CNS Tumors Lecture
Brain Tumors
Incidence and Mortality
The cumulative incidence of all primary malignant and non-malignant brain and CNS tumors is approximately 24.71 cases per 100,000 population annually.
The incidence rate for malignant tumors specifically is 7 per 100,000, indicating a significant health burden.
For non-malignant tumors, the incidence rate is higher at 17 per 100,000, highlighting their prevalence despite being non-cancerous.
Incidence rates are observed to be higher in females compared to males, and in non-Hispanic persons across various demographic studies.
Brain tumors are statistically more common in adults than in children, although pediatric brain tumors represent a leading cause of cancer-related mortality in young individuals.
More than 90,000 new cases of brain tumors are expected to be diagnosed annually in the United States alone.
The annual mortality rate due to brain tumors is 4.41 per 100,000 population, underscoring their severe impact.
5-year survival rates vary significantly by tumor type and malignancy:
For malignant tumors, the 5-year survival rate is a challenging 35.7%, reflecting the aggressive nature and difficulty in treatment.
For non-malignant tumors, the prognosis is much better, with a 5-year survival rate of 91.8%, although these can still cause significant morbidity due to compression.
Potential causes of brain tumors:
The exact causes of most brain tumors remain largely unknown, making prevention difficult.
There is evidence suggesting a potential familial link or genetic predisposition in a subset of cases, indicating inherited risk factors.
An association with certain toxic exposures, such as specific chemicals or radiation, has been hypothesized and is an area of ongoing research.
The influence of electromagnetic field exposure (e.g., from cell phones) remains a controversial topic with inconclusive scientific evidence.
Classification of Brain Tumors
Primary brain tumors:
These tumors originate within the brain tissue itself or its immediate surrounding structures (meninges, cranial nerves, pituitary, pineal gland).
They are distinct from the brain tissue in their cellular composition and growth patterns, though they may infiltrate surrounding healthy brain tissue.
Secondary (Metastatic) brain tumors:
These tumors spread to the Central Nervous System (CNS) from systemic cancer sites located elsewhere in the body.
Common primary sources that frequently metastasize to the brain include:
Lung cancer, often responsible for a high percentage of brain metastases.
Breast cancer, particularly certain aggressive subtypes, can frequently disseminate to the brain.
Kidney cancer (renal cell carcinoma), known for its propensity to metastasize widely, including to the brain.
Melanoma, a highly aggressive skin cancer that has a notable tendency for distant metastasis, including to the brain.
Primary Brain Tumors
Gliomas
Gliomas represent a broad category of primary tumors arising from the glial cells, which are the support structures of the brain and spinal cord, including astrocytes, oligodendrocytes, and ependymal cells.
Astrocytomas:
These are the most common type of primary brain tumor, originating from astrocytes.
They can broadly be categorized as:
Circumscribed astrocytomas: These are well-demarcated, often slow-growing tumors with limited tendency for local progression, such as pilocytic astrocytomas.
Diffuse astrocytomas: These are infiltrative tumors that spread into surrounding brain tissue, making complete surgical resection challenging, and are inherently more progressive.
Grading of astrocytomas (based on WHO classification, reflecting tumor aggressiveness):
Grade 1 & 2 (Low Grade): These are typically slow-growing tumors that are often amenable to total or subtotal surgical resection. While generally less aggressive, they have a notable likelihood to recur over time and can sometimes transform into higher-grade lesions.
Grade 3 (Anaplastic Astrocytoma): These tumors grow more rapidly and exhibit clear malignant cell traits, including increased cellularity, nuclear atypia, and mitotic activity. They have a strong tendency to progress to Grade 4.
Grade 4 (Glioblastoma Multiforme - GBM): This is the most aggressive and common primary malignant brain tumor in adults. GBMs are characterized by high malignancy, invasive growth into surrounding brain tissue, rapid progression, and often present as multifocal or bilateral lesions. They frequently exhibit areas of necrosis and microvascular proliferation.
Treatment for gliomas: Typically involves a multimodal approach combining surgical resection to remove as much tumor as safely possible, followed by radiation therapy to target remaining microscopic disease, and chemotherapy. The 5-year survival rate for high-grade gliomas is approximately 30%, reflecting the significant treatment challenges.
Oligodendrogliomas
Features:
These tumors are typically slow-growing and progressive but often present as multilobular lesions.
They are most commonly diagnosed in individuals aged 30-70 years, with a peak incidence in middle age.
Prognosis factors:
Age and tumor grade are significant determinants of patient outcome. Younger age and lower tumor grade are associated with better prognosis.
Patients over age 40, those with higher tumor grades, and individuals presenting with more severe neurological symptoms generally have a worse prognosis.
5-year survival rate: With current treatments, it ranges from 60-75%, better than GBM, partly due to the presence of specific genetic markers (1p/19q co-deletion) that predict better response to chemotherapy.
Treatment options: May involve an initial period of observation, especially for asymptomatic low-grade tumors, and symptomatic management with anti-convulsants. Definitive treatment includes surgical resection, radiation therapy, and/or chemotherapy.
Ependymomas
Derived from ependymal cells lining the ventricles of the brain and the central canal of the spinal cord.
Locations:
Most often found in the posterior fossa (infratentorial region), particularly the fourth ventricle, which is common in children.
Supratentorial ependymomas, sometimes referred to as ependymoblastomas (a less common and more aggressive variant), are also prevalent in children and tend to spread within the nervous system via the cerebrospinal fluid (CSF), necessitating spinal imaging.
Infratentorial ependymomas are particularly common in children, with approximately 40% occurring in those under 10 years of age.
Treatment approaches: Primary treatment involves maximal safe surgical resection, followed by adjuvant XRT (radiation therapy), especially for subtotal resections or high-grade tumors. These tumors often recur, sometimes requiring repeat surgeries or additional radiation.
5-year survival rate for ependymomas is approximately 60%, varying with grade, location, and completeness of resection.
Medulloblastoma
Originates from primitive embryonal tissue, making it a highly malignant pediatric brain tumor.
Most often found in the posterior fossa, specifically the cerebellum. Its location in the 4th ventricle can obstruct CSF flow, leading to hydrocephalus and significantly increased intracranial pressure (ICP) due to fluid buildup.
Represents approximately 25% of all primary brain tumors in children, making it one of the most common malignant brain tumors in this age group.
Treatment includes radical surgical resection, followed by craniospinal XRT (radiation therapy) because of its high propensity for CSF dissemination, and systemic chemotherapy.
May metastasize systemically (extracranial metastases occur in about 5% of cases) or to bone (with a higher incidence of up to 10-15% over time if not adequately treated); metastatic disease to the spine or other parts of the body leads to significantly poorer outcomes.
5-year survival is highly dependent on the presence of metastases at diagnosis, ranging from 30-70% for disseminated versus localized disease.
Meningiomas
Arise from the dura mater or arachnoid mater, the protective membranes surrounding the brain and spinal cord, rather than from brain tissue itself.
They are often asymptomatic for long periods and may be discovered incidentally during imaging for unrelated conditions.
More common in females and incidence increases with age.
When symptomatic, they can cause headaches, seizures, or focal neurological deficits depending on their size and location, due to compression of underlying brain tissue.
Treatment primarily involves surgical removal. For larger or inaccessible tumors, or those with atypical/anaplastic features, surgery is often followed by XRT. Observation is an option for small, asymptomatic tumors.
Tumors may recur even after complete resection, particularly if they are high-grade or incompletely removed.
Pituitary Adenomas
These are benign epithelial tumors that affect the pituitary gland, a pea-sized gland located at the base of the brain.
In adults, their incidence affects normal pituitary function, often leading to hormonal imbalances (e.g., hypersecretion of prolactin, growth hormone, or ACTH), and may compress the optic chiasm, causing visual field defects (classically bitemporal hemianopsia).
Treatment options include surgical resection (often transsphenoidal via the nose), drug therapy (e.g., dopamine agonists for prolactinomas, somatostatin analogs for growth hormone-secreting tumors), and occasionally radiation therapy.
Schwannomas
These are neoplasms of Schwann cells, which form the myelin sheath around cranial or spinal nerves.
They are most commonly found on the 8th cranial nerve (vestibulocochlear nerve), in which case they are often referred to as an acoustic neuroma or vestibular schwannoma.
These tumors augment within the internal auditory canal or extend to the cerebellopontine angle, compressing adjacent brain structures.
Symptoms can involve signs related to the 7th cranial nerve (facial nerve), leading to facial weakness or paralysis, and 8th cranial nerve dysfunction, causing hearing loss, tinnitus, and balance disturbances.
Treatment options include surgical resection to remove the tumor or stereotactic radiosurgery for smaller tumors or those in eloquent areas. Recurrence rates are infrequent after successful treatment, but surgical complications, particularly damage to cranial nerves, are common.
Primary CNS Lymphoma
An aggressive form of non-Hodgkin's lymphoma that originates within the brain, spinal cord, or eye, occurring primarily in immunocompromised individuals (e.g., HIV/AIDS patients, transplant recipients) but also in immunocompetent older adults.
Peak incidence is noted in individuals aged 50-70 years in the immunocompetent population.
Behavioral and cognitive changes, such as confusion, personality alterations, memory deficits, and focal neurological signs, are commonly observed due to the tumor's infiltrative nature.
Treatment involves high-dose radiation and systemic chemotherapy (often methotrexate-based); patients may experience significant delayed neural toxicity, including cognitive decline and leukoencephalopathy, following treatment.
5-year survival rate is approximately 25%, highlighting its poor prognosis despite treatment.
Metastatic Brain Tumors
Secondary tumors spread to the brain primarily via arterial circulation, with cancer cells detaching from the primary tumor and traveling through the bloodstream to seed in the brain.
20-30% of individuals with a history of systemic cancer have metastases present in the brain, making them more common than primary malignant brain tumors.
Characteristics of metastatic brain tumors:
They often manifest as multiple lesions scattered throughout the brain, although solitary metastases can occur.
Common primary cancer sources that frequently metastasize to the brain include lung, breast, kidney, and melanoma, exhibiting a particular tropism for brain tissue.
Treatment strategies often depend on the management of the primary cancer source, the number and size of brain lesions, and patient performance status. Additional considerations include corticosteroids to reduce surrounding brain edema, whole brain radiation for multiple lesions, stereotactic radiosurgery for a limited number of lesions, and surgical resection for larger, symptomatic, or solitary accessible metastases.
Clinical Manifestations of Brain Tumors
Common symptoms are often non-specific and depend on the tumor's size, location, and growth rate. They include:
Headache: Often described as progressively worsening, dull, constant, or intermittent, and sometimes worse in the morning. It can be due to increased ICP or direct irritation of pain-sensitive structures.
Seizures: Occur in a significant proportion of patients, especially with tumors involving the cerebral cortex. They can be focal or generalized.
Mental status changes: Ranging from mild to severe, including subtle personality shifts, memory problems, altered judgment, confusion, apathy, or profound cognitive decline.
Increased ICP, resulting from tumor mass effect, obstruction of CSF flow, or edema, may lead to drowsiness and altered levels of consciousness (LOC), progressing from lethargy to coma.
Papilledema: Swelling of the optic nerve head, detectable during fundoscopic exams, is a key sign of increased intracranial pressure due to impeded venous return from the retina.
A variety of focal neurological signs may be present, depending on the specific brain region affected, such as hemiparesis (weakness on one side of the body), aphasia (difficulty with language), visual field cuts, sensory deficits, or cranial nerve palsies.
Diagnosis of Brain Tumors
Static Imaging Techniques:
CT scan (Computed Tomography): Provides rapid, detailed images of bone and soft tissue structures, useful for identifying gross tumor location, size, and associated edema or hydrocephalus, especially with contrast enhancement.
MRI (Magnetic Resonance Imaging): Offers superior soft tissue contrast compared to CT, providing more detailed anatomical information about tumor boundaries, invasion into adjacent structures, and associated edema. Specific sequences (e.g., T1-weighted with contrast, T2-weighted, FLAIR) help characterize the tumor.
Dynamic Imaging Techniques:
PET scan (Positron Emission Tomography): Uses radioactive tracers (e.g., -FDG for glucose metabolism or amino acid tracers) to provide physiologic and metabolic information regarding tumor tissue, helping distinguish tumor recurrence from radiation necrosis or determine tumor aggressiveness, guiding biopsy.
Other modalities include functional MRI (fMRI) for mapping eloquent cortex and MR spectroscopy (MRS) to analyze biochemical changes within the tumor.
Biopsy/Stereotactic Biopsy: This is the definitive diagnostic procedure. A computer-guided needle biopsy, often stereotactic (using a precise coordinate system based on imaging), is performed to obtain tissue samples for histological confirmation, allowing pathologists to classify the tumor type and grade under a microscope.
Treatment of Brain Tumors
Steroids (e.g., Dexamethasone) are commonly used to regulate and reduce brain swelling (peritumoral edema), which helps alleviate symptoms caused by mass effect and increased ICP. They do not treat the tumor itself.
The overall treatment sequence is highly individualized and may vary, often involving a multimodal approach:
Typically, surgery is followed by radiation therapy or chemotherapy for adjuvant treatment to target residual disease.
In some cases, radiation therapy or chemotherapy may precede surgery (neoadjuvant treatment) to shrink the tumor and make it more resectable or to treat tumors not amenable to immediate resection.
Treatment Strategies
Biopsy Techniques
Include open biopsy (during craniotomy), needle biopsy, or stereotactic needle methods (imaging-guided), which provide accurate tissue sampling with minimal invasiveness.
Resection Techniques
May involve partial or complete resection, aiming to remove as much tumor as possible while preserving neurological function. Resection can be guided by intraoperative imaging (e.g., MRI in the operating room) to enhance precision and maximize tumor removal, or by functional mapping (stereotactic craniotomy) to avoid crucial brain areas.
Postoperative Complications
Postoperative issues may include:
Seizures: Can occur due to surgical irritation or underlying brain inflammation.
Bleeding: Risk of hemorrhage at the surgical site.
Swelling (edema): Postoperative brain swelling can exacerbate neurological deficits and increase ICP.
Infection, CSF leak, and neurological deficits related to the surgical approach are also possible.
Radiation Therapy
Various techniques are used to target tumor sites with high-energy beams to damage cancer cells' DNA.
Whole brain radiation is typically deployed for multiple lesions, widespread microscopic disease (e.g., leptomeningeal metastases), or as palliative treatment.
Stereotactic radiosurgery (SRS): A highly precise form of radiation therapy (e.g., Gamma Knife, CyberKnife) that targets tumors with high doses in a limited number of fractions, minimizing exposure to surrounding healthy brain tissue. It is suitable for small, well-defined tumors or limited metastases.
Potential complications of radiation therapy include:
Necrosis: Radiation-induced tissue death, which can sometimes form a mass (radiation necrosis) that mimics tumor recurrence.
Skin burns: Erythema, dry or moist desquamation at the treatment site.
Hair loss (alopecia): Often temporary within the radiation field.
Fatigue: A common and often debilitating side effect.
Considerations for Radiation Therapy
Possible acute and subacute side effects include:
Fatigue: Profound tiredness.
Anemia: Reduction in red blood cells.
Anxiety and Depression: Psychological distress related to diagnosis and treatment.
Infection: Increased susceptibility, especially if immunocompromised by concurrent treatments.
Skin changes: Within the radiation field, including:
Redness (erythema)
Pruritus (itching)
Sores or blistering (moist desquamation)
Swelling
Hair loss (alopecia): Can be temporary or permanent depending on dose and location.
Oral cavity dysfunction (if head and neck radiation is involved):
Mouth sores (mucositis), dry mouth (xerostomia) due to salivary gland damage.
Loss or changes in taste (dysgeusia or ageusia).
Increased risk of tooth decay, infections of gums, teeth, or tongue (e.g., candidiasis).
Jaw stiffness and bony changes (osteoradionecrosis).
Thickening of oral secretions.
Late Side Effects of Radiation
Can manifest months to years after treatment and include:
Memory changes: Difficulty with short-term or long-term recall.
Cognitive changes: Impairment in executive function, processing speed, attention, and overall intellectual function (radiation encephalopathy).
Personality changes: Alterations in mood, behavior, and emotional regulation.
Radiation necrosis: A sterile inflammatory lesion causing death of brain tissue within the radiation field, which can present as a new mass or worsening neurological symptoms, requiring differentiation from tumor recurrence.
Chemotherapy Agents
Commonly used agents in brain tumor treatment often have mechanisms that disrupt DNA synthesis, cell division, or cause cellular toxicity. These include:
Methotrexate: An antifolate agent that inhibits DNA synthesis.
Cisplatin and Carboplatin: Platinum-based agents that cross-link DNA, inhibiting tumor growth.
Vincristine: A vinca alkaloid that inhibits microtubule formation, disrupting cell division.
Temozolomide: An oral alkylating agent that directly damages DNA, inducing cell death, particularly effective in glioblastoma.
Complications of chemotherapy can involve widespread systemic effects due to their non-selective action:
Immune suppression (myelosuppression): Leading to neutropenia and increased infection risk.
Anemia: Reduction in red blood cells.
- Hair loss (alopecia): A common side effect for many agents.
Fatigue: Significant tiredness.
GI symptoms: Nausea, vomiting, mucositis, diarrhea, constipation.
Hormonal treatments like Tamoxifen may be employed to inhibit tumor growth, particularly in meningiomas that express hormone receptors.
Research in gene therapy seeks to introduce viruses (e.g., oncolytic viruses) or genetic material within the tumor, allowing retrovirals or other engineered agents to be applied for specific tumor eradication.
Antiangiogenesis therapies (e.g., Bevacizumab) aim to inhibit vascular development within the tumor by blocking signals like VEGF, thereby starving the tumor of blood supply and retarding its growth.
Considerations for Chemotherapy
Notable and critical side effects primarily related to myelosuppression include:
Myelosuppression: A decrease in the production of blood cells by the bone marrow, leading to a reduction in various blood cell lines.
Pancytopenia: A reduction in all three major blood cell types – red blood cells, white blood cells, and platelets. This includes:
Anemia: A drop in red blood cells, resulting in decreased oxygen-carrying capacity.
Thrombocytopenia: A drop in platelet count, increasing the risk of bleeding.
Leukopenia: A drop in overall white blood cell count.
Neutropenia: A specific and critically important drop in neutrophils (a type of white blood cell), dramatically increasing the risk of infection.
Granulocytopenia: A drop in granulocytes, which include neutrophils, basophils, and eosinophils.
Reductions in RBC (Red Blood Cell count), HCT (Hematocrit - percentage of RBCs in blood), and HGB (Hemoglobin - oxygen-carrying protein) may result in:
Fatigue and Weakness due to reduced oxygen delivery.
Shortness of breath (dyspnea), especially with exertion.
Tachycardia (increased heart rate) as the heart tries to compensate for reduced oxygen supply.
Dizziness or lightheadedness due to decreased oxygen to the brain.
Headaches and Chest pain (angina) in severe cases.
Pale skin and mucous membranes.
Medical Management of Low Cell Counts
Interventions may include:
Epoetin alfa (PROCRIT) or Darbepoetin (Aranesp): Erythropoiesis-stimulating agents (ESAs) that stimulate the bone marrow to produce red blood cells, used to manage anemia.
Iron supplements to support red blood cell production if iron deficiency is present.
A high protein diet to support overall nutritional status and recovery of blood cell production.
Blood transfusion for severe symptomatic anemia or immediate need for red blood cells.
Granulocyte colony-stimulating factors (G-CSFs) like filgrastim for neutropenia.
Management of Thrombocytopenia
Treatment options may include:
Oprelvekin (Neumega): A thrombopoietin mimetic that stimulates platelet production by the bone marrow.
Platelet transfusion for critically low platelet counts or active bleeding.
Activity management: Careful graded exercise programs, avoiding resistance training or activities that could increase bleeding risk, and adjusting activities to minimize fall risk and potential trauma.
Special Considerations Related to Cancer Treatment
Fluctuations in patient status are common due to the multifaceted impacts of the disease, its pathology, various medications, and invasive procedures.
Potential issues include:
Edema (swelling): May be tumor-related (due to tumor's direct effect or abnormal vessels) or procedure-related (e.g., post-surgical inflammation). This swelling can significantly exacerbate global or focal neurological signs and symptoms and often requires pharmacological management with corticosteroids to decrease inflammation and reduce fluid accumulation.