Embryonal (Primitive) Neuroepithelial Tumors

Most common primitive neuroepithelial tumor (PNET) in CNS; 0.5 per 100,000

Peak incidence: 5 to 10 years; adults cluster in 30s

20% of brain tumors in children

Most common malignant brain tumor of childhood

Several familial/hereditary disorders associated with medulloblastomas

Symptoms are mainly due to increased intracranial pressure, morning headache, listlessness, vomiting

About 75% of medulloblastomas arise from the vermis and fill the fourth ventricle

Cerebellar signs include ataxia and gait disturbances

Commonly disseminate via cerebrospinal fluid pathways with spinal “drop metastases”

30% of cases show CSF spread at initial presentation

WHO Grade IV

Overall 5-year survival is 65% with surgery/radiation

Treatment: maximal resection with chemotherapy radiation to the entire neuraxis

Poor prognostic factors:

• Clinical: <3 years old, subtotal resection, CSF dissemination at presentation

• Histologic/molecular: Large cell/anaplastic variants, C-MYK or N-MYC amplification, isochromosome 17q, 17 p loss

• Large cell/anaplastic medulloblastoma: aggressive and treatment resistant; systemic metastases have occurred (liver, lymph nodes, lungs, abdominal cavity postshunting)

Good prognostic factors:

• Clinical: >3 years of age but younger than 22 years at presentation, gross total excision, no CSF dissemination

• Histologic/molecular: accumulation of nuclear beta-catenin, overexpression of TrkC neurotrophin receptor, desmoplastic/nodular variant, extensively nodular variant, 17q balanced, monosomy chromosome 6

• Desmoplastic/nodular medulloblastoma: more common in lateral cerebellar hemisphere; older mean age

CT or MRI—solid heterogeneous enhancing mass adjacent to, or extending into, the fourth ventricle

Nodular desmoplastic variant characteristically arises in a cerebellar hemisphere

Extensively nodular variant has contrast-enhancing nodules that cluster (look grape-like)

Solid masses of friable gray-white tissue, apparently circumscribed

Usually involves surface of cerebellar folia and infiltrates leptomeninges

Nodular/desmoplastic variant more demarcated and firm; most often arise in lateral cerebellar hemisphere

Small round blue cell tumor composed of sheets of undifferentiated cells with indistinct cytoplasm, hyperchromatic angulated nuclei (“molding”)

Frequent mitoses; Homer Wright rosettes in about 40% of cases

Apoptosis or necrosis may be present but more prominent in large cell/anaplastic variants

Overall architecture may be swirling, fascicular, diffuse

Scanty stroma containing small blood vessels (occasional microvascular proliferation)

Nodular/desmoplastic medulloblastoma: reticulin-rich, proliferatively active cellular tumor with nodular reticulin-free “pale islands”

• Neuronal differentiation in nodules (synaptophysin, neurofilament immunoreactive)

• Reduced mitotic activity in nodules

Medulloblastoma with extensive nodularity (previously called “cerebellar neuroblastoma”): more advanced neurocytic maturation with more lobular (nodular), pale areas with neuropil-like stroma

• Predilection for children <3 years of age with a more favorable prognosis than other subtypes

• Greatly decreased proliferation index, linear pattern of tumor cell nuclei

• Rare maturation to benign ganglioneurocytic or gangliogliomatous elements

• “Neuroblastic” foci: may be found in any given tumor case

Large cell/anaplastic medulloblastomas are typically grouped together and probably represent a spectrum; they share frequent mitoses, apoptotic cells, pleomorphism, cell “wrapping”

• Large cell medulloblastoma: cells are large with rounded vesicular nuclei, prominent nucleoli, and conspicuous eosinophilic cytoplasm; discohesive with numerous mitotic and apoptotic cells

• Anaplastic medulloblastoma: marked variation in nuclear size and shape with some bizarre forms: multinucleated, giant cells, cell wrapping/molding

Other patterns:

• Melanotic medulloblastoma: pigmented cells disposed, stained for melanin

• Medullomyoblastoma: heterologous muscle elements

• Medulloblastoma with adipose tissue (also called “cerebellar liponeurocytomas”)

Most are synaptophysin immunoreactive

Evidence of neuronal differentiation (synaptophysin, neurofilament) in nodular foci

GFAP-positive elements appear to be focally entrapped

Positive for INI-1 (hSNF5/SMARCB1) using BAF47 antibody

• Critical to distinguish medulloblastoma from CNS atypical teratoid rhabdoid tumors, which are INI-1 negative

S-100 may be seen in melanocytic variant

Desmin and myoglobin positivity in myogenic cells

Ki-67 index is variable, but generally >20%

Classic medulloblastoma: most common genetic alteration: 17p loss with isochromosome 17q formation

Large cell/anaplastic medulloblastoma associated with C-MYC oncogene amplifications

WNT signaling pathway activation (suggested by nuclear b-catenin immunoreactivity) associated with better prognosis

Desmoplastic medulloblastoma: PTCH gene mutations (sonic hedgehog pathway)

• Nevoid basal cell carcinoma (Gorlin syndrome): autosomal dominant germline mutations of patched gene at 9q22.3 with odontogenic keratocysts, pitting of palms and soles, skeletal anomalies, lamellar calcium deposition in falx cerebri and diaphragma sellae, calcifying ovarian fibromas, and multifocal, early-onset basal cell carcinomas

Li-Fraumeni syndrome/p53 mutation syndromes

Type 2 Turcot syndrome: medulloblastoma arises in setting of autosomal dominant adenomatous polyposis of colon resulting from APC mutations on chromosome 5q21 APC

Rubinstein-Taybi syndrome (with meningiomas and oligodendrogliomas): mutations in CREB-binding protein gene on chromosome 16p13 with cognitive impairment, growth retardation, microcephaly, facies

Some research has implicated the JC virus in pathogenesis