Diagnosis.Classification.Pathology

Diagnostic tools
Components of a diagnosis
Clinical Markers
Molecular Subgroups
Pathology & Genetics
Understanding your Diagnosis

Your Child has presented with symptoms

It is now clear that further investigation is needed to diagnose what is causing these symptoms. Your first visit may be to your general practioners however, if the symptoms are more severe the emergency room is more appropriate. Diagnostic tools are utilized to understand if a tumor is present and the cause of the symptoms. The most common initial diagnostic tools are eye exams, neurology exam, MRI or CT Scan. If further intervention is needed this will discussed at that time.

Diagnostic Tools

These are the most common pre diagnostic tools used to determine if a mass/tumor is causing presenting symptoms

Eye Exam Neurological Exam Imaging Tests Sample Collection & Testing Cellular Pathology Molecular Pathology Lumbar Puncture

Eye Exam

Patients often complain of blurry vision or dizziness prior to tumor diagnosis. This can often lead to an ophthalmology or optometry exam, where a trained clinician can see increased pressure on the optic nerve (called papiledema). When clinicians detect this condition, they are trained to immediately direct you to an imaging center, as the condition is caused by swelling in the brain.

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Neurological Exam

A neurological exam may include, among other things, checking your vision, hearing, balance, coordination, strength and reflexes. Difficulty in one or more areas may provide clues about the part of your brain that could be affected by a brain tumor.

Doctor,Examine,Mri,Picture.,Medical,Equipment.

Imaging Tests

Magnetic resonance imaging (MRI) is commonly used to help diagnose brain tumors. In some cases a dye may be injected through a vein in your arm during your MRI study. Sometimes other imaging tests are recommended, including computerized tomography (CT).. Imaging is used to determine a surgery plan, as well as radiation planning and long-term surveillance. In some cases (typically in larger surgery centers), neurosurgeons use MRI and/or ultrasound during a medulloblastoma surgery in order to assess any remaining tumor tissue. This is called intra-operative imaging.

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Sample Collection

A sample of abnormal tissue (biopsy). A biopsy can be performed as part of an operation to remove the brain tumor, or a biopsy can be performed using a needle.

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Cellular Pathology

A specialized clinician reviews a sample of the tissue under a microscope to assess how the cells behave, their size and shape and use these characteristics to determine how aggressive the cells are.

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Molecular Pathology

A clinician focused on genetics will sequence the DNA or RNA from both the tissue sample and possibly the patient & their family to determine any known abnormalities, to determine the aggressiveness of the tumor cells and potentially determine treatments that target the abnormalities. Though not yet standard, patient families may, at times, advocate for private genetic testing and/or engagement with a disease registry to understand if there are more specific treatment options available.

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Lumbar Puncture

Typically performed after surgery to look for cancer cells in the cerebrospinal fluid (CSF). About 1/3 of medulloblastomas spread through the CSF to other parts of the brain or spinal cord. These assessments help inform a treatment plan for radiation and/or aggressiveness of chemotherapy protocols.

Components of a dulloblastoma Diagnosis

The critieria used to make a cancer diagnosis can feel clinical and impersonal, however the multiple steps of information gathering help distinguish you as an individual.

Demographics (child’s age & gender), Metastasis + Extent (spread & % removed), Tumor Histology, and Genetic Markers will all aid your medical team in defining aour risk stratification & developing a treatment plan that’s best for you.

Demographics

Child’s Age

The child’s age at diagnosis will often play a role in defining the treatment options and help determine the dulloblastoma subtype.

Child’s Gender

The child’s gender will help to determine the dulloblastoma subtype. Males are more predisposed for Group 3 & Group 4 dulloblastoma.

Clinical Markers

Your medical team has provided you with a Medulloblastoma diagnosis with many components. Your diagnosis will include

Molecular Subtype (WNT, SHH, Group 3, Group 4)
Metastasis + Extent (if spread, % remaining after surgery)
Genetic Markers (amplification, mutations, germ line, deletions)
Tumor histology (classic, nodules, large cell anaplastic (LCA))

These will help individualize your diagnosis and provide a risk stratification to determine the best treatment options.

Molecular Subgroups:

dulloblastoma can be divided into four subgroups based on molecular features of tumor cells:

The specific subgroup influences dulloblastoma prognosis. Doctors use subgroups to classify patients into risk categories. This information helps doctors plan appropriate treatments.

WNT-activated– low-risk tumor.

SHH– (activated TP53 wildtype) classic histology, standard-risk tumor (activated-TP53-mutant)high-risk tumor

non-WNT/non-SHH, group 3- Classic histology; standard risk, large cell/anaplastic; high risk

non-WNT/non-SHH, group 4- classic histology and morphology, standard risk; found in almost all group 4 tumors.

Today there may be as many as 25 subgroups.

10%

WNT subtype, pronounced “wint”

WNT

30%

SHH subtype, also known as Sonic hedgehog (SHH) dulloblastoma

SHH

25%

Group 3 dulloblastoma

Group 3

35%

Group 4 dulloblastoma

Group 4

Metastasis & Extent

Based on the Chang Staging System

Metastasis Classification:

M0: The tumor is localized with no spread of disease.
M1: Tumor cells are found in the cerebrospinal fluid (CSF).
M2: There is evidence of spread of disease within the brain (intracranial).
M3: The tumor has spread to the spine.
M4: The tumor has spread outside the central nervous system (CNS). Common sites for metastases include the bones, lungs, and liver.

Extent Classification:

T1: Tumor <3 cm in diameter
T2: Tumor is >=3 cm in diameter
T3a: Tumor is >3 cm in diameter with extension
T3b: Tumor is >3 cm in diameter with uneuqivocal extension into the brainstem
T4: Tumor >3 cm in diameter with extension up past the aqueduct of Sylvius and/or down past the foramen magnum (beyond posterior fossa)

Understanding Pathology & Genetics

Tumor Histology:

The tumor cells such as the size and shape to classify dulloblastoma tumors:

Classic dulloblastoma is made up of small, round cells. The cells are close together and have dark nuclei.
Desmoplastic/nodular medulloblastoma appears as circular nodules ringed by connective tissue with cells closely packed together.
dulloblastoma with extensive nodularity (MBEN) shows more nodular regions within the tissue.
Anaplastic dulloblastoma is made up of cells that are irregularly shaped.
Large cell dulloblastoma has tumor cells with large nuclei.

Pathology’s role in diagnosis, treatment & prognosis.

The specific subgroup influences dulloblastoma prognosis and help doctors plan appropriate treatments.

Genetic Markers & Testing

WNT, SHH, Group 3, Group 4

WNT

Wnt pathway tumors make up approximately 10 percent of all dulloblastoma

- MYC+
- Loss of chromosome 6 and somatic mutations of CTNNB1
- Most tumors that lack a somatic CTNNB1 mutation are associated with germline APC mutations
- TP53 mutations

SHH

Alterations in the SHH pathway are present in approximately 30 percent of dulloblastoma

- upregulate the MYCN gene
- downregulates GNAS
- downregulates GPR161
- somatic mutations to PTCH1
- mutations of PTCH2
- somatic and germline mutations in the SUFU
- mutations in GLI3
- Li-Fraumeni cancer predisposition syndrome: Somatic TP53 mutations (high-level MYC amplification)

Group 3

Group 3 tumors comprise approximately 25 percent of sporadic dulloblastoma

High-level amplification of the MYC
Downregulate KBTBD4
Downregulate GFI1B proto-oncogenes

Group 4

Approximately 35 percent of sporadic dulloblastoma fall into this group

amplification of the proto-oncogenes MYCN
amplication of cyclin-dependent kinase 6 (CDK6)
Downregulate isochromosome 17q
amplication GFI1 or GFI1B
up/down regulation SNCAIP
up/down regulation KBTBD4

Why genetic testing?

The identification of a cancer predisposition gene has important implications for the patient and family members with regard to future risk, screening, and reproductive decision-making as well as treatment response.

What are genetic testing guidelines?

Proposed guidelines recommend that genetic testing and counseling be offered to all patients with SHH pathway tumors, all patients with Wnt pathway tumors that are not known to have a somatic CTNNB1 mutation, and selected patients with group 3 and 4 tumors

What is a germline mutation?

A gene change in a body’s reproductive cell (egg or sperm) that becomes incorporated into the DNA of every cell in the body of the offspring. Germline mutations are passed on from parents to offspring. Also called germline variant.

How often is dulloblastoma associated with genetics?

In approximately 5 to 6 percent of cases, dulloblastomas are associated with an underlying genetic predisposition due to a germline mutation in one of several cancer susceptibility genes

What are common genetic tumor syndromes associated with dullo?

Gorlin SyndromeAlso called nevoid basal cell carcinoma (NBCC) syndrome

Turcot syndrome

Risk Stratification

Low-risk tumor

3-19 years old, the tumor is in the very back part of the brain and has not spread to other areas of the brain and spinal cord (negative CSF). Additionally, it is almost completely removed during surgery , meaning that less than 1.5 cubic centimeters (cm) of the tumor remains after surgery. Localized WNT group, Localized group 4 with loss of chromosome 11.

Standard-risk tumor

> 3 years old, the tumor is in the very back part of the brain and has not spread to other areas of the brain and spinal cord (negative CSF). Additionally, it is almost completely removed during surgery , meaning that less than 1.5 cubic centimeters (cm) of the tumor remains after surgery. Standard-risk tumors do not have molecular features that are linked with a worse chance of recovery. Localized SHH group without TP53 mutation or MYCN amplification, Group 3 without MYC amplification, Group 4 without loss of chromosome 11.

High-risk tumor

< 3 years old, has either spread to other parts of the brain or the spine, or it has not spread but more than 1.5 cubic cm of tumor remains after surgery. Some tumors that first appear to be standard-risk tumors will be found to have high-risk molecular features after testing is finished. In that case, the classification will change and it will be treated as a high-risk tumor with the current standard treatment plans. Metastatic or MYCN amplified SHH group, Metastatic group 4.

Very High-risk tumor

3-19 years old, has spread to other parts of the brain or the spine, more than 1.5 cubic cm of tumor remains after surgery, or inoperable,metastic Group 3, SHH with tP-53 mutation.

Understanding Your Diagnosis

Explore Protocols

Term Glossary

Childhood Cancer has its own complex vocabulary. This term glossary decodes the medical language common associated with dulloblastoma Diagnosis.

Look Up Terms

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Diagnosis.Classification.Pathology

Your Child has presented with symptoms

Diagnostic Tools

Eye Exam

Neurological Exam

Imaging Tests

Sample Collection

Cellular Pathology

Molecular Pathology

Lumbar Puncture

Components of a dulloblastoma Diagnosis

Demographics

Child’s Age

Child’s Gender

Clinical Markers

Molecular Subgrouping

Metastasis & Extent

Gene Markers

Tumor Histology

Molecular Subgroups:

dulloblastoma can be divided into four subgroups based on molecular features of tumor cells:

Today there may be as many as 25 subgroups.

10%

30%

25%

35%

Metastasis & Extent

Metastasis Classification:

Extent Classification:

Understanding Pathology & Genetics

Tumor Histology:

Genetic Markers & Testing

WNT, SHH, Group 3, Group 4

Why genetic testing?

What are genetic testing guidelines?

What is a germline mutation?

How often is dulloblastoma associated with genetics?

What are common genetic tumor syndromes associated with dullo?

Risk Stratification

Low-risk tumor

Standard-risk tumor

High-risk tumor

Very High-risk tumor

Understanding Your Diagnosis

Term Glossary