Neurooncology is the study of brain and spinal cord neoplasms, many of which are (at least eventually) very dangerous and life-threatening (astrocytoma, glioma, glioblastoma multiforme, ependymoma, pontine glioma, and brain stem tumors are among the many examples of these). Among the malignant brain cancers, gliomas of the brainstem and pons, glioblastoma multiforme, and high-grade (highly anaplastic) astrocytoma are among the worst. In these cases, untreated survival usually amounts to only a few months, and survival with current radiation and chemotherapy treatments may extend that time from around a year to a year and a half, possibly two or more, depending on the patient's condition, immune function, treatments used, and the specific type of malignant brain neoplasm. Surgery may in some cases be curative, but, as a general rule, malignant brain cancers tend to regenerate and emerge from remission easily, especially highly malignant cases. In such cases, the goal is to excise as much of the mass (tumor cells) and as much of the tumor margin as possible without endangering vital functions or other important cognitive abilities.
- 1 General information
- 2 Mechanisms
- 3 Initial patient evaluation and care
- 4 Diagnostic procedures
- 5 Commonly used treatments in neurooncology
- 6 Specific tumors
- 7 Approach to clinical problems in neurooncology
- 8 Pain and terminal care
- 9 References
1. Primary Tumors of the Central Nervous System
Primary brain tumors can occur at any age, from infancy to late in life. These tumors often afflict people during their prime years. Factors such as age, tumor location, and clinical presentation are helpful in differential diagnosis. Most types of primary brain tumors are more common in men with the exception of meningiomas, which are more common in women.
2. Metastatic Tumors of the Central Nervous System
Cancer spreads to the nervous system by direct invasion, compression, or metastasis. Direct invasion or compression from continuous tissues relates to the proximity of the nervous system to other structures, such as the brachial plexus, lumbosacral plexus, vertebral neuroforamina, base of skull, cranium, and pelvic bones.
- Intracranial Metastasis
There are three types of intracranial metastasis: brain metastasis, dural metastasis, and leptomeningeal metastasis. Brain metastasis can be single or multiple and involve any portion of the brain. Metastasis to dural structures generally occurs by hematogenous spread or direct invasion from a contiguous bone. Dural metastases can invade the underlying brain and cause focal edema and associated neurologic symptoms. These processes tend to cause seizures early in the course because of their cortical location. Metastasis to the leptomeninges is an uncommon but well-recognized clinical presentation in cancer patients. Leptomeningeal metastasis most commonly is due to breast, lung, or melanoma primary tumors.
- Skull Metastasis
Metastases to the skull are divided into two categories by general site: calvarium and skull base. Metastases to the calvarium usually are asymptomatic. Metastases to the skull base quickly become symptomatic because of their proximity to cranial nerves and vascular structures.
- Spinal Metastasis
The spine most often is affected by metastatic disease involving the epidural space. This usually occurs as direct tumor spread from a vertebral body (85%) or by invasion of paravertebral masses through a neuroforamin (10-15%).
1. Genetic Syndromes and Risk Factors
There multiple hereditary conditions that increase a person's chance of developing brain tumors.
2. Nongenetic Risk Factors
Few issues in medicine are as potentially contentious as the suspicion of environmental and occupational causes of cancer, including brain tumors. Prior cranial irradiation is the only risk factor that definitely predisposes to brain tumor formation. Some of the risk factors are ionizing radiation, nonionizing radiation, nitrosamines and industrial chemicals.
Seizures are common in patients with low-grade tumors such as dysembryoblastic neuroepithelial tumors, gangligliomas, and oligodendrogliomas. The rapid growth of fast-growing high-grade brain tumors may damage the subcortical network essential for electrical transmission, whereas slow-growing tumors have been suggested to induce partial deafferentation of cortical regions, causing denervation hypersensitivity and producing an epileptogenic milieu. Studies strongly suggest that genetic factors may play a role in tumor development and tumor-related epilepsy.
2. Tumor location
The location of tumors is closely related to their histology. The majority of glioneuronal tumors occur in the temporal lobe. Some data have shown that oligodendroglial tumors were more likely to be located in frontal lobe, whereas astrocytomas were more commonly found in temporal locations. It may be postulated that tumor-related seizures have unique characteristics, which may share some common genetic pathways with tumorigenesis.
3. Blood-brain barrier disruption (BBB)
Human and animal studies have suggested that perturbations in neurovascular integrity and breakdown of the BBB lead to neuronal hypersynchronization and epileptiform activity. Relevant molecular changes in brain tumors that affect BBB structure and function include decreased expression of transmembrane junctional proteins and heightened release of vascular endothelial growth factor. Results suggest that pathological disruption of thet BBB in brain tumor patients may contribute to seizure activity.
Contemporary imaging techniques provide testimony to the remarkable differences between the peri-tumoral brain and normal tissue.
1. Morphological changes
Certain morphological changes in the peri-tumoral brain tissue, such as persistent neurons in the white matter, inefficient neuronal migration, and changes in synaptic vesicles, are also believed to contribute to seizure generation.
2. Hypoxia, acidosis and metabolic changes
Tumors with insufficient blood supply often cause interstitial hypoxia, which subsequently contributes to acidosis. The intratumoral hypoxia and acidosis may extend to the surrounding tissue. Furthermore, hypoxia causes acidosis as a consequence of both heightened metabolic requirements of the proliferating tissue and impaired oxidative energy metabolism.
3. Ionic changes
Ionic changes in the peri-tumoral zone may influence neuronal activity. An interesting hypothesis was proposed by Sontheimer, who suggested that glioma invasion into the peri-tumoral zone is in part mediated by chloride channel overexpression, allowing cells to traverse the extracellular space through rapid changes in cell shape.
- Glutamate neurotransmission
Recent work has demonstrated a close link between seizure activity and high extracellular glutamate in tumor-related epilepsy. Glutamate activation of ionotropic receptors leads to a rapid excitatory signal based on cation influx that can cause release of calcium from intracellular stores.
Initial patient evaluation and care
1. Brain Tumor Presentations
In general, patients with primary brain tumors or single metastatic tumors can present with any of these signs and symptoms, whereas patients with multiple brain metastases tend to present with generalized symptoms and may lack localized findings.
Several clinical features warrant special comment:
- Seizures (partial or generalized) are the presenting symptom in 15-20% of patients with intracranial tumors. Seizures occur in up to 50% of patients with melanoma metastases, oligodendrogliomas, and tumors that have a hemorrhagic component. Seizures also are more common with cortically based tumors.
- Seizures are much less common in patients with infratentorial tumors than in those with supratentorial tumors.
- "Stroke-like" onset of symptoms is due to hemorrhage within the tumor or, less commonly, macroscopic tumor embolus from systemic cancer.
- Although intratumoral hemorrhage can occur in any primary or metastatic brain tumor, certain tumors have a greater tendency to bleed, including metastasis from melanoma, choriocarcinoma, and thyroid cancer and the primary brain tumors glioblastoma and oligodendroglioma.
2. Spinal Cord Tumor Presentations
- Pain is the first symptom in >90% of patients presenting with epidural metastasis and occurs less frequently with intradural tumors.
- Mechanisms of pain include spinal cord ischemia and traction on the periosteum, dura, nearby soft tissues, and nerve roots.
- Pain occasionally can be absent in adults and more often is absent in childhood. If other neurologic symptoms suggestive of myelopathy are present, without pain, the clinician should evaluate for spinal cord tumor.
- Changes in bowel and bladder habits, particularly urinary retention with overflow incontinence, usually occur late in the course of epidural spinal cord compression but are seen in a small percentage of patients at presentation.
3. Approach to the Evaluation of New Patients
The initial evaluation of a patient with a newly diagnosed tumor of the nervous system is a critical step toward appropriate management and patient care. The most important portions of the initial evaluation are a detailed history and a thorough examination. This process serves to identify the extent and nature of neurological deficit, provides diagnostic clues, can help disclose a source of metastasis, or may identify a genetic process associated with a primary central nervous system tumor.
4. Practical Strategies for Providing Appropriate Patient Care
There is no question that the clinical management of neurooncology patients is challenging. However, if we are to help patients and ultimately make advances in treating these tumors, meticulous and compassionate care of patients with neurological malignancies are crucial.
- Give instructions both orally and in written form for the patient to take home.
- Use a consistent format of written instructions, so that a patient can expect where to find information on the page.
- Write down new or important diagnoses for the patient to refer to at home.
- Identify one reliable caregiver to serve as a contact point.
- Pictures and diagrams are helpful.
- A team approach, using clinicians with different areas of expertise, is helpful.
- Provide a reliable and simple method for the patient to seek help.
- Minimize sedating drug use.
1. Diagnostic Imaging of the Brain and Spinal Cord
The imaging studies commonly used in neurooncology are computed tomography (CT) and magnetic resonance imaging (MRI). Less commonly used are myelography, positron emission tomography (PET), and diagnostic angiography.
2. Lumbar Puncture and Cerebrospinal Fluid Analysis
3. Pathologic Diagnosis
Accurate histologic diagnosis is critical for treatment planning and patient counseling. Surgically obtained tissue usually is required to make a histologic diagnosis. For certain tumors, a definitive diagnosis can be accomplished by vitreous aspirate, cerebrospinal fluid (CSF) cytology, or suggested by the presence of certain tumor markers in the CSF.
Commonly used treatments in neurooncology
Radiotherapy is an important treatment for central nervous system tumors and has been demonstrated to extend survival and improve the quality of life for patients with many of the primary and metastatic brain tumors.
Chemotherapy, or the use of drugs in the treatment of cancer, can lead to the long-term control of many malignancies. Some tumors, such as testicular cancer of Hodgkin's disease, may be cured even when they are widespread. As chemotherapy may be associated with severe toxicity, it should be given under the supervision of one skilled in the administration and monitoring of such agents.
Corticosteroids (CS) are commonly used in patients with a variety of neuro-oncologic conditions. CS treatment often is required to control symptoms related to increased intracranial pressure (ICP) or peritumoral edema.
4. Neurosurgical Interventions
Neurosurgical intervention is warranted in almost all cases of primary central nervous system tumors and for many metastatic tumors. A biopsy usually establishes a definitive histologic diagnosis. The role of surgery depends on the nature of the tumor. With modern neurosurgical techniques, most patients with extra-axial brain tumors are cured with minimal residual neurologic deficit.
1. Malignant Astrocytomas
Malignant astrocytomas are the most common primary brain tumors in adults. Malignant astrocytomas generate symptoms and signs by mass effect, local brain infiltration, tissue destruction, cerebral edema, and increased intracranial pressure. Headaches and seizures are the most frequent initial symptoms. Associated focal neurologic signs and symptoms occur depending on the anatomic location of the tumor. Confusion and mental status difficulties occur in patients with large tumors, those which cross the corpus callosum and those with a lot of associated edema.
2. Other Astrocytomas
Tumors of presumed or known astrocytic lineage other than the malignant astrocytomas include a variety of tumors categorized by histology, location, age of onset, and natural history.
The oligodendrogliomas include low-grade oligodendroglioma, anaplastic oligodendroglioma, and oligoastrocytoma (mixed glioma). This group of tumors, although less common than astrocytomas, has received increased attention in the past decade because of reports of chemosensitivity and a favorable survival rate when compared with astrocytomas of similar grade.
4. Brain Stem Gliomas
Brain stem glioma is a distinct category of central nervous system tumor because of its unique location and behavior. The histology of brain stem gliomas spans the spectrum of gliomas located elsewhere in the central nervous system. The cause of these tumors is still unknown. Researchers have not found any direct genetic link.
5. Pituitary Region Tumors
A wide variety of tumors can occur in and around the sella turcica. The most common tumors in this region are craniopharyngiomas, pituitary adenomas, meningiomas, and optic chiasm gliomas. Visual impairment is a common presenting symptom, due to compression or invasion of the optic chiasm.
6. Germ Cell and Pineal Region Tumors
Most tumors of the pineal region are either germinomas or pineal cell tumors, and are tumors of adolescents and young adults. Presentation relates to the location in the nervous system.
7. Medulloblastoma and Other Primitive Neuroectodermal Tumors
Medulloblastoma and other primitive neuroectodermal tumors (PNETs) are a group of highly aggressive central nervous system tumors with a tendency to spread via cerebrospinal fluid pathways. These typically are tumors of childhood and young adulthood.
8. Meningiomas and Other Meningeal Tumors
Meningioma is the most common tumor in the central nervous system. Although most are slow growing and histologically benign, they can induce significant symptoms depending on location.
9. Tumors of the Optic Nerve and Chiasm
These tumors include the tumors involving the orbit and optic pathways, which include optic nerve gliomas and optic nerve sheath meningiomas.
10. Primary Central Nervous System Lymphoma
Primary central nervous system lymphoma (PCNSL), a rare central nervous system tumor, occurs preferentially in immunocompromised patinets; however, it is increasing in incidence in both the HIV and non-HIV populations.
11. Primary Spinal Cord Tumors
Primary spinal cord tumors are uncommon and most are either astrocytomas or ependymomas.
1. Spinal Cord Metastasis
The management of spinal cord metastasis depends on whether or not the metastasis is causing epidural spinal cord compression as well as the overall status of the patient's systemic cancer.
2. Brain Metastasis
The occurrence of brain metastases represents a significant challenge in the care of patients with cancer. Symptoms may significantly alter the quality of life of affected patients, and brain metastases generally represent overall treatment failure. Long-term survival is poor.
3. Leptomeningeal Metastasis
Leptomeningeal metastasis (LM) is a rare complication of systemic cancer in which the leptomeninges are infiltrated by cancer cells. The overall incidence is 3-8% but is increasing as more cancer patients survive following initial treatment.
Approach to clinical problems in neurooncology
- Anorexia and Weight Loss
- Brain Tumors in Women of Childbearing Age
- Central Nervous System Infections
- Cranial Nerve Syndromes
- Deep Venous Thrombosis and Pulmonary Embolus
- Depression and Anxiety
- Differential Diagnosis of Brain Tumor Progression
- Fatigue and Weakness
- Fever and Neutropenia
- Gait Disturbances
- Increased Intracranial Pressure, Herniation Syndromes, and Coma
- Mental Status Changes
- Nausea and Vomiting
- Paraneoplastic Syndromes
- Peripheral Nerve Problems: Plexopathies and Neuropathies
- Seizures and Other Spells
- Stroke and Other Cerebrovascular Complications
- Urinary Problems
- Visual Symptoms
Pain and terminal care
1. Palliative and Terminal Care
Palliative care is a special type of care provided to improve the quality of life of patients who suffer from a serious or life-threatening disease, such as cancer. The purpose of palliative care is not to cure but to prevent or treat, as early as possible, the symptoms and side effects of the disease and its treatment, in addition to the related psychological, social, and spiritual problems. Palliative care is also called comfort care, supportive care, and symptom management.
Palliative care is provided throughout a patient’s experience with cancer. It usually begins at diagnosis and continues through treatment, follow-up care, and the end of life.
2. Cancer Pain Management
Key points for cancer pain management
- Cancer pain can be managed.
- Controlling pain is part of a patient's cancer treatment.
- Talking openly with the physician and health care team will help them manage one's pain.
- The best way to control pain is to stop it from starting or keep it from getting worse.
- There are many different medicines to control pain. Everyone's pain control plan is different.
- Keeping a record of one's pain will help create the best pain control plan for the patient.
- People who take cancer pain medicines as prescribed rarely become addicted to them.
- Your body does not become immune to pain medicine. Stronger medicines should not be saved for "later."
Studies on adult patients demonstrated that gross total resection or even extended lesionectomy could greatly improve seizure prognosis. The fact that both tumoral and peri-tumoral factors contribute to the pathogenesis of tumor-related epilepsy suggests that VPA should be considered as a first line therapy in treating tumor-related epilepsy.
- McAllister, L.D., Ward, J.H., Schulman, S.F., DeAngels, L.M. (2002). Practical Neuro-Oncology: A Guide to Patient Care. Woburn, MA: Butterworth-Heinemann.
- Smits, A. (2011). Seizures and the natural history of World Health Organization grade II gliomas: a review. Neurosurgery (2011): 1326-1333.
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