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
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
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.
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.
Here is an example of a brain stem glioma, not surgically resectable.
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.
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).
Tx of brain tumors in general
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
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.
