Many embryonal neoplasms are circumscribed, pink or gray neoplasms, which may contain areas of hemorrhage, necrosis, or calcification (Fig. 38.1). CNS neuroblastomas and medulloepitheliomas sometimes contain cysts. All embryonal neoplasms have the capacity to invade the brain and spinal cord, and this will often be evident microscopically, if not macroscopically. However, infiltration occurs to a variable degree, and is rarely as diffuse as demonstrated by some astrocytic tumors.

38.1 Medulloblastoma.
(a) A soft homogeneous mass destroys and occupies the fourth ventricle. (b) A sagittal midline MR image through the brain showing a medulloblastoma in the posterior fossa between the cerebellum and brain stem. (Dr N Sabin, St Jude Children’s Research Hospital.)

The texture of embryonal neoplasms varies. Some are soft, but some medulloblastomas in the lateral cerebellar cortex and some cerebral neuroblastomas tend to be firm because they contain areas of desmoplasia. Neoplastic cells occasionally metastasize through the CSF pathways (Fig. 38.2).

38.2 Supratentorial PNET in the subarachnoid space.
(a) There is an extensive infiltration of the subarachnoid space by basophilic cells from a PNET. Several distinct parenchymal deposits are also present. (b) From the same case, a mass of small cells fills the subarachnoid space and has begun to invade the pial surface of the cerebrum.

FAMILIAL CANCER SYNDROMES FEATURING MEDULLOBLASTOMAS

Nevoid basal cell carcinoma syndrome (Gorlin syndrome)

~ 2% of patients with medulloblastoma have NBCCS.

~ 4% of patients with NBCCS will develop a medulloblastoma.

Medulloblastomas usually develop in NBCCS patients aged < 3 years.

Other features of NBCCS include multiple basal cell carcinomas and odontogenic keratocysts of the jaw.

Most medulloblastomas in NBCCS are desmoplastic variants.

Turcot syndrome (type 2)

Medulloblastoma in the setting of familial adenomatous polyposis plus a germline mutation of the APC gene on 5q21 is indicative of this syndrome.

~ 20% of patients develop colorectal carcinoma.

Astrocytic tumors occur in type 1 Turcot syndrome.

Li–Fraumeni syndrome

Li–Fraumeni syndrome occurs in families with a germline TP53 mutation.

Most tumors in this syndrome are sarcomas (bone) and carcinomas (lung/breast).

~ 15% of primary neoplasms in affected families are in the CNS.

~ 10% of CNS tumors associated with germline TP53 mutations are medulloblastomas.

Other CNS tumors occurring in this syndrome include astrocytic tumors, ependymomas, choroid plexus tumors, schwannomas, and meningiomas.

GENETIC ASPECTS OF MEDULLOBLASTOMA

Nearly all medulloblastomas are sporadic, but they can occur in association with a familial tumor syndrome (see Familial cancer syndromes featuring medulloblastomas box).

Common chromosomal abnormalities include:

• Chromosome 17 abnormalities (~60%)

• Isodicentric chromosome 17q (~35%)

• Allelic losses on 9q (~15%)

• Allelic losses on 10q (~10%)

• Monosomy 6 (~10%).

Gene-specific abnormalities include:

• PTCH1 mutation (~15%)

• CTNNB1 mutation (~10%)

• TP53 mutation (~10%)

• MYC amplification (~5%)

• MYCN amplification (~5%)

• RASSF1A hypermethylation (~80%).

Molecular subgroups derived from gene expression profiling have been classified into four main groups (see Table 38.1):

• WNT pathway (activated) group

• SHH pathway (activated) group

• Group 3 (MYC overexpression)

• Group 4.

Molecular favorable-outcome indicators:

• β-catenin nuclear immunoreactivity (WNT pathway activation)

• CTNNB1 mutation (WNT subgroup)

• Monosomy 6 (WNT subgroup)

• TRKC overexpression (contentious).

Molecular poor-outcome indicators:

• MYC amplification

• MYCN amplification

• Loss of chromosome 17p (contentious)

• Gain of chromosome 17q (contentious).

MICROSCOPIC APPEARANCES

Medulloblastoma

The classic medulloblastoma is composed of isomorphic cells with a high nuclear:cytoplasmic ratio (Fig. 38.3). Sheets of hyperchromatic round or oval nuclei set against a neuropil-like matrix give a monotonous appearance, with scattered mitotic figures and apoptotic bodies in the background. Necrosis is variably present, but angiogenesis with endothelial hyperplasia is a rare feature in these neoplasms. Though frequently forming a mass in the fourth ventricle, the medulloblastoma is an invasive neoplasm. Its cells have a tendency to spread along the pial surface of the cerebellum, invading the underlying cortex in swathes. Infiltration of the leptomeninges can produce a striking desmoplasia (Fig. 38.3).