMP) status is the initial lesional event in the development of IDH1-mutant glioma. IDH1 mutant enzyme, when introduced into human astrocytes, induces DNA hypermethylation, resulting in changes seen in CIMP-positive grade II and III gliomas.
IDH mutation is a more powerful prognosticator than WHO grade in grade II and III astrocytomas. IDH-mutant tumors had TP53 mutations, PDGFRA overexpression, PTEN promoter methylation, and prolonged survival, whereas IDH wild-type tumors were associated with EGFR amplification, PTEN loss, and shorter survival.
With conventional treatment, including surgical resection, radiotherapy, and chemotherapy with the alkylating agent temozolomide, median survival time for patients with grade IV glioblastoma ranges from 14 to 18 months. In contrast, low-grade gliomas can be associated with a survival approaching a decade or more; however, patients 40 years or older with low-grade glioma generally have a more aggressive disease and their median survival time is usually less than 5 years. Oligodendroglial histology is favorable, and survival of patients with grade III disease can range from 7 years to more than 14 years if there is 1p/19q codeletion.
For a large proportion of patients with brain metastases, median survival is only 4 to 6 months after whole-brain radiotherapy. However, some patients (ie, those who are younger than 60 years, have a single lesion, or have controlled or controllable systemic disease) can achieve prolonged survival, and these individuals warrant a more aggressive therapeutic approach. Furthermore, most of these patients qualify for vigorous local therapy for their brain metastases, such as surgical resection or stereotactic radiosurgery. These approaches can achieve a median survival of 40 weeks or longer, and rarely some patients are cured.