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).

As with other CNS PNETs, the medulloblastoma has the capacity for divergent neuroepithelial differentiation (Fig. 38.4). Neuronal differentiation may take the form of rosettes that lack a central canal or capillary (Homer–Wright rosettes). A more obvious neuronal morphophenotype occurs in about 7% of classic medulloblastomas with the formation of nodules of neurocytic cells with a reduced growth fraction or regions containing both neurocytic and ganglion cells (ganglioneuroblastoma phenotype). These (biphasic) neoplasms do not show any desmoplasia. Groups of tumor cells without obvious neuronal morphology may show immunoreactivity for synaptophysin or neurofilament proteins. Ultrastructural examination reveals secretory granules in some cells. Medulloblastoma cells with a clear-cut astrocytic morphophenotype are very rare, but the cytoplasm of some neoplastic cells may be immunoreactive for GFAP. In searching for focal neuroepithelial differentiation, care should be taken to distinguish reactive astrocytes and entrapped native neurons from neoplastic cells (Fig. 38.4).

The range of nuclear size in medulloblastomas is more extensive than might initially be apparent. Nuclei in a classic medulloblastoma have less than half the area of nuclei in the large cell variant, which is characterized by groups of cells with round nuclei and a prominent single nucleolus. In the large cell variant, neoplastic cells that show considerably more pleomorphism than those in classic medulloblastomas are interspersed between the defining groups of large cells, assuming a polyhedral form as they flatten themselves into a pavement-like arrangement (Fig. 38.5). The term anaplastic medulloblastoma has been attached to medulloblastomas with both this phenotype and features of increased cell turnover, such as a high mitotic count and abundant apoptosis. The anaplastic medulloblastoma forms a continuum with the large cell variant (Fig. 38.6), and both have a more aggressive biologic behavior than the classic medulloblastoma.

Focal desmoplasia is common in embryonal neuroepithelial neoplasms, but the desmoplastic variant of medulloblastoma is also characterized by distinctive reticulin-free nodules of neurocytic cells among the reticulin-rich internodular areas, in which the cells appear more pleomorphic (Fig. 38.7). Nodules are distinctive tumor microenvironments. Cells in nodules often have a lower nuclear:cytoplasmic ratio than surrounding cells, and their uniform appearance matches that of the central neurocytoma. Relative to internodular cells, those in nodules have a reduced growth fraction and a greater apoptotic rate. The histology of the desmoplastic variant merges with that of the paucinodular desmoplastic medulloblastoma, and with a distinctive subtype of desmoplastic tumor, the medulloblastoma with extensive nodularity (MBEN). Nodules are not only frequent in this tumor, but are larger than in the standard desmoplastic medulloblastoma, having oval or reniform shapes (Fig. 38.8). A neuronal immunophenotype is typical of nodules in the MBEN. The MBEN usually presents in infancy, and is associated with a good outcome.

Focal melanin production and evidence of striated muscle differentiation are exceptional features in medulloblastomas, giving rise to two distinctive subtypes of the classic neoplasm: medulloblastoma with melanotic differentiation and medulloblastoma with myogenic differentiation (Figs 38.9, 38.10).

CNS (extracerebellar) PNET

The extracerebellar PNET and classic medulloblastoma have similar histologic appearances; both contain sheets of small cells with sparse cytoplasm, hyperchromatic nuclei, and a high mitotic count (Fig. 38.11). Dystrophic calcification is often found in supratentorial PNETs. The PNET may exhibit focal neuronal differentiation in the form of Homer Wright rosettes or scattered immunoreactivities for neurofilament proteins, class III β-tubulin, and synaptophysin. Immunohistochemistry may reveal coexisting GFAP-positive cells, providing evidence of divergent neuroepithelial differentiation. Desmoplasia may be found in PNETs, particularly if there is invasion of the leptomeninges.

A cerebral embryonal neoplasm that shows focal neurocytic differentiation is sometimes referred to as a central neuroblastoma, rather than PNET. When this differentiation amounts to the production of scattered neoplastic cells with the cytologic features of small or large neurons, then the term ganglioneuroblastoma is used (Fig. 38.12).

Ependymoblastoma

The ependymoblastic rosette is the key diagnostic feature of ependymoblastomas, which like other embryonal neuroepithelial neoplasms consist mainly of undifferentiated small cells (Fig. 38.13). Ependymoblastic rosettes are composed of multiple layers of small cells with hyperchromatic nuclei that surround a circular or elongated lumen. The lumen has a prominent internal limiting membrane, and mitotic figures are readily found in the rosettes. Ependymoblastic rosettes are not specific for PNETs; they occur rarely in atypical teratoid/rhabdoid tumors and in a tumor termed ‘embryonal tumor with abundant neuropil and true (ependymoblastic) rosettes’. The latter is now the most common setting for ependymoblastic rosettes, but this diagnosis has yet to be incorporated in the WHO classification of nervous system tumors. In time, this tumor is likely to supplant the term ‘ependymoblastoma’.

Medulloepithelioma

The defining histologic attribute of the medulloepithelioma is an arrangement of tightly-packed multilayered cells into tubules that resemble embryonic neural tube. Convoluted ribbons and papillary structures may also be seen (Fig. 38.14). The tubules have a periodic acid–Schiff (PAS)-positive external basement membrane, and, in some cases, PAS-positive material lines their luminal aspect. The neoplastic cells have hyperchromatic nuclei and very scanty cytoplasm, and the mitotic count is high.

The primitive epithelium does not label with antibodies to GFAP or synaptophysin, but focal glial and neuronal differentiation is occasionally detected in other regions of the neoplasm. The epithelium is immunoreactive for vimentin and nestin. Elongated cells with tapering processes and immunoreactivity for GFAP, ependymoblastic rosettes, neuroblastic rosettes, and ganglion cell formation have all been described in medulloepitheliomas. Mesenchymal differentiation has been reported in some examples, and very rarely manifests as bone, cartilage, or striated muscle.

Atypical teratoid/rhabdoid tumor (ATRT)

Cytologic polymorphism in an embryonal neoplasm often alerts the pathologist to the diagnostic possibility of an ATRT (Fig. 38.15). Small undifferentiated neuroepithelial cells with a high nuclear:cytoplasmic ratio occupy some areas of the ATRT, but cells elsewhere often have more cytoplasm and show more nuclear pleomorphism than expected in a typical PNET. Groups of classic rhabdoid cells with abundant eosinophilic cytoplasm and eccentrically placed nuclei can sometimes be found in the ATRT, and there may be large cells showing considerable nuclear pleomorphism. The mitotic count is high, and necrosis is common. Microvascular proliferation in an ATRT very rarely shows the endothelial proliferation characteristic of some gliomas.

The immunophenotype of the ATRT is characteristically diverse. There may be reactivities for GFAP and neuronal markers in the PNET-like areas, but cells elsewhere can label with antibodies to cytokeratins, EMA, vimentin, smooth muscle α-actin, and desmin.

The diagnosis of ATRT is made using immunohistochemistry with an antibody to the SMARCB1 gene product (INI1), which is a subunit of the SWI/SNF chromatin remodeling complex. In ATRTs, immunoreactivity for INI1 is lost in tumor cells, but preserved in normal tissue elements, such as blood vessels, which act as an internal positive control (Fig. 38.15).