Brain Tumors and Peripheral Neuropathies Flashcards
Genetic syndromes associated with increased risk of developing brain tumors?
Only 5% of primary brain tumors are hereditary and the most relevant genetic syndromes are NF1, NF2, TSC, VHL, mismatch repair deficiency syndromes.
What is Neurofibromatosis Type 1 (NF1), its genetic basis, clinical features, and associated tumor risks?
NF1 is an autosomal dominant disorder caused by an inactivating mutation of the NF1 gene, which encodes neurofibromin. Neurofibromin is a tumor suppressor protein that negatively regulates the RAS proto-oncogene, controlling cell growth and proliferation.
Clinical features include :
- Café-au-lait macules which are hyperpigmented flat spots on the skin.
- Axillary and inguinal freckles.
- Neurofibromas which are benign nerve sheath tumors that can present as either dermal neurofibromas or plexiform. - - - Long bone dysplasia which may include bowing of long bones or pseudarthrosis.
Can lead to optic pathway glioma, brainstem glioma and high grade glioma.
They are associated to neurofibromas, glioma and malignant peripheral nerve sheath tumors.
What is neurofibromatosis 2?
Genetic syndrome with an autosomal dominant inheritance characterized by a mutation of the NF2 tumor suppressor, encoding for the protein merlin.
NF2 causes Bilateral vestibular schwannomas are the most common cancer type (90%), followed by meningiomas (50%) and spinal or intracranial ependymomas (5%).
What is tuberous sclerosis 1 and 2?
Autosomal dominant inheritance. TSC1 is characterized by a mutation in the gene encoding for the hamartin protein and TSC2 for the tuberin protein.
Clinical features include epilepsy, cognitive impairment, autism and behavioral alterations.
What is Von Hippel-Lindau syndrome?
VHL is a syndrome characterized by autosomal dominant inheritance and the typical feature is the presence of hemangioblastomas within the CNS (cerebellum, brainstem, spinal cord) that are prone to bleed and show hyper-enhancement on MRI.
Brain metastasis?
Metastases are secondary brain malignancies and mostly come from the lung (20-50%), breast (5-20%), kidney (7-10%) and melanomas (7-16%).
Metastases arise due to hematogenous spread of cancer cells to the brain, after perforating the basement membrane, going into the blood stream, penetrating the BBB and acquiring brain tropism.
What is the seed and soil theory regarding brain metastasis?
The “seed and soil” theory states that metastasis depends on the interaction between cancer cells (“seeds”) and specific organ microenvironments (“soil”). In brain metastases, tumor cells must adapt to the brain’s unique environment, leading to molecular divergence between the primary tumor and its metastases. This divergence implies that targeted therapies effective against the primary tumor may not work on brain metastases if the relevant mutations differ. Consequently, brain biopsies are often performed to guide appropriate treatment strategies.
Common clinical findings of brain tumors?
Similar in primary and secondary malignancies, depends on the tumor location not on tumor type.
- Focal neurological deficits : hemiparesis (frontal lobe involvement and impairment), aphasia and
memory deficits (temporal), hypoesthesia and paresthesia (parietal), hemianopia (occipital), gait ataxia, vertigo, dysarthria, dysphagia (cerebellum), dysphagia, diplopia, long tract involvement with interference of sensory and motor function (brain stem). - Focal seizures, arising is a specific brain area. They could undergo generalization and could be motor seizures if the involvement is the frontal lobe or others, like paresthesia development, if the involvement is at the level of the parietal lobe.
These findings usually develop over days or weeks.
What is vasogenic edema?
Vasogenic edema, commonly associated with malignant brain tumors, results from the disruption of the BBB, leading to the accumulation of extracellular fluid in the brain parenchyma. On MRI FLAIR sequences, this edema appears as hyperintense areas surrounding the tumor mass, indicating increased water content in the affected regions. The presence of vasogenic edema can exacerbate neurological deficits, increase the risk of seizures and contribute to elevated intracranial pressure.
Treatment option include corticosteroids such as dexamethasone (IV,IM or orally, 2-24 mg per day), osmotic agents such as mannitol and hypertonic saline used in severe cases. Loop diuretic such as furosemide to enhance fluid removal.
A combination of these therapies can be used.
Intracranial hypertension?
Intracranial hypertension refers to elevated pressure within the skull, leading to a range of neurological symptoms.
Common manifestations include : headache, nausea, vomiting, visual disturbances, ocular deviations, altered consciousness.
In advanced stages Cushing’s triad may develop characterized by hypertension, bradycardia and irregular respiration.
Additionally it can cause brain herniation, a life threatening condition where the brain tissue is forced across structures with the skull.
IH can be caused by brain tumors, abscesses, head injuries, infections, vascular disorders and hydrocephalus.
IH can also be idiopathic.
Different types of brain herniation?
Brain herniation occurs when increased intracranial pressure forces brain tissue to shift across structures within the skull.
1. Subfalcine (Cingulate) Herniation : The cingulate gyrus is pushed beneath the falx cerebri, potentially compressing the anterior cerebral artery and leading to ischemia.
2. Uncal (Transtentorial) Herniation : The medial temporal lobe (uncus) shifts downward through the tentorial notch, compressing the brainstem and cranial nerve III, resulting in pupil dilation and impaired eye movement.
3. Central Herniation : The diencephalon and adjacent temporal lobes are forced downward through the tentorial notch, causing bilateral pupil constriction and altered consciousness.
4. Tonsillar Herniation : The cerebellar tonsils move downward through the foramen magnum, compressing the medulla oblongata and potentially leading to respiratory and cardiac dysfunction.
5. Transcalvarial Herniation : Brain tissue protrudes through a defect in the skull, such as a fracture or surgical opening, exposing it externally.
6. Upward (Ascending) Herniation: Increased pressure in the posterior fossa pushes cerebellar structures upward through the tentorial notch, compressing the midbrain.
What is hydrocephalus? Types? Treatment?
Hydrocephalus, characterized by an abnormal accumulation of CSF within the brain’s ventricles, can lead to increased intracranial pressure and requires prompt medical attention. The two primary types are obstructive (non-communicating) and communicating hydrocephalus, each with distinct causes and treatment approaches.
Obstructive : forms when CSF flow is blocked along the narrow pathways connecting the ventricles. Common causes include tumors in regions such as the pineal gland, brain stem, cerebellum and basal ganglia. Treatment options include : a third ventriculostomy which is a procedure that creates an opening between the third ventricle and the basal cistern to allow the CSF to bypass the obstruction or a ventriculoperitoneal shunt which involves a shunt system to diverts CSF from the lateral ventricle to the peritoneal cavity.
Communicating : no specific obstruction, CSF is not properly reabsorbed due to dysfunction at the arachnoid granulations. It is associated to conditions like meningeal carcinomatosis, certain secondary brain tumors and hematological disorders like waldenstroms macroglobulinemia. Treatment includes acetalozamide which decreases CSF production.
Imaging in an emergency setting?
After development of some of the previously described conditions the patients usually goes to to ER.
The first line imaging is CT scan, with or without contrast, to easily identify hypodense regions. After CT, a contrast MRI is done to confirm the neoplastic nature, followed by an amino acid PET (thiamine, dopa, fluoroethyl-tyrosine) to visualize metabolically active and highly proliferative regions.
T2 FLAIR and T1 after Gd injection are always performed. The first can show the tumor infiltration and boundaries and edema, while the second is helpful in case of BBB damage. Remember that the edematous area looks the same even in non-neoplastic conditions, but the central core will be different.
What other type of sequences can be used provide insight into brain tumors?
- Susceptibility-Weighted Imaging (SWI) : SWI is highly sensitive to magnetic field inhomogeneities caused by substances like hemosiderin, making it effective in detecting intratumoral hemorrhage and calcifications. Enhances visualization of microbleeds and vascular structures with tumors.
- Diffusion-Weighted Imaging (DWI) : measures the diffusion of water molecules within tissues, with areas of high cellular density, such as tumors, restricting diffusion and appearing hyperintense. This property assists in identifying tumor cellularity and guiding biopsy locations to ensure representative sampling.
- Perfusion-Weighted Imaging (PWI) : evaluates cerebral blood volume and cerebral blood flow, providing insights into tumor vascularity and angiogenesis. Increased CBV and CBF are indicative of high-grade tumors with elevated blood vessel density.
- Magnetic Resonance Spectroscopy (MRS) : analyzes the concentration of metabolites within brain tissue. Elevated choline levels and increased choline/creatine ratios suggest heightened cellular proliferation, common in tumors, while decreased N-acetyl aspartate (NAA) indicates neuronal loss or damage.
What is done after imaging?
After imaging biopsy or resection should be considered. Biopsy is generally preferred if surgery is not an option, in case of older patients, otherwise resection is the gold standard.
What is the WHO classification of tumors of the CNS?
The new classification takes into consideration both the histology and the molecular markers, sometimes essential to establish diagnosis.
- Stains like HE are used to highlight cellular morphology, necrosis, cell density and inflammatory infiltrates.
- Immunohistochemistry uses antibodies targeting specific proteins to determine the cellular lineage and expression of mutant proteins. GFAP identifies astrocytic cells, olig2 marks oligodendrocytic cells, CD34 labels endothelial cells.
- Proliferation index serves as an indirect measure of tumor aggressiveness.
What is the karnofsky performance status score?
The KPS score depicts patients autonomy in daily life to understand the possibility of certain treatments and clinical trials. 70 is the threshold, under it the patient needs assistance in his/her daily life and may not be a candidate for certain treatments.
Treatment for brain tumors? Different types? Complications?
- Chemotherapy —> with alkylating agents leading to cell apoptosis.
- Radiotherapy —> inducing double strand breaks and apoptosis.
Radiotherapy modalities include : conventional radiotherapy that uses x rays to target tumor cells and ion bean radiotherapy which used heavier particles and deliver a big punch without reduced toxicity to surrounding structures.
Radiotherapy techniques include : conformal radiotherapy which shapes the radiation beam to match the tumors geometry, whole brain radiotherapy which irradiates the entire brain (used for multiple metastasis), radio surgery which delivers high dose radiation precisely to the tumor (used for small well defined tumors), and craniospinal radiotherapy which targets both the brain and the spinal cord (used for tumors such as medulloblastoma).
Complications : early complications include acute encephalopathy which can cause headache, vomiting, drowsiness, and exacerbation of pre existing focal deficits.
Late complications include radiation necrosis, stroke and radiation induced leukoencephalopathy.
What is radiation necrosis?
Radiation necrosis involves the death of normal brain tissue post-radiotherapy, often due to thrombosis and obstruction of small arteries. It’s more frequently associated with radiosurgery. Distinguishing it from tumor progression, especially in glioblastoma and necrotic brain metastases, is challenging.
Diagnosis is done with perfusion MRI to assess blood flow as radiation necrosis typically shows reduced perfusion. Magnetic resonance spectroscopy can also be used as it detects metabolic changes, elevated lactate suggests necrosis.
Treatments include corticosteroids to reduce inflammation and edema, bevacizumab which targets vascular endothelial growth factor promoting BBB repair.
What is radiation induced leukoencephalopathy?
This condition involves extensive damage to the brain’s white matter following radiotherapy, characterized by neural loss, cortical atrophy, and microbleeds. It’s particularly associated with whole-brain radiotherapy.
Clinical manifestations include cognitive decline, dementia, movement disorders.
Treatment options are limited as corticosteroids and ventriculoperitoneal shunting have shown incomplete improvement.
Chemotherapy regimens? Side effects? CTCAE classification?
- For high grade gliomas, temozolomide is used as first line therapy, while lomustine or fotemustine as second line.
- For low grade gliomas the PVC protocol or temolozomide is used.
- For medulloblastoma there is the use of intra venous platinoids.
- For CNS lymphomas : high doses intravenous methotrexate.
They all share common side effects such as bone marrow toxicity, liver toxicity, peripheral neuropathy and kidney failure.
Common Terminology Criteria for Adverse Effects can be used to record the severity of the side effects. The scale goes from 1 to 5, 5 being death related to AE.
How is the treatment response assessed?
- Bidimensional Analysis : This method involves measuring the two major axes of the lesion on MRI slices. It provides a straightforward way to estimate tumor size and is especially effective for round lesions. For irregular shaped tumor this approach is insufficient.
- Volumetric analysis : This advanced method involves calculating the entire tumor volume, offering a more precise evaluation of the tumor’s size and response to treatment. Can be used for irregular shapes and heterogenous lesions.
- Tumor composition change : As a result of treatment, the tumor’s composition may change. This includes variations in cell density, necrotic areas, or other tissue alterations that can affect imaging results and interpretations.
Tumor recurrence and heterogeneity?
Recurrent tumors can differ significantly from the original lesion. These differences may include:
- Gene Expression Profiles : The genetic makeup of recurrent tumors can shift due to selective pressures from treatment.
- Heterogeneity : Tumors like glioblastomas are known for their genetic and structural heterogeneity, making evaluation and management challenging.
Primary brain tumors in children?
Primary brain tumors in children are not that frequent, as the incidence for ages between 0 and 14 is 6 cases per 100,000.
The most common tumors are pilocytic astrocytoma, medulloblastoma and malignant glioma. The most common location for these types of tumors are the cerebellum and the brain stem.
Pilocytic astocytoma?
Most common primary brain tumor in children. The most typical location is the cerebellum. It is a benign tumor as it grows slowly over time although due to the location it can cause insidious symptoms such as : difficulty swallowing, slurred speech, diplopia.
This tumor is always a WHO grade I tumor.
The most common pathway alteration is the MAPK signaling pathway. Genes involved are BRAF, FGFR1, FGFR2 and FGFR3.
Prognosis and treatment : it has a favorable prognosis and the 10 year survival rate is close to 100%. Primary treatment is surgery, once the tumor has been resected the patient can be considered cured. The patient must only do regular MRI scans to keep everything under control and in most cases we do not see reoccurrence (<5%).
If total resection is not possible reoccurrence rate is higher (up to 50%). In this case we can observe, radiation over the residue or use oral inhibitors of BRAF or MEK.
Medulloblastoma? Clinical features and subtypes?
Second most common tumor in children. The most frequent location is the cerebellum or the dorsal brain stem. It is an aggressive tumor that grows quite quickly and symptoms develop rapidly. Average age diagnosis is 6.
Clinical features : symptoms develop and consist of headache, nausea, vomiting and gait ataxia. Symptoms are caused either from the tumor mass itself or from obstructive hydrocephalus as the tumor mass often develops very close to the 4th ventricle. One distinct feature is its remarkable propensity for disseminating within the CNS, cancerous cells detach and traverse the CSF.
This tumor metastasis is called drop metastasis as dissemination often occurs due to the influence of gravity, it tend to follow the neuroaxis.
Medulloblastoma only exists as a WHO grade 4 tumor. There are 4 main histological subtypes : classic, desmoplastic/nodular, large cell and anaplastic.
Medulloblastoma main molecular subgroups?
- WNT : subgroup is characterized by mutations in the WNT signaling pathway, specifically involving the WNT/β-catenin pathway. These tumors typically have a favorable prognosis and are associated with children >4 years age old. Predominantly occur in the lower lateral cerebellum
- Sonic hedgehog (SHH): involves mutations in the Sonic Hedgehog signalin pathway. It is further subdivided into SHH-TP53 wildtype and SHH-TP53 mutant subtypes based on the presence or absence of TP53 mutations.
SHH-activated medulloblastomas are associated with a poorer prognosis and can occur in both children <3 years old and adolescent. - Group 3 : subgroup is characterized by high expression of the MYC oncogene and amplifications of the MYC and MYCN genes. Group 3 tumors are typically aggressive and have a poorer prognosis, often occurring in younger children.
- Group 4 : are the most common subtype of medulloblastoma and are characterized by a lack of specific
molecular alterations.
Treatment for medulloblastoma?
Treatment entails craniospinal irradiation with local boost of radiation over the cerebellar mass. This is followed by monthly cycle of IV platinum chemo such as cisplatin or carboplatin.
Very aggressive treatment but necessary to prevent metastasis along the spine.
All patients undergo this treatment scheme, not considering the grade, stage or molecular group. The specific treatment related to the subgroup is more of a reinforcement such as SHH inhibitors.
Diffuse intrinsic pontine glioma? Clinical features? Imaging?
Very aggressive tumor located within the pons diagnosed usually between 6 and 9 years of age.
Clinical features involve a variety of symptoms as patents are quite disabled by this type of tumor. It includes diplopia, facial palsy, motor deficits and cerebellar dysfunction.
Imaging features : extensive infiltration of the pons without contrast enhancement. Deep infiltration of the tumor mass which creates a cavity within the pons.
From a molecular point of view these tumors are defined by the H3 K27M (75%) mutation. These are specific mutations encoding for a histone that is one of the proteins responsible for variation in chromatin conformation, DNA shaping and transcription.
If this mutation is present it is directly considered a grade IV tumor.
Treatment for diffuse intrinsic pontine gliomas? Biopsy?
Due to their location they are generally not resectable.
Biopsy is often omitted due to high risk complications. Even stereotactic biopsy with a trans occipital approach could potentially cause fatal bleeding.
Liquid biopsy can be done to detect mutation. It is a viable way to confirm the diagnosis without the risks of surgery.
Radiotherapy is the standard treatment for DIPG. It is essential to understand that in this case radiotherapy is palliative rather than curative. DIPG are poorly responsive to conventional chemotherapy. Research is going on to look for other alternatives.
Prognosis is poor and the median overall survival around 9-12 month.
Primary brain tumors in adults?
Primary brain tumors are more frequent in adults than in children. Almost 43 cases per 100,000 per year.
The three most common pediatric ones are much less common in adults, the most common in adults are meningiomas, pituitary adenomas and glioblastoma.
The incidence of meningiomas and glioblastomas particularly increases with age until 45-50 years old and then hits a plateau.
Meningiomas? Clinical features? Imaging? Histo-molecular features?
Most common adult primary tumor. Risk developing it increases exponentially with age after 65 years of age.
They exhibit a notable female prevalence of 3.5:1, this is attributed to hormonal influences as meningiomas possess receptors for both estrogen and progesterone on their cell surfaces.
Predisposing factors include history of previous radiotherapy and individuals with NF2.
Clinical features : they are generally considered benign tumors as they develop very slowly. They cause insidious symptoms like headache, focal deficits and seizures. These all develop over several months or years.
Imaging : it is a very well defined lesion with homogenous contrast enhancement and a dural tail (linear image at base of mass which is the connection between the meningioma and the meninges), hyperostosis (abnormal thickening) of adjacent bone and intralesional calcifications. It is challenging to tell wether the tumor is growing inside the brain parenchyma (intra-axial) or outside (extra-axial).
How does menopause affect meningiomas prevalence in females?
Menopause, which entails a decline in estrogen and progesterone levels, may potentially reduce the female prevalence of meningiomas by diminishing hormonal stimulation of tumor growth, but we need to remember that the effect of estrogen/progesterone is cumulative, the tumor will develop after YEARS of stimulation.
