Pediatric Brain Tumors Flashcards
Beginning two weeks after birth, ES was noted to arch her back and hold her head sideways, and was not easily comforted by her parents. She was watched closely by her pediatrician, who at her 6 week check up, told her parents that she was doing well.
Parents brought her back to the pediatrician when she was 9 weeks old and fontanel was noted to be enlarged. Her head circumference measured in the 90th percentile. An ultrasound performed showed a mass. An MRI was performed next with demonstrated a mass. She underwent her first resection, which was subtotal. Her head size continued to increase so a VP shunt was then inserted.
A follow up MRI brain a month later showed progression and an MRI spine showed questionable metastasis. Repeat MRI brain one month later again demonstrated progression, while the spine was clear. She received another subtotal resection at that time. She then received 54GY conformal radiation approximately 4 months later at the age of 13 months. She has had another shunt insertion and several shunt revisions, however now attends elementary school and presents with a normal neurological examination, although with significant neurocognitive deficits.
MRI shows large right hemispheric mass with midline shift.
How common are pediatric brain tumors?
- Most common pediatric solid tumor accounting for 18-20% of all childhood cancers
- 2nd most common malignancy after leukemia
- Most common in 1st decade of life
- 2,200 cases/year or 3.3 cases per 100,000
Primary central nervous system (CNS) tumors are the second most common cancer, after hematologic (leukemia) malignancies, and the most common solid tumor in the pediatric population.
What brain tumors occur almost exclusively in children and young adults?
- Medulloblastomas, supratentorial primitive neuroectodermal tumors (PNETs) and pineoblastomas
- High grade gliomas (glioblastoma multiforme) are rare in the pediatric age group
___________ are the most common of the CNS tumors in the pediatric population, followed by PNETs, other gliomas, then ependymomas.
Astrocytomas
Unlike adults and older children, young children have a relatively high occurrence of malignancies where?
in the cerebellum and the brain stem.
In fact, in children younger than 10 years of age, brain stem malignancies were nearly as common as cerebral malignancies, and cerebellum malignancies were far more common than cerebral malignancies
What are the most common sites of brain tumors in children?
- Infratentorial (50 to 60%) (especially in those less than 10 yo)
- Supratentorial (30 to 50%)
- Midline (10 – 15%)
What are some infratentorial tumor locations?
75% in cerebellum and 4th ventricle
What are some supratentorial tumors?
Suprasellar Tumors: Chiasmal gliomas and Craniopharyngiomas
Hemispheric tumors: Low- and High- grade astrocytoma
Pineal Region tumors
What are some common posterior fossa tumors?
- Medulloblastoma
- Astrocytoma
- Brainstem glioma
- Ependymoma
What tumors are most common in children under 1 yo?
Supratentorial located gliomas, teratomas, PNET, or choice plexus tumors
What tumors are most common in children 1-11 yo?
Infratentorial or supratentorial medulloblastoma, ependymoma, or brain stem gliomas
What tumors are most common in children 11+ yo?
glioma, PNET/Medulloblastoma, and germ cell tumors
What are some predisposing factors for development of a brain tumor?
- Ionizing Radiation
- Other tumors: Kidney, Retinoblastoma
- Immune Suppression: Wiskott-Aldrich Syndrome, Ataxia-Telangiectasia, Acquire immunodeficiency
- Familial Conditions
What brain tumors are associated with turcot syndrome?
germline mutation in APC gene or mismatch repair genes hMLH1 and hPMS2 can cause medulloblastoms or glioblastoma multiforme
Different genetic syndromes are associated with brain tumors and it is important to routinely have neuroimaging surveillance in these patients with these syndromes.
What brain tumors are associated with Cowden syndrome?
loss of function mutations in PTEN, a tumor suppressor, leads to hyperactivity of the mTOR pathway causing dysplastic gangliocytoma of the cerebellum
What brain tumors are associated with Nevoid basal cell carcinoma/Gorlin syndrome?
mutations in the PCH (9q chromosome) caused medulloblastoma
CNS tumors are heterogeneous in regards to histology and clinical course.Because of the many relatively similar histopathological types and their rarity, it is necessary for epidemiologic purposes to group CNS tumors into rather broad histologic categories.
There are several classification systems that are used for describing CNS tumors and no system has yet emerged as the definitive gold standard.
Pediatric CNS tumors are usually classified according to the underlying histopathological features and/or anatomic location.
Where do most pediatric brain tumors arise?
- Most arise from the supporting cells of the brain (glia) and are called “gliomas”
- Others arise from the primitive nerve cells, that are much more common in children than in adults
- A third type of childhood brain tumor arises in the non-neuronal embryonal cells
Here’s a picture to show normal CNS differentiation of neural stem cells into glial cells which can differentiate into oligodendrocytes, astrocytes, or ependymomas. If any of these steps goes array, then a CNS tumor of that cellular origin is formed
What are the glial tumors?
- Astrocytomas
- Oligodendrogliomas
- Ependymal Tumors
- Choroid Plexus Tumors
- Mixed Gliomas
- GBM
What are the neuronal tumors?
- Gangliocytoma
- Anaplastic ganglioma
What are the primitive neuro-ectodermal tumors?
- PNET
- PNET with differentiation
- Medulloepithelioma
What are the pineal cell tumors?
pineocytoma
pineoblastoma
Here’s a diagram showing the frequency of each tumor type relative to other CNS tumors.
The clinical presentation of one with a brain tumor is largely dependent on what?
the location of the tumor and what part of the brain has direct pressure or involvement. For example, the R handed, L brain dominant person with a cortical hemispheric tumor, you can expect to see aphasia. With occipital lobe involvement, there could be visual loss.
How might a supratentorial tumor present?
localized findings including seizures, and hemiparesis
How might a midline (hypothalamic, optic, craniopharyngioma, pineal) tumor present?
Endocrinopathies or Growth disorders
Diabetes insipidus
Decreased vision or Visual field deficits
Signs of increased ICP
How might an infratentorial tumor present?
Infratentorial tumors, patients will have signs of increased ICP, due to compression of fourth ventricle.
How might a brainstem tumor present?
Brain stem tumors may present with CN deficits in this region, including diplopia, dysarthria, dysphagia, Crossed weakness= lesions rostral to the pyramidal decussation) in which there is upper motor neuron paralysis of the arm and leg contralateral to the lesion, and lower motor neuron paralysis involving a cranial nerve motor function ipsilateral to the lesion and occasional hydrocephalus
Hydrocephalus is associated with up to 80% of midline brain tumors, commonly due to obstruction in the ventricular system. How does this present?
•Initial symptoms are early morning intermittent headaches & nausea/vomiting
What is the prognosis of the hydrocephalus associated with midline brain tumors?
Hydrocephalus is important to recognize as it may require immediate surgical decompression of the tumor and/or shunt placement.
•Most resolve after mass resection, but 15% require placement of shunt or ventriculostomy
What are the complications of hydrocephalus?
Complications include shunt failure, infection or hemmorhage
Depending on the location of the tumor, one may have ocular findings such as proptosis or ptosis.
Will see blurring of optic disc margin as on right with increased ICP
Here’s the classic triad of increased ICP: N/V, AM HA, and lethargy Other signs to look for in children include:
bulging fontanelle, sundowning of eyes, CN 6 palsy, HA/N/V. Approximately 1/3 posterior fossa tumor patients will require permanent VP shunts following surgical debulking. Presentation before diagnosis is generally 4-6 months
An example of “sun-downing” eyes with increased ICP requiring immediate intervention.
Sagittal view of hydrocephalus
Axial view of hydrocephalus, transependymal flow seen with enlarged lateral ventricles
What is the most common childhood brain tumor?
A low grade astrocytome (40% of all CNS tumors (if including high grade then 50%))
Describe low grade pediatric astrocytomas?
- May be either supra or infratentorial
- Derived from astrocytes, which are major supportive cells (Astrocytes constitute 40% of CNS cell population & are widely spread throughout the CNS including the optic nerves)
Describe the grading of astrocytomas
- Low Grade Astrocytomas fall in the Grade I and II which are histologically benign
- Grade III (anaplastic astrocytoma) & IV are malignant (glioblastoma multiforme)
High grade gliomas represent 7-11% of all CNS tumors
How are low grade astrocytomas handled?
These are primarily surgical diseases with a greater than 75% 5 yr survival if gross total resection is achieves (50% if incomplete)
•Chemotherapy/Radiotherapy are options in those with residual tumor or recurrent disease
This is an example of an optic pathway JPA with involvement of optic chiasm and extension into optic nerves. It’s a contrast enhancing tumor and can be seen with solid and cystic components.
On left you can see this is a contrast enhancing tumor and on the right there is resolution of the disease on the right after therapy.
What is this?
Juvenile Pilocytic Astrocytoma- The term pilocytic refers to the the elongated hair-like projections from the neoplastic cells The presence of eosinophillic Rosenthal fibers are a characteristic feature, and hyalinization of blood vessels a common features.
What causes juvenile pilocytic astrocytomas?
PAs are driven by an oncogenic process activating the MAPK pathway.
KRAS activation or BRAF activation with either duplication on c’s 7 or v600E mutation causes activation of BRAF. Pts with NF1 have loss of inhibitory gene NF1 causing KRAS activation. Other activations in this pathway can lead to PAs.
Here is an example of the different BRAF fusions seen to the right which all activate RAF and the MAPK pathway leading to an oncogenic process.
Here you see the common locations of PAs with respect to the genetic aberrations. For instance, BRAF fusion is more common in cerebellar tumors vs noncerebellar. BRAF V600E mutation is more common in extracerebellar regions and NF1 loss is more common in optic pathway tumors.
How common are MEDULLOBLASTOMAs
These represent 20% of all CNS tumors (40% of posterior fossa tumors), are more common in children, and peak in incidence around 3-4 yo (M:F is 1.5:1)
Where do medulloblastomas arise from?
primitive nerve cells
Note that in the cerebellum, the term is medulloblastoma and in the cerebrum they are called primitive neuroectodermal tumors (PNETs)
What are the prognostic factors with medulloblastomas?
- Age
- Histology
- Size at diagnosis
- Metastatic spread
- Extent of resection
- Neurotrophin-3 receptor, TrkC, ErbB2, ErbB-4, C-myc overexpression
What is the prognosis of medulloblastomas?
- Malignant, WHO grade IV, grow rapidly, and tend to spread through the CSF
- Often infiltrate adjacent brain structures preventing total resection
How are medulloblastomas handled?
- Surgery with craniospinal radiation
- Adjuvant chemotherapy beneficial (especially in infants and in disseminated or recurrent disease)
It is a posterior fossa tumor seen with contrast-enhancement
Densely cellular, Round, oval or angulated (‘carrot-shaped’), Low vascular density, Homer-Wright rosette= are pseudorosettes consisting of tumor cells surrounding a fibrillar area Hyperchromatic
What caused medulloblastomas?
Normally, in the inactive Shh pathway, Ptch receptors inhibit Smoothened receptors (red, inactive Smoothened receptors), preventing Smoothened relocating to the cilium.
Some Smoothened receptors undergo endocytosis and are incorporated by endosomes (blue).
SuFu binds Gli2 and Gli3, downstream effectors in the cytoplasm and primary cilium. Gli2 is also targeted for degradation through the proteosomal pathway. In the active Shh pathway, Ptch does not suppress Smoothened (active Smoothened receptors, green), which relocates to the cilium with the aid of Kif7. SuFu no longer binds to Gli2 and Gli3, so Gli2 relocates to the nucleus and is a transcriptional activator. Gli3 is a repressor.
In the inactive Wnt pathway, Frizzled receptors are inactive (red) and b-catenin is phosphyorylated and bound in a protein complex, which is targeted for proteosomal degradation. In the active Wnt pathway, frizzled receptors are active (green) and b-catenin complex is disrupted allowing translocation to the nucleus where it is a transcriptional activator.
These are the new molecular classification of MB subtypes.
WNT tumors usually have a good prognosis and are classic histology. SHH tumors involving PTCH mutation can have good prognosis in infants, and intermediate in other ages.
Group 3 is a very poor prognosis with MYC amplification. Group 4 has an intermediate prognosis.
How common are brainstem gliomas?
These represent 15% of all CNS tumors and are uniformly fatal in 18-24 months and have a less than 10% 5 yr survival rate
How are brainstem gliomas tx?
Surgery contraindicated
radiation therapy provides temporary relief
supportive care
Here is an example of a brain stem glioma, not surgically resectable.
Describe diffuse intrinsic pontine gliomas
These represent 8-10% of all pediatric CNS tumors, and have a terrible prognosis with mean survival ranging from 9-11 months with only 20% surviving past one year (median age of onset is 7 yo)
What are the symptoms of diffuse intrinsic pontine gliomas?
Corticospinal long tract signs (weakness or hemiparesis), ataxia and CN 6,7,8 deficits
Diagnosis of an Diffuse Intrinsic Pontine Glioma is made via MRI. What are the classic findings?
Engulfs basilar artery by tumor, diffuse extension into pons
How are diffuse intrinsic pontine gliomas tx?
Not resectable, radiation helps prolong life
Biopsy is seldom necessary since MRI is diagnostic.
Radiotherapy is standard treatment and can be ameliorative. Unfortunately, the improvement of clinical and radiographic signs are typically short lived.
Describe ependymomas
These represent 9% of all CNS tumors, and have the highest incidence in the first 7 yrs of life (arise from ependymal cells)
Where are ependymomas commonly found?
posterior fossa (60%)
spinal cord (10%)
Classic ependymomas (WHO grade 2) typically exhibit perivascular pseudorosettes of glial tumor cells that are radially arranged around the blood vessels (Figure 2A) and true ependymal rosettes of tumor cells that form a central lumen on their own (Figure 2B).
Describe the typical pt who gets ependymoma
- Male to female ratio is 1:1
- 50% of patients are < 5 yo at presentation
How do ependymomas commonly behave?
- Tumors are locally invasive
- CNS dissemination is 7-10%
- May be low grade or anaplastic
The PNET variant of an ependymoma is called what?
ependymoblastoma
•Staging should include CSF examination and spinal MRI
How are ependymomas tx?
- Surgery & radiotherapy remain the cornerstone of treatment
- Chemotherapy has failed to improve survival
- Overall survival: 65%
What are the prognostic factors for survival with an ependymoma?
- Surgical resection
- Brain stem involvement
- Age
- Stage at presentation
Tx of brain tumors in general
Radiotherapy is indicated for what brain tumors?
- Low grade astrocytoma and High grade astrocytoma
- Medulloblastoma/PNET
- Ependymoma
- Germ cell tumors
- Craniopharyngioma
- Brainstem glioma
How does radiation affect the developing brain?
The development (axonal growth & synaptogenesis) is most rapid in the first 3 years of life. Rate of growth & development slows after age 6. However, maturation (degree of myelinization) isn’t complete until puberty
Therefore, we try to delay RT until after age 3 yo, but after age 7 yo is even better.
What are the effects of radiation on the brain?
- Radiation effects can be delayed (months to years) after treatment
- Neuropsychological effects include: intellectual impairment, memory deficits and inability to acquire new knowledge
- Cognitive impairment is most pronounced in children younger than 4-7 years of age
Since the 1970s and 1980s, several prospective, randomized trials have shown that adjuvant chemotherapy improves overall survival for patients compared with those treated with radiation alone
When should chemo be used?
- Intermediate and High-risk Medulloblastoma
- High Grade Gliomas/PNET/ATRT
- Germ Cell Tumors
- Low Grade Astrocytomas (Optic pathways/hypothalamus)
In general, the number of available chemotherapeutics are limited for brain tumor treatment because of the blood-brain barrier. However, several conventional drug regimens have proven beneficial in these patients.
What chemo is used for a low grade glioma?
–Vincristine, carboplatin or vinblastine
–PCV (Procarbazine, CCNU, Vincristine)
What chemo is used for a high grade glioma?
–Temozolomide, CCNU
What chemo is used for a medulloblastoma?
Lomustine, cisplatin, carboplatin, vincristine, or cyclophosphamide
What chemo is used for an ependymoma?
–Vincristine, cyclophosphamide, etoposide, cisplatin
Chemo
In general, children with CNS cancer do not share the favorable prognosis compared to those with many other common pediatric neoplasms as seen by the graph of the survival curve on the right. ALL has reached 80% cure rates, while CNS tumors are 65% cure rates.
The future direction of classification of brain tumors is including the histology and anatomical location but also considering molecular stratification which brings optimism and hope for decreasing toxicity of harsher treatments and directing therapy to molecular targets in these tumors.
