Neuroepithelial neoplasms displaying neuronal features

Neoplastic cells with morphologic and/or immunohistochemical characteristics of neurons may occur in neuroepithelial neoplasms as:

large neuron-like ‘ganglion’ cells

small but well-differentiated neurocytes

poorly differentiated, proliferating neuroblast-like cells.

Neuroblast-like cells are present in embryonal neoplasms such as primitive neuroectodermal tumors (PNETs), and are admixed with ganglion cells in ganglioneuroblastomas, which are classified with embryonal neoplasms (see Chapter 38). Ganglion cells and/or neurocytes, but not neuroblasts, form a significant component of neoplasms grouped as neuronal and mixed neuronal-glial tumors in the WHO classification (2007):

ganglion cell neoplasms (i.e. gangliocytoma, ganglioglioma, anaplastic ganglioglioma)

desmoplastic infantile ganglioglioma (DIGG) and its variant desmoplastic infantile astrocytoma

neurocytomas (i.e. central and extraventricular neurocytoma, and cerebellar liponeurocytoma)

papillary glioneuronal tumor

rosette-forming glioneuronal tumor of the fourth ventricle

paraganglioma (of the filum terminale)

dysembryoplastic neuroepithelial tumor (DNET)

dysplastic gangliocytoma of the cerebellum (Lhermitte–Duclos disease).

With the exception of very rare anaplastic variants, tumors in this category display an indolent behavior, unlike biologically aggressive embryonal tumors.

GANGLIOCYTOMA AND GANGLIOGLIOMA

These tumors contain well-differentiated ganglion cells, either alone (gangliocytoma) or with a neoplastic glial component (ganglioglioma). Rarely, the glial component of a ganglioglioma progresses to an anaplastic form (anaplastic ganglioglioma). However, gangliogliomas containing a diffusely infiltrating astrocytic component do not undergo anaplastic progression with the same frequency as diffuse astrocytomas.

Ganglion Cell Tumors

Are rare, accounting for <1% of CNS neoplasms.

Are mostly gangliogliomas.

Have a predilection for the temporal lobe.

Usually present in the first three decades with complex partial seizures.

Are the commonest neoplasms associated with refractory temporal lobe epilepsy.

Are associated with congenital abnormalities in 5% of cases.

TUMOR-RELATED TEMPORAL LOBE EPILEPSY

Leading causes are:

Ganglioglioma – 40%.

Dysembryoplastic neuroepithelial tumor – 20%.

Pilocytic astrocytoma – 20%.

MACROSCOPIC APPEARANCES

Ganglion cell neoplasms are generally circumscribed; only rare examples have a diffuse glial element (Fig. 37.1). They are usually firm and gray, and frequently contain flecks of calcification and small cysts. They may appear as a mural nodule in a large cyst.

37.1 Ganglioglioma.
The ganglioglioma is usually well circumscribed, but the glial element of this example shows invasion and expansion of midline structures.

MICROSCOPIC APPEARANCES

Cursorily, neoplastic ‘ganglion’ cells look like large neurons, possessing a round nucleus, prominent nucleolus, and Nissl substance, but many have obvious cytologic atypia on closer inspection. Their distribution is characteristically disorganized. Ganglion cell neoplasms exhibit a range of histologic appearances; ganglion cells may either dominate the picture or be part of a polymorphous population of cells.

Gangliocytomas consist of disorganized ganglion cells set against a neuropil-like background or a lacy, fibrillary background containing a few reactive astrocytes (Fig. 37.2). Groups of ganglion cells may appear in nests enclosed by thin fibrovascular septa. In some cases, extensive desmoplasia may surround elongated cells that have a neuronal immunophenotype. Neoplastic ganglion cells possess abnormal, thickened processes and some have double nuclei. Small round cells with a relatively high nuclear:cytoplasmic ratio, but without nuclear hyperchromasia, represent a further neuronal phenotype encountered in these neoplasms (Fig. 37.2).

37.2 Gangliocytoma.
(a) and (b) This neoplasm is composed of large and small cells with a neuronal morphophenotype. Many cells have a prominent nucleolus, and some contain basophilic Nissl substance in the periphery of the cytoplasm. (c) Some ganglion cells have double nuclei.

Gangliogliomas also contain neoplastic glial cells, which may greatly outnumber the ganglion cells. Neoplastic glia in gangliogliomas may have an obvious astrocytic morphology, but some ganglion cell neoplasms contain cells of an indeterminate nature (Figs 37.3, 37.4). While the glial component of some gangliogliomas appears as a fibrillary astrocytoma, other gangliogliomas manifest as a pilocytic astrocytoma or pleomorphic xanthoastrocytoma with a ganglion cell component. Eosinophilic granular bodies and neovascularization, of the type seen in pilocytic astrocytomas, may be evident. Degenerative cytologic changes take the form of nuclear pleomorphism and hyperchromasia, in the absence of mitoses. Some gangliogliomas are focally desmoplastic, or may spread into the subarachnoid space, provoking desmoplasia.

37.3 Ganglioglioma.
(a) Ganglion cells are seen among disorganized neoplastic cells with an astrocytic morphology. (b) A microcystic pattern is found in another part of the same neoplasm. (c) Astrocytic cells with fibrillary processes surround ganglion cells. While the glial component of a ganglioglioma may clearly have an astrocytic phenotype, its features may not be sufficiently typical to allow classification as fibrillary or pilocytic. (d) The histogenesis of some cells is unclear; in standard histologic preparations, some cells are not readily classified as neuronal or glial.

37.4 Ganglioglioma.
(a) Ganglion cells are surrounded by the processes of astrocytic cells that are immunoreactive for GFAP. (b) The cytoplasm of ganglion cells and a meshwork of neuritic processes are immunoreactive for synaptophysin. (c) The cell bodies of ganglion cells and some fine processes are also immunoreactive for neurofilament proteins. (d) The low growth fraction of a ganglioglioma is illustrated by the paucity of Ki-67-labeled nuclei.

Ganglion cell neoplasms may contain aggregates of lymphoid cells, many of which are perivascular. Finding a mitotic figure in a ganglion cell neoplasm is unusual. If mitoses accompany cytologic pleomorphism in the glial element of a ganglioglioma, the possibility of its anaplastic transformation should be considered. However, this event occurs in less than 5% of gangliogliomas, and it is important to recall that invasion of gray matter by an anaplastic astrocytoma enters the differential diagnosis of these histopathologic features.

Ganglion cells are immunoreactive for NEU-N, synaptophysin, and neurofilament proteins (Fig. 37.4). Electron microscopy reveals dense-core synaptic vesicles.

Small round undifferentiated cells with a high nuclear:cytoplasmic ratio and nuclear hyperchromasia are combined with ganglion cells in the ganglioneuroblastoma, which is regarded as a variant of PNET (Fig. 37.5). Mitoses and apoptotic bodies are usually identifiable among the small cells. Recognition of the embryonal element is important because its presence confers a much poorer prognosis and has implications for therapy. The combination of neoplastic neuronal and glial cells that are both undifferentiated and differentiated (i.e. ganglioneuroblastoma/glioblastoma, or malignant glioma/PNET) is recognized as an entity, but extremely rare. Like the ganglioneuroblastoma, these neoplasms should probably be regarded as variants of PNET.

37.5 Ganglioneuroblastoma.
A closely packed group of small undifferentiated cells with hyperchromatic nuclei is seen among ganglion cells.

DIFFERENTIAL DIAGNOSIS OF GANGLION CELL NEOPLASMS

Diagnostic difficulty sometimes surrounds the separation of ganglion cell neoplasms from gliomas that diffusely invade gray matter or from other neuroepithelial neoplasms that contain ganglion cells or large non-neuronal cells with prominent nucleoli. In making a diagnosis, consider the following:

Are neoplastic ganglion cells present? Disorganized neoplastic ganglion cells do not show the uniform orientation and orderly arrangement of neurons in the cerebral cortex, may be identified away from gray matter in the deep white matter or subarachnoid space (though a few scattered neurons are normally found in the subcortical white matter – especially of the temporal lobe), and have abnormal cytologic characteristics, including double nuclei.

Are proliferating neuroblasts combined with neoplastic ganglion cells? Consider a diagnosis of ganglioneuroblastoma, which is a variant of PNET.

Are ganglion cells present in a parenchymal neoplasm with the architectural and cytological features of a neurocytoma? If so, it may be an example of the rare extraventricular neurocytoma.

Not all cells with large nuclei and prominent nucleoli are ganglion cells. Similar cells are found in giant cell glioblastoma, pleomorphic xanthoastrocytoma, and the subependymal giant cell astrocytoma of tuberous sclerosis. Check the immunophenotype of the cells. Ganglion cells are immunoreactive for NEU-N, synaptophysin, and neurofilament proteins, but not for glial fibrillary acidic protein (GFAP).

Mitoses are exceptional in gangliogliomas. The presence of scattered mitoses in limited biopsy material indicates either infiltration of gray matter by an anaplastic astrocytoma or rare anaplastic transformation of a ganglioglioma. In either event, the prognosis is much worse than that of a ganglioglioma or an astrocytoma.

DESMOPLASTIC INFANTILE GANGLIOGLIOMA (DIGG)

The DIGG is a supratentorial neuroepithelial neoplasm of infancy with a good prognosis (WHO grade I). It is closely related to the desmoplastic infantile astrocytoma (DIA), which has a similar clinical presentation and an identical histopathology, except that it lacks ganglion cells. Both DIGG and DIA are large superficial cerebral neoplasms, which are associated with cysts.

MACROSCOPIC APPEARANCES

The desmoplastic nature of a DIGG gives it a firm texture. Part of the neoplasm may lie in the subarachnoid space and be attached to the dura. Cysts are usually evident, and a single cyst may occupy a large volume.

DIFFERENTIAL DIAGNOSIS OF DIGG

DIGG is closely related to the desmoplastic cerebral astrocytoma of infancy, which shares the clinical and histologic features of DIGG, but contains no cells with neuronal differentiation.

DIGG shows some similarity to the pleomorphic xanthoastrocytoma, which is uncommon in infancy, has a predilection for the temporal lobe, and contains large pleomorphic occasionally lipidized cells.

DIGGs can closely resemble gangliogliomas, but a combination of ultrastructural findings plus widespread desmoplasia and occasional groups of poorly differentiated neuroepithelial cells in the DIGG help to distinguish them.

MICROSCOPIC APPEARANCES

In areas of prominent desmoplasia, neoplastic glial cells are spindle-shaped with elongated hyperchromatic nuclei (Fig. 37.6). In some areas, the fascicular architecture and desmoplasia give way to foci of plump astrocytic cells or even limited numbers of poorly differentiated neuroepithelial cells. Ganglion cells with large nuclei are found within DIGGs (Fig. 37.6), but not DIAs, and can be numerous, mimicking a ganglioglioma. A small number of mitoses with a normal configuration may be present among the poorly differentiated cells.