Neuronal and Glioneuronal Neoplasms

Definitions and Synonyms

Ganglioglioma and gangliocytoma belong to a family of low-grade tumors defined by the presence of a mature yet cytologically atypical ganglion cell component, either alone (gangliocytoma) or in combination with a well-differentiated glial component (ganglioglioma). Since these two patterns are often considered part of a continuum with limited if any clinical differences, they are often lumped under the umbrella heading of “ganglion cell tumor.” These tumors are slowly growing and are often associated with epilepsy. Besides the conventional subtypes, there are also several clinicopathologically distinct variants that are discussed separately (e.g., desmoplastic infantile ganglioglioma and dysplastic ganglioglioma of the cerebellum).

Incidence and Demographics

Together, the ganglion cell tumors constitute approximately 1.3% of all CNS tumors. The vast majority occur in children and young adults, although they may be first encountered at virtually any age. Data derived from large case series in the literature suggest a median age of clinical presentation of 8.5 to 25 years and a slight male predominance. A recent Surveillance, Epidemiology and End Results (SEER) study for the years 2004 to 2010 uncovered 348 pediatric patients (0–19 years old) with gangliogliomas and noted that 63% of them occurred in children under 10 years of age; 60% occurred in males; and 50% were localized to the temporal lobes.

Clinical Manifestations and Localization

Ganglion cell tumors arise throughout the central neuraxis and are most common in the cerebral hemispheres, with a strong predilection for the temporal lobes. Indeed, this location accounts for 50% to 70% of all gangliogliomas, depending on the study population. Other cerebral hemispheric locations in decreasing order of frequency are the frontal, parietal, and occipital lobes. Rare locations include the brainstem, cerebellum, and spinal cord.

Clinical manifestations of these slow-growing tumors generally reflect their location. Cerebral examples are associated with protracted epilepsy that is frequently medically refractory. They account for at least 20% of lesions resected for temporal lobe epilepsy, making them the most common neoplasm encountered in this clinical setting (see Chapter 25 ). The mean preoperative duration of symptoms exceeds 5 years. Spinal cord tumors most often present with paraparesis and segmental pain. In addition, a spinal location is occasionally associated with scoliosis, which may be the presenting manifestation.

Gangliogliomas generally arise sporadically, but have occasionally been described in the setting of neurofibromatosis types 1 and 2 (NF1, NF2), Down syndrome, Type 1 Turcot syndrome, and Martin–Bell [fra(x)-XLMR] syndrome (see Chapter 22 ). Gangliogliomas are often associated with microscopic glioneuronal malformations and cortical disorganization that arise due to disordered neuronal migration (i.e., adjacent cortical dysplasia ). Isolated accounts describe gangliogliomas arising in association with vascular malformations and Rasmussen encephalitis.

Radiologic Features and Gross Pathology

Gangliogliomas and gangliocytomas exhibit a constellation of computed tomography (CT) and magnetic resonance (MR) features. One common pattern on neuroimaging is the cyst with mural nodule ( Fig. 10.1A ), an arrangement typical of other low-grade brain tumors as well, such as pilocytic astrocytoma and pleomorphic xanthoastrocytoma. The mural nodule almost always shows strong contrast enhancement and is T1 hypointense and T2 hyperintense on MR imaging. Less common and less specific patterns include relatively discrete enhancing (homo­geneously or heterogeneously) or even nonenhancing tumors. There is typically minimal mass effect and surrounding edema, a useful differential diagnostic feature that helps distinguish it from more aggressive contrast-enhancing tumors, such as high-grade gliomas. Foci of calcification are frequently noted on CT and the scalloping of the calvaria that is occasionally seen with peripherally located tumors attests to their slow expansion.

Spinal cord ganglion cell tumors have neuroimaging features that overlap considerably with intramedullary fibrillary astrocytomas and ependymomas. Features that favor ganglioglioma include greater tumor length (eight vertebral segments for gangliogliomas versus four for astrocytomas and ependymomas), the presence of intratumoral cysts, bone changes (scoliosis or erosion), mixed signal intensity on T1-weighted images, absence of associated edema, and patchy contrast enhancement with extension to the cord surface.

Ganglion cell tumors are typically well circumscribed and do not diffusely infiltrate the adjacent CNS structures. A serous fluid-filled cyst often accompanies a mural nodule in the most common growth pattern ( Fig. 10.1B ). In other instances, these tumors may exhibit a more limited cystic component or may be composed entirely of solid tan or gray-white tumor tissue. Most are relatively demarcated, especially the cystic variants, and can acquire a firm texture owing to desmoplasia or a palpable grittiness due to calcification.

Histopathology

Gangliocytomas are tumor masses consisting of well-differentiated ganglion cells that display architectural disarray and cytologic dysmorphism ( Fig. 10.2 ). The cell density is generally in excess of the native CNS, which is an important diagnostic feature. More importantly, these neuronal elements are often clustered and spatially disordered, with no evidence of shared polarity, layering, or respect for anatomic boundaries. Individual neurons possess large vesicular nuclei, prominent and centrally positioned nucleoli, abundant cytoplasm with Nissl substance, and multipolar processes. Cellular gigantism, coarse cytoplasmic vacuolization, and multinucleation are common. Gangliocytomas occasionally show evidence of neurodegenerative changes, including well-defined neurofibrillary tangles. The pleomorphic and disorientated neurons of gangliocytoma are usually embedded within a loose or rarefied meshwork comprised mostly of their dysplastic cell processes and hyperplastic astrocytes. To be classified as a gangliocytoma, a neoplastic glial population must be absent. Some investigators suggest that nearly all ganglion cell tumors contain at least a minor neoplastic glial component and that true gangliocytomas are either rare or nonexistent.

Gangliogliomas are similar to gangliocytomas, but by definition contain an additional neoplastic glial population ( Fig. 10.3 ). The relative representation of glial and neuronal constituents varies considerably, usually arranged in an intermixed fashion, although rare examples appear more spatially divided. Neuronal elements may be easily seen, occasionally dominating the histologic picture, or are evident only after extensive searching, in some cases being sparsely distributed or regionally segregated. Well-differentiated ganglion cells possess round vesicular nuclei that are centrally placed and typically prominent nucleoli, amphophilic or eosinophilic cytoplasm, and peripherally distributed Nissl substance. As with gangliocytomas, the neuronal cells in gangliogliomas usually lie in obvious architectural disarray, often clustering in anomalous fashion, and may exhibit pronounced morphologic abnormalities including multinucleation, cytoplasmic vacuolation, and thickened, tortuous neuritic processes that sprout irregularly from cell bodies. The demonstration of neuronal differentiation of large, morphologically atypical cells may sometimes require immunohistochemistry.

In the majority of cases, the glial component of gangliogliomas is astrocytic ( Fig. 10.3 ) and assumes the appearance of a low-grade fibrillary or pilocytic astrocytoma. Rarely, gemistocytic elements may be present, and some gangliogliomas contain patterns similar to PXA. Oligodendrocyte-like populations can be identified in select cases, but immunohistochemical assessment is required to distinguish these from neurocytes and pilocytic cells with rounded nuclei.

A characteristic feature of ganglion cell tumors is the presence of perivascular and interstitial infiltrates of lymphocytes and plasma cells (see Fig. 10.3C ). Stromal fibrosis of gangliogliomas consisting of a reticulin or collagenous network can be minor, with wispy bridges between blood vessels, or more substantial with a fascicular pattern of spindle cell proliferation. Particularly in neuron-rich zones are stromal calcifications, sclerosis of blood vessels, and eosinophilic granular bodies (EGBs) ( Fig. 10.3C ). The latter are lysosomally derived spherical proteinaceous deposits dispersed in the parenchyma and cell processes of gangliogliomas, as well as other low-grade CNS tumors, including pilocytic astrocytoma and PXA. Both EGBs and perivascular lymphocytic infiltrates serve as signposts of low-grade biology in CNS tumors and are generally absent in higher grade neuroepithelial lesions. Additionally, Rosenthal fibers may be seen, although they are most commonly found at the periphery of the tumor and may therefore represent a component of adjacent “piloid gliosis.”

Cerebral gangliogliomas are frequently associated with nearby cortical dysplasia (see Chapter 25 ), although it may not always be possible to distinguish a small focus of invasion by the ganglioglioma itself from adjacent cortical dysplasia. In general however, cortical dysplasia should not form a true mass lesion, but merely show neuronal architectural disarray and dysmorphism within a region of relatively normal cortical thickness.

Histologic Variants and Grading

Grading of gangliogliomas is controversial since the vast majority behave in a benign fashion. However, some have advocated grading based on characteristics of the glial component. Unfortunately, standard criteria used for grading of astrocytomas (e.g., mitotic activity, microvascular proliferation, and necrosis) appear to less reliably predict the clinical behavior for gangliogliomas. Conventional WHO grade I gangliogliomas exhibit little if any mitotic activity, and then only in the glial elements. Isolated mitoses, glial atypia, microvascular proliferation, leptomeningeal invasion, and microscopic infiltration of adjoining brain tissue are not predictors of outcome. The current WHO classification designates gangliocytomas and gangliogliomas as grade I neoplasms. The designation of “atypical ganglioglioma” has been occasionally used for tumors that display increased cellularity and proliferative activity in the glial component.

A small subset of gangliogliomas show frankly malignant histology on initial assessment or upon recurrence. Such transformation sometimes occurs many years (even decades) into the clinical course and may follow radiation therapy. Interestingly, anaplastic gangliogliomas do not show the strong predilection for the temporal lobe that grade I lesions do, but are more evenly distributed among the cerebral hemispheric lobes and the spinal cord. High-grade elements are almost invariably astrocytic, rarely assuming oligodendroglial appearances. These tumors are difficult to define precisely, but are generally characterized by dense cellularity, elevated mitotic activity, and in some cases necrosis (see Fig. 10.3 ). The histologic appearance of this high-grade glial component may be indistinguishable from glioblastoma. These rare anaplastic gangliogliomas are currently considered WHO grade III.

Differential Diagnosis

The differential diagnosis of ganglion cell tumors includes those entities with a mature neuronal component containing large atypical cells with eosinophilic cytoplasm. Ganglion cell tumors with extension into the subarachnoid space and contact with the pia-arachnoid may provoke a florid fibroblastic response, with occasional gangliogliomas developing dural attachments. This phenomenon may prompt a differential diagnostic consideration of desmoplastic infantile ganglioglioma (DIG; see next section). There is also substantial clinical, neuroimaging, and pathologic overlap of ganglion cell tumors with pleomorphic xanthoastrocytomas (see Chapter 7 ). Both are circumscribed tumors, generally of the young, that contain large tumor cells with abundant cytoplasm, prominent nuclei, lymphocytic infiltrates, EGBs, generalized circumscription, and frequent BRAF V600E mutation. The large cell component of PXA is glial in derivation and should be predominantly GFAP positive in contrast to the synaptophysin staining of the ganglion cells of gangliogliomas. Unfortunately, scattered synaptophysin immunoreactive cells are seen in roughly a fourth of PXAs, but often the positive cells do not otherwise look like ganglion cells. The clusters of multiple disoriented, well-differentiated neurons that characterize gangliocytomas or gangliogliomas with only a minor glial component can be mistaken for focal cortical dysplasia (see Chapter 25 ), although the latter is not typically associated with a discrete mass, cyst formation, EGBs, or perivascular inflammation. The dysembryoplastic neuroepithelial tumor (DNT; see later section) also contains mature ganglion cells and a low-grade neuroepithelial component. DNTs tend to be nodular or multinodular and have a characteristic architecture with microcysts, floating neurons, and linear arrangements of oligodendrocyte-like tumor cells. A newly described entity, the multinodular and vacuolated neuronal tumor (MVNT), is a cerebral hemispheric lesion composed of clustered mature atypical neurons, but only occasionally with full ganglionic differentiation, which occurs within the cerebral cortex and subcortical white matter as multiple discrete or coalescing nodules with vacuolated neuropil. These share some clinical and histopathologic features with gangliocytoma, but are distinguished by their multinodularity ( Fig. 10.4A ), vacuolated neuropil ( Fig. 10.4B ), clinical presentation in adulthood, their lack of EGBs and a lymphocytic infiltrate, and an abnormal neuronal population that does not show immunoreactivity for most neuronal markers such as synaptophysin, neurofilament, or NeuN ( Fig. 10.4C ); in contrast, these cells express OLIG2 ( Fig. 10.4D ). Another overlapping entity known as polymorphous low-grade neuroepithelial tumor of the young (PLNTY) was reported. Shared features with ganglioglioma include a predilection for children/young adults with chronic epilepsy and a tendency toward heavy calcification ( Fig. 10.5A and B ). Although both may harbor BRAF V600E mutations and feature CD34 immunoreactivity, the latter is typically more intense and diffuse in the PLNTY ( Fig. 10.5C ), which also features a more oligodendroglioma-like cytology ( Fig. 10.5A ), lacks mature ganglion cells, and may show mutations of the FGFR2 or FGFR3 genes. As with MVNTs, the lesional cells are strongly positive for OLIG2 ( Fig. 10.5D ), with more traditional neuronal markers being negative.

Lastly, gangliogliomas must be distinguished from diffuse gliomas with entrapped cortical neurons. Distinguishing features include the more infiltrative growth pattern and secondary structure formation of the latter (e.g., perineuronal satellitosis). Although the neurons in the latter should look normal, it is not unusual to get some reactive or slightly “dysmorphic” changes in neurons that are caught up in tumor, presumably from disruption of their processes. Occasionally, such neurons will even show synaptophysin or neurofilament positivity within their cell bodies. Therefore, this feature alone should not be overinterpreted as proof of a neuronal component when the tumor otherwise looks typical of a diffuse glioma. Additionally helpful is the presence of IDH1 R132H positivity, since this alteration is limited to the diffuse gliomas and is not seen in gangliogliomas.

Ancillary Diagnostic Studies

Gangliogliomas readily show immunoreactivity for neuronal markers, including neurofilament protein and synaptophysin (see Fig. 10.3D ). Antibodies to neurofilament proteins often highlight the perikarya of dysmorphic ganglion cells as well as their abnormal neuritic processes. The tendency for synaptophysin to label tumor cell surfaces in a coarsely granular or linear fashion is not typical of native cortical neurons, but is not absolutely specific; cytoplasmic positivity in tumoral ganglion cells is also common. A large number of other neuronal antigens have been demonstrated within the neuronal component of gangliogliomas, including chromogranin, class III β-tubulin and MAP-2, the neuronal nuclear protein NeuN, and synapsin. Oddly, however, the majority of ganglion cells in most gangliogliomas are NeuN negative, even in large cells showing obvious features of neuronal differentiation such as Nissl substance. This pattern can also be useful, since entrapped non-neoplastic cortical neurons within a diffuse glioma are always strongly positive (see left side of Fig. 10.4C ). The neurofibrillary tangles that occur in a small subset of gangliogliomas label for tau protein, ubiquitin, and phosphorylated neurofilaments.

GFAP immunoreactivity is restricted to the cytoplasm of glial cells within gangliogliomas. Glial cells also label for S-100 protein and vimentin. Oligodendrocyte-like cells may be reactive for OLIG2, SOX10, or S-100 protein but negative for GFAP, vimentin, and all neuronal markers or they may lie in a synaptophysin-rich matrix and exhibit nuclear NeuN immunoreactivity. Laminin and type IV collagen deposition are more common in gangliogliomas than in conventional gliomas, especially in those with inflammatory infiltrates and long preoperative symptom intervals.

Over 80% of gangliogliomas have some immunoreactivity for CD34. This epitope is normally expressed exclusively by endothelial cells in the adult brain, but is also transiently expressed by early developmental precursors in the CNS. Cells that stain with CD34 in gangliogliomas are thought to be neuronal, although their precise identity has not been determined. Since normal brain and spinal cord do not express CD34, this marker can be helpful in establishing a diagnosis in histologically ambiguous cases by identifying an abnormal population, often with a stellate appearance due to highly ramified processes (see Fig. 10.3E ). CD34 immunolabeling may aid in distinguishing gangliogliomas from other glial and glioneuronal tumors, since CD34 is only rarely expressed by astrocytomas, oligodendrogliomas, and DNT. It has been suggested that the coexpression of CD34 and MAP2 by neuronal cells is a specific finding in gangliogliomas, although caution is warranted since neither marker is absolutely specific.

An antibody specific to the mutant BRAF V600E protein has been developed and can be used to identify the cases that have this mutation. Immunoreactivity for the mutant protein localizes to both components in some cases (see Fig. 10.3I ), but in others, is predominantly or exclusively limited to the neuronal component of these tumors ( Fig. 10.3J ).

The proliferative activity of gangliogliomas is generally low as determined by investigations of MIB-1 (Ki-67) immunolabeling (see Fig. 10.3G ), with foci of anaplastic transformation being a rare exception ( Fig. 10.3H ). In nearly all cases, nuclear MIB-1 reactivity has been restricted to the glial elements. MIB-1 labeling indices reported in larger series vary from less than 1.0% to over 10.0%, with mean values in the 1.1% to 2.7% range. Although the WHO classification does not include MIB-1 proliferation activity as a criterion for grading, some investigators suggest that MIB-1 labeling of 5% is a feature of “atypical” ganglioglioma, with increased risk of subsequent recurrence. Other investigations have demonstrated that elevated MIB-1 indices correlate with high-grade (anaplastic) histologic features ( Fig. 10.3H ) or recurrence. However, care must be taken not to overinterpret proliferation in endothelial or inflammatory cells. Additional immunostains for detecting intratumoral lymphocytes, macrophages, and microglial cells (e.g., CD45, CD68, CD163 ) may be helpful to gauge this possibility. In addition, anaplastic (grade III) gangliogliomas show a lower frequency of CD34 reactivity as compared to their grade I counterparts.

Genetics

The complete spectrum of molecular genetic alterations in gangliogliomas has not been defined. However, the recent recognition of the role of activating BRAF mutations and subsequent activation of the MEK/ERK pathway in low-grade gliomas of childhood has led to their study in gangliogliomas as well. These studies have shown that activating V600E mutations of BRAF are present in a substantial subset of gangliogliomas and anaplastic gangliogliomas (20% to 50%). Immunoreactivity for the mutant specific BRAF V600E protein has been demonstrated in over 40% of cases and correlates well with the presence of mutation. It is not settled whether BRAF mutations have prognostic significance for ganglioglioma; however, they are generally present in younger patients. Anaplastic gangliogliomas also harbor BRAF mutations at a frequency similar to low-grade gangliogliomas.

Unlike the diffusely infiltrating gliomas, mutations in isocitrate dehydrogenase 1 or 2 (IDH1, IDH2) are rare or absent in ganglioglioma. One study suggested that approximately 8% of gangliogliomas had mutations in IDH1; however, this subset was shown to have a greater risk of recurrence and a higher risk of malignant transformation, suggesting that they were more likely diffusely infiltrative gliomas with entrapped dysmorphic neurons. Similarly, reports of ATRX deletion, K27M H3F3A mutations, and TERT promoter mutations within anaplastic gangliogliomas will need to be further studied, since some of these could also represent high-grade gliomas with entrapped mature neurons.

One the most complete studies of cytogenetic alterations in 61 gangliogliomas found aberrations in 66%. The most common gains were noted on chromosomes 7 (21%), 5 (16%), 8 (13%), and 12 (12%), with losses on 22q (16%), 9 (10%), and 10 (8%). Recurrent partial imbalances comprised the minimal overlapping regions dim(10)(q25) and enh(12)(q13.3-q14.1). Unsupervised cluster analysis of genomic profiles detected two major subgroups: (1) complete gain of 7 and additional gains of 5, 8, or 12; and (2) no major recurring imbalances or mainly losses. Interestingly interphase FISH demonstrated that cytogenetic aberrations were localized to the glial rather than neuronal cells.

Due to the histologic similarity of gangliogliomas to some malformative lesions such as focal cortical dysplasia and the cortical tubers of tuberous sclerosis complex (TSC), in which the TSC1 and TSC2 genes have been implicated, these genes have been investigated in gangliogliomas. One study of the TSC2 locus uncovered polymorphisms in intron 4 at a significantly higher incidence in gangliogliomas than in control patients or in patients with other forms of brain tumors. A more detailed analysis of 20 epilepsy patients with gangliogliomas identified 7 polymorphisms of the TSC1 gene and 28 polymorphisms as well as a single mutation in the TSC2 gene. The frequency of TSC2 polymorphisms in intron 4 and exon 41 in gangliogliomas was much higher than seen in the control population. The clustering of these TSC2 polymorphisms near the GAP-related domain and the hamartin-interacting domain of the gene suggest that these alterations could have functional significance, but further studies are needed.

Treatment and Prognosis

Conventional gangliocytomas and gangliogliomas are well-differentiated, clinically indolent tumors that carry an excellent prognosis. Rates of recurrence following complete resection are low, and dissemination throughout the nervous system is rare. Of chronic epilepsy patients who were treated by neurosurgery and diagnosed with ganglioglioma, 88% were seizure free after 7 years of follow-up. Tumor recurrence in these patients occurs in less than 2% of cases within this interval. Local recurrence of spinal gangliogliomas is higher, occurring in approximately 30% of cases in one study. Patients with ganglioglioma do not generally succumb to disease, with an overall survival of 84% at 10 years.

Anaplastic gangliogliomas can behave in a locally aggressive fashion, seed the leptomeninges, and lead to death. However, there are also documented cases of anaplastic tumors faring well following complete excision, likely reflecting that some of these neoplasms retain compact, relatively noninfiltrative growth patterns that lend them to surgical excision. A predictably poor outlook is associated with partial resection or biopsy of grade III tumors, but the optimal management of these remains to be defined. A recent study using Surveillance, Epidemiology, and End Results (SEER) cancer registry data determined that the median overall survival for anaplastic ganglioglioma was 28.5 months and that unifocal disease and surgical treatment were the most important predictors of survival.

In one study of clinical features associated with an increased risk of recurrence, older patient age, the presence of seizures, a supratentorial location, and a greater extent of resection were associated with longer recurrence-free survivals on univariate analysis. On multivariate analysis, the extent of resection was the only significant factor. In a large series of gangliogliomas affecting children, there was an association of BRAF V600E mutations with a shorter recurrence-free survival. However, this finding has not been confirmed.

With the finding of activating BRAF V600E mutations in a large percentage of gangliogliomas, there have been attempts to treat recurrent or aggressive forms of the disease with specific BRAF inhibitors such as vemurafenib and dabrafenib with variable success.

Definitions and Synonyms

The desmoplastic infantile ganglioglioma (DIG) is a low-grade neuroepithelial tumor with a prominent desmoplastic stroma and a mature neuronal component that affects the very young. It is typically classified together with the desmoplastic infantile astrocytoma (DIA), which differs histologically by its lack of a mature neuronal component. Accordingly, they are linked under the designation of “desmoplastic infantile astrocytoma/ganglioglioma” in the current WHO classification of CNS tumors. These lesions have previously been described by a variety of terms, including “superficial cerebral astrocytomas attached to dura” and “desmoplastic supratentorial neuroepithelial tumors of infancy with divergent differentiation.”

Incidence and Demographics

These tumors are rare and account for approximately 1% of all pediatric CNS neoplasms, but may account for up to 15% of brain tumors in infants. They typically arise within the first 2 years of life (mean age, 6 months). Several reports have now described such tumors arising in older children, adolescents, and young adults. A survey of 84 published cases revealed a 1.7 to 1 male–female case ratio.

Localization and Clinical Manifestations

Desmoplastic infantile astrocytomas and gangliogliomas occur in the supratentorial compartment of infants. Clinical manifestations most commonly include rapidly increasing head circumference, bulging fontanels, hypertonus, and forced downward deviation of the eyes. Seizures and paresis may also be observed, as may cranial nerve VI and VII palsies.

Radiologic Features and Gross Pathology

Desmoplastic infantile astrocytomas and gangliogliomas share a neuroradiologic presentation sufficiently distinctive to suggest the diagnosis in patients of appropriate age. Supratentorial in location, these most often arise in the frontoparietal regions, are typically alarmingly large, and often involve more than one cerebral lobe. Particularly characteristic is the finding on CT or MR imaging of a superficially positioned, multinodular, and brightly contrast-enhancing mass with plaque-like attachment to the dura and a subjacent, uniloculated or multiloculated cyst ( Fig. 10.6A ). The large cystic component of these lesions is frequently responsible for their mass effect. Solid components may appear isodense or slightly hyperdense in nonenhanced CT studies, isointense relative to cortex in precontrast, T1-weighted MR images, and heterogeneous in signal pattern on T2-weighted assessment. Cystic elements are typically T1 hypointense and T2 bright. Despite the large size of these lesions, there is only mild edema and communication with the ventricular system is rare. Other common features include erosion of the inner table of the skull.

At operation, desmoplastic infantile astrocytomas and gangliogliomas are often large, occasionally measuring an average of 10 cm in greatest dimension. Their solid component is usually superficial to the brain, often attached to adjacent dura, gray-white, and rubbery or firm due to the large amounts of collagen. Although these relatively discrete neoplasms do not truly infiltrate adjacent cerebral cortex, tumor and brain may be firmly adherent to one another.

Histopathology

Histologic examination of desmoplastic infantile astrocytomas and gangliogliomas confirms that they are largely extracerebral in location, with variable, superficial extension of tumor into the brain along Virchow-Robin spaces. A distinctly biphasic morphology is characteristic. Collagen- and reticulin-rich regions populated principally by spindled cells in loose fascicular or storiform array dominate most examples, leading to a mesenchymal appearance that abruptly gives way to tissue with a neuroepithelial character (see Fig. 10.6 ). The latter typically contain small cells of embryonal or astroglial appearance densely aggregated within a reticulin-free fibrillar matrix. Fairly subtle small polygonal ganglion cells and gemistocytic cells may be seen in both fibrillar and desmoplastic regions. The presence of mature neuronal elements leads to the designation of desmoplastic infantile ganglioglioma rather than astrocytoma. Neuronal cells are most conspicuous in the noncollagenous portions, range considerably in size, and may include ganglion cells of fully differentiated or atypical appearance. EGBs can occasionally be found, but are usually inconspicuous in comparison to classic gangliogliomas. Calcifications may be encountered, but lymphocytic infiltrates are less frequent and prominent than classic ganglioglioma. Mitotic activity and necrosis are not usually present and are typically restricted to primitive small cell components. Examples with high mitotic rate, microvascular proliferation, and necrosis have been documented, yet this has not translated into poor prognosis for most of these patients.

Differential Diagnosis

Neuroepithelial neoplasms that exhibit fibrosis and contain spindle-shaped, astrocytic tumor cells invested by basal lamina include the well-characterized pleomorphic xanthoastrocytoma (PXA) and tumors that have been referred to as “gliofibromas.” “Gliofibromas” are a heterogeneous, poorly characterized, and controversial group of neoplasms that have no stereotypical age of onset, localization within the CNS, or neuroradiologic features. PXAs usually arise in older children or young adults and exhibit bizarre cytologic alterations and cellular lipidization not found in desmoplastic infantile tumors. Neither PXAs nor gliofibromas contain the primitive-appearing components of desmoplastic infantile ganglioglioma. Such cellular aggregates are also foreign to conventional ganglion cell tumors, although these may demonstrate considerable reticulin and collagen deposition. More conventional areas of ganglioglioma are occasionally seen in transition with DIG and may reflect a maturation type of phenomenon. Fibroblastic meningiomas, fibrohistiocytic tumors, and other mesenchymal neoplasms do not contain the neuroepithelial constituents of DIG that are identified by immunolabeling for GFAP or neuronal antigens.

Ancillary Diagnostic Studies

Immunohistochemistry for GFAP labels the astrocytic component of both DIA and DIG (see Fig. 10.6E ) and can constitute a surprisingly large percentage of the spindle cells in the desmoplastic regions. Individual tumor cells in these areas are also outlined by antibodies to type IV collagen, mirroring the pattern of reticulin stains and indicating basal lamina deposition. The visualization of mature neuronal constituents is aided by their immunoreactivity for synaptophysin ( Fig. 10.6F ), class III β-tubulin, and neurofilament. These neuronal markers may also be expressed by the less differentiated, small cell populations, as may MAP-2, the neuron-associated Hu antigen, and occasionally GFAP and desmin. MIB-1 labeling indices have ranged from less than 0.5% to 7%, but may be particularly brisk in primitive-appearing foci.

Genetics

The complete spectrum of genetic alterations present in these tumors has not been defined. Classic cytogenetic analysis has been carried out on only a limited number. In each case, either a normal karyotype or nonclonal abnormalities were described. Molecular studies of DIA revealed no loss of heterozygosity on chromosomes 10 and 17 and no TP53 mutations. A comparative genomic hybridization study of three cases of DIA and DIG did not reveal any consistent chromosomal gains or losses. One DIG showed a loss on 8p22-pter, while one DIA showed gain on 13q21. Hypermethylation of the p14 ^ARF gene was reported in one tumor.

A more recent genome-wide copy number analysis of 4 DIA and 10 DIG uncovered focal recurrent losses at 5q13.3, 21q22.11, and 10q21.3, while frequent gains were noted at 7q31, which includes the locus for MET , with less frequent gains of 4q12 ( KDR, KIT , and PDGFR ) and 12q14.3 ( MDM2 ).

Because DIGs are rare, large studies of BRAF gene fusions and activating mutations have not fully characterized their frequency. The largest series to date demonstrated BRAF V600E mutations in 1 of 14 cases and another identified them in 2 of 18 DIA/DIGs. Thus far, BRAF gene fusions have not been reported.

Treatment and Prognosis

Desmoplastic infantile astrocytomas and gangliogliomas are classified as WHO grade I tumors, and long-term follow-up studies have demonstrated a favorable outcome for patients with resectable lesions. Gross total resection results in long-term survival in cases of DIA and DIG. In one study, with a follow-up period of 8.3 to 20 years (median 15.1 years), six of eight patients with desmoplastic infantile astrocytoma survived (two died perioperatively). In another study of 14 patients, mean survival was 8.7 years (range, 1 to 14.1 years), and no deaths resulted from a residual or recurrent tumor. In the case of subtotal resection or biopsy, most tumors are stable or regrow slowly, while occasional tumors show radiologic evidence of tumor regression following subtotal resection. On the other hand, some cases do behave more aggressively. One desmoplastic infantile ganglioglioma that could not be surgically resected owing to an unusually deep location progressed and caused death. Dissemination of these tumors through the CSF has been reported, but this should be considered a rare event. The presence of primitive appearing cellular aggregates with mitotic activity and foci of necrosis does not appear to affect prognosis.

Definitions and Synonyms

The dysplastic gangliocytoma of the cerebellum, commonly known as Lhermitte-Duclos disease, is a rare lesion that unilaterally enlarges the cerebellum, but maintains a cortical foliar architecture. It is characterized by the replacement of the granular cell layer by mature, enlarged, and mildly dysmorphic ganglion cells with subsequent increase in cerebellar size. The clinical behavior is that of a slowly growing mass in the posterior fossa, yet it is unclear if this lesion is best considered a neoplasm or hamartoma. The spectrum of names attached to the dysplastic gangliocytoma of the cerebellum— Purkinjeoma, gangliomatosis of the cerebellum, granule cell hypertrophy of the cerebellum, and diffuse hypertrophy of the cerebellar cortex —reflects the diversity of opinions regarding its histogenesis.

Incidence and Demographics

These lesions are rare. They usually come to clinical attention in the third or fourth decades, although a congenital presentation has been described and patients up to 74 years of age have been affected. There is no significant predilection for either sex.

Clinical Manifestations and Localization

The neurologic manifestations are chronic in evolution, with mean intervals of 40 months. In the majority of cases, symptoms include ataxia and seizures, or are related to obstructive hydrocephalus, increased intracranial pressure, or cerebellar injury. Cranial nerve deficits may be observed, with atypical presentations including severe orthostatic hypotension and acute subarachnoid hemorrhage.

Both the vermis and hemispheres of the cerebellum may be involved. Patients with cerebellar disease may show evidence of extracerebellar brain dysfunction, which generally takes the form of mild cognitive disability, seizure disorders, or a variety of less common CNS and systemic anomalies. These include neuronal heterotopias in the white matter, olivary nuclear hypertrophy, hydromyelia, cervical syrinx, vascular malformations, polydactyly, and partial gigantism. Dysplastic gangliocytoma of the cerebellum has been recognized as a component of Cowden syndrome, an autosomal dominant cancer predisposition disorder that has been linked to germline mutations of the PTEN gene (see Chapter 22 ).

Radiologic Features and Gross Pathology

Dysplastic gangliocytoma is typically a nonenhancing, unilateral hemispheric expansion of the cerebellum. These lesions are hypointense on T1-weighted MR images and hyperintense on T2-weighted images ( Fig. 10.7A ). In both instances, parallel linear striations are present on the surface of the lesion (tiger stripes) that are nearly pathognomonic and represent affected, abnormally thickened cerebellar folia. If present, calcifications can be seen best on CT. Advanced MR imaging has shown that these lesions have mildly increased diffusivity, and perfusion imaging demonstrates increased relative cerebral blood volume, blood flow, and mean transit time.

On macroscopic examination, regions of cerebellar foliar thickening blend into adjacent, unaltered cortex. The enlarged folia often exhibit surface pallor or yellow-white discoloration reflecting aberrant myelination, may be unusually firm, and frequently have some cavitation of their white matter cores.

Histopathology

This lesion is defined by the variable replacement of the internal granule layer of the cerebellar folia by moderate- to large-sized hypertrophic ganglion cells (see Fig. 10.7 ). The abnormal cell processes of the latter further contribute to the enlargement of the folia. These changes range from the modest replacement of only the most superficial cells of the granular layer by ganglion cells to replacement of the entire population. In the most severe cases, the molecular layer also shows increased numbers of atypical neuronal cells. Occasionally a collection of granular and abnormal ganglion cells are seen in the subpial zone of the molecular layer, suggesting an altered neuronal migration of the external granular cell layer during cerebellar development. Another consistent finding is the abnormal myelination of the molecular layer, which results from the myelination of the abnormal neurons that populate the granule cell layer, extending axons into the molecular zone. Myelinated axons run in parallel to the pial surface in deeper layers and perpendicular to it more superficially. Other histologic findings include a reduction in the number of Purkinje cells, microcalcifications, large bizarre neurons, dense capillary networks, and vacuolization of the cerebellar white matter.

Differential Diagnosis

The primary diagnostic consideration for a ganglion cell containing lesion of the cerebellum would be a conventional ganglioglioma/gangliocytoma. These conventional ganglion cell tumors, however, are distinct from the dysplastic gangliocytoma of the cerebellum in their imaging and histopathology. Conventional gangliogliomas are typically circumscribed mass lesions that displace adjacent brain and often have a cyst and mural nodule appearance on MRI, as opposed to the global foliar enlargement of the cerebellar hemisphere noted in dysplastic gangliocytomas. Histologically, conventional ganglion cell tumors show a more disordered growth of the ganglionic cell component and there is usually a lymphocytic infiltrate noted. In the case of ganglioglioma, a well-developed, low-grade glial component is present and may dominate the histology, whereas a glial component is not a component of dysplastic gangliocytoma. Conventional gangliogliomas frequently harbor BRAF V600E mutations, which can be detected by immunohistochemistry or sequence analysis, whereas dysplastic gangliocytomas have PTEN mutations and show increased expression of phospho-AKT by immunohistochemistry.

Ancillary Diagnostic Studies

Immunohistochemical and electron microscopic studies suggest that the neuronal populations in dysplastic gangliocytomas of the cerebellum are heterogeneous and include large, polygonal neurons with prominent nucleoli as well as a class of smaller neurons with hyperchromatic nuclei. Both neuronal variants contain clear and dense-core vesicles, with synapse formation being apparent in some cases. Neurons and their abnormal processes are recognized by antibodies to neurofilament, chromogranin, and synaptophysin (see Fig. 10.7E and G ). In contrast, GFAP often highlights abundant reactive astrocytes, but is negative in the tumor cells ( Fig. 10.7F ). The notion that the dysmorphic ganglion cells arise from overgrowth of internal granular cell neurons is supported by immunoreactivity for NeuN ( Fig. 10.7H ), given that Purkinje cells are normally negative for this marker. The aberrant myelination can be highlighted with an LFB-PAS stain.

Genetics

Germline intragenic PTEN mutations have been demonstrated in 81% of patients with Cowden syndrome; at least some of the nonmutated cases may be accounted for by alterations of the PTEN promoter. The precise relationship between PTEN mutations, Cowden syndrome, and dysplastic gangliocytoma remains to be defined, however, as not all patients with dysplastic gangliocytoma develop other manifestations of Cowden syndrome. Similarly, some patients with dysplastic gangliocytoma or Cowden syndrome do not have germline PTEN mutations. In particular, pediatric patients with dysplastic gangliocytoma may not have evidence of either PTEN mutations or other manifestations of Cowden syndrome. In a subset of patients with partial or complete clinical manifestations of Cowden syndrome, but who lack PTEN mutations, germline mutations of succinate dehydrogenase B (SDHB) or SDHD have been described and are thought to activate downstream signaling pathways similar to PTEN mutations. To date, however, SDHB and SDHD mutations have not been associated with dysplastic gangliocytoma.

Patients with germline PTEN mutations are at risk of developing various hyperplastic growths, hamartomas, and neoplasms, chief among which are multifocal mucocutaneous lesions (trichilemmomas, hyalinizing mucinous fibromas, oral papillomas, and acral keratoses), thyroid lesions (goiter, follicular adenoma, or, rarely, carcinoma), breast lesions (benign fibroepithelial proliferations, papillomas, and ductal adenocarcinomas ), gastrointestinal polyps of varying type, ovarian cysts, and macrocephaly/megalencephaly (see Chapter 22 ). Patients with Cowden syndrome should be screened for dysplastic gangliocytomas of the cerebellum, which may be discovered incidentally. Conversely, dysplastic gangliocytomas of the cerebellum may predate the appearance of other manifestations of Cowden syndrome; therefore, these patients should be screened for possible Cowden disease.

Treatment and Prognosis

Dysplastic gangliocytoma is considered a WHO grade I tumor, and surgical excision is the treatment of choice. Surgical resection is curative in the majority of cases, but local recurrence also occurs in a substantial percentage of cases with long-term follow-up. Many have suggested that recurrence of these dysplastic gangliocytomas favors a neoplastic rather than hamartomatous designation for these lesions. Others have speculated that clinical recurrence may be caused by hypertrophy of residual, genetically affected tissue rather than a recurrence related to proliferation.

Definitions and Synonyms

The central neurocytoma is an intraventricular tumor composed of small mature neurons resembling neurocytes, the neoplastic counterpart to neurons normally found in the dentate fascia of the hippocampus or the internal granular layer of the cerebellum. It has a characteristic location within the lateral ventricles in the region of the foramen of Monro. The neuronal nature of this tumor was first described in a report of two cases that developed in young adults, were located in the midline of the brain extending into lateral ventricles, and were composed of small round oligodendroglioma-like cells that displayed unequivocal neuronal differentiation by electron microscopy. The name “central neurocytoma” was proposed to distinguish these well-differentiated tumors from the more malignant neuroblastoma. Prior to this report, most of these lesions were misinterpreted as intraventricular oligodendrogliomas or ependymomas. Histologically similar tumors presenting in the cerebral cortex, spinal cord, or other nonventricular sites have been referred to as extraventricular neurocytomas (EVN). A neurocytic component may also be encountered in other rare glioneuronal tumors, such as the papillary glioneuronal tumor and the rosette-forming glioneuronal tumor; these entities are discussed separately.

Incidence and Demographics

Neurocytomas account for 0.25% to 0.5% of all intracranial tumors. According to a comprehensive literature review of central neurocytoma, the majority were found in young adults; the mean age at clinical presentation was 29 years, 46% being diagnosed in the third decade with approximately two-thirds presenting between the ages of 20 and 40 years. However, the age at presentation ranges from infancy to 82 years. No significant gender predisposition has been described.

Localization and Clinical Manifestations

The majority of patients present with signs and symptoms of increased intracranial pressure, such as headache, nausea, and vomiting, rather than with a distinct neurologic deficit. Other patients experience mental disturbances, visual changes, paresthesias, lethargy, loss of balance, or tinnitus. The clinical history is usually short (mean 3.2 months). Hormonal dysfunction (amenorrhea, gigantism, tumor hypersecretion of vasopressin and growth hormone) may be associated with neurocytoma of the septum pellucidum, the third ventricle, and the hypothalamus.

Central neurocytomas are typically located supratentorially in the lateral ventricles and/or the third ventricle. The anterior portion of one lateral ventricle is the most frequent site (50%), followed by the combined involvement of the lateral and third ventricles (15%) and the involvement of both lateral ventricles (13%). Tumors that grow exclusively in the third ventricle account for less than 3% of cases. Small neurocytomas have been documented with precise sites of origin at the foramen of Monro, the septum pellucidum, the corpus callosum, the hypothalamus, and the thalamus.

Occasionally, tumors with histopathologic, immunohistochemical, and biologic features similar to central neurocytoma may be found outside the ventricles, within the cerebral hemispheric parenchyma or other scattered sites throughout the neuroaxis. For example, neurocytomas have been reported in the fourth ventricle, cerebellum, brainstem, spinal cord, and cauda equina. Neurocytic tumors such as these do not fit the classic definition of central neurocytoma and have been termed “extraventricular neurocytomas.” There are yet other neoplasms that contain neurocytic elements, but represent distinct pathologic entities. The cerebellar liponeurocytoma in particular appears to be a unique variant defined both by its peculiar predilection for the posterior fossa and for its cytoplasmic lipidization, resembling fat metaplasia (see later section).

Radiologic Features and Gross Pathology

On CT scans, central neurocytomas and EVNs are isodense or slightly hyperdense, well-demarcated, lobulated intraventricular masses. In about half of the cases, the lesion is calcified. Low-density areas suggestive of cystic degeneration are less frequent. T1- and T2-weighted MR imaging typically shows a solid mass with occasional cystic components that is heterogeneously isointense or slightly hyperintense relative to the cortex ( Fig. 10.8A and B ). These tumors usually display moderate contrast enhancement, which can be irregular, especially in cases with calcification or cysts. Hydrocephalus due to obstruction of the foramen of Monro may be present in central neurocytoma. Proton MR spectroscopy (MRS) has demonstrated elevated choline and alanine, with reduced and decreased creatine and NAA. More specific to central neurocytoma on MRS is a highly elevated glycine peak, which can be useful for establishing a radiologic diagnosis in the proper setting. Grossly, central neurocytomas are relatively well-demarcated gray masses. In the case of central neurocytoma, they often adhere to the ventricular lining or septum pellucidum. If heavily calcified, they may be gritty.