Embryonal neuroepithelial neoplasms of the CNS

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Embryonal neuroepithelial neoplasms of the CNS

EMBRYONAL NEUROEPITHELIAL NEOPLASMS

Embryonal (primitive) neuroepithelial neoplasms make up approximately 5% of CNS neoplasms. Their features include:

a predominance in children

a tendency to disseminate through CSF pathways

a dominant population of small undifferentiated cells

a high mitotic index and widespread apoptosis

a potential for divergent neuroepithelial differentiation.

Table 38.1

Medulloblastomas are divided into four molecular subgroups on the basis of gene expression profiling, each with characteristic clinicopathological and genetic features

LC/A, large cell/anaplastic; CNAs, copy number abnormalities.

In the WHO classification (2007), listed embryonal neuroepithelial neoplasms are:

Medulloblastoma and its variants:

• desmoplastic/nodular (D/N) medulloblastoma

• medulloblastoma with extensive nodularity (MBEN)

• anaplastic medulloblastoma

• large cell medulloblastoma.

CNS primitive neuroectodermal tumor (PNET) and its variants:

• CNS neuroblastoma

• CNS ganglioneuroblastoma

• medulloepithelioma

• ependymoblastoma.

Atypical teratoid/rhabdoid tumor (ATRT).

Controversy surrounding the ontogeny of CNS embryonal neoplasms ensures that a revision to their classification appears in each new edition of the WHO ‘blue book’. In the latest version (2007), medulloblastoma is separated from CNS PNET, implying that the latter is extracerebellar. Four variants of medulloblastoma are listed, all of which have a biological behavior distinct from that of the classic tumor. Ependymoblastoma and medulloepithelioma are now listed under CNS PNET, alongside focally differentiated variants of the archetypal tumor, the CNS neuroblastoma and ganglioneuroblastoma.

EMBRYONAL NEUROEPITHELIAL NEOPLASMS

Medulloblastoma

Represents about 5% of intracranial primary neoplasms.

Represents about 20% of childhood CNS neoplasms.

Represents over 90% of childhood CNS PNETs.

Can present at any age, but 60% occur in patients less than 10 years of age.

Generally midline, filling the fourth ventricle.

Belongs to the SHH molecular subgroup, when in the lateral cerebellar cortex.

Regarded as high-risk if presenting with metastatic disease or significant tumor remains post-surgery.

Regarded as high-risk if a large cell or anaplastic pathological variant.

Has a 5-year survival of 80% in standard-risk patients.

Has a 5-year survival of 25% in high-risk patients.

Therapies are associated with significant adverse effects, e.g. cognitive impairment.

CNS (extracerebellar) PNET

Occurs mainly in patients under 5 years of age.

Is usually supratentorial, but can affect any level of the CNS.

Commonly disseminates through CSF pathways.

Has a poorer outcome than medulloblastoma.

Atypical teratoid/rhabdoid tumor

May be associated with the rhabdoid tumor predisposition syndrome.

Nearly always presents in children under 5 years of age.

Can affect any level of the CNS.

Has a poorer outcome than medulloblastoma.

A population of small undifferentiated cells with a high turnover is a common feature of CNS embryonal neoplasms. This and shared clinical features, such as presentation in childhood and an aggressive clinical course, originally encouraged the thesis that these neoplasms, including the medulloblastoma, have a common histogenesis and should thus be grouped as CNS PNETs. Initially, this approach had diagnostic and therapeutic utility. However, current biological evidence suggests that CNS embryonal neoplasms develop in anatomically restricted neural stem cells or progenitors and harbor distinct genetic aberrations, prompting a move away from the concept of ‘PNET’ as a unifying label. As molecular subgroups of these neoplasms are shown to be biologically distinct and targeted therapeutic agents are developed to their molecular aberrations, a classification based on detailed histopathological and molecular characteristics will evolve.

MACROSCOPIC APPEARANCES

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.

NBCCS is related to mutations in the PTCH1 gene on 9q22.

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)

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

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