Neuro-oncology


Neuro-oncology is the study of brain and spinal cord neoplasms, many of which are very dangerous and life-threatening. Among the malignant brain cancers, gliomas of the brainstem and pons, glioblastoma multiforme, and high-grade 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 and as much of the tumor margin as possible without endangering vital functions or other important cognitive abilities. The Journal of Neuro-Oncology is the longest continuously published journal in the field and serves as a leading reference to those practicing in the area of neuro-oncology.

General information

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.

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 or by invasion of paravertebral masses through a neuroforamin.

Genetic syndromes and risk factors

There are multiple hereditary conditions that increase a person's chance of developing brain tumors.

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.

Mechanisms

Tumor factors

Histology

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.

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.

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 the BBB in brain tumor patients may contribute to seizure activity.

Peri-tumoral factors

Contemporary imaging techniques provide testimony to the remarkable differences between the peri-tumoral brain and normal tissue.

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.

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.

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:
2. Spinal Cord Tumor Presentations
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.

Diagnostic imaging of the brain and spinal cord

The imaging studies commonly used in neurooncology are computed tomography and magnetic resonance imaging. Less commonly used are myelography, positron emission tomography, and diagnostic angiography.

Lumbar puncture and cerebrospinal fluid analysis

and cerebrospinal fluid analysis are important for the evaluation of some primary tumors, metastatic conditions, and neurologic complications of cancer.

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 cytology, or suggested by the presence of certain tumor markers in the CSF.

Commonly used treatments

  1. Radiotherapy
    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.
  2. Chemotherapy
    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.
  3. Corticosteroids
    Corticosteroids 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 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.

    Specific tumors

Primary tumors

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 that 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.
3. Oligodendrogliomas
The oligodendrogliomas include low-grade oligodendroglioma, anaplastic oligodendroglioma, and oligoastrocytoma. 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 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, a rare central nervous system tumor, occurs preferentially in immunocompromised patients; 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.

Metastatic tumors

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 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

  1. Anorexia and Weight Loss
  2. Brain Tumors in Women of Childbearing Age
  3. Central Nervous System Infections
  4. Constipation
  5. Cranial Nerve Syndromes
  6. Deep Venous Thrombosis and Pulmonary Embolus
  7. Depression and Anxiety
  8. Differential Diagnosis of Brain Tumor Progression
  9. Fatigue and Weakness
  10. Fever and Neutropenia
  11. Gait Disturbances
  12. Headaches
  13. Hiccups
  14. Increased Intracranial Pressure, Herniation Syndromes, and Coma
  15. Insomnia
  16. Mental Status Changes
  17. Nausea and Vomiting
  18. Paraneoplastic Syndromes
  19. Peripheral Nerve Problems: Plexopathies and Neuropathies
  20. Seizures and Other Spells
  21. Stroke and Other Cerebrovascular Complications
  22. Urinary Problems
  23. Visual Symptoms

    Pain and terminal care

Palliative and terminal 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.

Cancer pain management

Key points for cancer pain management:
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.