Dysembryoplastic neuroepithelial tumor
Dysembryoplastic neuroepithelial tumors are rare, indolent, low-grade tumors found in children and young adults. Most commonly affecting the temporal
Mar. 22, 2021
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Pleomorphic xanthoastrocytoma (PXA) is a rare subtype of low grade glioma that affects predominantly a pediatric and young adult population. Theses tumors frequently arise in the temporal lobes and often present with seizures. This review covers the latest developments in our understanding of pleomorphic xanthoastrocytoma, including its more aggressive anaplastic variant, the ability of low grade form to transform into a high grade form, and the new efforts to classify unique molecular alterations.
• Pleomorphic xanthoastrocytoma (PXA) is a WHO grade 2 neoplasm that is most often diagnosed in children and young adults.
• An anaplastic variant exists with poorer overall prognosis; furthermore, classic pleomorphic xanthoastrocytoma (WHO grade 2 PXA) has the potential for malignant transformation into a high grade glioma (WHO grade 3 PXA).
• WHO 2016 criteria define anaplastic pleomorphic xanthoastrocytoma by the presence of 5 or more mitotic figures per 10 high-power microscopic fields (0.23 mm2 field size). Necrosis may be present, but alone does not raise the grade.
• Epilepsy is the most common presentation.
• Pathologic features include nuclear and cytoplasmic pleomorphism, xanthomatous changes, multinucleated cells, presence of pericellular reticulin, and eosinophilic granular bodies (EGBs).
• Pleomorphic xanthoastrocytoma has the potential to spread via the cerebrospinal fluid (CSF).
• WHO grade is a prognostic factor. Presence of V600E BRAF mutation is also a prognostic factor. Extent of resection also has important implications for prognosis.
• The majority of cases have been shown to harbor CDKN2A/B homozygous deletions and MAPK pathway alterations, the most common of which is the BRAF V600E mutation.
Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytic tumor. The first cases were reported in 1973 as meningocerebral fibrous xanthomas, which were presumed to be of mesenchymal origin (26). In 1978, the discovery of the astrocytic marker GFAP allowed Kepes and coworkers to reevaluate these previously reported cases, along with several new ones, and to confirm their astrocytic lineage. Their subsequent report of 12 patients with pleomorphic xanthoastrocytoma was the first to systematically describe its features and to name this new entity—one that reflects its most salient pathologic characteristics (27). An evaluation of a pleomorphic xanthoastrocytoma excised in 1930 from a patient who survived for 40 years has yielded what is apparently the earliest known example of this tumor (12). The recognition of this tumor is critical for patient care because of the difference from the natural history of most astrocytic tumors and the consequent implications for management. Moreover, identification of the targetable molecular alterations can help define subtypes of this tumor and offers new potential treatment avenues.
Pleomorphic xanthoastrocytomas are tumors most often found in supratentorial cortical regions (53; 20), often with a cystic component on imaging, which can make them difficult to distinguish from pilocytic astrocytoma (20) or high-grade infiltrating astrocytomas. Most frequently, temporal lobe is affected, in up to 65% of cases; the parietal lobe next in frequency, and the occipital and frontal lobes less commonly involved (51; 71; 14). They can rarely occur within deeper structures such as the thalamus and the cerebellum (34; 75; 53; 62). Rare primary occurrence in the spinal cord has been reported (07; 78; 18; 08), but 2 unusual cases involving the retina in young women with glaucoma have also been documented (77). There have also been additional reports of multicentric tumor occurrence (46; 63; 78). Pleomorphic xanthoastrocytoma primarily arises in children and young adults, with a median age in the early 20s, but it can also arise in children less than 1 year of age and adults reaching their ninth decade of life (53). There is no significant gender predilection.
Patients most commonly present with seizures, often harboring epilepsy for some time prior to diagnosis, given the more indolent nature of pleomorphic xanthoastrocytoma. The median duration of seizures prior to diagnosis is 3 years (14). One patient had focal epilepsy for 32 years before his tumor was diagnosed (71). Studies of patients in tertiary referral centers have shown that 15% of patients with chronic epilepsy have a brain tumor, with 1% of such tumors being pleomorphic xanthoastrocytomas (47). This is influenced by selection bias. Patients may also present with signs of increased intracranial pressure (nausea, vomiting, papilledema), or focal neurologic deficits, or both (40; 20; 62).
The prognosis for pleomorphic xanthoastrocytoma is generally more favorable than what is observed in patients with high-grade infiltrating gliomas. In the most recently reported series of 67 pleomorphic xanthoastrocytomas, grade 2 tumors had a 60% 5-year progression-free survival and 81% overall survival rates whereas its anaplastic (grade 3) counterparts had a 40% 5-year progression-free survival and 48% overall survival rates, corroborating the data from prior studies (53; 11; 48; 20; 15; 73). Tumor grade (grade 2 pleomorphic xanthoastrocytoma versus grade 3 anaplastic pleomorphic xanthoastrocytoma) has been implicated in the prediction of overall survival, with extent of resection and age also proving significant in a number of studies (53; 11; 20; Oh et al 2015; 62; 73).
Subsequent work that differentiates anaplastic pleomorphic xanthoastrocytoma from conventional grade 2 pleomorphic xanthoastrocytoma revealed that the anaplastic variant more closely resembles higher grade gliomas with less favorable outcomes, even following gross total resection (20; 66; 05; 62). Conventional grade 2 pleomorphic xanthoastrocytoma is known to undergo late recurrences. Kepes’s original report of 12 patients included 1 patient who suffered her first recurrence 18 years after initial resection and subsequently died of a second recurrence 25 years after her original diagnosis. Other studies have reported primary recurrences and survival greater than 25 years following initial diagnosis (53; 20). It has been consistently shown 5-year and IOS rates are significantly different between grade 2 and grade 3 tumors (74; 73). Conventional grade 2 pleomorphic xanthoastrocytoma is also thought to possess the ability to transform into high grade glioma—specifically glioblastoma—even in a delayed fashion from initial diagnosis and treatment, which confers it an extremely poor prognosis similar to de novo glioblastoma (74). It is unclear if this represents a true transformation of pleomorphic xanthoastrocytoma to glioblastoma or an initial misdiagnosis of infiltrating astrocytoma (IDHwt or IDH mutated) to a higher grade tumor.
More recent work has shown that the majority of pleomorphic xanthoastrocytomas harbor MAPK alterations, the most common one being the BRAF V600E mutation, generally estimated to occur in up to 80% of tumors and which is associated with a favorable overall prognosis (09; 30; 20; 66; 62; 72; 73). This represents an exciting avenue for further research given the development of targeted BRAF inhibitors such as dabrafenib and vemurafenib that may augment surgical resection. BRAF mutations have been shown to promote cell proliferation, differentiation, and survival via the RAS/RAF/MEK/ERK kinase pathway (64). It is possible that tumors that histopathologically are consistent with pleomorphic xanthoastrocytoma may be divided into 2 groups, those with MAPK pathway aberrancies and those without.
An 8-year-old girl presented to the clinic with a 3.5-year history of medically refractory partial complex seizures. She had a febrile convulsion at the age of 2, but she developed spontaneous seizures at 4.5 years of age, consisting of 20 to 40 seconds of staring with bilateral arm twitching, sometimes accompanied by chewing movements or picking at her clothes. These occurred daily despite concurrent treatment with 4 anticonvulsants. Neurologic examination was normal. MRI scan demonstrated a 1.5 cm lesion centered in the right superior temporal gyrus, which was felt to be consistent with a cavernous hemangioma. In retrospect, this lesion was thought to have been present on a scan done at 2 years of age, albeit without the dense calcification seen subsequently.
On video-EEG monitoring, her seizures were not well localized. Right temporal resection was performed 6 months after the MRI diagnosis, with pathology demonstrating a pleomorphic xanthoastrocytoma. She was tapered to a single anticonvulsant and remained seizure-free. Eighteen months after her initial resection, a routine follow-up MRI revealed recurrent tumor, which was gross totally resected and pathologically verified. The recurrent mass was partially cystic.
One year after her second resection she was well and without recurrent seizures.
Comment. This case illustrates the typical age, location, and presentation of this tumor in a patient. If her initial febrile seizure is considered symptomatic, the interval between initial symptom and diagnosis was 6 years. It also illustrates the potential for recurrence even with benign histology and no symptoms.
The etiology of this tumor is unknown.
Pleomorphic xanthoastrocytoma is pathologically distinct from other astrocytomas.
Grossly, the tumor is firm and yellow, often with a prominent cystic component filled with golden or xanthochromic fluid (37). Leptomeningeal involvement can be prominent. Histologically, it is moderately cellular, consisting of astrocytes with pleomorphic nuclei, bizarre multinucleated giant cells, and fascicles of elongated or polygonal cells. Many of these cells stain strongly for GFAP, a glial immunohistochemical marker. Lipid droplets are present in many cells (hence, the prefix "xantho-") and are sometimes large enough to force the cytoplasm into a thin rim around the droplet. The nonlipidized portion of the cytoplasm stains positive for GFPA (27; 79). In addition to nuclear pleomorphism, GFAP positivity, and lipidization, the fourth cardinal histologic feature is the presence of reticulin fibers surrounding many of the cells.
This feature led to its initial misclassification as a mesenchymal tumor, as pure gliomas are reticulin-negative. Notably, lipidization and reticulin staining may each be present focally. A less-appreciated finding is that of eosinophilic granular bodies, which are often present (14). A variable amount of lymphoplasmacytic infiltrate may also be present. Mitoses are rare, and necrosis is generally absent in a classic pleomorphic xanthoastrocytoma. Electron microscopic studies demonstrate basal laminae, an ultrastructural correlate of positive immunohistochemical staining for reticulin, between the cells.
A number of cases that have all the cardinal features of classic pleomorphic xanthoastrocytoma, and additionally exhibit anaplastic features such as frequent mitoses, necrosis, nuclear pseudopalisading, microvascular proliferation, and hypercellularity, have been described (42; 01; 20; 05; 66; 62).
Although the original description of this tumor expressly excludes such features, an apparent consensus stipulates that the remarkable pathologic and clinical similarity to more typical xanthoastrocytomas justifies the labeling of these tumors as anaplastic pleomorphic xanthoastrocytomas. The addition of "anaplastic" is important because these tumors tend to behave more aggressively, and treatment plans may be modified (20; 05; 66; 62).
This tumor can sometimes coexist with other types of tumors or developmental malformations. At least 12 cases of pleomorphic xanthoastrocytoma coexisting with ganglioglioma have been documented (32; 36; 57; 54; 06). These neoplasms have a greater tendency to display anaplastic features, and 3 were located in the cerebellum. Some of these exhibited a single tumor histology initially and a second histology on recurrence. One report described a combined xanthoastrocytoma and dysembryoplastic neuroepithelial tumor (DNET) (22), another report described a pleomorphic xanthoastrocytoma as a component of a ganglioglioma (65), whereas another one described an atypical teratoid rhabdoid tumor arising from within a pleomorphic xanthoastrocytoma (69). Pleomorphic xanthoastrocytomas associated with areas of hamartomatous or dysplastic cortex have also been observed (36; 21), and there are 2 separate reports of this tumor arising directly from an area of cortical dysplasia (58; 29).
Pleomorphic xanthoastrocytoma is comprised of cells with a glial and neuronal lineage. One study of 7 xanthoastrocytomas (one of which had concurrent ganglioglioma) found that a small number of cells in each tumor stained positively for both GFAP and a neuronal marker (57). Another study of 40 cases, including 2 with concurrent ganglioglioma, demonstrated staining for GFAP and S-100, another glial marker, in every case, and staining for neuronal markers such as beta-tubulin or synaptophysin in 38% to 73% of cases (15). A later study corroborates this, with the glial marker GFAP and the neuronal marker MAP2 identified in all 6 tumors studied (21).
These reports have fueled speculation about the cellular origin of this tumor. The cells of a xanthoastrocytoma are GFAP-positive and have basal laminae between them. Thus, the prevailing hypothesis has been that this tumor derives from the subpial astrocyte, as these are the only astrocytes that possess a basal lamina (25). That these tumors are nearly always superficial and frequently involve the leptomeninges has supported this hypothesis. The observed association of gangliogliomas and dysplasias, as well as the finding of tumor cells that stain with both glial and neuronal markers has led some to hypothesize that the xanthoastrocytoma derives from a primitive neuroectodermal precursor that can differentiate along either neuronal or glial lines with a marked tendency toward the latter. The formation of the tumor may then be associated with abnormal neuronal migration and a tendency for the dysplastic cells to become neoplastic. Such a hypothesis places pleomorphic xanthoastrocytoma in close relationship to other indolent, mixed glioneuronal tumors associated with epilepsy such as ganglioglioma, dysembryoplastic neuroepithelial tumor, and the subependymal giant-cell astrocytoma of tuberous sclerosis (SEGA) (36; 57).
In the last decade, more has become known about the molecular biology of this neoplasm. Earlier studies failed to consistently reveal aberrations commonly found in other glioma types (24), and in the following years some of those were elucidated. Mutations of the oncogene p53 were found in 2 of 8 (25%) patients in one study (52), but a different group describing 55 tumors demonstrated that only 2% had a high degree of p53 immunostaining (13). Recently, only a single anaplastic pleomorphic xanthoastrocytoma case with a p53 mutation was reported in a cohort of low- and high-grade pleomorphic xanthoastrocytomas (73). A group of 50 xanthoastrocytomas was studied using comparative genomic hybridization, revealing loss of material from chromosome 9 in 50% of cases; this genetic abnormality was not seen in any of a control group of more typical astrocytomas (76). A genetic study of several types of grade I gliomas found a consistent pattern of subtelomeric duplications and deletions among 3 different xanthoastrocytoma cases, involving 10 different chromosomes, that was not seen in any material from pilocytic astrocytomas (16). Finally, a unifying mutation in the BRAF gene, a component of the MAPK pathway, was found and confirmed in the majority (up to 80%) of xanthoastrocytomas (09; 20; 66; 62; 72), including 96% of tumors arising in the temporal lobe (09; 30). Both low- and high-grade PCXA were noted to harbor it. However, its presence was much less frequent in anaplastic pleomorphic xanthoastrocytoma compared to classic grade 2 pleomorphic xanthoastrocytoma. Significantly longer overall survival has been reported in the V600E-mutant tumors (20). The observation that the BRAF V600E mutations occur frequently in several other glial and glioneuronal tumors, including gangliogliomas, pilocytic astrocytomas, chordoid gliomas, and astroblastomas, further supports the hypothesis that pleomorphic xanthoastrocytoma shares a common cell of origin with them (06; 39). Pleomorphic xanthoastrocytomas without the canonical V600E mutation have been shown to harbor other MAPK/ERK signaling pathway alterations, such as mutations and fusions in the RAF family of kinases (08; 73). Another recurrent alteration found in pleomorphic xanthoastrocytomas more recently is homozygous deletion of CDKN2A/B, reported in 60% to 94% of cases (76; Vaubel et al 2018; 55). Interestingly, concurrent MAPK alterations and CDKN2A/B deletions are frequent in epithelioid glioblastoma, pediatric secondary high-grade glioma types, and a recently defined high-grade astrocytoma with piloid features (Kleinschmidt-DeMasters et al 2013; Mistry et al 2015; Alexandrescu et al 2016; Matsumura et al 2017; 60). Some studies also reported TERT promoter mutations and amplifications, more prevalent in recurrent anaplastic pleomorphic xanthoastrocytomas, suggesting that it may be a late genetic event associated with anaplastic transformation and recurrence (55; 73). The definitive prognostic significance of some of these alterations in pleomorphic xanthoastrocytomas still remains to be elucidated in larger studies.
One report found high MIB-1 labeling indices (greater than 2%) in only 21% of 29 cases (14). A flow cytometry study found that xanthoastrocytomas had G2 phase DNA fractions and proliferative indices that were similar to those of high-grade gliomas and significantly higher than those of low-grade astrocytomas (61). However, the DNA fractions and proliferative indices of individual pleomorphic xanthoastrocytomas failed to predict which ones would manifest in recurrence or transformation into more aggressive tumors. An epigenetic study examined methylation in a group of 10 both conventional (n=8) and anaplastic xanthoastrocytomas (n=2), and found that the 2 anaplastic cases had increased methylation of 5 different genes (CD81, HCK, HOXA5, ASCL2 and TES) that have been described in glioblastomas (43). The most recent genome-wide methylation profiling study of 46 cases performed against a comprehensive reference data set assigned 40 of them to the pleomorphic xanthoastrocytoma methylation class, with the remaining 6 cases grouped with the methylation classes of glioglioma, pilocytic astrocytoma, anaplastic pilocytic astrocytoma, or control tissue (73). No prognostic difference was reported in association with the methylation class.
Due to the extreme rarity of this tumor, no precise information regarding its incidence or prevalence is available. It is estimated to account for less than 1% of astrocytic tumors (37), and it represented 1.5% of all pediatric low grade gliomas in one Canadian based population study (33). In the setting of epilepsy referral centers, chronic epilepsy is found to be due to pleomorphic xanthoastrocytoma in roughly 1 out of every 650 cases (47).
No means of preventing these tumors is available. Pleomorphic xanthoastrocytoma is not associated with any other disorders, nor is any particular group (besides the young) known to be at risk. Several case reports of xanthoastrocytomas occurring in patients with Sturge-Weber syndrome or neurofibromatosis are available, but whether these are chance occurrences or harbingers of a population at risk has yet to be determined (50; 35; 61; 28; 63; 67).
The differential diagnosis for this lesion consists of all the other glioma subtypes, including pilocytic, diffuse, and anaplastic astrocytomas, glioblastoma, oligodendroglioma, chordoid glioma and ganglioglioma (17). Leptomeningeal involvement is uncommon in all of these except pilocytic astrocytoma. Dysembryoplastic neuroepithelial tumor may also arise in this location. Meningioma is an important diagnostic consideration as well because of the superficial location of these lesions, which may even produce a "dural tail" on imaging (56). Cavernous hemangioma is another important consideration in an enhancing temporal lobe lesion that fails to change over time. Metastases may produce a similar appearance but usually is not a consideration in the younger age group in which these tumors most frequently arise.
Pleomorphic xanthoastrocytoma are frequently associated with seizures. Epilepsy is the most common presenting sign, likely due to the tumor predilection for the temporal lobes, particularly the cortical (as opposed to subcortical) involvement. It is also possible that the tumor biology and the tumor cell-microenvironment interactions facilitate the epileptogenicity of the tumor.
As with all brain neoplasms, the diagnosis of pleomorphic xanthoastrocytoma generally requires cerebral imaging for identification and localization followed by surgical resection (or biopsy) for pathologic examination. MRI, the imaging modality of choice, often demonstrates a cyst with a mural nodule. The nodule is usually hyperintense on T2-weighted images and hypo- or isointense on T1-weighted images, with gadolinium enhancement in almost all cases (20). CT scan reveals a superficial cortical tumor with a cyst visible in 50% to 60% of cases (51; 71; 14). The tumor itself frequently appears as a solid mural nodule and may be hypodense or isodense to the surrounding brain. Calcification is rare, as is bony erosion. Contrast enhancement is an almost invariable feature, but the pattern of enhancement is variable (40). Edema is not prominent.
Angiography is usually normal, though occasional tumors are hypovascular (51). Pathologic identification of this tumor is usually straightforward because the superficial location allows for gross total or subtotal resection; however, small-volume biopsies may make diagnosis difficult because lipidization and reticulin staining may be patchy, and a single tumor may be histologically variable.
A study of positron emission tomography with fluorodeoxyglucose (FDG-PET), though it included only 3 tumors, showed a strong correlation between the degree of metabolism and the tumor grade (10). The clinical utility of this, however, is unclear.
The mainstay of treatment for this tumor is surgical resection (73). Most evidence supports more favorable outcomes with greater extent of resection (53; 11; 48; 20; 62). Several large case series and reviews have found 5-year progression-free survival and overall survival rates of 28% to 71% and 48% to 81%, respectively, for pleomorphic xanthoastrocytomas of all grades (53; 11; 48; 20), and extent of resection proved significant in a number of studies (53; 11; 20; Oh et al 2015; 73).
The role for adjuvant radiation and chemotherapy remains less clear, with multiple studies unable to reconcile the risks and benefits (42; 51; 68; 04; 44; 31; 49; 59; 45; 53). It appears that pleomorphic xanthoastrocytoma does not frequently possess MGMT methylation, raising doubts about the benefits of temozolomide, despite scattered attempts to use it within the literature. Chemotherapy overall does not appear to have a definitive role in treatment (14; 53; 74), though other reports note some success with carboplatin and vincristine (41; 49).
The use of targeted therapies has been an active area of investigation, particularly in the BRAF V600E-mutant pleomorphic xanthoastrocytoma. The overall survival of patients with V600E-mutant tumors was significantly higher than of those with wildtype tumors, which included 74 pleomorphic xanthoastrocytomas of all grades, 35 of which were treated with adjuvant therapies after recurrence or progression (20). This could be confounded by the increased prevalence of the mutation in the low-grade pleomorphic xanthoastrocytoma group compared to anaplastic cases. Case reports and case series have demonstrated radiographic stability of disease and partial responses in some patients treated with BRAF inhibitors vemurafenib and dabrafenib, which appear to be tolerable in this patient population (03; 19; 70; 38; 02). The VE-BASKET study reported the highest response rate to vemurafenib in low-grade tumors, particularly pleomorphic xanthoastrocytoma (n=7), with promising efficacy data (23).
Seizures in xanthoastrocytoma patients are managed with standard anticonvulsant medications and resection of the lesion. Most case reports indicate that these patients’ epilepsy responds well to tumor resection.
To our knowledge, no cases of pleomorphic xanthoastrocytoma in pregnancy have been reported to date. One patient is reported as having delivered a normal child 4 years after gross total resection and whole-brain radiation for xanthoastrocytoma (32).
No information is available regarding the use of various types of anesthesia in patients with this tumor.
Rimas V Lukas MD
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novocure for speaking engagements, honorariums from Novocure for advisory board membership, and research support from BMS.See Profile
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