Overview

Question 1

Estimate the annual incidence of medulloblastoma (MB) in the United States. What is its frequency relative to other CNS tumors in children?

Answer 1

∼500 cases/yr of MB in the United States. It is the 2nd most common pediatric CNS tumor (20% of cases; #1 is low-grade glioma at 35%–50%). It is the most common malignant brain tumor in the PF in children and adolescents, comprising 40% of all PF tumors.

Question 2

What is the median age of MB at Dx?

Answer 2

MB has a bimodal age distribution, with a median age of 7 yrs in children (peak incidence b/t 5 and 9 yrs) and 25 yrs in adults.

Question 3

Is there a sex predilection to MB?

Answer 3

Yes. Males are more commonly affected than females (2:1).

Question 4

What is the cell of origin?

Answer 4

Neuroectodermal cells from the sup medullary velum (germinal matrix of cerebellum) or cerebellar vermis.

Question 5

MB is a subtype of what class of tumors?

Answer 5

MB is a subtype of embryonal tumor (along with PNET and atypical teratoid rhabdoid tumor [ATRT]).

Question 6

Mutation of which gene distinguishes ATRT from MB?

Answer 6

Loss of INI1 distinguishes ATRT from MB. INI1 is found on chromosome 22 and functions as a tumor suppressor gene.

Question 7

What % of pts present with CSF spread at Dx?

Answer 7

30%–40% of MB cases present with CSF spread at Dx.

Question 8

For what MB age group is CSF spread more common?

Answer 8

This is more common in younger pts.

Question 9

Does extra-axial spread occur in MB? If so, where?

Answer 9

Extra-axial spread is rare, but when it does occur it is typically to bone.

Question 10

What are the characteristic histologic features and markers for MB?

Answer 10

MB appears as small round blue cells. 40% have Homer Wright rosettes, and most stain + for NSE, synaptophysin, and nestin.

Question 11

What are some other types of small round blue cell tumors?

Answer 11

Small round blue cell tumors of childhood:

Lymphoma

EWS

Acute lymphoblastic leukemia

RMS

NB

Neuroepithelioma

MB

Retinoblastoma

(Mnemonic: LEARN NMR)

Question 12

What are the 3 histologic variants of MB?

Answer 12

Histologic variants of MB:

1. Classic
2. Nodular/Desmoplastic (better prognosis)
3. Large cell/Anaplastic (worse prognosis)

Question 13

The desmoplastic histologic variant of MB is associated with what clinical features?

Answer 13

The desmoplastic variant is associated with:

1. LOH 9q
2. Older age at Dx
3. Better prognosis

Question 14

What is the most aggressive histologic variant that also has a particularly high rate of CSF dissemination?

Answer 14

Large cell/Anaplastic is the most aggressive MB variant.

Question 15

What % of MBs are familial, and what are some associated genetic syndromes?

Answer 15

2%–5% of MBs are familial. Associated genetic syndromes include Gorlin syndrome (PTCH1 mutation, associated with nevoid basal cell carcinoma syndrome) and Turcot syndrome (APC mutation, associated with FAP).

Question 16

What are the common cytogenetic abnormalities in MB?

Answer 16

Common cytogenetic abnormalities in MB include:

1. Deletion of 17p (40%–50%)
2. Isochromosome 17q
3. Deletion of 16q
4. LOH 9q (desmoplastic variant)

Question 17

Where does MB most commonly arise?

Answer 17

Midline cerebellar vermis (75%), with the rest in cerebellar hemispheres.

Question 18

What is the DDx for a PF mass?

Answer 18

DDx for a PF mass includes:

1. MB
2. Ependymoma
3. ATRT
4. Astrocytoma
5. Brainstem glioma
6. Juvenile pilocytic astrocytoma
7. Hemangioblastoma
8. Mets

Question 19

What are the 4 genetic MB subgroups and what mutations tend to occur in each subgroup?

Answer 19

1. Wingless homolog (WNT) group: CTNNB1 mutation. Associated with Turcot syndrome. Least common (10%) subgroup.
2. Sonic hedgehog (SHH) group: PTCH1, GLI3, MYCN. 30% of MB, often desmoplastic. Overrepresented in infants and adults (bimodal).
3. Group 3: MYC amplification, GABAergic expression. Enrich for large cell histology and are frequent mets at Dx. Worst prognosis.
4. Group 4: MYCN, CDK6 amplification

(Northcott PA et al., JCO 2011)

Question 20

Describe the prognosis for each subgroup.

Answer 20

Good prognosis: WNT group and infants in SHH group

Intermediate prognosis: Group 4 and SHH group

Poor prognosis: Group 3

Question 21

What percentage of pediatric CNS tumors do medulloblastomas comprise?

What genetic syndromes are associated with this diagnosis?

Answer 21

20%. This makes it the second most common pediatric CNS tumor behind low-grade glioma (35%–50%). The United States incidence is 500 cases per year. Gorlin syndrome (nevoid basal cell carcinoma syndrome) and desmoplastic medulloblastoma are associated through the Sonic Hedgehog Pathway. Turcot syndrome, which is associated with the APC gene, is associated with medulloblastoma that develop via the WNT pathway. Li-Fraumeni syndrome, which results from p53 mutations, accounts for a small percentage of medulloblastoma.

Question 22

What are poor prognostic factors for medulloblastoma?

Answer 22

Male gender, age less than 5 years, less than GTR, and M+ disease