Primitive neuronal tumors

Question 1

Major subgroups of medulloblastomas

Answer 1

WNT-activated

SHH-activated

non-WNT, non-SSH activated

Question 2

Answer 2

Medulloblastoma

Divided into four groups:
1. Medulloblastoma, WNT activated
2. Medulloblastoma, SHH-activated, TP53 WT
3. Medulloblastoma, SHH-activated, TP53 mutant
4. Medulloblatoma, non-WNT/non-SHH activated

Primitive neuronal tumor with significant biological heterogeneity. Second most common CNS tumor of childhood (to pilocytic astrocytoma), accounting for 20% of childhood primary CNS neoplasms. Median age of diagnosis is around 10.

Usually located in the cerebellum or 4th ventricle. SHH-activated are most likely to be confined to a single cerebellar hemisphere, while WNT-activated are most likely to arise from the posterior brainstem.

Histologically, primitive small-round-blue cell tumor with a syncytial arrangement of densely packed undifferentiated cells (embryonal cells), frequent mitoses and apoptotic bodies, and some Homer Wright rosettes (shown below).

A nodular morphology and reticulin pattern portends a more favorable overall prognosis.

Can be distinguished from other primitive tumors by its strong synaptophysin positivity.

Question 3

Answer 3

Cribriform neuroepithelial tumor

SMARCB1/INI1 deficient, dedifferentiated neoplasm

Relatively favorable prognosis, despite INI loss, as compared to ATRT.

IHC: Synapto highlights the apical membrane, keratin positive, GFAP negative

Provisionally defined entity which does not have a CNS WHO grade as of yet.

Question 4

Answer 4

Atypical teratoid/rabdoid tumor

CNS WHO Grade 4

INI1 deficient (95% of cases) or rarely BRG1 deficient (about 5% of cases), dedifferentiated neoplasm.

Generally poorly differentiated, but can display features of differentiation along epithelial, mesenchymal, or neuroepithelial cell lineages. Cells often show vesicular chromatin, prominent nucleoli, and small round blue cell-to-rhabdoid cytology, the latter having pink cytoplasmic blobs.

Separated into three molecular subgroups:
ATRT-SHH (44% of cases), with SHH/Notch pathway alterations
ATRT-TYR (34% of cases), with tyrosinase/BMP/OTX2 pathway alterations
ATRT-MYC (22% of cases), with myc or HOXC cluster gene alterations

If found in a young child, you should be suspicious for a germline tumor syndrome.

Question 5

Interpreting beta-catenin and SHH pathway IHC for medulloblastoma typing

Answer 5

OTX2 staining is also frequently lost in SHH pathway medulloblastomas

Question 6

Medulloblastoma staging

Answer 6

A little atypical, based mostly on cytology of CSF and gross/radiologic features:

M0 No evidence of subarachnoid or haematogenous metastasis

M1 Microscopic tumour cells found in the cerebrospinal fluid

M2 Gross nodular seeding demonstrated in the cerebellar/cerebral subarachnoid space or in the third or lateral ventricles

M3 Gross nodular seeding in the spinal subarachnoid space

M4 Metastasis outside the cerebrospinal axis

Question 7

SHH-activated medulloblastoma is associated with _ syndrome.

Answer 7

Gorlin syndrome

aka, nevoid basal cell carcinoma syndrome

This is particularly true for the Desmoplastic / nodular medulloblastoma morphologic variant, shown below.

Nodules can be highlighted by reticulin, and these areas are preferentially neuron-specific enolase (NSE) positive.