Pathology of Expansile Astrocytomas

Astrocytomas are represented by a wide variety of histologic forms and grades of tumors with a common histologic lineage. Tumors classified as astrocytomas can be further subdivided into the diffusely infiltrative astrocytomas, as well as the expansile, or circumscribed, astrocytomas. The latter include the pilocytic astrocytomas (World Health Organization [WHO] grade I), pleomorphic xanthoastrocytoma (WHO grade II), pituicytoma (WHO grade I); chordoid glioma (WHO grade I); and desmoplastic astrocytoma (WHO grade I). ^[1]

The subependymal giant cell astrocytoma is a slow-growing neoplasm arising from a hamartoma of periventricular cells with neuronal and glial lineage differentiation, but its inclusion derives from its historical taxonomic relationship to astrocytomas. The pilomyxoid astrocytoma is an entity with not only pilocytic features, but also intercellular mucin and aggressive growth tendencies that distinguishes it from the more indolent pilocytic astrocytoma.

Tumors of a controversial nature and, therefore, not discussed in this article include the astroblastoma that is now best considered to be of uncertain histologic origin with ultrastructural features of tanycytes. Although the polar spongioblastoma has historically been considered to be of primitive glial origin, the evidence of the polar spongioblastoma's very existence is questionable and is thought to be more akin to a growth pattern than a specific histologic type that may occur in either gliomas or tumors of neuronal origin.

The image below is an example of the histologic appearance of a pilocytic astrocytoma.

Background

Pilocytic astrocytomas are slow growing tumors with an expansile growth pattern and little propensity to disseminate resulting, overall, in an excellent prognosis, as represented in the WHO grade (grade I). These tumors primarily arise in children and young adults but may remain asymptomatic until later in life. Clinically, the tumors are most commonly associated with either headaches or seizures and rarely present with focal deficits, except when they occur in the optic pathway.

Of clinical importance is the occurrence of these tumors in the brainstem, where they may be mistaken for a diffusely infiltrating fibrillary astrocytomas. In contrast to the fibrillary astrocytomas, the prognosis of the brightly enhancing, exophytically growing pilocytic astrocytoma is much better. ^{[2, 3, 4]} Rare examples of these tumors have been described to progress, the most common ones being derived from the optic nerves diagnosed in patients older than 20 years. ^{[5, 6]} Similarly, the pilomyxoid astrocytoma, which is most commonly found in or around the optic chiasm and hypothalamus, has a propensity to early recurrence and infiltration, a fact that resulted in the WHO Committee upgrading this particular variant to a grade II tumor. ^[7]

Pilocytic astrocytoma is the most common intracranial tumor in patients with neurofibromatosis type I, and these lesions are largely confined to the optic nerve. ^[6]

Clinical Features

The overall incidence of pilocytic astrocytomas is 0.31 per 100,000 persons per year. They constitute 23.5% of pediatric central nervous system (CNS) tumors and are the most common variant of glioma in children. ^[8] The tumors most frequently affect persons in the first 2 decades of life when the age-specific incidence rises to 0.70 per 100,000 persons per year. ^[8] In the United States, pilocytic astrocytomas exhibit apparent differences in racial predisposition, with an incidence of 0.31 in white persons and 0.16 in black individuals. ^[8] However, there is no sexual predominance. ^[8]

The clinical history of patients with pilocytic astrocytomas is usually prolonged due to the nonspecificity of the symptoms. The common anatomic sites of origin include the cerebellum, hypothalamus, thalamus, optic pathway, brainstem, and spinal cord, with symptoms most commonly referable to mass effect in these areas. Thus, patients may present with generalized symptoms of increased intracranial pressure (ICP), including headaches, visual loss, nausea and vomiting, and cognitive impairment. Symptoms may be exacerbated by cystic expansion of the tumor, such that the tumor is represented as a small mural nodule along the wall of the cyst.

The etiology of pilocytic astrocytoma remains unknown in most cases. Pilocytic astrocytomas may occur in the context of neurofibromatosis type I in which the optic pathway is a typical site of origin. Although rare tumors may exhibit p53 accumulation by immunohistochemistry, mutations of the TP53 gene are not common and the tumors are not encountered in the Li-Fraumeni syndrome.

Imaging Studies

Imaging studies of the brain and spinal cord are essential to make the diagnosis of pilocytic astrocytoma. On computed tomography (CT) scans, pilocytic astrocytomas most often appear as an enhancing nodule along the wall of a large cyst that is hypodense to its surroundings, and the associated cyst is of water density. An occasional tumor will exhibit calcification.

Magnetic resonance imaging (MRI) with and without contrast is the study of choice for these lesions. T1-weighted images reveal the nodule to be isointense to gray matter, whereas T2-weighted images reveal the nodule to be hyperintense. With enhancement, the solid nodular component of the tumor usually enhances brightly and homogeneously.

Pathology

The gross and histologic pathology of pilocytic astrocytomas are briefly discussed below.

Gross findings

The gross appearance of pilocytic astrocytomas is typically that of a well-circumscribed mass, except in those tumors arising in the region of the third ventricle and some lesions in the cerebellum, in which the tumors may take on an infiltrative appearance. As described earlier, tumors arising in the cerebellum and cerebrum may be associated with prominent cysts filled with proteinaceous fluid, with the tumor represented by a nodule along the wall. These tumors appear to have a preference for arising along the midline or adjacent to the lateral ventricles.

Histologic findings

Histologically, the pilocytic astrocytoma is composed of elongated bipolar astrocytes with round to oval nuclei that are most frequently monotonous. These cells are most commonly encountered in the cerebrum, where the stout tumor cells are arranged in irregular fascicles associated with eosinophilic granular bodies and Rosenthal fibers in the tightly packed tumors, as depicted in the image below.

This pattern is commonly interrupted by microcysts surrounded by spindle cells oriented haphazardly toward the cyst with loose fibrillar tails extending into the watery filled microcysts, as illustrated below.

This alternating pattern of compact and microcystic regions is what is referred to as a biphasic growth pattern in these tumors. However, other histologic variations occur, including regions reminiscent of oligodendroglial differentiation and regions with an infiltrative appearance, a feature commonly encountered in tumors arising in the cerebellum.

The aforementioned eosinophilic granular bodies are membrane-bound, anuclear collections of bubbly eosinophilic material that may be encountered in pilocytic astrocytomas but are not unique to the tumor and that may also be found in pleomorphic xanthoastrocytoma; similarly, protein droplets, which are balls of eosinophilic solid proteinaceous material are encountered in this tumor.

It is also important to recognize that some examples of pilocytic astrocytomas exhibit unexpected degrees of pleomorphism that may be associated with microvascular proliferation and infarctlike necrosis. These findings are of no prognostic importance.

Immunohistochemistry

Pilocytic astrocytomas are strongly and diffusely immunoreactive for glial fibrillary acidic protein (GFAP) and S100. Rosenthal fibers are immunoreactive for α-B-crystallin.

The Ki-67 labeling index is variable, with those tumors arising in children younger than 12 years generally showing a higher labeling index than those of older individuals. Although studies indicate that Ki-67 labeling index is not associated with overall survival, ^[9] one study suggested that labeling indices greater than 2% may be associated with a short progression free survival. ^[10] A study indicates that the immunohistochemical demonstration of a high labeling index for insulinlike growth factor 2 mRNA binding protein 3 is indicative of an aggressive tumor with a shortened disease-free interval. ^[11]

Molecular pathology

Pilocytic astrocytomas of the optic nerve are commonly encountered in neurofibromatosis type 1. ^[12] The vast majority of tumors exhibit a normal karyotype, and one study, using comparative genomic hybridization, found an increased incidence of gains of chromosome 19p. ^[13] Aldehyde dehydrogenase 1 family member L1 (ALDH1L1) has been found to be underexpressed in clinically aggressive pilocytic astrocytomas. ^[14] Relatively recently, it was found that pilocytic astrocytomas exhibit a duplication at band 7q34, containing a BRAF-KIAA1549 gene fusion in the majority of cases. ^{[15, 16]} Korshunov and colleagues demonstrated that by testing for the BRAF fusion protein (hyperexpressed in pilocytics) and for isocitrate dehydrogenase 1 (IDH1) (wild type in pilocytics), one could differentiate pilocytic astrocytomas from diffuse fibrillary astrocytomas. ^{[17, 18]}

A small minority of pilocytic astrocytomas, particularly those of extracerebellar origin, demonstrate a BRAFv600e mutation. ^[19]

NTRK2 gene fusions (gene arrangements, copy number alterations) appear to be uncommon in pilocytic astrocytomas, regardless of patients' clinincopathologic and molecular features. ^[20]

Prognosis

The overall survival with pilocytic astrocytoma is quite good, with 5-year survival rates of 89% and 10-year survival rates of 85% ^[8] ; exceptionally prolonged survival has been described. ^[21] Because the tumor arises in the midline and the periventricular regions, both morbidity and mortality are related to site of origin and effects of therapy. Tumors of the optic nerve more commonly infiltrate and are less amenable to surgical extirpation. The description of a high labeling index for IMP3 has been noted to be an independent predictor of disease-free survival. ^[11]

Prognostically unfavorable sites include the optic chiasmatic location, tumors that allow only partial resection, and the pilomyxoid variant. Rare tumors disseminate along the cerebrospinal fluid (CSF) pathways while retaining their typical histopathologic appearance. Exceptionally rare instances of malignant transformation have been recorded and have thus received the designation as anaplastic pilocytic astrocytoma. Radiation has been implicated in these instances. ^[22]

Background

The pilomyxoid astrocytoma is a tumor of young children, described as a grade 1 tumor by the World Health Organization. ^[23] It is most commonly encountered in the first 5 years of life as a circumscribed tumor in and around the optic tract to include the chiasm and hypothalamus. Although these tumors may be recognized in the reports of Janisch and colleagues ^[24] and Cottingham et al, ^[25] Tihan et al put forth the contention that the pilomyxoid astrocytoma is a variant of pilocytic astrocytoma with an aggressive clinical course. ^[7]

Subsequent to the Tihan et al report, the scientific literature has supported the idea that this tumor is more aggressive when compared with age-matched children bearing pilocytic astrocytomas. ^[26] Furthermore, the literature has recorded examples of morphologically similar tumors arising in locations beyond the hypothalamic/chiasmatic regions, tumors arising in older individuals, and tumors with recurrences that appeared more typical of the pilocytic astrocytoma. ^[27] These latter tumors challenge the nosology of this entity, raising the issues of cell of origin, biologic significance of the morphology, and prognostic and therapeutic significance. In a redress to these questions, Ceppa and colleagues, including Tihan, indicated that "questions remain regarding the 'sufficient' criteria for pilomyxoid astrocytoma." ^[28]

Regardless of the outstanding issues, the vast majority of pilomyxoid astrocytomas arise in children younger than 4 years; when these tumors occur in the hypothalamus/chiasmatic region, they confer a more aggressive course, at least among this subset of patients. ^[28]

Pathophysiology

No familial tendency or inherited genetic syndrome has been described in the development of pilomyxoid astrocytomas. In a review of 100 central nervous system (CNS) tumors arising in people with neurofibromatosis type 1, two individuals were diagnosed with pilomyxoid astrocytomas—which contrasts with the 49 people who were diagnosed with typical pilocytic astrocytomas, a tumor known to arise in this setting. ^[6]

Epidemiology

Insufficient data are available to indicate a typical incidence, racial predominance, and/or sexual predominance. However, pilomyxoid astrocytomas, as originally described, affect children in the first 5 years of life. Although cases in older persons have been described, such examples are less well studied from a clinicopathologic perspective regarding survival, recurrence, and morphologic appearance.

Clinical Features

Pilomyxoid astrocytoma arising in the third ventricle most commonly presents with symptoms of increased intracranial pressure or parenchymal compression, including failure to thrive, developmental delay, altered level of consciousness, vomiting, feeding difficulties, and generalized weakness. ^[26] In infants, rising intracranial pressure may present as an increase in head circumference, diastasis of the sutures, and a bulging fontanelle. Later in the disease course, children can become irritable and lethargic with altered vital signs, such as bradycardia and slowed respiration. Local symptoms, such as visual disturbances and hypothalamic dysfunction, may also be encountered in older patients.

There are no specific laboratory tests that are helpful in making a diagnosis of pilomyxoid astrocytoma.

Imaging Studies

Pilomyxoid astrocytomas are well-circumscribed tumors that most commonly originate in the hypothalamic/chiasmatic region. Radiographically, the tumors lack both peritumoral edema and central necrosis. Mass effect and hydrocephalus are also common. Approximately 50% of the tumors will appear solid and half cystic.

The majority of these tumors will appear to be hyperintense on both T1- and T2-weighted magnetic resonance images. All tumors will appear hyperintense on fluid-attenuated inversion recovery (FLAIR) sequences and hypointense on diffusion-weighted imaging (DWI). With contrast administration, the majority will enhance heterogeneously and many will enhance homogeneously. ^{[26, 29]}

Pathology

Histologically, the tumor has a resemblance to the pilocytic astrocytoma with elongated bipolar cells, but pilomyxoid astrocytoma is distinguished by its intercellular myxoid content and the perivascular or angiocentric radial orientation of the tumor cells, ^{[7, 23, 30]} a pattern reminiscent of an ependymoma. ^[31] A typical pilomyxoid astrocytoma lacks eosinophilic granular bodies and Rosenthal fibers, ^[23] but some tumors reportedly will merge with the more classic pilocytic appearance either in the primary or in its recurrence. ^[28]  There may be a blue myxoid substance in the background. ^[23] Mitotic figures are rare, although Ki-67 labeling index can be brisk. See the images below.

Prognosis

In the original report by Tihan and colleagues, progression-free survival at 1 year was 38.7% compared with 69.2% for a control group of 13 classic pilocytic astrocytomas in the same age range and location. ^[7] In a subsequent comparative study, the mean progression-free survival times for those with pilomyxoid astrocytoma was 26 months; for the pilocytic astrocytoma group, it was 147 months. ^[26] The mean overall survival times for the pilomyxoid astrocytoma group has been reported as 63 months, whereas for the pilocytic astrocytoma group, it was 213 months. ^[26]

Background

The pleomorphic xanthoastrocytoma (PXA) was originally described as a xanthosarcoma, ^[32] until it was recognized that a group of these tumors was not only slowly growing, but also productive of glial fibrillary acidic protein (GFAP). As a result of these findings, the tumor was set aside as a subset of astrocytomas and given the name pleomorphic xanthoastrocytoma, which reflects its histologic appearance of large, often multinucleated cells with abundant foamy cytoplasm and astrocytic phenotype.

At first, pleomorphic xanthoastrocytomas were proposed to be benign tumors akin to the pilocytic astrocytoma as grade I. ^[32] However, subsequent follow-up of these tumors proved that up to 20% of pleomorphic xanthoastrocytomas had a tendency to recur over the years and progress to either infiltrative tumors or more rapid recurrence, a tendency that has been recognized by the World Health Organization (WHO) with a grade II designation. ^[12]

Pathophysiology and Epidemiology

Little is known of the pathologic mechanisms involved in the etiology of pleomorphic xanthoastrocytoma, which accounts for less than 1% of all astrocytic neoplasms. ^{[12, 33]} No racial predominance is known, and no sexual predominance has been noted in the United States. However, pleomorphic xanthoastrocytoma most frequently affects persons in the first 3 decades of life, with an apparent peak in the second decade. ^[12]

Clinical Features

The literature indicates that the majority of patients with pleomorphic xanthoastrocytoma present with epilepsy. Sometimes the prediagnostic period is long, up to years in length, but most patients are diagnosed within 6 months of developing seizures. Other patients present with headaches, but localizing neurologic symptoms are rare. The tumors most commonly arise in the temporal or frontal lobes, but lesions arising in all regions of the central nervous system (CNS) have been described. ^[34]

Imaging Studies

There is a reported spectrum of radiographic manifestations of pleomorphic xanthoastrocytoma from a cystic mass with a mural nodule to a solid tumor that is adherent to the brain surface. ^[35] Dural attachment may be associated with meningeal thickening. The nodule in the cystic lesions is superficial and subpial in location. The cyst may have a diffusely infiltrating interface with the adjacent parenchyma. ^[36]

Pleomorphic xanthoastrocytoma is a slow-growing tumor with secondary findings of indolent growth, including scalloped erosion of the inner table of the calvarium. On computed tomography (CT) scans, pleomorphic xanthoastrocytomas can be cystic (43%) or solid (15%). ^[37] The cystic portion of the tumor is of low density, and the solid component demonstrates mixed density. The mural nodule is hypodense and enhances strongly with contrast. The cyst wall may or may not enhance.

Pathology

A brief discussion of the histologic, immunohistochemical, and molecular findings of pleomorphic xanthoastrocytomas is presented below.

Histologic findings

Pleomorphic xanthoastrocytoma is characterized by elongated, spindle-shaped cells with eosinophilic cytoplasm and occasional giant cells, some of which may demonstrate foamy, or xanthomatous change (see the images below). Eosinophilic granular bodies, a degenerative cellular phenomenon of unknown etiology that may also be encountered in pilocytic astrocytomas, are almost always present. ^[38] The majority of these tumors also exhibit pericellular reticulin, a feature that was initially considered diagnostic but was subsequently found to be less reliable. ^[38] The reticulin corresponds to a basal lamina associated with each tumor cell. Lymphocytic and plasma cellular infiltrates are also a common finding.

Immunohistochemistry

Pleomorphic xanthoastrocytoma has a strong tendency to show nonphosphorylated neurofilament protein immunoreactive cells. Indeed, several of these tumors have been described to be a component of gangliogliomas, but it is unlikely that there is more to the relationship between pleomorphic xanthoastrocytoma and ganglioglioma. Neurofilament protein localization may be a useful way to distinguish this tumor from giant cell glioblastomas. ^[39] CD34 has also been seen in these tumors.

Molecular pathology

Pleomorphic xanthoastrocytoma has had reports of chromosomal abnormalities, with the largest study to date finding a loss on chromosome 9 (most commonly affecting 9p21 locus) being the most common but also noting abnormalities including losses (in order of frequency) on chromosomes 17, 8, 18, and 22, with gains (in order of frequency) on X, 7, 9q, 20, 4, 5, and 19. A subsequent study also noted irregular gains and losses on four additional pleomorphic xanthoastrocytomas not necessarily corresponding to the loci noted above. ^[40] BRAFv600e mutations have been described in approximately 50% of pleomorphic xanthoastrocytomas ^{[19, 41]} ; the prevalence of grade II and III tumors is reported to be 60-80%. ^[42] More recent discoveries also include CDKN2A/B deletions and TERTp mutations as among the frequent alterations in pleomorphic xanthoastrocytomas. ^[33]

Prognosis

In general, the prognosis is relatively favorable, but their morphology is heterogenous and biological behavior has the potential for recurrence and dissemination throughout the central nervous system. ^[33]  The BRAF mutation may not significantly impact overall survival (OS) and progression-free survival (PFS). ^[42] However, grade III pleomorphic xanthoastrocytomas are associated with a worse OS and PFS than their grade II counterparts. ^[42]

One series of 72 patients with pleomorphic xanthoastrocytoma indicated a 5-year survival rate of 72% and a 10-year rate of 61%. ^[38] Aggressive features including large nuclei, brisk mitotic activity, and regions of tumoral necrosis are occasionally encountered in these tumors. A brisk Ki-67 labeling index has a poor prognosis. ^{[38, 43, 44]}

The diagnosis of pleomorphic xanthoastrocytoma with anaplastic features remains a controversial designation, as there is insufficient experience to adequately identify it according to the WHO guidelines. However, the WHO notes that tumors exhibiting 5 or more mitoses per 10 high-power fields, necrosis, and a relative increase in small cells are features more commonly encountered in recurrent tumors. ^{[12, 45]} No specific WHO grade has been assigned to such variants of this tumor. ^[12]

Background

The desmoplastic astrocytoma (DA) is a tumor of infants that may be found throughout the central nervous system (CNS) but that has a preference for the supratentorial regions. ^[46] This tumor and the closely related mixed tumor, the desmoplastic infantile ganglioglioma (DIG), are characterized by an attachment to the dura, cystic features, as well as by a dense collagenous stroma in which are entrapped fibrillar cells with glial and, sometimes, neuronal, immunohistochemical features. ^[47]

Clinical Features

Desmoplastic astrocytomas and desmoplastic infantile gangliogliomas are rare tumors largely confined to infants. ^[48] They typically seem to evolve rapidly as large supratentorial complex tumors adherent to the dura and producing significant mass effect. ^{[46, 49]} Neurologic symptoms and signs affecting infants with desmoplastic astrocytomas can be either general or focal and reflect the location of the tumor.

The most common anatomic site of origin for desmoplastic astrocytoma is a frontoparietal location with attachment to the dura and an association with a prominent cyst. Increasing head circumference, bulging fontanelles, and downward deviation of the eyes are common manifestations. Nonlocalizing symptoms are typical with lethargy and irritability, and seizures, although cranial nerve palsies are also encountered.

The incidence of these tumors is exceedingly rare and no useful epidemiologic data are available; no known racial or sex predominance is known, although the tumor most frequently affects persons in their first 2 years of life, and as such, desmoplastic astrocytomas are considered tumors of infancy. However, recurrences and rare initial presentation in adults can occur later in life. ^{[49, 50]}

Imaging Studies

Radiographically, desmoplastic astrocytomas are characterized by a dense, plaquelike attachment to the dura, bright enhancement by both computed tomography (CT) scanning and magnetic resonance imaging (MRI) (see the following image), and frequently, an associated cyst. ^[47]

Desmoplastic infantile gangliogliomas can present with large size, often associated with cerebral shifts and even herniations. ^[51] In fact, the radiographic appearance is so characteristic as to be diagnostic in infants. ^[52] The tumor is a large, multilobulated mass with one or more cysts that is adherent to the dura. Mass effect is related to its enormous size due to the cystic expansion. Solid regions are isodense to slightly hyperdense on CT scans, whereas MRI T1-weighted images exhibit isointensity to gray matter, and T2-weighted images are heterogeneous. Fluid attenuated inversion recovery (FLAIR) images show the mass to be hyperintense.

Pathology

Gross findings

Desmoplastic astrocytomas and desmoplastic infantile gangliogliomas raise the issue of meningioma due to their broad-based dural attachments, tough rubbery consistency (owing to their collagenous contents), and their sharp demarcation from the underlying brain parenchyma.

Histologic findings

Desmoplastic infantile gangliogliomas can present with histologically disturbing features that may be easily mistaken for a primitive neuroectodermal tumors (PNETs). Indeed, desmoplastic infantile ganglioglioma was originally identified by Van den Berg et al from a group of tumors previously published as desmoplastic neuroblastomas with divergent differentiation. ^[49] Proliferation indices, such as by Ki-67, can be helpful in that even the small cell components of desmoplastic infantile gangliogliomas are less than 10% in the proliferation index, whereas the more mature regions such as typify the desmoplastic astrocytoma are significantly lower. ^[53]

Histologically, the tumor exhibits striking variability, ranging from intense hypercellularity of a small blue cell tumor to the sparse, fibrotic appearance of a fibroblastic meningioma (see the images below). Embedded within the spindle-shaped cells of the latter appearance are glial fibrillary acidic protein (GFAP)–immunoreactive astrocytes and an occasional synaptophysin immunoreactive neuron. ^[54] The finding of regions with embedded astrocytes may raise the issue of gliosarcoma; however, the Ki-67 labeling index of this portion is low.

Desmoplastic infantile gangliogliomas may show sharp transitions between the densely hypercellular regions and the fibrotic regions. Other regions are typical of ganglion cell tumors, with protein droplets and eosinophilic granular bodies present. ^[53] This histologic variability may not be evident in small biopsies of tumors arising in eloquent areas such as the brainstem, and they may not become apparent until later biopsies suggest a completely different diagnosis.

The juxtaposition of spindle-cell features adjacent to primitive neuroectodermal tumor–like features should raise the possibility of desmoplastic infantile ganglioglioma. Similarly, examples with pseudopalisading necrosis have been described in otherwise typical examples of desmoplastic infantile gangliogliomas without evidence of aggressive behavior following resection. ^[53]

Immunohistochemistry

Immunohistochemistry can be useful in characterizing these lesions as astrocytes, and neurons may be found embedded within collagenized spindle cells. ^[55] The desmoplastic regions are characterized by pericellular reticulin. ^[49] Ki-67 labeling indices are typically low and do not appear to exceed 10%, even in the most hypercellular regions. ^[55] Tumors with higher labeling indices have been reported to be associated with a poor prognosis and an anaplastic histologic appearance, ^[56] although apparently this is not completely reliable. ^[57] See the following images.

Molecular pathology

Little is known of the molecular pathology of desmoplastic astrocytomas/desmoplastic infantile gangliogliomas. ^[58] One report indicated EGFR and MYCN amplification in separate tumors, ^[59] but no p53 mutations have been identified. ^[60] Few cases have been studied by comparative genomic hybridization, with no common genetic events identified. ^[60] One case has been reported in a child with neurofibromatosis type 1. ^[14]

Prognosis

Despite the small cell histologic appearance of desmoplastic infantile gangliogliomas, both desmoplastic astrocytomas and desmoplastic infantile gangliogliomas are assigned a World Health Organization (WHO) grade I and appear to have little mortality if surgically removed. ^[12] Indeed, despite their large size, desmoplastic infantile gangliogliomas are amenable to surgical cure, if location permits, even in the presence of high mitotic count. ^[49]

Reports of recurrence with relatively short survivals have been recorded among tumors with significantly elevated Mib1 labeling indices and anaplastic features, especially when incompletely resected. ^[56] However, even in cases demonstrating rapid recurrence or anaplastic variants, as well as among incompletely resected tumors, prolonged stable disease have also been described. ^[56]

Background

The chordoid glioma is a rare, intraventricular tumor of the third ventricle, so named because of its resemblance to the chordoma, with glial fibrillary acidic protein (GFAP)–positive epithelioid cells arranged in cords and clusters in a mucinous background. Although this tumor was officially designated as a new entity in 1998 by Brat et al, ^[61] chordoid glioma was likely first described by Wanschitz et al in 1995 as a meningioma with GFAP expression. ^{[12, 61, 62, 63]} There are approximately 50 cases reported in the literature. ^[64]

The tumor generally arises as a slow-growing, noninvasive mass in the anterior portion of the ventricle and has an overall low-grade appearance histopathologically, lacking mitoses, vascular proliferation or necrosis. However, chordoid glioma is categorized as a grade II tumor, ^[65] because its location within the ventricle and attachment to hypothalamic and suprasellar structures adjacent to the third ventricle often results in an incomplete resection. ^{[12, 66]}

Pathophysiology

The origin of chordoid gliomas is still unknown. ^[67] Ultrastructural studies have revealed abnormal cilia and apical microvilli, suggesting a possible ependymal origin. ^{[68, 69]} Genetic analysis of four chordoid gliomas by conventional comparative genomic hybridization detected no chromosomal imbalances. Molecular characterization of these tumors revealed no abnormalities in TP53, CDKN2A, EGFR, CDK4, or MDM2, all important in the pathogenesis of astrocytomas, indicating that the pathogenesis of chordoid gliomas involves unrelated pathway(s). ^{[10, 70]}

A study of five chordoid gliomas by Horbinski et al using the method of fluorescent in situ hybridization (FISH) revealed no EGFR amplification. ^[68] FISH studies using specific probes for 9p21 and 11q13 found consistent losses at both loci in all five tumors studied. No TP53 mutations were identified in these cases. ^[63]

More recently, a study of 16 patients with chordoid glioma of the third ventricle who presented with histories of headache and vision loss found PRKCA mutation in 14 patients and BRAFV600E mutation in 2 patients.98 

Epidemiology

Chordoid gliomas are generally found in adults, with a mean age presentation of 46 years, and the majority of tumors arise in patients aged 35-60 years. ^[12] There is a female predominance of 2:1. Only two cases have been reported in children, one of which occurred in a juxtaventricular location and is the only reported case that did not present in the anterior third ventricle. ^{[13, 71]}

Clinical Features

Clinical symptoms generally manifest over a period of months or years and reflect the development of obstructive hydrocephalus or invasion/compression of normal structures around the third ventricle. ^{[61, 69]} Reported symptoms include headache, nausea, visual disturbances, ataxia, endocrine dysfunction, memory loss, and psychiatric abnormalities. ^{[12, 72]}

There are no laboratory tests that are specific to a diagnosis of chordoid glioma. However, in the setting of panhypopituitarism, chordoid glioma should be considered as part of the differential diagnosis.

Imaging Studies

Chordoid gliomas typically range in size from 1.6 to 4 cm in the greatest dimension, with a mean diameter of 2.8 cm. On imaging, these tumors are generally solid, round to ovoid, well-circumscribed masses, involving the anterior third ventricle and hypothalamus. ^{[73, 74]} Most of these tumors exhibit physical continuity with the hypothalamus, and some appear to have an intrinsic hypothalamic component, suggesting a potential origin for this neoplasm. ^[7]

Magnetic resonance imaging (MRI) of the brain generally shows the tumor to be isointense on T1-weighted images and slightly hyperintense on T2-weighted images. With the administration of gadolinium, the chordoid glioma is intensely and uniformly contrast-enhancing. ^{[64, 74]} Mass effect is not uncommon and is generally distributed symmetrically, causing vasogenic edema with T2-weighted hyperintensity in the adjacent compressed structures, such as the optic tracts, basal ganglia, and internal capsules. ^[74]

Gadolinium warning

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the Medscape topic Nephrogenic Systemic Fibrosis. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans.

NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

Pathology

The histologic and immunohistochemical findings of chordoid gliomas are briefly discussed.

Histologic findings

Chordoid gliomas exhibit cords and clusters of epithelioid tumor cells in a mucinous, often vacuolated, periodic acid Schiff [PAS]–positive background. In areas where the chordoid arrangement is less prominent, the tumor cells can form solid sheets, with decreased extracellular mucin. The cells themselves are generally oval, with a large quantity of eosinophilic cytoplasm, moderate in size, and relatively uniform in appearance. The tumor has a low grade histologic appearance, without nuclear pleomorphism or mitotic activity. A stromal lymphoplasmacytic infiltrate and Russell bodies are often associated with these tumors, providing a helpful clue in the classification of chordoid gliomas and distinguishing them from other gliomas arising in the hypothalamus. ^{[12, 75]} See the images below.

Immunohistochemistry

Immunohistochemical stains also help to identify these tumors, as chordoid gliomas generally exhibit a strong, diffuse reactivity for GFAP, vimentin, and CD34. ^{[75, 76]} Additionally, the tumors invariably show immunoreactivity for epidermal growth factor receptor (EGFR) and schwannomin/merlin with no nuclear accumulation of p53, p21 (Waf-1) or MDM2 proteins. ^[71] S100 immunoreactivity is variable, and epithelial membrane antigen (EMA) can be focally positive, but it is generally more conspicuous in stromal plasma cells.

Proliferation measures reveal a proliferation index consistent with that of other low-grade gliomas, with MIB-1 rates consistently lower than 2%. Neuronal markers, such as synaptophysin and chromogranin, are characteristically negative, ^[70] though there are published examples of focal synaptophysin reactivity. ^[63]

Molecular studies have not identified consistent abnormalities, though the number of tested cases are few. ^[63]

Prognosis

The location of chordoid gliomas and the intimate association with the hypothalamic and suprasellar structures of necessity affects the surgical approach and ultimate prognosis. Gross total resection is the treatment of choice, with no recurrence reported after macroscopically complete resection; unfortunately, this procedure is considered too risky in a significant proportion of patients.

In a literature review of 51 reported cases of chordoid glioma, only 23 patients received a gross total resection. The majority of the remainder (22 patients) received subtotal resections. ^[64] Postoperative follow-up information was available on 38 patients, revealing an overall 32% mortality rate in the immediate postoperative period; the mortality rate was higher in patients who received total resections (8/22) than in those who underwent subtotal resections (4/23). ^[64] Nonfatal complications included hypothalamic disorders such as transient diabetes insipidus, hypotension, hypothermia, as well as mental alterations.

Background

Pituicytoma is defined as a solid, circumscribed, low-grade, spindle-cell astrocytic tumor of adults having an origin in the posterior pituitary or its stalk. Also known as infundibular astrocytoma (infundibuloma), these tumors are considered by the World Health Organization (WHO) to be grade I.

Although some authors have noted that pituicytomas may be indistinguishable from the classic pilocytic astrocytoma encountered elsewhere in the brain, Brat et al pointed out that their collection of tumors lacked the biphasic compact and microcystic patterns, Rosenthal fiber accumulation, and eosinophilic granular bodies that typify the classic pilocytic type. ^[77] In Brat et al's large series, all were "solid architecturally and consisted of elongate, bipolar spindle cells arranged in interlacing fascicles and/or a storiform pattern." ^[77] Of five cases in which adjacent normal tissue was seen, no infiltration was noted.

A common clinical problem with pituicytomas is third ventricular occlusion. Thus, an origin in the neurohypophysis cannot be established, and it becomes impossible to distinguish these tumors on radiographic examination from: (1) the chordoid glioma of the third ventricle and (2) the pilocytic astrocytoma of the optic chiasm and nerves. However, Lopes and colleagues noted that the downward infiltration of a centrally located glioma through the stalk and into the posterior pituitary is common among pituicytomas and very uncommon in other gliomas. ^[78]

Pathophysiology

Pituicytomas are thought to originate from specialized glial cells of the posterior lobe called pituicytes ^{[79, 80, 81]} and correlate with their origin in the pituitary stalk and neurohypophysis. However, a study of four ependymomas of the sella region suggested a commonality with the pituicytoma and raised the issue of an alternative cell of origin, the ependymal pituicyte. ^[81]

Epidemiology

Insufficient data are available to indicate a typical incidence and/or a sexual predominance of pituicytomas; however, these tumors are exceedingly rare, and one report indicated a slight male predominance. ^[77] The tumor arises in adults, and a tumor was incidentally discovered at autopsy, as it was asymptomatic during life. ^[82]

Clinical Features

Arising in and around the infundibulum, the signs and symptoms of pituicytoma are secondary to a mass effect, such as encountered with Rathke cleft cyst, craniopharyngioma, and colloid cyst. These symptoms include visual disturbances, hypopituitarism, and headache. ^{[83, 84]}

There are no specific laboratory tests that are helpful in making a specific diagnosis of pituicytoma, although they are in the differential diagnosis of tumors of the sellar and suprasellar region causing hypopituitarism and/or hyperprolactinemia.

Imaging Studies

Imaging features of pituicytomas are nonspecific, but magnetic resonance images (MRIs) combined with angiograms are critical for surgical planning. ^[85] The tumors are isointense on T1-weighted images and enhance homogeneously with gadolinium administration. See the image below.

Necrosis, calcification, and flow voids are not found. The example described by Gibbs and colleagues on angiography exhibited a delayed blush and was extremely vascular. ^[85] To the researchers, the prominent arterial feeding from the superior hypophyseal arteries, which supplied both the diaphragma sella and the pituitary stalk, and the appearance of a thickened stalk suggested the infundibular origin of the tumor. Gibbs et al suggested that distinguishing this vascular pattern from diaphragma sella meningioma or posterior clinoid meningioma can be problematic, but the absence of external carotid artery dural feeders favors pituicytoma. ^[85]

Gadolinium warning

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the Medscape topic Nephrogenic Systemic Fibrosis. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans.

NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

Pathology

A few pathology features are discussed in brief.

Gross findings

Pituicytomas arises as a solid, well-circumscribed mass along the tract of the neurohypophysis. The tumor is described as firm and rubbery and is often attached to its surrounding structures.

Histologic findings

Pituicytomas are composed of fascicles of bipolar astrocytes that interweave in haphazard patterns. In contrast to the piloid astrocyte, the individually discrete tumor cells are more plump and cluster together in a fashion likened to heads of wheat. Their nuclei are monomorphic, elongated ovals with little atypia or variation in size with only rare mitoses encountered. ^[77] The tumor is distinguished from the pilocytic astrocytoma by a lack of Rosenthal fibers and eosinophilic granular bodies and from the pilomyxoid astrocytoma by its lack of intercellular mucin. The plump cytoplasm may bring to mind the granular cell tumor or the oncocytoma, but its lack of cytoplasmic granularity rules this option out. See the following images.

Immunohistochemistry

Immunohistochemically, all tumors in a series evaluated by Brat and colleagues were strongly positive for vimentin and S-100 protein ^[84] ; eight of the tumors were immunopositive for glial fibrillary acidic protein (GFAP), but the intensity varied from mild to moderate; one tumor was nonreactive. None of the tumors were immunoreactive for synaptophysin or neurofilament protein. Another study indicated that these tumors exhibit strong nuclear staining for the thyroid transcription factor 1 (TTF-1). ^[86]  The World Health Organization classification of posterior pituitary tumors uses TTF-1 positivity as its basis. ^[87]  

MIB-1 labeling indices are uniformly low in these tumors, ranging from 0.5% to 2%.

Ultrastructure

Ultrastructural examination of three lesions revealed bipolar spindle cells containing abundant cytoplasmic intermediate filaments. Scattered intermediate junctions can be identified, and basal lamina is present at the junction of tumor cells with stromal blood vessels but not present between tumor cells. A report by Lieberman and colleagues suggested that a tumor of "identical histology" that they termed a tanycytoma had a tanycytic origin. ^[88]

Prognosis

There are insufficient data concerning the management of pituicytomas, or their long-term prognosis, although there is little reason to suspect that their biology would be any less favorable than that of astrocytomas of the pilocytic type arising elsewhere. In such situations, surgical accessibility, rather than tumor biology, will be the decisive prognostic determinant.

Background

The subependymal giant cell astrocytoma (SEGA) is a tumor that occurs in patients with tuberous sclerosis (TS). ^[89] This tumor is a benign, well-circumscribed grade I proliferation of large cells that occasionally share phenotypic features of both astrocytes and neurons, ^[90] and it arises in the lateral ventricles, becoming clinically evident by obstruction of cerebrospinal fluid (CSF) that results in hydrocephalus and headache. ^[91]

Pathophysiology

Patients with tuberous sclerosis are prone to develop these tumors, whereas subependymal giant cell astrocytomas are rarely, if ever, encountered outside of patients with the disease. Such patients exhibit a germline mutation of either the TSC1 or TSC2, with no clinical distinction evident on which gene is mutated. ^[92] Indeed, the only known risk factor for developing a subependymal giant cell astrocytoma is a germline mutation of one of these two genes.

Epidemiology

Tuberous sclerosis is estimated to occur in 1 in 9,400-10,000 births, ^[93] with variable penetrance rendering accurate rates fallible. The prevalence of subependymal giant cell astrocytomas in the general population of tuberous sclerosis has been estimated to be 1:20,000 to 1:150,000. ^[94] No racial or sexual predilection is known, and the tumor is most commonly diagnosed during the first 2 decades of life.

In a study of data from the TuberOus SClerosis registry comprising information from 170 sites in 31 countries, investigators found SEGA in 25% of patients (554 of 2216), of whom 42.1% were symptomatic. ^[95] The median age at diagnosis was 8 years, with 18.1% diagnosed after age 18 years (age range, < 1 year to 51 years). This tumor also occurred more often in those with TSC2 versus the TSC1 variants by nearly 2.6-fold.

Clinical Features

As subependymal giant cell astrocytomas are limited to persons with tuberous sclerosis, it is difficult to dissect the manifestations of these tumors away from those of its host disease. Patients with tuberous sclerosis may manifest in a variety of ways, including infantile spasms, autism spectrum disorder, or mental retardation. ^[94] Epilepsy is manifest in up to 85% of these patients. In a report of 23 patients with subependymal giant cell astrocytoma, the majority of patients presented with visual disturbances (82.6%) in the form of decreased vision (60.8%) and blindness (21.7%), generalized tonic clonic seizures (43.4%), and focal motor seizures (4.37%). ^[96] Clearly, hydrocephalus is a manifestation of a large obstructive subependymal giant cell astrocytoma.

The incidence of clinically significant subependymal giant cell astrocytomas in patients with tuberous sclerosis is low. In a review of 134 patients with tuberous sclerosis, 11 (8.2%) had undergone resection of a pathologically confirmed subependymal giant cell astrocytoma. ^[91] Of these, 4 individuals were asymptomatic, whereas the other 7 patients presented subacutely with fatigue, decreased appetite, headache, increased seizure frequency, visual field deficit, cognitive decline, or behavioral problems. ^[91]

The recommendation of this study was that the clinical diagnosis of subependymal giant cell astrocytoma should be reserved for subependymal lesions in patients with tuberous sclerosis that are associated with symptoms, papilledema, or radiologic evidence of hydrocephalus or interval growth. ^[91] In addition, annual screening by magnetic resonance imaging (MRI) with or without contrast is indicated until at least age 21 years, even if subependymal nodules are absent on initial imaging. A diagnosis of subependymal giant cell astrocytoma or probable subependymal giant cell astrocytoma warrants more frequent monitoring or surgical intervention. ^[91]

There are no specific laboratory tests that are helpful in making a diagnosis of subependymal giant cell astrocytoma.

Imaging Studies

Computed tomography (CT) scans without contrast reveal the tumors to be either iso- or hyperdense, with occasional tumors exhibiting cystic change. Nearly all lesions will exhibit calcifications, and all subependymal giant cell astrocytomas exhibit homogeneous enhancement. On T1-weighted MRI without contrast, the tumors are isointense or slightly hyperdense and homogeneous. With gadolinium, the tumors will homogeneously enhance (see the image below). ^[97]

In a review of 19 patients with symptomatic subependymal giant cell astrocytoma, 1 patient had ventricles of normal size, 8 had discrete ventriculomegaly for their age, 5 had moderate hydrocephalus, and 5 had major hydrocephalus before surgery. ^[98] The distinction between subependymal nodule and subependymal giant cell astrocytoma appears to be radiographic size, with the cut-off being 1 cm (subependymal nodule, smaller; subependymal giant cell astrocytoma, larger). ^[99]

Gadolinium warning

Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the Medscape topic Nephrogenic Systemic Fibrosis. The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or MRA scans.

NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

Pathology

A brief review of the gross, histologic, and immunohistochemical findings of subependymal giant cell astrocytomas is presented.

Gross findings

Grossly, the tumors are well circumscribed, exophytic lesions that may be uniformly gray white or mottled pink on cut section.

Histologic findings

Subependymal giant cell astrocytoma are histologically identical to the subependymal nodules, or so-called candle drippings, which are also found intraventricularly and constitute one of the diagnostic criteria of tuberous sclerosis. ^[99] Indeed, subependymal giant cell astrocytoma is distinguishable from subependymal nodules only by a propensity to grow, the biologic events inducing such a change in growth is unclear, although some tumors show loss of heterozygosity for either the TSC1 or TSC2 gene. ^{[89, 96]}

Microscopically, both subependymal giant cell astrocytomas and subependymal nodules may be composed of large ganglioid or balloon cells ranging in size from gemistocytes to balloon-shaped ganglion cells. Prominent nucleoli are a rule. Spindle-shaped cells may also be encountered and predominate in some tumors. ^[89]

The tumor cells may appear to intertwine in compact arrangements and suggest a more aggressive gemistocytic astrocytoma. The location in the lateral ventricle and the diagnosis of tuberous sclerosis should urge caution in the designation of a grade higher than I. Even Ki-67 labeling indices as high as 10% have been associated with prolonged stable disease after resection. ^[98]

Immunohistochemistry

Immunohistochemically, the tumor cells will exhibit a heterogeneous immunoreactivity with both the astrocytic marker glial fibrillary acidic protein (GFAP) and the neuronal markers neurofilament protein and synaptophysin. ^[96] The phenotypic ambiguity also extends to the cortical tubers with their balloon cells and less prominent gemistocytic type cells. ^[89] See the following images.

Prognosis

The overall survival in patients with subependymal giant cell astrocytomas is excellent even with partial resection. The tumors are slow growing and may assume prolonged stability.

The authors gratefully acknowledge the significant input of Drs. Thomas Cummings, Linda Gray, and Allan Friedman. Dr. McLendon is supported by the Pediatric Brain Tumor Foundation, Pediatric Brain Tumor Consortium, NIH/NINDS 5P50-NS-20023-26 and 5 R01 CA118822-05.