CHAPTER 4
Tumors of the Brain SEONG-JIN MOON, MD • DANIEL T. GINAT, MD, MS • R. SHANE TUBBS, MS, PA-C, PHD • MARC D. MOISI, MD, MS
BACKGROUND Tumors of the brain present a special challenge for both patients and physicians. Every year, a new brain tumor is discovered in 6.4 cases per 100,000 persons with an overall 5-year survival rate of approximately 33.4%.1 Nearly 700,000 Americans live with a primary brain tumor. Brain tumors can occur at any age, but the greatest incidence is with ages 65 years and older, and there is a slightly higher predominance in men than in women.2,3 Over a person’s lifetime, there is an approximately 0.6% risk of being diagnosed with a central nervous system cancer. The impact that a diagnosis of brain tumor has on a patient cannot be overstated: some brain tumors can cause significant disability and drastically worsen quality of life, whereas others do not. New treatments offer opportunities to extend life and minimize disability.
CLASSIFICATION Intracranial tumors are generally classified into either malignant or benign tumors. Furthermore, malignant tumors can be either primary or metastatic. Metastatic lesions are more common than primary tumors.4 Generally, the proportion of adults with brain tumors increases with age, given that metastatic lesions are more prone to develop over time. The most prevalent brain tumor types in adults are meningiomas, which make up nearly 33.8% of all primary brain tumors5; gliomas (i.e., glioblastomas, ependymomas, astrocytomas, oligodendrogliomas) make up almost 80% of malignant brain tumors.6 Intracranial tumors are often divided into World Health Organization (WHO) classification scale, which can provide patients and clinicians with further information regarding prognosis and management.7 The WHO scale divides brain tumors into four different
classes, from 1 through 4. WHO grade 1 tumors are generally nonmalignant, slower growing, better prognostic lesions. WHO grade 2 tumors are generally nonmalignant but can also be malignant and have a higher propensity for recurrence than grade 1 tumors. WHO grade 3 tumors are aggressive malignant lesions and often recur as higher grade lesions. WHO grade 4 tumors exhibit the most aggressive of lesions and generally exhibit a very high recurrence ratedthey demonstrate the poorest prognosis for patients.
CLINICAL PRESENTATION The clinical presentation of intracranial tumors can vary widely and run the spectrum from a patient who presents with clinical obtundation to an asymptomatic presentation. The location of an intracranial tumor along with its size and mass effect dictates its clinical presentation. Many patients present with clinical signs and symptoms of increased intracranial pressure: headache, nausea/vomiting, ocular palsies, altered mental status, loss of balance, seizures, or papilledema.8 Some patients can present solely with one clinical symptom, whereas others present with no symptoms at all. For lesions within the frontal lobe, memory, reasoning, personality, and thought processing can be affected. For lesions within the temporal lobe, behavior, memory, hearing, vision, emotion, and speech can be affected. For lesions within the parietal lobe, sensory perception and spatial relations can be affected. For lesions within the occipital lobe, vision can be affected. For lesions within the brainstem or cerebellum, balance and coordination can be affected. A pituitary tumor can compress the optic nerve and cause a bitemporal hemianopsia. A tumor within Broca’s area can present with expressive
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aphasia, whereas a tumor within Wernicke’s area can present with fluent aphasia. Meningiomas are duralbased lesions; they are found alongside the dural meninges, and their clinical effects are often related to local mass effect on surrounding tissue. Glioblastomas are very aggressive WHO grade 4 neoplasms
with a poor prognosis for recovery. Primary cerebellar lesions that are not metastatic in origin are often hemangioblastomas.9 Often, such lesions can cause considerable mass effect on surrounding tissue and structures and also have significant surrounding edema as well.
Meningioma. Axial postcontrast T1 MR images show a dural-based mass along the inferior aspect of the left tentorium cerebellum, with a dural tail that extends to the left internal auditory canal.
Meningioma. Axial T2 and postcontrast T1 MR images show an enhancing mass centered in the left sphenoid triangle with associated vasogenic edema in the left temporal lobe and extension into the left orbit.
CHAPTER 4 Tumors of the Brain
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Glioblastoma. FLAIR and postcontrast T1 MR images show a heterogeneously enhancing mass that spans posterior corpus callosum.
Lung cancer metastases. Axial postcontrast T1 MRI shows multiple enhancing nodules in the bilateral cerebral hemispheres.
Breast cancer metastasis. Sagittal postcontrast T1 MRI shows a heterogeneously enhancing dural-based mass along the frontal convexity.
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Hemangioblastoma. Axial postcontrast T1 MR images show cystic tumors in the cerebellum with enhancing nodules.
Primitive Neuroectodermal Tumor (PNET). Axial FLAIR and postcontrast T1 MR images show a mass in the right frontal lobe with irregular peripheral enhancement and surrounding edema with midline shift.
CHAPTER 4 Tumors of the Brain
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PHYSICAL EXAMINATION
MANAGEMENT
A thorough physical and neurologic examination should be performed on all patients with intracranial tumors. Neurologic examination consists of a mental status examination with a complete cranial nerve assessment, along with motor/sensory testing, reflex testing, and cerebellar testing. Elements of complex motor system testing and speech and memory testing should also be assessed. As stated previously, the location of an intracranial tumor dictates its presentation. For example, a patient with a tumor present within the motor strip may present with profound contralateral motor weakness, whereas a patient with a pituitary tumor may complain of visual blurriness or generalized hormone discrepancy. A cerebellar tumor may present in a patient with primary gait imbalance, or a patient with hearing difficulty may present with a vestibular schwannoma. A thorough cranial nerve assessment can also provide further clues for the astute clinician in localizing the location and most likely differential diagnoses of intracranial tumors.
Adult intracranial tumors are best managed by a multidisciplinary team of clinicians. Management options include observation surveillance, surgical resection, chemotherapy, radiation therapy, or a combination thereof. No two intracranial tumors are the same, which means that no two intracranial tumors are managed the same. A variety of scales may aid the patient and clinician in determining the baseline functional status of a patient, which aids in the patient’s decision-making. In neuro-oncology, some notable examples include the Karnofsky performance status scale12 (outlined in the following section) and the Eastern Cooperative Oncology Group (ECOG )13 performance status. Such scales assist the patient and clinician in making the most informed decision regarding further therapies and different treatment modalities.
DIAGNOSIS
Able to carry on normal activity and to work; no special care needed.
Diagnosis of adult intracranial lesions is generally through a combination of history and physical examination findings, corroborated by imaging support. A clinician approaching a patient with either known or suspected concern for intracranial tumors should collect a thorough history, which often provides clues to the location, duration, and classification of intracranial tumors. In general, a physician will order a computed tomography (CT) scan of the head or a magnetic resonance imaging scan of the brain to better evaluate intracranial tumors. The aforementioned imaging sequences provide structural and anatomic characteristics of the intracranial tumors in question, which aids clinicians in generating a differential diagnosis as well as in further management. MR spectroscopy and PET scans offer further clues into the nature of such intracranial tumors, which in turn can aid in making an accurate diagnosis.10 For some intracranial tumors, identification of the vascular supply is critical to the subsequent management. These intracranial tumors warrant further vascular imaging, in the form of CT angiography/ magnetic resonance angiography (CTA/MRA), as well as venous modalities as well i.e., CT venography/ magnetic resonance venography (CTV/MRV). For intracranial tumors that warrant critical vascular findings and close affinity with vascular structures, a diagnostic cerebral angiogram may be necessary.11
Karnofsky Performance Status Scale Definitions Rating (%) Criteria 100 90
80
Unable to work; able to live at home and care for most personal needs; varying amount of assistance needed.
70
60
50
Unable to care for self; requires equivalent of institutional or hospital care; disease may be progressing rapidly.
40 30
20
10 0
Normal no complaints; no evidence of disease. Able to carry on normal activity; minor signs or symptoms of disease. Normal activity with effort; some signs or symptoms of disease. Cares for self; unable to carry on normal activity or to do active work. Requires occasional assistance, but is able to care for most of his/her personal needs. Requires considerable assistance and frequent medical care. Disabled; requires special care and assistance. Severely disabled; hospital admission is indicated although death not imminent. Very sick; hospital admission necessary; active supportive treatment necessary. Moribund; fatal processes progressing rapidly. Dead
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Eastern Cooperative Oncology Group (ECOG) Performance Status* Grade ECOG 0 1
2
3 4 5
Fully active, able to carry on all predisease performance without restriction Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours Capable of only limited self-care, confined to bed or chair more than 50% of waking hours Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair Dead
*Published in Oken MM, Creech RH, Tormey DC, Horton J, Davis TE,
McFadden ET, Carbone PP. Toxicity And response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649e655.
Management of the patient with an intracranial tumor requires addressing the tumor itself as well as its neurologic sequelae. For example, a patient who is acutely obtunded from a large brain tumor should have his/her airway evaluated and stabilized first. Seizures should be controlled either with medication or, if sometimes required, deep sedation. Hydrocephalus due to obstruction caused by an intracranial tumor can be managed in the acute setting with an external ventricular drain versus emergent decompressive surgery for resection of said lesion. If hydrocephalus persists, the patient may require cerebrospinal fluid diversion, likely in the form of a ventriculoperitoneal shunt.14 If surgical resection is a possibility, a consultation with a neurosurgeon should be made so that the details and feasibility of such a surgery, as well as risks and benefits, could be explained to the patient and his/her family. Some intracranial lesions are more amenable to gross total resection, whereas other tumors will require a surgical biopsy first, which in turn will dictate further management. The neurosurgeon may discuss with the patient which surgical approach and operative management would be best to treat the patient’s intracranial tumor. For example, a neurosurgeon may discuss with the patient the possibility of approaching a pituitary tumor via a transsphenoidal approach or by a pterional craniotomy. How the neurosurgeon delivers such medical information is often as important as the medical information itself.15 Different surgical approaches that are specific to the individual
characteristics and location of the tumor may be utilized; however, the basic operative principle is to provide the neurosurgeon the maximal exposure through the operative corridor, without any or minimal damage to the surrounding normal tissue. Supratentorial tumors are often approached with a standard pterional craniotomy, whereas infratentorial tumors are often approached with a retrosigmoid craniotomy.16 Some intracranial tumors are not amenable to surgical resection, or the characteristics of such a lesion make it more appropriate to be managed with radiation therapy instead. For example, if a lesion is small, or present in several parts of the brain, or within an area of the brain where surgical resection may potentially cause more harm than benefit, radiation therapy is a consideration. A consultation with a radiation oncologist can provide the patient with a variety of radiotherapy treatment options to target the tumor(s). For example, a patient with diffuse multiple metastases that are too many for surgical resection may benefit from whole brain radiation therapy, whereas a patient with a single small lesion that is radiosensitive may benefit from stereotactic radiosurgery. Patients who also undergo surgical resection of their intracranial tumors often receive radiation therapy to the surgical resection bed.17 Chemotherapy is also utilized as an adjunct for some tumors. A consultation with a neuro-oncologist should be made, and the variety of chemotherapeutic regimens should be discussed. Traditionally, the utilization of chemotherapy within the brain was limited, as the unique nature of the blood-brain barrier limited the efficacy of the medication traveling across the barrier.18 Recent studies and research have paved the way for new chemotherapeutic drugs, however, and some patients receive a combination of surgery, radiation therapy, and chemotherapy as a result. Taxol is a wellknown example.19 While chemotherapy and radiation regimens have evolved, some guidelines have proven successful in changing the standard of care. One prominent example is the advent of the Stupp protocol in 2005. The Stupp regimen tackled the most aggressive of primary intracranial neoplasms, glioblastoma multiforme (GBM). For newly diagnosed GBM, the Stupp regimen called for maximal surgical resection, followed by radiation therapy, in conjunction with either simultaneous or adjuvant chemotherapy, specifically temozolomide.20 Temozolomide is an alkylating/methylating drug, where its mechanism is to alkylate usually the N-7 or
CHAPTER 4 Tumors of the Brain O-6 positions of guanine residues in DNA. The Stupp regimen compared those patients undergoing surgery with chemotherapy and radiation to those patients undergoing external beam radiation alone: the study demonstrated a median survival of 14.6 months in the former group compared with 12.1 months in the latter group. Other agents such as PCV (procarbazine, lomustine, vincristine) have found success in the treatment of recurrent low-grade oligodendrogliomas/ astrocytomas, whereas other patients have benefitted from carmustine (Gliadel) wafers which are implanted in the surgical resection cavity after craniotomy.21 Preoperative embolization to reduce the vascular supply to a tumor and potentially aid in surgical resection is also a consideration.22
POSTMANAGEMENT COURSE Postoperative management is equally as important as the surgical resection of the tumor itself. For intracranial tumors that undergo surgical resection, postoperative management is critical, with close neurologic monitoring and strict blood pressure control, generally provided in the ICU. One of the most common issues that patients with resection of their intracranial tumors experience is an acute hypertensive episode, which can generally be managed with careful neurologic checks in the ICU.23 Patients can sometimes have a weaning steroid protocol as well, and there are a variety of tools that the neurosurgeon or neurointensivist can utilize in the immediate perioperative setting to enable a smooth transition to recovery. Postoperative seizures remain a major concern as well.24, Some studies have suggested that the prevalence of seizures can be as much as 30%e40% of patients with supratentorial brain tumors.24e26 One study compared the efficacy of levetiracetam versus phenytoin and found that the levetiracetam group experienced a lower frequency of postoperative seizures.27 Many patients who undergo surgical resection then undergo a phase of radiation therapy to the surgical resection bed. For patients who have undergone their initial treatment phase, it is often the case that patients will have to follow through generally every 2e4 months to make sure there are no recurrent signs. This is generally managed with serial imaging and close follow-up with their neuro-oncologist, neurosurgeon, and radiation oncologist. The primary purpose of such follow-up is to ensure that the patient does not have any further recurrence of the intracranial tumor and to have the patient and patient’s family involved in all aspects of recovery, as well.
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Family support and social needs is also an important factor in the general recovery and the total care of the patient with an intracranial tumor. For many patients and their families, a revelation that their loved one has an intracranial tumor is often met with much consternation and sometimes outright fear. It is therefore critical to guide the patient and their family through this trying time and to not only address the patient’s medical concerns but also social needs, as well.28
CONCLUSION Intracranial tumors in the adult patient present a challenging clinical problem for physicians and often require a general management combination of surgical resection, radiation therapy, and chemotherapy. Patients who undergo such a combination require strict follow-up and close postoperative care, including overarching rehabilitation needs and social support. Such attention to a multifaceted approach for patients with intracranial tumors allows the clinician to provide the best overall care for the patient, in some of their most trying moments.
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8. Comelli I, Lippi G, Campana V, Servadei F, Cervellin G. Clinical presentation and epidemiology of brain tumors firstly diagnosed in adults in the Emergency Department: a 10-year, single center retrospective study. Ann Transl Med. 2017;5(13):269. https://doi.org/10.21037/atm.2017.06.12. 9. Hussein MR. Central nervous system capillary haemangioblastoma: the pathologist’s viewpoint. Int J Exp Pathol. 2007;88(5):311e324. https://doi.org/10.1111/j.13652613.2007.00535.x. 10. Bruzzone MG, D’incerti L, Farina LL, Cuccarini V, Finocchiaro G. CT and MRI of brain tumors. Q J Nucl Med Mol Imaging. 2012;56(2):112e137. 11. Wetzel SG, Cha S, Law M, et al. Preoperative assessment of intracranial tumors with perfusion MR and a volumetric interpolated examination: a comparative study with DSA. AJNR Am J Neuroradiol. 2002;23(10):1767e1774. 12. Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The use of the nitrogen mustards in the palliative treatment of carcinoma e with particular reference to bronchogenic carcinoma. Cancer. 1948;1(4):634e656. 13. Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649e655. 14. Reddy GK, Bollam P, Caldito G, et al. J Neurooncol. 2011; 103:333. https://doi.org/10.1007/s11060-010-0393-4. 15. Jagadeesh H, Bernstein M. Patients’ anxiety around incidental brain tumors: a qualitative study. Acta Neurochir. 2014;156(2):375e381. https://doi.org/10.1007/s00701013-1935-2. 16. Schödel P, Schebesch K-M, Brawanski A, Proescholdt MA. Surgical resection of brain metastasesdimpact on neurological outcome. Int J Mol Sci. 2013;14(5):8708e8718. https://doi.org/10.3390/ijms14058708. 17. Chan MD, Tatter SB, Lesser G, Shaw EG. Radiation oncology in brain tumors: current approaches and clinical trials in progress. Neuroimaging Clin N Am. 2010;20(3):401e408. 18. Vick NA, Khandekar JD, Bigner DD. Chemotherapy of brain tumors. The "Blood-Brain barrier" is not a factor. Arch Neurol. 1977;34(9):523e526. https://doi.org/ 10.1001/archneur.1977.00500210025002. 19. Joo KM, Park K, Kong DS, et al. Oral paclitaxel chemotherapy for brain tumors: ideal combination treatment of paclitaxel and P-glycoprotein inhibitor. Oncol Rep. 2008; 19(1):17e23. 20. 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):987e996. 21. Ewend MG, Brem S, Gilbert M, et al. Treatment of single brain metastasis with resection, intracavity carmustine polymer wafers, and radiation therapy is safe and provides excellent local control. Clin Cancer Res. 2007;13(12): 3637e3641.
22. Kuroiwa T, Tanaka H, Ohta T, Tsutsumi A. Preoperative embolization of highly vascular brain tumors: clinical and histopathological findings. Noshuyo Byori. 1996; 13(1):27e36. 23. Hanak BW, Walcott BP, Nahed BV, et al. Post-operative intensive care unit requirements following elective craniotomy. World Neurosurg. 2014;81(1):165e172. https://doi.org/10.1016/j.wneu.2012.11.068. 24. Gokhale S, Khan SA, Agrawal A, Friedman AH, McDonagh DL. Levetiracetam seizure prophylaxis in craniotomy patients at high risk for postoperative seizures. Asian J Neurosurg. 2013;8(4):169e173. https://doi.org/ 10.4103/1793-5482.125658. 25. Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2000;54(10):1886e1893. 26. Van breemen MS, Rijsman RM, Taphoorn MJ, Walchenbach R, Zwinkels H, Vecht CJ. Efficacy of antiepileptic drugs in patients with gliomas and seizures. J Neurol. 2009;256(9):1519e1526. 27. Iuchi T, Kuwabara K, Matsumoto M, Kawasaki K, Hasegawa Y, Sakaida T. Levetiracetam versus phenytoin for seizure prophylaxis during and early after craniotomy for brain tumours: a phase II prospective, randomised study. J Neurol Neurosurg Psychiatr. 2015;86(10):1158e1162. 28. Ownsworth T, Goadby E, Chambers SK. Support after brain tumor means different things: family caregivers’ experiences of support and relationship changes. Front Oncol. 2015;5:33. https://doi.org/10.3389/fonc.2015.00033.
FURTHER READING 1. Pekmezci M, Perry A. Neuropathology of brain metastases. Surg Neurol Int. 2013;4(suppl 4):S245eS255. https:// doi.org/10.4103/2152-7806.111302. 2. Vargo M. Brain tumor rehabilitation. Am J Phys Med Rehabil. 2011;90(5 suppl 1):S50eS62. 3. Pace A, Parisi C, Di lelio M, et al. Home rehabilitation for brain tumor patients. J Exp Clin Cancer Res. 2007;26(3): 297e300. 4. Greenberg E, Treger I, Ring H. Rehabilitation outcomes in patients with brain tumors and acute stroke: comparative study of inpatient rehabilitation. Am J Phys Med Rehabil. 2006;85(7):568e573.