Tumor.

Abstract

Tumors involving the central nervous system (CNS) include a wide variety of primary and metastatic entities. This chapter provides a neurosurgical perspective regarding some of the most common brain and spine tumors. Each subsection presents a specific tumor in the setting of a case presentation. The goal for each subsection is to review diagnostic and management pearls for the specific type of tumor presented and provide the reader with a starting point for more in depth reading. The first chapter presents a patient with a glioblastoma, which is the most common primary malignant brain tumor. Glioblastoma is the most malignant type of glioma, and despite aggressive management including surgery, radiation and chemotherapy have a poor prognosis. Clinical trials are often important components of treatment for patients with gliomas in general, and glioblastoma in particular. Tumors involving the skull base occur outside of the brain parenchyma and may involve the leptomeninges or cranial nerves. Subsections devoted to skull base tumors include those for meningioma, vestibular schwannoma, pituitary adenoma, and Cushing's disease. Of note, meningioma and schwannoma can occur throughout the CNS including the spine. Schwannomas can also occur in the peripheral nerves. Essentially, any site with leptomeninges can harbor a meningioma, and schwannomas can arise in cranial nerves, spinal nerve roots, and peripheral nerves. Vestibular schwannoma, also sometimes called acoustic neuroma, is the most common type of intracranial schwannoma, and arises from the vestibular portion of cranial nerve VIII. Cranial nerves V and VII are less common nerves of origin for schwannomas. Patients with neurofibromatosis type 2 (NF-2) typically have bilateral vestibular schwannomas, among other findings. Surgical options require careful selection of the approach based on the status of the patient's hearing and size of the tumor. Meningiomas are among the most common primary intracranial neoplasms. The vast majority are benign (grade 1), although atypical (15%) and malignant (1%) meningiomas do occur. Benign tumors can grow very slowly and reach a large size prior to patients developing neurological symptoms. Management of these tumors varies based on size, anatomic location, and presenting symptoms. Tumors that are large or causing neurological symptoms may require surgical intervention. Because these tumors can occur anywhere in the leptomeninges, the complexity of surgical approach can vary significantly. Radiation is an option for tumors that cannot be completely removed. For smaller or asymptomatic tumors, especially in older patients, conservative management with serial imaging is also an option. Pituitary adenomas are benign tumors of the pituitary gland with a unique management algorithm due to their potential to secrete stimulating hormones such as adrenocorticotrophic hormone (ACTH), growth hormone (GH), and prolactin (PRL). Classic presenting symptoms may reflect this aberrant endocrine activity or manifest as visual symptoms such as bitemporal hemianopsia due to direct compression of the overlying optic chiasm. Endocrinologists and ophthalmologists are involved in diagnosis and management, which may include surgical intervention for large, nonsecreting adenomas or medical management for prolactinomas. Some subtypes of pituitary adenoma have high potential for long-term medical morbidity due to their endocrine activity. One example is Cushing's disease, which is caused by an ACTH-releasing pituitary adenoma. Aggressive surgical management, even for tumors not visible on magnetic resonance imaging (MRI), is important for preventing long-term endocrine morbidity in these patients. Metastatic tumors due to cancer such as melanoma, lung cancer, and breast cancer can involve any part of the CNS. As systemic treatments for cancer improve and patients live longer, there may be an increase in the incidence of cancer spreading to the brain and spine. Presenting symptoms are typically reflective of the anatomic site of involvement. Sections regarding brain metastasis and vertebral column metastasis discuss the management of 2 of the most common CNS manifestations of systemic cancer. The 7 sections within the tumor section of this handbook provide a primer for the diagnosis and management of some of the most common neurosurgical oncology entities. However, there are many other types of primary brain and spine tumors, each with unique nuances in diagnostic workup and surgical management. Careful attention to a patient's history and neurological examination, as illustrated in the cases presented here, and an understanding of published evidence supporting various diagnostic and management strategies are key first steps in providing optimal treatment for these patients. CHAPTER 1: GLIOBLASTOMA MULTIFORME Case Presentation A 58-yr-old male with past medical history that includes type II diabetes mellitus and hyperlipidemia presents with progressive headaches over the past few weeks. Symptoms started with tussive headaches and progressed until he was having frequent, daily global headaches. He also complains of disequilibrium. He says when he reaches for things, especially with the left hand, he will sometimes miss the target. He smokes about a pack a day. He does not have a cancer history. He takes a baby aspirin daily. He denies weakness, numbness, or tingling. He denies blurry vision or visual issues. A brain MRI study with and without contrast revealed a heterogeneously enhancing mass in the right temporal lobe (Figure 1). Patient vitals: Temp-99.8 | Pulse-88 | Resp Rate-18 | BP-142/68 | WBC-9.6 | HgB-15.4.FIGURE 1.: MRI of the brain showing different views of a right temporal glioblastoma. T1-weighted postcontrast coronal, axial, and sagittal images (left to right) reveal a heterogeneously enhancing lesion with mass effect and edema consistent with glioblastoma. Far right is a diffusion-weighted MRI which shows no significant restriction of diffusion, which helps to rule out abscess as the underlying lesion.Questions The presentation and MRI findings are most consistent with which clinical presentation? Brain abscess Stroke Low grade brain tumor Parkinson's disease High-grade brain tumor Which MRI sequence is most able to help distinguish between a primary brain tumor from a cerebral abscess? T1 with contrast T1 without contrast T2 sequence Diffusion weighted imaging (DWI) Fluid-attenuated inversion recovery (FLAIR) Which craniotomy is most suitable for resection of the following lesion? Right pterional craniotomy Right temporal craniotomy Right frontal craniotomy Interhemispheric craniotomy The current first line treatment paradigm for glioblastoma multiforme (GBM) is? Radiation treatment only Radiation treatment and gross total resection Chemotherapy and gross total resection Gross total resection only Gross total resection, radiation, and chemotherapy Epidemiology Primary malignant brain tumors remain a daunting challenge in medicine, with grade 4 astrocytoma (also known as grade 4 glioma or GBM) being the most common and aggressive of these cancers. GBM epitomizes a class of brain tumors called gliomas that represent a broad diagnostic category with diffuse malignant cells known for their ability to infiltrate surrounding brain parenchyma. Based on population-based incidence data from the Cancer Brain Tumor Registry of the United States (CBTRUS), gliomas account for 30% of all primary brain and CNS tumors based on histology and 80% of all primary malignant tumors of the CNS. Astrocytomas and glioblastomas account for 76% of all gliomas. The incidence of GBM is ∼3/100 000 people per year with a mean age of 64 yr and a peak incidence between the ages of 65 and 74 yr with a male-to-female ratio of 1.5:1. Imaging Characteristics The appearance of GBM on MRI reflects major microenvironmental changes that characteristically develop in GBM tumors. These include multiple areas of necrosis as well as tissue edema and leaky tumor vessels, which result in strong peripheral gadolinium contrast enhancement on MRI, often associated with a nonenhancing central necrotic area. All of these factors combine to create unique microenvironmental features in GBMs that contrast sharply with normal brain tissue on histopathological analysis. While head computed tomography (CT) may be an initial screening study to identify brain masses, brain MRI with and without gadolinium is the preferred study of choice for brain tumors. GBMs and high-grade gliomas can readily be distinguished from low-grade gliomas because of their predilection to have heterogeneous enhancement on MRI as well as significant surrounding edema. GBMs are rapidly growing tumors and usually exhibit mass effect, edema, hemorrhage, necrosis, and secondary evidence of increased intracranial pressure. DWI may help distinguish GBM from cerebral brain abscesses because the latter tends to strongly restrict on DWI (Figure 2). FLAIR sequences can determine the extent of edema surrounding a tumor.FIGURE 2.: Axial MRI scans showing paired T1-weighted postcontrast and DWI sequences of 2 patients with deep brain lesions. Note the ring-enhancing lesion seen in the patient with a GBM on the far left and the ring-enhancing lesion of the patient with the cerebral abscess on the middle right. DWI may help distinguish GBM on the middle left from cerebral brain abscesses far right because the latter tends to strongly diffusion restrict on DWI as can be seen in this case example. The purulent necrotic center of the abscess strongly diffusion restricts and a component of this purulence has already breached in the ventricular system and is layered in the left occipital horn.Functional MRI may play a critical role in the workup of GBM patients because it can readily identify areas of eloquent or functionally important cortex and their relationship to the tumor (Figure 3). This can guide resection and is important for preoperative planning. In the case depicted in Figure 3, the patient presented with a large left temporal lobe GBM. Functional MRI localized Wernicke's area (receptive speech) immediately adjacent to the tumor in the posterior banks of the left superior temporal gyrus. This patient underwent an awake craniotomy with speech mapping to help maximize tumor resection while minimizing risks of permanent aphasia. During awake surgery, the patient is asked to perform a variety of neurological tasks related to speech while the surgeon stimulates the brain with an electrical probe. Any critical speech areas identified are not removed, even if the tumor infiltrates these areas.FIGURE 3.: Functional MRI scans identifying white matter tract mapping (left panel), speech mapping (middle panel) and bilateral hand grasp (right panel).Genetic Abnormalities and Natural History Most GBMs appear to be sporadic in origin with no mechanistic link to environmental or behavioral factors such as smoking or electromagnetic fields. GBMs either arise de novo (primary GBM) or progress from lower-grade astrocytomas (secondary GBM) through multiple genetic alterations. Amplifications of epidermal- and platelet-derived growth factor signaling pathways, p53 mutations, retinoblastoma pathway alterations, and chromosome 10 alterations, including PTEN (phosphatidylinositol 3-phosphatase) mutations, are among the most common molecular alterations associated with progression of astrocytomas to GBMs. Alterations in several intracellular signaling pathways leading to the loss of senescence and cell cycle checkpoints contribute to pleomorphism and karyotypic heterogeneity in GBM cells. O6-methylguanine DNA methyltransferase (MGMT) gene methylation status and isocitrate dehydrogenase (IDH) mutations have been 2 recent genetic discoveries that have had prognostic clinical implications in GBM patients. The MGMT gene codes for a DNA repair enzyme that repairs damaged DNA. Patients with hypermethylated MGMT status have reduced DNA repair capacity and have improved survival responses to treatment with alkylating chemotherapeutics such as temozolimide. Alternatively, IDH mutations have been found predominantly in secondary GBM and in the vast majority of low-grade gliomas. IDH mutations are associated with improved survival in patients with gliomas via a mechanism the remains largely unknown at this time. Clinical Presentation GBMs either arise de novo or progress from lower grade astrocytomas through multiple genetic alterations as mentioned above. Patients with secondary GBM will often have a clinical course that starts in their 20 to 30 s, with an initial low-grade glioma (grade 2) that progresses with time into a high-grade glioma (grade 3 or 4). Primary GBM patients will usually present later in life between the fifth and seventh decade and lack a history of a previously identified lesion. Their symptoms usually develop over a short period of time and they present with a sizeable enhancing mass on MRI. Because of their rapid proliferative rate, GBMs often outstrip their vascular supply and develop numerous foci of necrosis and hypoxic gradients that stimulate angiogenesis. Unfortunately, newly recruited blood vessels to the tumor are often faulty, with multiple shunts and a leaky blood brain barrier that often leads to focal edema and mass effect on surrounding brain. Patients will commonly present with elevated intracranial pressure, which manifests with global headaches that are exacerbated by coughing or lying down. Patients will often develop other symptoms including nausea and emesis, blurred vision, papilledema and possibly even cranial nerve palsies with motor and sensory deficits. If the mass effect on the brain is large enough and there is profound midline shift, mental status and arousal can be compromised. Alternatively, as tumors infiltrate eloquent structures in the brain, both vision and speech can be affected on initial presentation. Extent of Resection The percentage of tumor that is removed surgically (extent of resection) has been shown to impact overall survival in that increasing the amount of tumor removed improves survival. Gliomas are notoriously invasive and readily infiltrate normal brain making complete surgical resection essentially impossible. So devastating is the prognosis of this disease that despite aggressive surgical resection followed with optimized radiation and chemotherapy treatment, the median survival for a GBM patient today remains at around 15 mo. To put the dismal prognosis of this cancer more into perspective, a majority of patients succumb to their disease within 2 yr and nearly all that survive die by 5 yr, making GBM an inevitably fatal cancer. Extent of resection for GBM appears to correlate with overall survival and patient outcomes but is largely based on retrospective case series with inherent study biases and confounders. Randomized controlled trials directly testing this concept are lacking due to lack of clinical equipoise to execute them. The aggressive biology of this neoplasm, as evidenced by clinical survival metrics and basic science data, has led some experts to insightfully point out that “significant improvements in survival will not result from more extensive surgery” (Stummer et al, Neurosurgery, 2008). Although advances in imaging, surgical technique, drug delivery and molecular stratification of these cancers have demonstrated modest improvements in our management in the past 3 decades, significant breakthroughs in treatment are still lacking and will come from better insight into the disease process and more rational molecular targeting. Surgical and Medical Management Patients who acutely present with large enhancing lesions, surrounding brain edema and mass effect are often symptomatic and will require hospitalization and palliation with steroids in addition to an oncological work up to determine if the lesion is a primary or metastatic brain tumor. Dexamethasone is typically used to treat the edema initially and often leads to improvements in the presenting neurological symptoms. If patients present with seizures, antiepileptic drugs (AEDs) are administered. At this point, surgical decisions are made. The goal of surgery is maximal resection with minimal neurological morbidity. Patients with deep-seated tumors or tumors involving eloquent structures may not be candidates for aggressive surgery or instead undergo biopsy to achieve diagnosis and provide tissue for molecular testing. Patients with surgically accessible tumors undergo maximal safe resection. Once surgical resection is complete, patients can be weaned off their steroids or reduced to a basal rate based on the extent of their residual disease, degree of edema and preference of the neuro-oncologist and radiation oncologist. The mainstay treatment protocol after surgery is based on a randomized control trial that was shown to improve 2-yr survival rates and now has conventionally been called the Stupp Protocol: Radiotherapy – Total 60 Gy – 2 Gy per daily fraction (Monday to Friday) over 6 wk Temozolomide – During radiotherapy: 75 mg per square meter of body-surface area per day, 7 d per week – Postradiotherapy (adjuvant): 6 cycles consisting of 150 to 200 mg per square meter for 5 d during each 28-d cycle The goals of surgery for any GBM patient is (1) obtain tissue for a histopathological diagnosis (2) decompress the brain from the mass effect, and (3) cytoreduction of the tumor burden. Gross total resection is often the goal with the intent to minimize postoperative functional deficits. The use of preoperative navigation systems has helped guide surgical resection and makes preoperative craniotomy planning more efficient and safe by avoiding critical neural and vascular structures. Video 1 demonstrates a typical operative room set up and patient positioning for the case presented here. Patients are positioned to optimize the approach to the tumor, and stereotactic navigation systems are oriented to register patient's facial landmarks preoperatively with anesthesia and surgical tables oriented for efficient and functional workflow. Once the patient's facial landmarks are registered, the tumor can be topographically projected on the surface of the scalp and an appropriate incision can be mapped out. Patient positioning and incision planning is critical and is often the key to a good approach. Navigation systems that rely on preoperative high resolution MRI allow for excellent incision and craniotomy planning, however once resection of the tumor begins and brain fluid shifts result from dissection, navigations systems cannot be confidently relied on intraoperatively for accuracy. Intraoperative MRI and intraoperative ultrasound are important tools in the surgeon's armamentarium that allow for live imaging feedback of the brain as it responds to dynamics shifts. Both intraoperative imaging modalities allow for immediate assessment of residual tumor and can help maximize extent of resection. The use of intraoperative microscopes can dramatically improve visualization of tumor brain interfaces and allows for 2 surgeons to visually see the field and participate in surgery (Figure 4). {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"VIDEO 1.","caption":"Operative setup and surgery for resection of the right temporal glioblastoma shown in Figure 1. This video can be accessed in the HTML version of the article. Please visit www.operativeneurosurgery-online.com to view this article in HTML and play the video.","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_vwmrdd13"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} FIGURE 4.: Intraoperative setup and patient positioning for a brain tumor resection. The patient is in the supine position with his head turned to the left, optimizing access to the right temporal region. The patient's head is rigidly fixed to the bed using pins. Navigation equipment and an intraoperative ultrasound are ready for use. The incision is mapped and marked, and then the area is prepped and draped. The final panel shows use of the operative microscope during tumor resection. The preoperative MRI is displayed in the background. This is the same case as shown in Figure 1 and the operative experience further described in the accompanying video (Video1).Finally, the integration of neuromonitoring and the use of awake craniotomies have been important advances that have allowed surgeons to navigate around eloquent areas of the brain while focusing their resection to areas of disease and avoiding critical structures. More recently the introduction of dyes, like 5-aminolevulinic acid that is preferentially taken up the tumor has helped surgeons define infiltrating margins of the tumor to maximize extent of resection, although further clinical trials are needed to validate these agents. Answers E. GBMs demonstrate strong heterogeneous enhancement with central areas of necrosis; they usually do not diffusion restrict. In addition, the patient has no stigmata of infection in this case presentation. D. DWI may help distinguish GBM from cerebral brain abscesses because the latter tends to strongly restrict on DWI (see Figure 2). B. A temporal craniotomy is the most suitable approach for a temporal lobe lesion; a pterional approach is less favored since it is more of front-temporal approach and in this case the lesion is predominantly in the temporal lobe. E. The Stupp protocol which includes resection, chemotherapy and radiation treatment has been tested in randomized control trials and is currently the standard of care for GBM patients. Pearls ✓ GBM is the most common primary malignant primary brain tumor and carries a poor prognosis. ✓ The differential for peripherally enhancing lesions is broad and MRI can help distinguish GBM from other pathologies ✓ The current first line treatment paradigm for GBM is maximal safe resection, followed by radiation and chemotherapy ✓ The goals of surgery for any GBM patient is (1) obtain tissue for a histopathological diagnosis and genetic/molecular studies (2) decompress the brain from the mass effect, and (3) cytoreduction of the tumor burden. SUGGESTED READING Stummer W, Reulen HJ, Meinel T, et al. Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery. 2008;62(3):564-576; discussion 564-76. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-996. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. The Lancet Oncology. 2006;7(5):392-401. Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997-1003. Ostrom QT, Gittleman H, Liao P, et al. CBTRUS Statistical Report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro Oncol. 2014;16(Suppl 4):iv1-63. CHAPTER 2: MANAGEMENT OF BRAIN METASTASES Case Presentation A 59-yr-old male with a history of 30 pack-year of smoking presents with 3 wk of progressive headaches and unsteady gait. He denies history of seizures, weakness, or vision changes. His neurological exam is significant for right-sided dysmetria and gait ataxia. Brain MRI was obtained and is shown in Figure 5. CT of the chest shows a lung mass.FIGURE 5.: T1-weighted MRI sequences A, with and B, without contrast showing right cerebellar heterogeneously enhancing lesion consistent with a brain metastasis.Questions The 5 most common sources of brain metastases are: Lung, breast, melanoma, colorectal, and renal Lung, breast, prostate, melanoma, and ovarian Lung, breast, melanoma, prostate, and renal Breast, prostate, thyroid, melanoma, renal Breast, melanoma, GI tract, thyroid, renal All the following are part of the treatment and workup for this patient except: Steroids Hyperosmolar therapy Brain radiation Craniotomy for resection of mass Biopsy of chest mass The most important factor that predicts the prognosis of patients with brain metastases is: Age Extent of extracranial disease Karnofsky Performance Scale (KPS) Number of brain metastases Specific tumor type All the following are evidence supported treatment options for a patient with solitary brain metastasis except: Surgical resection followed by stereotactic radiosurgery (SRS) SRS alone Chemotherapy Surgical resection followed by whole brain radiation All the following tumors are considered ‘radiation sensitive’ except: Lymphoma Melanoma Small cell lung cancer Germ cell tumors Epidemiology Brain metastases are the most common type of malignant brain tumors. They constitute over 50% of all malignant brain tumors seen in the population. Almost all types of cancer can metastasize to the brain. However, lung and breast cancer account for the majority of diagnosed metastases due to the higher incidence of these tumors among the population. Other common sources of brain metastases are listed in Table 1. TABLE 1. - Most Common Sources of Metastatic Brain Tumors Based on Autopsy Data Primary tumor Percentage (%) Lung 40-50 Breast 10-20 Renal 5-10 Melanoma 5-10 Colorectal 1-5 Reported incidence of brain metastasis varies widely among studies. In the USA, the incidence of newly diagnosed brain metastasis is about 170 000 per year. In autopsy studies, more patients are found to harbor brain metastases than reported in premortem studies. This is likely because patients die from their primary tumor prior to developing symptoms from brain metastasis. On the other hand, studies also show that the number of newly diagnosed brain metastases is increasing. There are various reasons for the observed increased incidence of brain metastasis. The more frequent use of sensitive diagnostic studies (MRI and positron emission tomography [PET] scans) is 1 reason for the increased rate of diagnosis. However, the most likely reason for this observed increase is the development of more efficacious systemic cancer treatments leading to longer patient survival. For example, the development of HER2 targeted therapy for HER2 positive breast cancer has led to an increase in median patient survival by many months. However, these therapeutic agents show poor CNS penetration and therefore do not efficaciously treat brain metastases. Patients surviving longer due to better treatment of their systemic disease give an opportunity for existing brain metastases to continue to grow and become symptomatic, and also give more time for systemic disease to potentially spread to the brain. Both scenarios effectively increase the incidence of brain metastases. Similar observations have been made in many other cancers. Pathophysiology Metastatic brain tumors are thought to mainly spread to the brain via hematogenous routes. Tumor cells first accumulate enough genetic transformation to grow in their primary location. Further genetic transformation promotes angiogenesis and local invasion. Eventually tumor cells are shed into the systemic circulation and make their way into the pulmonary circulation. Here some tumor cells get trapped in the pulmonary capillary beds where they form metastatic deposits in the lungs. Eventually tumor cells may escape the pulmonary capillary bed and reach the brain where they enter the local capillary beds. Tumor cells are able to penetrate the blood brain barrier and form metastatic deposits. As such, brain metastasis tend appear at the junction of the gray and white matter where the smaller arterial diameters act as a trap for metastatic cells. In agreement with this mechanical spread theory, the probability of finding a brain metastasis in any area of the brain is proportional to the percentage of total brain blood flow it receives. As such, 80% of metastases appear in the cerebrum vs 20% in the posterior fossa. This theory also explains why a majority of brain metastases are usually diagnosed either concurrently or after the discovery of lung metastases. On the other hand, this theory does not explain the predilection of certain tumors to seed other areas of the brain preferentially (eg, pelvic and GI tumor seem to favor the posterior fossa) or for certain tumors to target the brain more preferentially than other organs (eg, melanoma). Once tumor cells reach the brain, they can remain dormant or divide and grow. As they grow, brain metastases produce symptoms by local invasion of normal cortex. A second mechanism through which tumors produce symptoms is due to surrounding cerebral edema. The cerebral edema is a result of disruption of the blood brain barrier. This disruption is primary mediated by effect of growth factors, especially vascular endothelial growth factor, on endothelial cells. As a result, fluids start leaking into the brain extracellular space through the leaky endothelium of blood vessels surrounding metastases. Clinical Presentation Patients with brain metastases can present with a variety of symptoms (Table 2). TABLE 2. - Common Symptoms on Presentation General symptoms Focal symptoms Headache Focal seizure Nausea/emesis Face/arm/leg weakness Generalized Seizure Aphasia Confusion Visual field deficits Lethargy Dysphagia Headache Headache is the most common presentation. The headache may be related to increased intracranial pressure from tumor size or tumor-related cerebral edema, obstruction of a ventricle leading to hydrocephalus, or due to direct meningeal irritation from dural-based metast