Neurosurgery Department, University General Hospital of Alicante, Foundation for the Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Alicante, Spain
Most frequently occurs in children and teenagers.
They usually arise supratentorial > 90 % and superficially from the cerebral hemispheres (upper most sections) of the brain and in contact with the leptomeninges, rarely they arise from the spinal cord.
Histologically, they can be associated with inflammatory cell infiltration and reticulin deposits.
A rich reticulin network surrounds individual cells and small cell nests. Verification of a rich reticulin network is helpful in differentiating PXA from high grade gliomas.
Pilocytic astrocytomas also tend not to display the extent of pleomorphism or reticulin network found in PXA, and are usually less compact in their architecture, frequently exhibiting loose microcystic areas containing cells with typical piloid processes.
MIB-1 index is usually < 1 %.
The term “PXA with anaplastic features” is reserved for those tumors with > 5 mitoses/10 high power fields, and/or necrosis.
Although histology may not reliably predict aggressive behavior in pleomorphic xanthoastrocytomas, the presence of increased mitosis, necrosis, and increased cell proliferation labeling indices may be indicative of a higher grade tumor 1)
They have certain morphological similarities to fibrous histiocytoma (or fibrous xanthoma) of the meninges and brain, namely the occurrence of lipid-laden neoplastic cells and, frequently, a dense reticulin fiber network. The detection of glial fibrillary acidic (GFA) protein in the tumor cells helped to establish its astrocytic derivation, but it has been advanced that, in spite of this agreed observation, the tumor should still be regarded as a fibrous xanthoma of meningeal origin. Although many patients have a long symptom-free postoperative survival, local recurrences at varying intervals after surgery have been noted in some instances. Weldon-Linne et al. first reported that such a recurrence had the morphology of a small-cell glioblastoma. We are reporting three further examples of locally recurrent neoplasms in patients whose original meningocerebral tumors had the typical features of PXA; the recurrences (developing 7 months, 7 years and 15 years, respectively, after surgery) were small-cell glioblastomas. The rich reticulin network present in the initial tumor was mostly lost in the recurrences. This anaplastic evolution further confirms the astrocytic nature of the PXA 2).
PXAs are notable for their biphenotypic glial and neuronal staining pattern.
Expression of neuronal markers, including synaptophysin, neurofilament, MAP2, and Class III b-tubulin, may be detected in individual pleomorphic cells; these markers will also highlight any true ganglion cell component.
CD34 expression is also frequently encountered.
Given their superficial “meningo-cerebral” localization, patients typically present with a history of sudden onset seizures, often of a longstanding nature.a Headaches may also occur.
70% arise as a cyst with solid mural nodule, the remainder being predominantly solid with variable small cystic areas.
Their solid component is iso to hypodense on CT.
Intratumoral hemorrhage or calcifications are uncommon; peritumoral edema may be present, but is typically minimal.
They may rarely show multifocality or leptomeningeal dissemination.
solid component iso to hypointense c.f. grey matter cystic component low signal leptomeningeal involvement seen in over 70% of cases
T1 C+ (Gd)
solid component usually enhances vividly
solid component iso to hyperintense c.f. grey matter
cystic component high signal
on T2 FLAIR sequence, cystic areas show hyperintensity relative to CSF due to higher protein contents little surrounding vasogenic oedema
Main differential diagnosis is that of other cortical tumours, with helpful distinguishing features including:
Ganglioglioma can look very similar contrast enhancement often less prominent calcification in ~50% of cases no dural tail sign.
The analysis of the methylation profile suggested the diagnosis of an anaplastic pleomorphic xanthoastrocytoma and as a differential diagnosis an anaplastic ganglioglioma 3).
Dysembryoplastic neuroepithelial tumors (DNET) contrast enhancement uncommon 'bubbly appearance' common
Oligodendroglioma calcifications common
Desmoplastic infantile ganglioglioma young children dural involvement prominent large often multiple lesions
Epithelioid glioblastoma (eGBM) and pleomorphic xanthoastrocytoma (PXA) with anaplastically transformed foci (ePXA) show overlapping features. Eleven eGBMs and 5 ePXAs were reviewed and studied immunohistochemically. Fluorescence in situ hybridization for EGFR amplification, PTEN deletion and ODZ3 deletion was also performed, with Ilumina 450 methylome analysis obtained in five cases. The average age for eGBM was 30.9 (range 2-79) years, including five pediatric cases and a M : F ratio of 4.5. The ePXA patients had a M : F ratio of 4 and averaged 21.2 (range 10-38) years in age, including two pediatric cases. Six eGBMs and two ePXAs recurred (median recurrence interval of 12 and 3.3 months, respectively). All tumors were composed of solid sheets of loosely cohesive, “melanoma-like” cells with only limited infiltration. ePXAs showed lower grade foci with classic features of PXA. Both tumor types showed focal expression of epithelial and glial markers, retained INI1 and BRG1 expression, occasional CD34 positivity, and lack of mutant IDH1 (R132H) immunoreactivity. BRAF V600E mutation was present in four eGBMs and four ePXAs. ODZ3 deletion was detected in seven eGBMs and two ePXAs. EGFR amplification was absent. Methylome analysis showed that one ePXA and one eGBM clustered with PXAs, one eGBM clustered with low-grade gliomas, and two eGBMs clustered with pediatric-type glioblastomas. Common histologic, immunohistochemical, molecular and clinical features found in eGBM and ePXA suggest that they are closely related or the same entity. If the latter is true, the nomenclature and WHO grading remains to be resolved 4).
The primary treatment of PXA is surgical resection, and the outcome is generally favorable. Pathology is notable for anaplasia in ∼15% of PXAs, but there is no consensus regarding any advantage of adjuvant postsurgical therapy 5).
Pleomorphic xanthoastrocytoma (PXA) has characteristic histologic features and is regarded as a WHO grade II lesion. Overall survival is reported to be >60%, but published series usually consist of a range of ages and treatment modalities. Gross total resection is associated with superior survival but recurrence rates after gross total resection are not well described, particularly in a pediatric population.
Perioperative neurological complications are relatively common, but do not affect long-term functional outcome or mortality.
Pleomorphic xanthoastrocytomas (PXA) may recur and demonstrate aggressive clinical behavior with a mortality rate between 15% and 20%, and a new concept of anaplastic PXA has been proposed.
No histopathologic features currently are known to reliably predict recurrence or tumor progression.
Malignant PXAs are higher risk for perioperative complications and, ultimately, death from tumor progression, despite increased use of adjuvant radiation and chemotherapy.
Gross total resection without adjuvant therapy provides prolonged disease control, as seen in 6 of 7 patients (85%) in the series of Fouladi et al. 6).
Both pediatric and adult PXAs may be resected with good functional outcomes. Perioperative neurological complications are relatively common, but do not affect long-term functional outcome or mortality. Malignant PXAs are higher risk for perioperative complications and, ultimately, death from tumor progression, despite increased use of adjuvant radiation and chemotherapy 10).
A literature review of 79 patients with PXAs is described and confirms a favorable prognosis in 80% of patients. The sex ratio in the reported cases was almost equal, and the median age at time of diagnosis was 14 years. Seventy-nine percent of the patients presented with seizures. Nine of the 15 deaths from PXA are associated with histological evidence of necrosis at initial presentation or in a recurrent tumor, confirming the poor prognosis associated with the presence of necrosis in these neoplasms. Survival curves confirm that the optimal treatment for PXAs without necrosis is primary surgical resection with subsequent operation for recurrent tumor. The roles of surgery or radiotherapy in necrotic PXA are not clear from the literature 11).
Gaba et al retrospectively identified 39 patients who underwent surgery for intracranial PXA between 1994 and 2011. Demographic factors were recorded along with Karnofsky Performance Status (KPS), complications, and mortality.
Mean patient age was 31 years at the most recent surgery. A majority of patients (24; 62%) had multiple surgeries with a mean of 2 operations per patient. Eleven PXAs (28%) were malignant (grade III or IV). Perioperative complications included permanent neurological worsening in 4 patients (10%), regional complications in 4 (10%), and medical complications in 3 (8%). Preoperative KPS was ≥70 in 34 of 38 patients (89%). Long-term postoperative KPS was ≥70 in 36 of 37 patients (97%), suggesting good functional outcomes. There was no perioperative mortality, but 7 patients (18%) died of tumor progression. Patients with malignant PXAs trended toward higher risk of regional complications (3 of 11 patients [27%]; P = .06), received adjuvant therapy more often (10 of 11 patients [91%]; P < .001), had higher mortality from tumor progression (7 of 11 patients [64%]; P < .001), and were significantly larger (mean, 6.05 ± 0.73 cm standard error of the mean; n = 7; P < .01).
Both pediatric and adult PXAs may be resected with good functional outcomes. Perioperative neurological complications are relatively common, but do not affect long-term functional outcome or mortality. Malignant PXAs are higher risk for perioperative complications and, ultimately, death from tumor progression, despite increased use of adjuvant radiation and chemotherapy 12).
16 cases over 20 years of pediatric PXA treated with surgical resection alone with a 5-year relapse-free survival of 40% (95% confidence interval, 20%-82%) and overall survival of 76% (95% confidence interval, 55%-100%). Gross total resection was associated with superior relapse-free survival (P<0.05). Some cases have a very long period between symptom onset or radiologic detection and resection, but neither length of symptoms nor radiologic signs of slow growth were associated with survival. PXA is a rare and unusual entity with unpredictable behavior. Complete surgical resection is optimal but does not guarantee relapse-free survival. We propose separation of PXA from other low-grade gliomas in childhood given differing biology and behavior. 13).
16 adult patients with reviewed PXA diagnosis. No IDH neither histone H3.3 mutations were found; BRAF V600E mutation was recorded in six patients. Ten patients presented with anaplastic features. BRAF mutations were associated with lower Ki67, OLIG2 expression, and lack of p16 expression. Median PFS and OS were 41.5 months (95% CI: 11.4-71.6) and 71.4 months (95% CI: 15.5-127.3), respectively. BRAF mutation tended to be associated with greater PFS (p = 0.051), whereas anaplastic features were associated with minimal PFS (p = 0.042).
PXA in adults PXA may present features distinct from pediatric PXA. Anaplastic features and BRAF mutation may potentially identify specific subgroups with distinct prognoses 14).
A total of 214 patients were identified with PXA using the November 2010 submission. Patient demographics, tumor characteristics, extent of surgical resection, the use of radiotherapy, and overall survival were evaluated. Overall survival for PXA was then compared to that of pilocytic astrocytoma, oligodendroglioma, ependymoma and glioblastoma also using the SEER database. Kaplan Meier analysis, univariate and multivariate analyses were performed. The majority of patients were found to be young adults with the most common tumor location being temporal lobe. Surgery was performed on most (95 %) patients, while 25 % of patients received radiation therapy. Five and 10 year overall survival rates were 75 and 67 %, respectively. Grade was only available for a limited number of patients but appeared to affect prognosis. Patients with grade IV tumors had a median overall survival of 45 months, whereas median survival was not reached for grade I-III patients. On multivariate analysis, male gender and increasing age were associated with worse overall survival (p values 0.05 and <0.006, respectively). Extent of resection trended towards significance in favor of gross total resection. PXA is a rare diagnosis that affects young adults. Surgical resection is the primary modality of treatment with an overall good prognosis. Elderly patients, those with higher grade disease and patients with incomplete resections may have a worse prognosis. The role of radiation therapy for PXA remains unclear but is more often used for patients with high grade tumors. Compared to other common brain tumors, PXA's appear to fare worse than pilocytic astrocytoma and oligodendroglioma, especially in younger patients. However, even high grade PXA patients have significantly better overall survival compared to glioblastoma 15).
Pleomorphic xanthoastrocytomas with malignant transformation have been reported in three out of eight patients operated on for this type of tumor in the Neurosurgery Department, Regional Hospital of Treviso-Padova University, Italy. in the last 15 years. The three patients were two adult women and a child, the primary tumors were located in the cortex of the right temporal lobe, and treatment consisted of complete surgical resection. Histological examination revealed simple PXA in two patients and a PXA with anaplastic foci in the other. Mean recurrence time was 5.7 years, with the original xanthoastrocytoma evolving to glioblastoma in two cases and anaplastic astrocytoma in the third. All three patients underwent a second operation, followed by adjuvant therapies. Two died from tumor progression and one from brain edema after intracerebral haemorrhage. A review of the available PXA literature dating back to 1979 revealed 16 cases of primary anaplastic astrocytoma and 21 cases of PXA with malignant transformation. The experience adds three more cases of malignant transformations, outlining once again the potential malignancy of pleomorphic xanthoastrocytomas and the fact that prognosis in these cases is the same as for primary anaplastic astrocytoma and glioblastoma. Analysis of glioneuronal markers, Ki67 and p53 in all pleomorphic xanthoastrocytomas did not prove to be a discriminating factor to identify a subgroup of xanthoastrocytomas prone to malignancy. Accordingly, these tumors demand close long-term clinical and radiological follow-up. 16).
Fouladi et al reviewed data on 13 children who had histologically confirmed PXA and were referred to the neuro-oncology service between 1985 and 1999. Neuro-imaging with CT and/or MRI documented the anatomic location, tumor extent, and degree of resection. There were 3 males and 10 females; median age was 12.9 years (range, 8.2-17.2 years). The most frequent presentations included seizures (n = 8) and headache (n = 5). Tumor sites included temporal (n = 5), parietal (n = 3), frontal (n = 1), frontoparietal (n = 1), parietooccipital (n = 1), and temporoparietal (n = 1) lobes and the spinal cord (n = 1). CT/MRI revealed a cystic component in 6 patients, with cyst wall enhancement in 3 patients. The solid component was uniformly enhancing in 11 patients. Vasogenic edema was present in 9 patients, and calcification was noted in 4 patients. Histopathologic findings included meningeal invasion in 12 patients, calcifications in 4, and necrosis in 2. Mitotic figures (1-12 per high-power field) were seen in 8 patients. Gross total resection was achieved in 8 patients, near total resection in 1, and subtotal resection in 4. Ten patients were alive with a median follow-up of 41 months at this writing. Two patients died of progressive disease, and 1 died of an unrelated cause. In conclusion, pleomorphic xanthoastrocytoma is a rare neoplasm in childhood, commonly presenting with seizures. Gross total resection without adjuvant therapy provides prolonged disease control, as seen in 6 of 7 patients (85%) in this series 17).
71 cases with available information regarding clinical and therapeutic data and follow-up. Diagnostic features included cellular pleomorphism, giant and/or xanthic cells, eosinophilic granular bodies, desmoplasia, and leptomeningeal involvement. The mitotic index (MI), the presence of necrosis, and endothelial proliferation were recorded in all primary resection specimens.
The study included 35 females and 36 males, age 26+/-16 years (mean +/- standard deviation). Approximately 98% of tumors were supratentorial, with 49% in the temporal lobe. Seizures were the presenting symptoms in 71% of patients. Extent of tumor removal was macroscopic total resection in 68% of cases and subtotal resection (STR) in 32% of cases. Postoperative radiotherapy, alone or with chemotherapy, was administered in 29% and 12.5% of cases, respectively. The recurrence free survival rates (RFS) were 72% at 5 years and 61% at 10 years, whereas overall survivals rates (OS) were 81% at 5 years and 70% at 10 years. In univariate analysis, the extent of resection was the single factor associated most strongly with RFS (P=0.003), followed by MI (P=0.007) and atypical mitoses (P=0.04). Necrosis was not found to be significant. The extent of resection and MI were confirmed as independent predictors of RFS by multivariate analysis. MI (P=0.001), atypical mitoses (P=0.02), and necrosis (P=0.04) were associated with OS by univariate analysis. In multivariate analysis, only MI was an independent predictor of survival. Information regarding MIB-1 labeling index and the use of adjuvant therapy was too limited to explore their prognostic significance confidently.
The study confirms that PXA is an astrocytic tumor with a relatively favorable prognosis. MI and extent of resection appear to be the main predictors of RFS and OS. Given the slow growth of the tumor, more studied cases and longer periods of follow-up will be essential to confirm our findings regarding prognostic factors affecting this unusual tumor 18).
Finch et al., presented the case of a 16-year-old male who responded to vemurafenib monotherapy initially and had an additional response to vemurafenib following progression after a brief time off the medication 19).
A case of PXA that was initially diagnosed as GBM is presented. A 42-year-old man visited the clinic because of right hemiparesis and total aphasia. Head magnetic resonance imaging demonstrated enhanced multiple cystic lesions in the left temporal lobe suggesting an intra-parenchymal brain tumor. The lesion was partially removed and GBM with a Ki-67 index of 20 % was diagnosed by pathological examination of the resected specimen. Despite receiving radiation and chemotherapy, the patient died 6 months after the first admission. At autopsy, the boundary between the tumor and normal brain tissue was clear. Large parts of the tumor demonstrated typical features of PXA, including pleomorphism, clear xanthomatous cells with foamy cytoplasm, positive silver staining, and a Ki-67 index of less than 1 %.
GBM should be diagnosed only when the majority of the tumor cells are undifferentiated. Although the operative specimen appeared typical GBM histologically, the diagnosis of GBM was subsequently excluded by the autopsy finding that much of the tumor had the characteristic features of a benign PXA. Therefore, the final diagnosis in this case was PXA with anaplastic features. PXA with anaplastic features should be carefully distinguished from GBM to facilitate appropriate decisions concerning treatment 20).
Combined pleomorphic xanthoastrocytoma (PXA) and ganglioglioma (GG) is an extremely rare tumor, with fewer than 20 cases reported. Cicuendez et al report a case of combined PXA-GG in an 18-year-old man with a history of seizures. The tumor showed necrosis and the BRAF V600E mutation on histological examination, with no evidence of tumor recurrence 1 year after gross-total resection. The BRAF V600E mutation was present, which suggests that both cell lineages may share a common cellular origin 21).
Yamada et al report the case of a 56-year-old man presenting with seizures and headaches. Magnetic resonance imaging revealed a large right temporal lobe mass with low T1 and high T2/FLAIR signal and a discrete contrast-enhancing focus. Histologically, the tumor showed 2 distinct components: an infiltrating astrocytoma harboring 5 mitoses/10 high-power fields and a relatively circumscribed focus, resembling PXA with, at most, 2 mitoses/10 high-power fields. No microvascular proliferation or necrosis was present in either component. The infiltrating astrocytoma component contained numerous axons, whereas the PXA-like component had sparse axons, as demonstrated by the neurofilament immunostain. Both components were positive for the mutant IDH1 R132H and showed loss of ATRX expression, whereas BRAF V600E was restricted to the PXA-like component. On sequencing of the 2 components separately after microdissection, both showed identical IDH1 R132H and TP53 R273C point mutations, whereas the BRAF V600E mutation was limited to the PXA-like component. These findings are consistent with clonal expansion of a morphologically distinct focus, harboring a private BRAF V600E mutation within an IDH1-mutant glioma. Intratumoral heterogeneity and clonal evolution, as seems to have occurred here, suggest reevaluation of “collision tumors” as a concept 22).
Cases of cerebellar PXA are rare, and those associated with neurofibromatosis type 1 (NF1) are even less common, with only 2 cases reported to date. Takei et al present a third case of PXA-NF1 with unusual features. A 33-year-old woman presented with a history of headache. Her medical and family history was significant for NF1. Brain MRI revealed a 3.4 cm ill-defined lesion with a gyriform enhancing pattern in the left cerebellum, superficially mimicking Lhermitte-Duclos disease. The patient underwent a gross total resection of the lesion and had an unremarkable postoperative course. While the lesion had histological features typical of “pure” PXA (WHO grade II) it had an unusual growth pattern with thickening of the superficial cerebellar folia and predominant leptomeningeal involvement. No BRAF, IDH-1, or IDH-2 mutation was identified. Three months after surgery, local recurrence was detected, and the patient was treated with radiation therapy. One year after the first surgery, she underwent surgical resection of the recurrent/residual tumor. Histologically, the recurrent tumor showed very similar features to the initially resected tumor, with no anaplastic features. Most cerebellar PXAs have an indolent clinical behavior as do most cerebral PXAs. Whether co-existence of NF1 was a factor in altering the clinical course and biologic behavior of this patient's tumor is currently unknown 23).
An illustrative case of a PXA transforming to glioblastoma multiforme is presented 24).
A 16-year-old female, with unremarkable medical and family history, presented with a huge dural-based mass in the right frontotemporal fossae, manifesting as headache. The patient underwent subtotal tumor resection. Intraoperative findings revealed focal erosion in the temporal fossa dura mater and skull adjacent to the lesion. Most of the tumor was located extraaxially, but a part of the tumor had invaded the temporal lobe, and had tightly adhered to the middle cerebral artery and its perforating vessels. Histological examination revealed cellular pleomorphism with mitotic activity, focal necrosis, but lacking endothelial proliferation, consistent with anaplastic pleomorphic xanthoastrocytoma (PXA) with component of anaplastic astrocytoma. Postoperatively, the patient underwent local irradiation and temozolomide administration, but the tumor relapsed 13 months later. Second tumor resection was performed followed by gamma knife radiosurgery, but the residual tumor progressively grew, extending into the contralateral hemisphere, and formed an enormous mass in the left frontal lobe at 17 months. Magnetic resonance imaging performed at 18 months revealed extracranial infiltration of the frontal tumor, through the cribriform plate, with enormous extension into the paranasal sinuses, nasal cavity, and orbit during the next month. The patient died at 20 months after the initial surgery. PXA with anaplastic appearance may have a component of anaplastic astrocytoma with more aggressive behavior 25).
A 28-year-old man presented with a short history of headache, visual and aphasic speech disturbances. MR scans revealed a large, partly cystic, contrast-enhancing lesion of the left temporal lobe that upon microscopic examination was diagnosed as pleomorphic xanthoastrocytoma (PXA) with anaplastic features (WHO grade III). Remarkably, this tumor featured an unusual gliovascular, rosette-like histoarchitecture, which had previously been hypothesized to possibly indicate a greater likelihood of PXA recurrence. Indeed, only 14 months later, the patient presented with a recurrent lesion, which contained the previous histology, but now also featured a distinct fibrosarcoma-like component replete with numerous osteoclast-type giant cells. In addition, whereas eosinophilic granular bodies were plentiful at the lesion's periphery, numerous CD34 - positive satellite cells were found in the adjacent non-infiltrated cortex. Regarding the origin of this recurrent tumor and in reflection of its composition of distinct PXA as well as sarcomatous components, the diagnosis of a pleomorphic xanthoastrosarcoma, to be conceptually considered as a gliosarcoma subtype, was made.To our knowledge, this is an unprecedented case of sarcomatous transformation of a PXA. Particular attention should be given to gliovascular pseudopapillary structures in PXAs, the presence of which may potentially herald a more aggressive clinical behavior 26).
A 59-year-old woman who presented with tumor bleeding onset and cerebrospinal fluid dissemination. The patient had sudden-onset right hemiparesis, aphasia, and consciousness disturbance and was admitted to a local area hospital. After emergency surgery had removed the hematoma, postoperative contrast-enhanced CT scan revealed a left temporal tumor. A second surgery was therefore performed for initial tumor removal 2 months later. Histopathological findings showed that the tumor was typical PXA with strong pleomorphism and xanthomatous changes and contained an ependymoma-like component in the center area. However, endothelial proliferation and mitosis were more remarkable compared to ordinary PXA. The MIB-1 labeling index was 9.8% high. From these findings, the histopathological diagnosis was anaplastic PXA. The patient underwent surgery to remove recurrent tumors 5 and 16 months later. The patient died 36 months after the first onset, and CT revealed glioblastoma-like findings and cerebrospinal fluid dissemination. This case report is the first case in which PXA presented with tumor bleeding onset. Histopathological findings suggested anaplastic PXA from the first surgical specimens, and PXA recurred many times. We thus believe that the patient displayed primary anaplastic PXA rather than secondary anaplastic PXA that results in malignant transformation 27).
Lipidized glioblastoma multiformis (LGB) and pleomorphic xanthoastrocytoma (PXA) are often supratentorial in location and occur in the second to fourth decade. This report presents two young patients, one having LGB and the other having PXA in the cerebellum. Histological differentiation between LGB and PXA is discussed 28).