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Peritumoral Edema Affects the Prognosis in Adult Pleomorphic Xanthoastrocytoma: Retrospective Analysis of 25 Patients
Original Article
Peritumoral Edema Affects the Prognosis in Adult Pleomorphic Xanthoastrocytoma: Retrospective Analysis of 25 Patients Joonho Byun, Seok Ho Hong, Young-Hoon Kim, Jeong Hoon Kim, Chang Jin Kim
BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) is a very rare glial neoplasm. The clinical behavior of PXA is not uniform, and the purpose of this study was to investigate the clinical characteristics of adult PXA and identify prognostic factors.
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METHODS: Twenty-five patients aged 18 years or older who were diagnosed with PXA between 2002 and 2016 were analyzed.
prognostic factors for adult PXA. Also, peritumoral edema may be associated with recurrence in PXA WHO grade II. PXA showed a high recurrence rate, and thus close followup is needed.
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RESULTS: Twenty-one patients (84%) had PXA World Health Organization (WHO) grade II and 4 patients (16%) had anaplastic PXA (WHO grade III). The median overall survival of PXA WHO grade II and III was 97 and 56 months, respectively. The 3-year progression-free survival of PXA WHO grade II and III was 65.1% and 50%, respectively (P [ 0.37 and 0.21). Diffusion-weighted imaging, perfusion-weighted imaging, and positron emission tomography findings failed to predict the histologic grade of PXA and recurrence of PXA WHO grade II. Tumor size >40 mm and presence of evident peritumoral edema (ePTE) were prognostic factors for poor progressionfree survival (hazard ratios, 4.4 and 15.2, respectively; P [ 0.03 and 0.01) according to a univariate analysis. In the recurrent and silent PXA grade II groups, ePTE was present in 87.5% and 23.1% of cases, respectively (P <0.01).
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CONCLUSIONS: The clinical and radiologic features of PXA are not uniform. Tumor size and ePTE are possible
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Key words Peritumoral edema - Pleomorphic xanthoastrocytoma - Recurrence -
Abbreviations and Acronyms ADC: Apparent diffusion coefficient CI: Confidence interval DWI: Diffusion-weighted imaging EOR: Extent of resection ePTE: Evident peritumoral edema GIC: Glioblastoma initiating cell GTR: Gross total resection HPF: High-power field HR: Hazard ratio MRI: Magnetic resonance imaging OS: Overall survival PET: Positron emission tomography PFS: Progression-free survival
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INTRODUCTION
P
leomorphic xanthoastrocytoma (PXA) was first described by Kepes et al. in 1979.1,2 This rare neoplasm accounts for 1% of all astrocytic tumors.3 It was originally added to the World Health Organization (WHO) classification of tumors in 1993.4 The latest updated 2016 WHO classifications reclassified PXA to include “anaplastic PXA,” which requires 5 or more mitoses per 10 high-power fields (HPF). PXA tumors are considered WHO grade II and anaplastic PXA tumors WHO grade III.5 Because PXA usually occurs at a young age, prediction of its prognosis is crucial for proper decisions on the long-term management of patients.6 PXA is known to have a relatively benign clinical course, but this clinical course does not always proceed in a uniform fashion.7,8 Recurrence rates for PXA have been reported to range from 29% to 33%, with overall mortality of 15%e30%.3,9 There has been increasing recognition that PXA may have an unpredictable clinical behavior and it seems to have a high tendency to recur and undergo malignant transformation.2 A nonsuperficial location, a high mitotic index 5/10 HPF, the extent of resection, nonegross total resection (GTR), old age, and
PTE: Peritumoral edema PWI: Perfusion-weighted imaging PXA: Pleomorphic xanthoastrocytoma RT: Radiotherapy STR: Subtotal resection WHO: World Health Organization Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea To whom correspondence should be addressed: Seok Ho Hong, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.03.007 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
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non-BRAF V600E mutations are associated with a poor prognosis for PXA.1,10,11 Etzl et al.12 claimed that a hypermetabolic positron emission tomography (PET) finding was associated with aggressive clinical behavior of PXA,1 and a recent report by Tonse et al.13 suggested that anaplastic pathology, subtotal resection, and nonmutated BRAF V600E were associated with poor prognosis. However, the factors predicting aggressive PXA behaviors have not been fully elucidated. The purpose of this report was therefore to investigate the clinical characteristics of adult PXA through our institutional experience and to identify the prognostic factors associated with recurrence and poor prognosis, and the potential value of radiologic findings as an indicator of recurrence and aggressive behavior. PATIENTS AND METHODS This study was approved by our institutional review board. Our institutional database was searched for patients aged 18 years or older who underwent surgery and were diagnosed with PXA between 2002 and 2016. Only newly diagnosed cases and those who underwent surgery in our institution were enrolled; recurrent tumors with unavailable information on the primary tumor were excluded. A total of 27 patients (aged >18 years) with PXA who were treated in our institute between January 2002 and December 2016 were identified. Clinical data were unavailable for 1 patient, and 1 patient who harbored recurrent tumor underwent initial surgery in an outside hospital. This situation left 25 adult patients with PXA for inclusion in this study, and a review of all their clinical, radiologic, and surgical records was performed. Histologic specimens were re-examined by our institutional neuropathologist, who reclassified PXA (WHO grade II) and anaplastic PXA (WHO grade III) according to the 2016 WHO classification of central nervous system tumors. The extent of resection (EOR) was defined according to the following criteria. GTR was defined as the tumor being totally removed under gross examination, whereas subtotal resection (STR) was defined as incomplete resection of the tumor but with <10% of the tumor left in place. Biopsy was defined as tissue obtained for histopathologic examination with >10% of the tumor remaining. The size of the tumor was defined by the maximal tumor diameter in 2 dimensions. The type of tumor was classified into 4 subtypes: solid; solid plus cystic; hemorrhagic and solid plus cystic; and hemorrhagic. The extent of peritumoral edema (PTE) was defined by a region of very bright signal intensity surrounding the tumor on T2-weighted magnetic resonance imaging (MRI). Axial scans were available for most patients, and additional coronal and sagittal scans were available for some patients. Axial T2-weighted images and/or coronal and sagittal T2-weighted images were analyzed. To minimize interobserver variance and increase the reliability of measurement stratification, edema extending further than 5 mm from the tumor margin to the outer edge was defined as presence of evident PTE (ePTE), and edema extending less than 5 mm from the tumor margin or the absence of high signal intensity surrounding the tumor on T2-weighted imaging was defined as absence of ePTE. The findings of MRI diffusion-weighted imaging (DWI), MRI perfusion-weighted imaging (PWI), and [18F]-fluorodeoxyglucosePET scans were also obtained. DWI was performed using a
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spin-echo sequence with diffusion weightings of b ¼ 0 and b ¼ 1000 seconds/mm2. Apparent diffusion coefficient (ADC) maps were generated with a monoexponential fit on a voxel-tovoxel basis for all imaging planes. High signal intensity on DWI and low value on ADC were considered to indicate diffusion restriction. PWI involved a dynamic susceptibility contrast study with injection of 0.1 mL/kg Gadovist at a 1 mmol/L concentration at 5 mL/second. The PET scans were performed with [18F]-fluorodeoxyglucose, a measure of cerebral glucose metabolism. An infusion of 0.143 mCi per kilogram body weight was administered. Initial follow-up involved clinical evaluation and MRI at 1 month, 6 months, and 1 year after surgery, with annual checks thereafter. Subgroup comparisons were performed using Student t tests, Mann-Whitney tests, c2 tests, and Fisher exact tests. We also investigated the overall survival (OS) and progression-free survival (PFS) of our patients, as well as the prognostic factors. The OS was defined as the time between the date of the initial diagnosis and the date of death, and the PFS was defined as the time between the date of the initial treatment and the date of tumor recurrence or progression according to radiologic findings. OS and PFS were analyzed using Kaplan-Meier survival analysis, and subgroup comparisons were performed using log-rank tests. Potential prognostic factors for OS and PFS, including age, sex, histology, tumor size, EOR, calcification, ePTE, DWI, PWI, and PET findings, were analyzed using a Cox proportional hazards model. The proportional hazards assumption was confirmed by testing of Schoenfeld residuals, and no relevant violations were found. All statistical analyses were conducted using SPSS version 18.0 (SPSS Inc., Chicago, Illinois, USA). A P value < 0.05 was considered statistically significant. RESULTS Patient Demographics There were 8 male (32%) and 17 female (68%) patients, with a mean age of 29.9 years (range, 18e60 years). The most common presenting symptom was seizure (48%), followed by headache (32%), motor weakness (8%), visual disturbance (4%), and dizziness (4%). The most common location of PXA was the temporal lobe (n ¼ 11; 44%), followed by the frontal lobe (n ¼ 7; 28%), occipital lobe (n ¼ 2; 8%), cerebellum (n ¼ 2; 8%), suprasellar area (n ¼ 1; 4%), fourth ventricle (n ¼ 1; 4%), and thalamus (n ¼ 1; 4%). The mean tumor size was 33.6 mm (range, 10e70 mm). The tumor types were divided between the 4 subgroups as follows: solid type tumor, n ¼ 12 (48%); solid plus cystic portion, n ¼ 10 (40%); hemorrhagic tumor, n ¼ 1 (4%); and solid plus cystic with hemorrhagic tumor, n ¼ 2 (8%). Twenty-one patients (84%) were diagnosed with PXA WHO grade II, and 4 patients (16%) were diagnosed with PXA WHO grade III (anaplastic PXA). The detailed basal demographic findings of adult PXA are shown in Table 1. Radiologic Findings Brain computed tomography scans from 21 of the 25 patients were examined. Seven patients (33.3%) presented with an isodense mass, 13 (61.9%) with a hyperdense mass, and 1 (4.8%) with a hypodense mass. On T1-weighted MRI, 22 patients (88%) showed
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Table 1. Characteristics of All Enrolled Patients with Adult Pleomorphic Xanthoastrocytoma Characteristic Sex
Table 1. Continued Characteristic Absent
14 (56)
Present
11 (44)
Male, n (%)
8 (32)
WHO grade II
8/21 (38.1)
Female, n (%)
17 (68)
WHO grade III
3/4 (75)
Male/female ratio
0.47
Pattern, n (%)
Age (years) Mean
Local recurrence 29.9 (range, 18e60)
Presenting symptoms, n (%)
10 (90.9)
Distant recurrence
1 (9.1)
High-grade transformation
4 (36.4)
Seizure
12 (48)
Death
6 (24)
Headache
8 (32)
Mean
51.4 (range, 10e112)
Motor weakness
2 (8)
Median
Visual disturbance
1 (4)
PXA, pleomorphic xanthoastrocytoma; WHO, World Health Organization.
Dizziness
1 (4)
Incidental findings
1 (4)
Tumor location, n (%) Frontal
7 (28)
Temporal
11 (44)
Parietal
0
Occipital
2 (8)
Cerebellum
2 (8)
Suprasellar
1 (4)
th
4 ventricle
1 (4)
Thalamus
1 (4)
Tumor size (mm) Mean
33.6 (range, 10e70)
Tumor type, n (%) Solid
12 (48)
Solid þ cyst
10 (40)
Hemorrhagic tumor
1 (4)
Solid þ cyst and hemorrhage
2 (8)
Histology PXA (WHO grade II) Anaplastic PXA (WHO grade III)
21 (84)
21 (84)
Subtotal resection
4 (16)
Adjuvant treatment, n (%)
Chemotherapy
7 (28) 0
Recurrence, n (%) Continues
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a low signal intensity lesion, 2 patients (8%) showed an isosignal intensity lesion, and 1 patient (4%) showed a mixed signal intensity lesion. On T2-weighted MRI, 24 patients (96%) showed a high signal intensity lesion and 1 patient (4%) showed a mixed signal intensity lesion. Twenty-four patients (96%) showed enhancement on gadolinium-enhanced T1-weighted MRI. Calcification of the tumor was noted in 3 patients (12%), and ePTE was seen in 13 patients (52%). We compared the advanced MRI (DWI and PWI) and PET findings between PXA WHO grade II and III. In the PXA WHO grade II group, diffusion restriction on DWI was shown in 6 of 11 patients (54.5%), increasing perfusion on PWI was shown in 6 of 9 patients (66.7%), and hypermetabolism was shown on brain PET scan in 8 of 11 patients (72.7%). In the PXA WHO grade III group, all examined patients showed diffusion restriction on DWI, increased perfusion on PWI, and hypermetabolism on brain PET scan; however, the differences between PXA WHO grade II and III patients did not reach statistical significance (P ¼ 0.23, 0.48, and 0.52, respectively). The detailed radiologic findings of PXA are shown in Table 2. Representative cases of PXA WHO grade II with and without the radiologic finding of an ePTE are presented in Figure 1, and a case showing the radiologic findings of PXA WHO grade III is presented in Figure 2.
4 (16)
Extent of resection
Radiation therapy
46
Treatment and Prognosis Twenty-one patients (84%) underwent GTR and 4 patients (16%) underwent STR. Seven patients (28%) received adjuvant radiation therapy; 4 of these had PXA WHO grade III, 1 patient had GTR for PXA WHO grade II (diagnosed PXA with anaplastic features according to the 2007 WHO classification), and 2 patients had STR for PXA WHO grade II. No patient received adjuvant chemotherapy. Recurrence occurred in 11 patients (44%): local recurrence in 10 patients (90.9%) and a distant recurrence in 1 patient (9.1%). High-grade transformation was observed in 4
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Table 2. Radiologic Findings of Patients with Adult Pleomorphic Xanthoastrocytoma Radiologic Findings
n (%)
Computed tomography scan Isodense
7 (33.3)
Hyperdense
13 (61.9)
Hypodense
1 (4.8)
MRI T1-weighted imaging Low signal intensity Isosignal intensity High signal intensity Mixed signal intensity
22 (88) 2 (8) 0 1 (4)
MRI T2-weighted imaging Low signal intensity Isosignal intensity High signal intensity Mixed signal intensity
0 0 24 (96) 1 (4)
MRI contrast enhancement No enhancement Enhancement
1 (4) 24 (96)
Calcification Present
3 (12)
Absent
22 (88)
Peritumoral edema Absent
12 (48)
Present
13 (52)
MRI diffusion-weighted imaging Diffusion restriction
10 (66.7)
No diffusion restriction
5 (33.3)
MRI perfusion-weighted imaging Normal perfusion
3 (23.1)
Hyperperfusion
10 (76.9)
Brain positron emission tomography scan No hypermetabolism
3 (20)
Hypermetabolism
12 (80)
MRI, magnetic resonance imaging.
patients (36.4%). Postoperative surgical complications of epidural hematoma occurred in 2 patients (8%). The seizure control rate after surgery was 100% (12 of 12 patients). Six patients (24%) died during the follow-up period, with the cause of death being disease progression in all 6. The mean follow-up period was 51.4 months (range, 2e112 months). The detailed treatment regimens for the adult PXA are shown in Table 1.
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The OS of PXA WHO grade II at 1, 2, 3, 5, 7, and 10 years was 100%, 89.5%, 89.5%, 89.5%, 61.4%, and 40.9%, respectively, whereas the OS of PXA WHO grade III at 1, 2, 3, 5, 7, and 10 years was 100%, 100%, 100%, 0%, 0%, and 0%, respectively. The PFS of PXA at 6 months and 1, 2, 3, 5, and 7 years was 90.5%, 81%, 70.5%, 65.1%, 65.1%, and 52%, respectively, whereas the PFS of PXA WHO grade III at 6 months and 1, 2, 3, 5 and 7 years was 100%, 75%, 50%, 50%, 0%, and 0%, respectively. The differences in OS and PFS between PXA WHO grade II and III were not statistically significant (P ¼ 0.38 and 0.21, respectively). The Kaplan-Meier survival curves are presented in Figure 3A and B. Potential prognostic factors for PFS in adult PXA were examined, including age, sex, histology, size, EOR, presence of calcification, ePTE, diffusion restriction on DWI, increasing perfusion on PWI, and hypermetabolism on PET. Tumor size larger than 40 mm (hazard ratio [HR], 4.39; 95% confidence interval [CI], 0.2e10.3; P ¼ 0.03) and presence of ePTE (HR, 15.23; 95% CI, 1.9e121.5; P ¼ 0.01) were prognostic factors for a poor PFS according to the univariate analysis. A detailed description of the univariate analysis is given in Table 3. For PXA with the absence of ePTE, the OS at 1, 2, 5, 7, and 10 years was 100%, 100%, 100%, 100% and 66.7%, respectively, and the PFS at 6 months and 1, 2, 3, and 6 years was all 100%. For PXA with the presence of ePTE, the OS at 1, 2, 5, 7, and 10 years was 100%, 83.3%, 69.4%, 23.1%, and 23.1%, and the PFS at 6 months and 1, 2, 3, and 5 years was 84.6%, 61.5%, 38.5%, 30.8%, and 20.5%. The differences in OS and PFS between PXA with an absence of ePTE and PXA with the presence of ePTE were statistically significant (P ¼ 0.02 and < 0.01, respectively; Figure 3C and D). We also compared the characteristics of sex, age, tumor location, tumor size, presence of calcification, presence of ePTE, EOR, and adjuvant treatment between the posttreatment silent PXA WHO grade II group and the recurrent PXA WHO grade II group. All parameters except ePTE showed no significant between group differences. In the recurrent PXA WHO grade II group, the presence of ePTE was 87.5%, whereas in the silent PXA WHO grade II group, it was 23.1%. This difference was statistically significant (P < 0.01). We then analyzed the value of advanced magnetic resonance and PET findings for predicting recurrence rate in PXA WHO grade II. In the recurrent PXA WHO grade II group, diffusion restriction on DWI was shown in 3 of 5 patients (60%), increasing perfusion on PWI was shown in 3 of 4 patients (75%), and hypermetabolism on PET was shown in 4 of 6 patients (66.7%). In the silent PXA WHO grade II group, 3 of 6 patients (50%) showed diffusion restriction on DWI, 3 of 5 patients (60%) showed increasing perfusion on PWI, and 4 of 5 patients (80%) showed hypermetabolism on PET. There were no significant differences in DWI, PWI, and PET findings between the silent and recurrent PXA WHO grade II groups (P ¼ 1.00, 1.00, and 1.00, respectively). A detailed description of the values is given in Table 4. For PXA WHO grade II with an absence of ePTE, the OS at 1, 2, 5, 7, and 10 years was 100%, 100%, 100%, 100%, and 66.7%, whereas for PXA WHO grade II with the presence of ePTE, the OS at 1, 2, 5, 7, and 10 years was 100%, 77.8%, 77.8%, 25.9%, and 25.9%. For PXA WHO grade II with an absence of ePTE, the PFS at 6 months and 1, 2, 3, and 5 years was all 100%, whereas for PXA WHO grade II with the presence
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Figure 1. Magnetic resonance imaging (MRI) findings of adult pleomorphic xanthoastrocytoma (PXA). (A, B) MRI of a 31-year-old male patient with a tumor located in the right temporal lobe. (A) The tumor was round and solid with a well-demarcated margin on T2-weighted imaging. There was no peritumoral edema (PTE) around the tumor. (B) The tumor showed high enhancement on gadolinium-enhanced T1-weighted imaging. This patient was diagnosed with PXA World Health Organization (WHO) grade II and did not experience recurrence during follow-up. (C, D) MRI of a 40-year-old female patient with a tumor located in the right frontal lobe. (C) The tumor was round, contained a cystic portion, and its margin was well demarcated on T2-weighted imaging. There was evident PTE around the tumor. (D) The
of ePTE, the PFS at 6 months and 1, 2, 3 and 5 years was 80%, 60%, 40%, 30%, and 30%. The differences in OS and PFS between PXA WHO grade II with absence of ePTE and PXA WHO grade II with presence of ePTE were statistically significant (P ¼ 0.02 and 0.03, respectively) (Figure 3E and F).
DISCUSSION PXA was first described by Kepes et al.1 and was originally added to the WHO classification of tumors in 1993.4 In 2007, the WHO classification classified PXA as a WHO grade II tumor and mentioned PXA “with anaplastic features.” PXA with anaplastic features showed variable levels of necrosis and/or 5 mitoses per HPF.14 However, in 2007, the WHO classifications of PXA and PXA with anaplastic features were both classified as grade II tumors. The latest updated 2016 WHO classification of the
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solid portion of the tumor showed high enhancement on gadolinium-enhanced T1-weighted imaging. This patient was diagnosed with PXA WHO grade II and experienced recurrence 15 months after surgery. (E, F) MRI of an 18-year-old female patient with a tumor located in the right medial temporal lobe. (E) The tumor was well delineated in T2-weighted imaging. High signal lesion around tumor (red arrow) and its thickness of high signal lesion about 3 mm. This case was considered to have absence of evident PTE. (F) The tumor showed enhancement on gadolinium-enhanced T1-weighted imaging. This patient was diagnosed with PXA WHO grade II and did not experience recurrence during the follow-up period.
tumors redefined anaplastic PXA as requiring 5 or more mitoses per 10 HPF and categorized it as a WHO grade III tumor.5 Clinical and Histologic Findings PXA is known to be a very rare low-grade glial neoplasm and usually occurs in a younger age group, so symptomatic control and long-term survival outcomes are the most important consideration in the management of PXA.6 PXA is known to have a predilection for locations in the temporal lobe and frequently produces seizures.3,15 In our series, the mean age of patients was 29.9 years, and the tumors did show a predilection for the temporal lobe (44%), with the most common presenting symptom being seizure (48%). Our study results are therefore consistent with those of previously reported studies. Although PXA usually occurs in young adults, the oldest patient in our series was 60 years old, and Jagtap et al.16 recently reported a 75-year-old patient
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Figure 2. Conventional and advanced magnetic resonance imaging findings in a 37-year-old female patient with anaplastic pleomorphic xanthoastrocytoma. (A) The tumor was located in the left frontal lobe and showed mixed low and high signal intensity on T2-weighted imaging. There was evident peritumoral edema around the tumor. (B) The tumor showed high
diagnosed as having PXA WHO grade II. PXA may therefore affect all ages. Twenty-one of 25 patients (84%) had PXA WHO grade II, and 4 of 25 patients (16%) had anaplastic PXA of WHO grade III. However, we could not find any significant survival differences between PXA WHO grade II and III, but we suspect that this might be because of insufficient PXA WHO grade III patient numbers; our study included only 4 patients with PXA WHO grade III. Although our study included patients with PXA WHO grade III, the recurrence and malignant transformation rates (44% and 36.4%, respectively) found in our study were high, especially considering that most patients had PXA WHO grade II. The histologic criteria of PXA include pleomorphic tumor cells with giant nuclei, xanthomatous cells, and abundant reticulin fiber deposition in the stroma. The presence of glial fibrillary acidic protein suggests an astrocytic origin. In anaplastic PXA, significant mitotic activity (5 mitoses per 10 HPF) should be observable. Necrosis and endothelial hyperplasia are known histologic characteristics of glioblastoma multiforme; however, necrosis and endothelial proliferation also can be seen in PXA. Pahapill et al.17 reported that necrosis of PXA was associated with poorer OS. Furthermore, Nasuha et al.18 reported that the typical histologic features, which include an absence of mitoses, necrosis, and endothelial proliferation, were generally considered to be the reason for the slow growth of PXA. However, Nakajima et al.19 reported a case of PXA WHO grade II that transformed to
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enhancement on gadolinium-enhanced T1-weighted imaging. (C) The tumor showed diffusion restriction on diffusion-weighted imaging. (D) The tumor showed hyperperfusion on a perfusion image. (E) Increased fluorodeoxyglucose uptake in the periphery of the tumor was identified on the fluorodeoxyglucose-positron emission tomography scan.
glioblastoma without mitosis, necrosis, or endothelial hyperplasia in the initial histology. The clinical impact of necrosis and endothelial hyperplasia in PXA is still under debate and should be included in future studies. Alterations in the B-RAF gene have been shown in low-grade glioma,20 and nearly 50%e60% of PXA tumors have been shown to harbor the BRAFV600E mutation.13,21 Radiologic Findings Regarding the imaging aspects of PXA, Lucato22 mentioned that the features of PXA are variable and the key is in the term PXA. Consistent with the term pleomorphic, the imaging features of PXAs are varied, which makes preoperative diagnosis difficult. Yu et al.23 reported magnetic resonance findings of 19 patients with PXA and found that 89.4% of tumors were located at the brain surface, whereas the other 10.6% were located in a deeper area. These investigators divided tumors into 3 morphologic subgroups, with 21% of tumors being cystic, 36.8% of tumors being mixed cystic-solid, and 42.1% being solid. Solid components of tumors were low signal intensity or isosignal intensity on T1-weighted imaging and slightly hyperintense on T2-weighted imaging, whereas 89.4% of tumors showed contrast enhancement. In our series, 80% of tumors were cortical tumors and 20% were located in deeper areas. The unusual locations were 2 (8%) in the cerebellum, 1 (4%) in the suprasellar area, 1 (4%) in the fourth ventricle, and 1 (4%) in the thalamus. We divided the tumor
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ORIGINAL ARTICLE JOONHO BYUN ET AL.
Figure 3. Kaplan-Meier survival analysis of adult pleomorphic xanthoastrocytoma. (A and B) Overall survival (OS) and progression-free survival (PFS) of patients with PXA WHO grade II or grade III. (C and D)
morphologic types into 4 subgroups: solid, solid with cyst, hemorrhagic, and solid with hemorrhage and cyst. The most common type of tumor was solid (n ¼12; 48%). On T1-weighted imaging, 96.3% of tumors showed low signal intensity or isosignal intensity, whereas on T2-weighted imaging, 96% of tumors showed high signal intensity. These MRI findings are consistent with previous reports. PTE can be seen in various brain tumors. The mechanism of PTE development in brain tumors is known to be vasogenic, but there are suggestions of a complex mechanism.24,25 PTE is considered one of the main characteristics of malignant glioma. Schoeneggera et al.26 reported that PTE is an independent factor for a poor prognosis in high-grade glioma. In an early report, Tien et al.27 speculated that PTE is related to the aggressive clinical behavior of PXA; however, these investigators experienced only 1 case of a tumor with PTE that was subject to recurrence. We defined edema extending further than 5 mm from the tumor margin to the outer edge as ePTE, and edema extending less than 5 mm from the tumor margin to the outer edge or the
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OS and PFS of patients with or without evident peritumoral edema (ePTE). (E and F) OS and PFS of PXA WHO grade II patients with or without ePTE.
absence of high signal intensity surrounding the tumor on T2-weighted images as absence of ePTE. In our study, 52% of tumors showed ePTE, with ePTE being a prognostic factor for poor PFS in the univariate analysis (HR, 15.23; 95% CI, 1.9e121.5; P ¼ 0.01). In the comparison between nonrecurrent (silent) and recurrent PXA WHO grade II, the percentage of tumors with ePTE was significantly higher in the recurrent PXA group (87.5% vs. 23.1%; P < 0.01). According to this result, we speculate that ePTE in PXA tumor might be associated with recurrence. The cause of PTE was extravasation of the fluid through flaws in the brain tumor microvasculature; however, some investigators have described the cause of PTE as complex and have suggested that vascular endothelial growth factor has a role.24,25 The role of the PTE area in PXA has not been clearly elucidated. In glioblastoma, glioblastoma stemlike or glioblastoma initiating cells (GICs) have been identified in the PTE area.28 These GICs have enhanced migratory and invasive capabilities compared with GICs from the tumor mass, which are the source of tumor recurrence.29,30 Although this evidence from patients with glioblastoma cannot be applied
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Table 3. Univariate Analysis of Prognostic Factors for Disease Progression of Adult Pleomorphic Xanthoastrocytoma Progression-Free Survival
Hazard Ratio
95% Confidence Interval
2.51
0.7e8.7
Silent Group (n [ 13)
Recurrence Group (n [ 8)
Male
7 (53.8)
1 (12.5)
Female
6 (46.2)
7 (87.5)
0.09
25.8
33.6
0.12
0.07
Variables P Value
Age (years) 30
Table 4. Comparison of the Characteristics of Posttreatment Silent Pleomorphic Xanthoastrocytoma (Grade II) and Recurrent Pleomorphic Xanthoastrocytoma (Grade II) Groups
0.14
Sex
Sex
Age (years) Mean
Male Female
Tumor location 6.04
0.7e48.0
0.08
Histology, World Health Organization grade II III
2.28
0.5e8.8
0.23
Size
Frontal
2 (15.4)
3 (37.5)
Temporal
8 (61.5)
1 (12.5)
Parietal
0
0
Occipital
1 (7.7)
1 (12.5)
0
2 (25)
Cerebellum
>40 mm
4.39
1.1e2.4
0.03
Location Cortical Deep
Gross total resection
0.5e8.3
0.26
0.1 1.68
13.3
0.62
Radiologic findings Calcification (þ)
0.49
0.0e4.0
0.50
0
1 (7.7)
0
0
1 (12.5)
<40
11 (84.6)
4 (50)
>40
2 (15.4)
4 (50)
Absent
11 (84.6)
8 (100)
Present
2 (15.4)
0
Tumor size (mm) 0.15
Calcification
Diffusion restriction
Absence 15.23
1.9e121.5
0.01
0.51
Diffusion restriction
1.14
0.2e5.8
0.87
Hyperperfusion
1.09
0.1e9.4
0.93
3/5 (60)
1.00
3/5 (60)
3/4 (75)
1.00
Brain positron emission tomography scan (11 of 21 patients) Hypermetabolism
4/5 (80)
4/6 (66.7)
1.00
Absent
10 (76.9)
1 (12.5)
Present
3 (23.1)
7 (87.5)
Gross total resection
11 (84.6)
7 (87.5)
Subtotal resection
2 (15.4)
1 (12.5)
1.00
2/13 (15.4)
1/8 (12.5)
1.00
56.4
48.0
0.61
Peritumoral edema
Positron emission tomography findings 3.58
3/6 (50)
Magnetic resonance imaging perfusion-weighted imaging (9 of 21 patients) Hyperperfusion
Advanced magnetic resonance imaging findings
Hypermetabolism
1 (7.7)
Fourth ventricle
Magnetic resonance imaging diffusion-weighted imaging (11 of 21 patients)
Peritumoral edema
Presence
Suprasellar
Thalamus 2.16
Extent of resection
Subtotal resection
P Value
0.3e32.3
0.25
Bold values indicate statistical significance.
<0.01
Extent of resection
directly to PXA, some factors associated with the PTE may affect the prognosis of PXA. The role of PTE in the recurrence of PXA has not been fully shown, and the mechanism and clinical impact of PTE in PXA require further research. DWI has been used extensively in the evaluation of brain tumors; it can help with evaluation of tumor grading and the differential diagnosis of tumors.31 High signal intensity on DWI and a low ADC value in the brain tumor reflect high cellularity. High cellularity among the glial neoplasms suggests high-grade tumor.32
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Adjuvant treatment Radiation therapy Follow-up period (months) Mean
Values are number (%) except where indicated otherwise. Rate of presence of peritumoral edema shows statistical significance.
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Perfusion MRI findings can indicate higher-grade tumor and can distinguish treatment effects from true tumor progression in glial neoplasms,33 although from the limited results of our study, it seems that DWI and PWI may not reflect the aggressiveness and histologic grade of PXA. However, this result should be cautiously interpreted because of the low number of patients with anaplastic PXA (4 patients); if the number of patients were higher, the result could be different. PXA is a rare and unique circumscribed astrocytic neoplasm, and as mentioned earlier, it showed variable clinical and radiologic findings. Brain PET studies have been widely used to evaluate brain tumors, and PET findings of glioma may provide an independent measure of the aggressiveness of a brain tumor and may play a supplementary role in pathologic grading.34 PET is an adjunct radiologic tool for brain tumor, and has been used with DWI and PWI to make differential diagnoses of brain tumors. However, in our study, PET findings were not able to differentiate the tumor grade (PXA grade II vs. anaplastic PXA) or predict aggressiveness, the ability of PET to predict the aggressive clinical behavior of other brain tumors could not be directly applied to patients with PXA. Future studies to evaluate the clinical predictive abilities of DWI, PWI, and PET are needed. Treatment and Prognosis of PXA In our study, 21 patients (84%) underwent GTR and 4 patients (16%) underwent STR. Seven patients also underwent postoperative adjuvant radiotherapy (RT). The standard treatment guidelines for PXA have not been established. In our institute, after GTR of PXA grade II, we do not routinely give further treatment such as RT and chemotherapy. However, in PXA WHO grade III, postoperative adjuvant RT is routinely given to patients, even although GTR is normally performed. In their SEER (Surveillance Epidemiology and End Results) analysis, Perkins et al.6 reported that the EOR is an independent prognostic factor for PXA. Giannini et al.15 reported that the EOR of PXA is a single factor associated with recurrence-free survival but not OS. However, some investigators3,10 have also reported that EOR was not associated with OS and PFS. In our study, EOR did not affect the OS and PFS of PXA. Thus, EOR remains an equivocal factor for OS and PFS in PXA. The effectiveness of RT and chemotherapy for PXA are still controversial, and the role of adjuvant RT is unclear. Macaulay et al.35 reported that postoperative RT may have a benefit for reducing the recurrence of PXA. However, several investigators have reported that adjuvant RT showed no benefit for the prognosis of PXA.3,10,11,35 Because of our high recurrence rate for PXA, we cannot help but consider adjuvant therapy. In our series, adjuvant RT was given to 7 patients: 4 with anaplastic PXA, 1 after GTR for PXA WHO grade II (diagnosed PXA with anaplastic features according to previous 2007 WHO classification), and 2 after STR for PXA WHO grade II. In our study, of the 3 patients with PXA grade II who received adjuvant RT, 1 experienced recurrence. In the patients with PXA WHO grade III who received RT, 3 of 4 experienced recurrence during the follow-up period.
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Chemotherapy for PXA has generally been considered ineffective.1,3,15 In our institute, we did not give chemotherapy as a primary adjuvant therapy, and we used chemotherapy only as a salvage therapy for recurrent disease. We only used temozolomide and the vascular endothelial growth factor inhibitor bevacizumab after recurrence. Cartmill et al.36 reported the benefit of vincristine and carboplatin chemotherapy for 1 case of recurrent PXA, and in a case report, Koga et al.37 reported that nimustine and temozolomide achieved long-term control of disseminated recurrent PXA. These 2 reports were case reports, and thus, their results should be interpreted cautiously. The efficacy of chemotherapy for PXA is still controversial; future study should include the effect of RT and chemotherapy for PXA. Giannini et al.15 investigated 71 patients with PXA and reported favorable outcomes of 81% 5-year OS and 72% 5-year recurrencefree survival. However, recurrence rates of 29%e33% and overall mortality of 15%e30% have been reported for PXA,3,9 and furthermore, PXA can undergo malignant transformation with reported progression rates ranging from 10% to 38%.3,38 A recent report by Oh et al. showed a PXA recurrence rate of 78% and a malignant transformation rate of 28%.10 In our series, 6 deaths (24%) occurred during the mean follow-up period of 51.4 months, and recurrence occurred in 11 patients (44%). The 10-year survival was 40.9% for PXA WHO grade II. The 5-year PFS of PXA grade II was 65.1%, and the 3-year PFS of PXA WHO grade III was 50%. These are higher recurrence rates than found in other low-grade gliomas. Previously, we considered PXA as an indolent tumor with a relatively good prognosis; however, over time, we have increasingly recognized that PXA has an unpredictable clinical behavior and higher recurrence and malignant transformation rates. Considering the high recurrence rate of PXA, close follow-up of patients with PXA and regular brain imaging are needed. Although subject to debate, the prognostic factors for PXA reported in the previous literature include age, mitotic index, necrosis on histology, EOR, and BRAF V600E mutation.2,13,39 Tumor size and ePTE were statistically significant factors for poor PFS according to the univariate analysis. Age, EOR, histologic grade, and adjuvant therapy were not found to be prognostic factors in our study. Limitations Because of the rarity of PXA, our study contains only 25 adult patients. The study was also retrospectively designed, which thus precludes a fully meaningful analysis, because it could possibly be subject to a selection bias. Moreover, only 4 patients with anaplastic PXA were enrolled, and the preoperative imaging and immunohistochemical studies were not uniform across patients. This low number of patients with anaplastic PXA is insufficient to elicit a meaningful analysis. We also included the 4 patients with anaplastic PXA in the risk factor analysis, in which they may have acted as possible confounding factors. However, in the comparison of the silent and recurrent PXA WHO grade II groups, we were able to identify that ePTE was a distinguishing factor for the recurrent group. In addition, this is a single-institutional series
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spanning a 14-year study period, and the variable length of the follow-up data means that it is difficult to show the definitive clinical characteristics of PXA and draw conclusions on the best treatment strategies and outcomes. This study is the first to review the details of radiologic findings and their association with the clinical outcomes of adult PXA in a single institute, so our results may become a cornerstone study for future meta-analysis or prospective studies. CONCLUSIONS PXA is a very rare glial neoplasm, and the clinical and radiologic features of PXA are not uniform. As with other gliomas, our study
REFERENCES 1. Kepes JJ, Rubinstein LJ, Eng LF. Pleomorphic xanthoastrocytoma: a distintive meningocerebral glioma of young subjects with relatively favorable prognosis. A study of 12 cases. Cancer. 1979;44: 1839-1852. 2. Ida CM, Rodriguez FJ, Burger PC, Caron AA, Jenkins SM, Spears GM, et al. Pleomorphic xanthoastrocytoma: natural history and long term follow-up. Brain Pathol. 2015;25:575-586. 3. Lim S, Kim JH, Kim SA, Park ES, Ra YS, Kim CJ. Prognostic factors and therapeutic outcomes in 22 patients with pleomorphic xanthoastrocytoma. J Korean Neurosurg Soc. 2013;53:281-287. 4. Kleihues P, Burger PC, Scheithauer BW. The new WHO classification of brain tumours. Brain Pathol. 1993;3:255-268. 5. Louis DN, Perry A, Reifenberger G, Deimling Av, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803-820. 6. Perkins SM, Mitra N, Fei W, Shinohara ET. Patterns of care and outcomes of patients with pleomorphic xanthoastrocytoma: a SEER analysis. J Neurooncol. 2012;110:99-104. 7. Vu TM, Liubinas SV, Gonzales M, Drummond KJ. Malignant potential of pleomorphic xanthoastrocytoma. J Clin Neurosci. 2012;19:12-20. 8. Weldon-Linne CM, Victor TA, Groothuis DR, Vick NA. Pleomorphic xanthoastrocytoma ultrastructural and immunohistochemical study of a case with a rapidly fatal outcome following surgery. Cancer. 1983;52:2055-2063. 9. Cervoni L, Salvati M, Santoro A, Celli P. Pleomorphic xanthoastrocytoma: some observations. Neurosurg Rev. 1996;19:13-16. 10. Oh T, Kaur G, Madden M, Bloch O, Parsa AT. Pleomorphic xanthoastrocytomas: institutional experience of 18 patients. J Clin Neurosci. 2014;21: 1767-1772. 11. Rutkowski MJ, Oh T, Niflioglu GG, Safaee M, Tihan T, Parsa AT. Pleomorphic xanthoastrocytoma with anaplastic features: retrospective case series. World Neurosurg. 2016;95:368-374.
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findings suggest that PXA is not a homogenous disease entity. Tumor size and PTE are possible prognostic factors of adult PXA, and PTE may be associated with recurrence in PXA WHO grade II. Subject to the limitations of the study, PTE in PXA was found to be associated with a poorer prognosis. DWI, PWI, and PET findings failed to predict the clinical behavior and histologic grade of PXA. PXA showed a high recurrence rate, and thus, close follow-up is needed. In the future, collaborative international study is needed to show the natural history of PXA and establish the standard treatment. Also, a study of molecular marker that can accurately predict the prognosis is needed.
12. Etzl MM Jr, Kaplan AM, Moss SD, Spataro J, Bonstelle CT, Lawson MA, et al. Positron emission tomography in three children with pleomorphic xanthoastrocytoma. J Child Neurol. 2002;17:522-527. 13. Tonse R, Gupta T, Epari S, Shastri JG, Gurav M, Bano N, et al. Impact of WHO 2016 update of brain tumor classification, molecular markers and clinical outcomes in pleomorphic xanthoastrocytoma. J Neurooncol. 2018;136:343-350. 14. Louis DN, Ohagki H, Wiestler OD, Cavenee WK. WHO Classification of Tumours of the Central Nervous System. 4th ed. Geneva, Switzerland: International Agency for Research on Cancer; 2007. 15. Giannini C, Scheithauer BW, Brat PCBDJ, Wollan PC, Lach B, O’Neill BP. Pleomorphic xanthoastrocytoma what do we really know about it? Cancer. 1999;85:2033-2045. 16. Jagtap SV, Gupta SO, Jokhi CD, Jagtap SS. Pleomorphic xanthoastrocytoma. Int Surg J. 2017;4: 3789-3791. 17. Pahapill PA, Ramsay DA, Maestro D FR. Pleomorphic xanthoastrocytoma: case report and analysis of the literature concerning the efficacy of resection and the significance of necrosis. Neurosurg Rev. 1996;38:822-829. 18. Nasuha NA, Daud AH, Ghazali MM, Yusoff AAM, Zainuddin N, Abdullah JM, et al. Molecular genetic analysis of anaplastic pleomorphic xanthoastrocytoma. Asian J Surg. 2003;26:120-125. 19. Nakajima T, Shamoto TKH, Watanabe M, Suzuki H, Tominaga T. Malignant transformation of pleomorphic xanthoastrocytoma. Acta Neurochir. 2006;148:67-71. 20. Lassaletta A, Zapotocky M, Mistry M, Ramaswamy V, Honnorat M, Krishnatry Rahul, et al. Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas. J Clin Oncol. 2017;35:2934-2948. 21. Venneti S, Huse JT. The evolving molecular genetics of low-grade glioma. Adv Anat Pathol. 2015; 22:94-101. 22. Lucato LT. Clinical, histological and imaging aspects of pleomorphic xanthoastrocytomas: the key is in the name. Arq Neuropsiquiatr. 2013;71:3-4.
23. Yu S, He L, Zhuang X, Luo B. Pleomorphic xanthoastrocytoma: MR imaging findings in 19 patients. Acta Radiol. 2010;52:223-2228. 24. Criscuolo Gregory R. The genesis of peritumoral vasogenic brain edema and lumor cysts: a hypothetical role for tumor-derived vascular permeability factor. Yale J Biol Med. 1993;66:277-314. 25. Stummer W. Mechanisms of tumor-related brain edema. Neurosurg Focus. 2007;22:E8. 26. Schoeneggera K, Oberndorfere S, Wuschitze B, Struhale W, Hainfellnerb J, Prayerc D, et al. Peritumoral edema on MRI at initial diagnosis: an independent prognostic factor for glioblastoma? Eur J Neurol. 2009;16:874-878. 27. Tien RD, Cardenas CA, Rajagopalan S. Pleomorphic xanthoastrocytoma of the brain: MR findings in six patients. Am J Roentgenol. 1992;159:1287-1290. 28. Yamahara T, Numa Y, Oishi T, Kawaguchi T, Seno T, Asai A, et al. Morphological and flow cytometric analysis of cell infiltration in glioblastoma: a comparison of autopsy brain and neuroimaging. Brain Tumor Pathol. 2010;27:81-87. 29. Chen J, Li Y, Yu T-S, McKay RM, Burns DK, Kernie SG, et al. A restricted cell population propagates glioblastoma growth following chemotherapy. Nature. 2012;488:522-526. 30. Mangiola A, Bonis PD, Maira G, Balducci M, Sica G, Lama G, et al. Invasive tumor cells and prognosis in a selected population of patients with glioblastoma multiforme. Cancer. 2008;113: 841-845. 31. Hygino da Cruz LC Jr, Vieira IG, Domingues RC. Diffusion MR imaging: an important tool in the assessment of brain tumors. Neuroimaging Clin North Am. 2011;21:27-49. 32. Kono K, Inoue Y, Nakayama K, Shakudo M, Morino M, Ohata K, et al. The role of diffusionweighted imaging in patients with brain tumors. AJNR Am J Neuroradiol. 2001;22:1081-1088. 33. Korfiatis P, Erickson B. The basics of diffusion and perfusion imaging in brain tumors. Appl Radiol. 2014;43:22-29. 34. Alavi JB, Alavi A, Chawluk J, Kushner M, Powe J, Hickey W, et al. Positron emission tomography in patients with glioma: a predictor of prognosis. Cancer. 1988;62:1074-1078.
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35. Macaulay JB, Jay V, Hoffman HJ, Becker LE. Increased mitotic activity as a negative prognostic indicator in pleomorphic xanthoastrocytoma. J Neurosurg. 1993;79:761-768.
38. Marton E, Feletti A, Orvieto E, Longatti P. Malignant progression in pleomorphic xanthoastrocytoma; Personal experience and review of the literature. J Neurol Sci. 2007;252:144-153.
36. Cartmill M, Hewitt M, Walker D, Lowe J, Jaspan T, Punt J. The use of chemotherapy to facilitate surgical resection in pleomorphic xanthoastrocytoma: experience in a single case. Childs Nerv Syst. 2001;17:563-566.
39. Gallo P, Cecchi PC, Locatelli F, Rizzo P, Ghimenton C, Gerosa M, et al. Pleomorphic xanthoastrocytoma: long-term results of surgical treatment and analysis of prognostic factors. Br J Neurosurg. 2013;27:759-764.
37. Koga T, Morita A, Maruyama K, Tanaka M, Ino Y, Shibahara J, et al. Long-term control of disseminated pleomorphic xanthoastrocytoma with anaplastic features by means of stereotactic irradiation. Neuro Oncol. 2008;11:446-451.
Conflict of interest statement: The authors declare that the article content was composed in the absence of any
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commercial or financial relationships that could be construed as a potential conflict of interest. Received 4 December 2017; accepted 1 March 2018 Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.03.007 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
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Peritumoral Edema Affects the Prognosis in Adult Pleomorphic Xanthoastrocytoma: Retrospective Analysis of 25 Patients Joonho Byun, Seok Ho Hong, Young-Hoon Kim, Jeong Hoon Kim, Chang Jin Kim
BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) is a very rare glial neoplasm. The clinical behavior of PXA is not uniform, and the purpose of this study was to investigate the clinical characteristics of adult PXA and identify prognostic factors.
-
METHODS: Twenty-five patients aged 18 years or older who were diagnosed with PXA between 2002 and 2016 were analyzed.
prognostic factors for adult PXA. Also, peritumoral edema may be associated with recurrence in PXA WHO grade II. PXA showed a high recurrence rate, and thus close followup is needed.
-
RESULTS: Twenty-one patients (84%) had PXA World Health Organization (WHO) grade II and 4 patients (16%) had anaplastic PXA (WHO grade III). The median overall survival of PXA WHO grade II and III was 97 and 56 months, respectively. The 3-year progression-free survival of PXA WHO grade II and III was 65.1% and 50%, respectively (P [ 0.37 and 0.21). Diffusion-weighted imaging, perfusion-weighted imaging, and positron emission tomography findings failed to predict the histologic grade of PXA and recurrence of PXA WHO grade II. Tumor size >40 mm and presence of evident peritumoral edema (ePTE) were prognostic factors for poor progressionfree survival (hazard ratios, 4.4 and 15.2, respectively; P [ 0.03 and 0.01) according to a univariate analysis. In the recurrent and silent PXA grade II groups, ePTE was present in 87.5% and 23.1% of cases, respectively (P <0.01).
-
CONCLUSIONS: The clinical and radiologic features of PXA are not uniform. Tumor size and ePTE are possible
-
Key words Peritumoral edema - Pleomorphic xanthoastrocytoma - Recurrence -
Abbreviations and Acronyms ADC: Apparent diffusion coefficient CI: Confidence interval DWI: Diffusion-weighted imaging EOR: Extent of resection ePTE: Evident peritumoral edema GIC: Glioblastoma initiating cell GTR: Gross total resection HPF: High-power field HR: Hazard ratio MRI: Magnetic resonance imaging OS: Overall survival PET: Positron emission tomography PFS: Progression-free survival
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INTRODUCTION
P
leomorphic xanthoastrocytoma (PXA) was first described by Kepes et al. in 1979.1,2 This rare neoplasm accounts for 1% of all astrocytic tumors.3 It was originally added to the World Health Organization (WHO) classification of tumors in 1993.4 The latest updated 2016 WHO classifications reclassified PXA to include “anaplastic PXA,” which requires 5 or more mitoses per 10 high-power fields (HPF). PXA tumors are considered WHO grade II and anaplastic PXA tumors WHO grade III.5 Because PXA usually occurs at a young age, prediction of its prognosis is crucial for proper decisions on the long-term management of patients.6 PXA is known to have a relatively benign clinical course, but this clinical course does not always proceed in a uniform fashion.7,8 Recurrence rates for PXA have been reported to range from 29% to 33%, with overall mortality of 15%e30%.3,9 There has been increasing recognition that PXA may have an unpredictable clinical behavior and it seems to have a high tendency to recur and undergo malignant transformation.2 A nonsuperficial location, a high mitotic index 5/10 HPF, the extent of resection, nonegross total resection (GTR), old age, and
PTE: Peritumoral edema PWI: Perfusion-weighted imaging PXA: Pleomorphic xanthoastrocytoma RT: Radiotherapy STR: Subtotal resection WHO: World Health Organization Department of Neurological Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea To whom correspondence should be addressed: Seok Ho Hong, M.D., Ph.D. [E-mail: [email protected]] Citation: World Neurosurg. (2018). https://doi.org/10.1016/j.wneu.2018.03.007 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2018 Elsevier Inc. All rights reserved.
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non-BRAF V600E mutations are associated with a poor prognosis for PXA.1,10,11 Etzl et al.12 claimed that a hypermetabolic positron emission tomography (PET) finding was associated with aggressive clinical behavior of PXA,1 and a recent report by Tonse et al.13 suggested that anaplastic pathology, subtotal resection, and nonmutated BRAF V600E were associated with poor prognosis. However, the factors predicting aggressive PXA behaviors have not been fully elucidated. The purpose of this report was therefore to investigate the clinical characteristics of adult PXA through our institutional experience and to identify the prognostic factors associated with recurrence and poor prognosis, and the potential value of radiologic findings as an indicator of recurrence and aggressive behavior. PATIENTS AND METHODS This study was approved by our institutional review board. Our institutional database was searched for patients aged 18 years or older who underwent surgery and were diagnosed with PXA between 2002 and 2016. Only newly diagnosed cases and those who underwent surgery in our institution were enrolled; recurrent tumors with unavailable information on the primary tumor were excluded. A total of 27 patients (aged >18 years) with PXA who were treated in our institute between January 2002 and December 2016 were identified. Clinical data were unavailable for 1 patient, and 1 patient who harbored recurrent tumor underwent initial surgery in an outside hospital. This situation left 25 adult patients with PXA for inclusion in this study, and a review of all their clinical, radiologic, and surgical records was performed. Histologic specimens were re-examined by our institutional neuropathologist, who reclassified PXA (WHO grade II) and anaplastic PXA (WHO grade III) according to the 2016 WHO classification of central nervous system tumors. The extent of resection (EOR) was defined according to the following criteria. GTR was defined as the tumor being totally removed under gross examination, whereas subtotal resection (STR) was defined as incomplete resection of the tumor but with <10% of the tumor left in place. Biopsy was defined as tissue obtained for histopathologic examination with >10% of the tumor remaining. The size of the tumor was defined by the maximal tumor diameter in 2 dimensions. The type of tumor was classified into 4 subtypes: solid; solid plus cystic; hemorrhagic and solid plus cystic; and hemorrhagic. The extent of peritumoral edema (PTE) was defined by a region of very bright signal intensity surrounding the tumor on T2-weighted magnetic resonance imaging (MRI). Axial scans were available for most patients, and additional coronal and sagittal scans were available for some patients. Axial T2-weighted images and/or coronal and sagittal T2-weighted images were analyzed. To minimize interobserver variance and increase the reliability of measurement stratification, edema extending further than 5 mm from the tumor margin to the outer edge was defined as presence of evident PTE (ePTE), and edema extending less than 5 mm from the tumor margin or the absence of high signal intensity surrounding the tumor on T2-weighted imaging was defined as absence of ePTE. The findings of MRI diffusion-weighted imaging (DWI), MRI perfusion-weighted imaging (PWI), and [18F]-fluorodeoxyglucosePET scans were also obtained. DWI was performed using a
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spin-echo sequence with diffusion weightings of b ¼ 0 and b ¼ 1000 seconds/mm2. Apparent diffusion coefficient (ADC) maps were generated with a monoexponential fit on a voxel-tovoxel basis for all imaging planes. High signal intensity on DWI and low value on ADC were considered to indicate diffusion restriction. PWI involved a dynamic susceptibility contrast study with injection of 0.1 mL/kg Gadovist at a 1 mmol/L concentration at 5 mL/second. The PET scans were performed with [18F]-fluorodeoxyglucose, a measure of cerebral glucose metabolism. An infusion of 0.143 mCi per kilogram body weight was administered. Initial follow-up involved clinical evaluation and MRI at 1 month, 6 months, and 1 year after surgery, with annual checks thereafter. Subgroup comparisons were performed using Student t tests, Mann-Whitney tests, c2 tests, and Fisher exact tests. We also investigated the overall survival (OS) and progression-free survival (PFS) of our patients, as well as the prognostic factors. The OS was defined as the time between the date of the initial diagnosis and the date of death, and the PFS was defined as the time between the date of the initial treatment and the date of tumor recurrence or progression according to radiologic findings. OS and PFS were analyzed using Kaplan-Meier survival analysis, and subgroup comparisons were performed using log-rank tests. Potential prognostic factors for OS and PFS, including age, sex, histology, tumor size, EOR, calcification, ePTE, DWI, PWI, and PET findings, were analyzed using a Cox proportional hazards model. The proportional hazards assumption was confirmed by testing of Schoenfeld residuals, and no relevant violations were found. All statistical analyses were conducted using SPSS version 18.0 (SPSS Inc., Chicago, Illinois, USA). A P value < 0.05 was considered statistically significant. RESULTS Patient Demographics There were 8 male (32%) and 17 female (68%) patients, with a mean age of 29.9 years (range, 18e60 years). The most common presenting symptom was seizure (48%), followed by headache (32%), motor weakness (8%), visual disturbance (4%), and dizziness (4%). The most common location of PXA was the temporal lobe (n ¼ 11; 44%), followed by the frontal lobe (n ¼ 7; 28%), occipital lobe (n ¼ 2; 8%), cerebellum (n ¼ 2; 8%), suprasellar area (n ¼ 1; 4%), fourth ventricle (n ¼ 1; 4%), and thalamus (n ¼ 1; 4%). The mean tumor size was 33.6 mm (range, 10e70 mm). The tumor types were divided between the 4 subgroups as follows: solid type tumor, n ¼ 12 (48%); solid plus cystic portion, n ¼ 10 (40%); hemorrhagic tumor, n ¼ 1 (4%); and solid plus cystic with hemorrhagic tumor, n ¼ 2 (8%). Twenty-one patients (84%) were diagnosed with PXA WHO grade II, and 4 patients (16%) were diagnosed with PXA WHO grade III (anaplastic PXA). The detailed basal demographic findings of adult PXA are shown in Table 1. Radiologic Findings Brain computed tomography scans from 21 of the 25 patients were examined. Seven patients (33.3%) presented with an isodense mass, 13 (61.9%) with a hyperdense mass, and 1 (4.8%) with a hypodense mass. On T1-weighted MRI, 22 patients (88%) showed
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ADULT PLEOMORPHIC XANTHOASTROCYTOMA
Table 1. Characteristics of All Enrolled Patients with Adult Pleomorphic Xanthoastrocytoma Characteristic Sex
Table 1. Continued Characteristic Absent
14 (56)
Present
11 (44)
Male, n (%)
8 (32)
WHO grade II
8/21 (38.1)
Female, n (%)
17 (68)
WHO grade III
3/4 (75)
Male/female ratio
0.47
Pattern, n (%)
Age (years) Mean
Local recurrence 29.9 (range, 18e60)
Presenting symptoms, n (%)
10 (90.9)
Distant recurrence
1 (9.1)
High-grade transformation
4 (36.4)
Seizure
12 (48)
Death
6 (24)
Headache
8 (32)
Mean
51.4 (range, 10e112)
Motor weakness
2 (8)
Median
Visual disturbance
1 (4)
PXA, pleomorphic xanthoastrocytoma; WHO, World Health Organization.
Dizziness
1 (4)
Incidental findings
1 (4)
Tumor location, n (%) Frontal
7 (28)
Temporal
11 (44)
Parietal
0
Occipital
2 (8)
Cerebellum
2 (8)
Suprasellar
1 (4)
th
4 ventricle
1 (4)
Thalamus
1 (4)
Tumor size (mm) Mean
33.6 (range, 10e70)
Tumor type, n (%) Solid
12 (48)
Solid þ cyst
10 (40)
Hemorrhagic tumor
1 (4)
Solid þ cyst and hemorrhage
2 (8)
Histology PXA (WHO grade II) Anaplastic PXA (WHO grade III)
21 (84)
21 (84)
Subtotal resection
4 (16)
Adjuvant treatment, n (%)
Chemotherapy
7 (28) 0
Recurrence, n (%) Continues
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a low signal intensity lesion, 2 patients (8%) showed an isosignal intensity lesion, and 1 patient (4%) showed a mixed signal intensity lesion. On T2-weighted MRI, 24 patients (96%) showed a high signal intensity lesion and 1 patient (4%) showed a mixed signal intensity lesion. Twenty-four patients (96%) showed enhancement on gadolinium-enhanced T1-weighted MRI. Calcification of the tumor was noted in 3 patients (12%), and ePTE was seen in 13 patients (52%). We compared the advanced MRI (DWI and PWI) and PET findings between PXA WHO grade II and III. In the PXA WHO grade II group, diffusion restriction on DWI was shown in 6 of 11 patients (54.5%), increasing perfusion on PWI was shown in 6 of 9 patients (66.7%), and hypermetabolism was shown on brain PET scan in 8 of 11 patients (72.7%). In the PXA WHO grade III group, all examined patients showed diffusion restriction on DWI, increased perfusion on PWI, and hypermetabolism on brain PET scan; however, the differences between PXA WHO grade II and III patients did not reach statistical significance (P ¼ 0.23, 0.48, and 0.52, respectively). The detailed radiologic findings of PXA are shown in Table 2. Representative cases of PXA WHO grade II with and without the radiologic finding of an ePTE are presented in Figure 1, and a case showing the radiologic findings of PXA WHO grade III is presented in Figure 2.
4 (16)
Extent of resection
Radiation therapy
46
Treatment and Prognosis Twenty-one patients (84%) underwent GTR and 4 patients (16%) underwent STR. Seven patients (28%) received adjuvant radiation therapy; 4 of these had PXA WHO grade III, 1 patient had GTR for PXA WHO grade II (diagnosed PXA with anaplastic features according to the 2007 WHO classification), and 2 patients had STR for PXA WHO grade II. No patient received adjuvant chemotherapy. Recurrence occurred in 11 patients (44%): local recurrence in 10 patients (90.9%) and a distant recurrence in 1 patient (9.1%). High-grade transformation was observed in 4
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Table 2. Radiologic Findings of Patients with Adult Pleomorphic Xanthoastrocytoma Radiologic Findings
n (%)
Computed tomography scan Isodense
7 (33.3)
Hyperdense
13 (61.9)
Hypodense
1 (4.8)
MRI T1-weighted imaging Low signal intensity Isosignal intensity High signal intensity Mixed signal intensity
22 (88) 2 (8) 0 1 (4)
MRI T2-weighted imaging Low signal intensity Isosignal intensity High signal intensity Mixed signal intensity
0 0 24 (96) 1 (4)
MRI contrast enhancement No enhancement Enhancement
1 (4) 24 (96)
Calcification Present
3 (12)
Absent
22 (88)
Peritumoral edema Absent
12 (48)
Present
13 (52)
MRI diffusion-weighted imaging Diffusion restriction
10 (66.7)
No diffusion restriction
5 (33.3)
MRI perfusion-weighted imaging Normal perfusion
3 (23.1)
Hyperperfusion
10 (76.9)
Brain positron emission tomography scan No hypermetabolism
3 (20)
Hypermetabolism
12 (80)
MRI, magnetic resonance imaging.
patients (36.4%). Postoperative surgical complications of epidural hematoma occurred in 2 patients (8%). The seizure control rate after surgery was 100% (12 of 12 patients). Six patients (24%) died during the follow-up period, with the cause of death being disease progression in all 6. The mean follow-up period was 51.4 months (range, 2e112 months). The detailed treatment regimens for the adult PXA are shown in Table 1.
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The OS of PXA WHO grade II at 1, 2, 3, 5, 7, and 10 years was 100%, 89.5%, 89.5%, 89.5%, 61.4%, and 40.9%, respectively, whereas the OS of PXA WHO grade III at 1, 2, 3, 5, 7, and 10 years was 100%, 100%, 100%, 0%, 0%, and 0%, respectively. The PFS of PXA at 6 months and 1, 2, 3, 5, and 7 years was 90.5%, 81%, 70.5%, 65.1%, 65.1%, and 52%, respectively, whereas the PFS of PXA WHO grade III at 6 months and 1, 2, 3, 5 and 7 years was 100%, 75%, 50%, 50%, 0%, and 0%, respectively. The differences in OS and PFS between PXA WHO grade II and III were not statistically significant (P ¼ 0.38 and 0.21, respectively). The Kaplan-Meier survival curves are presented in Figure 3A and B. Potential prognostic factors for PFS in adult PXA were examined, including age, sex, histology, size, EOR, presence of calcification, ePTE, diffusion restriction on DWI, increasing perfusion on PWI, and hypermetabolism on PET. Tumor size larger than 40 mm (hazard ratio [HR], 4.39; 95% confidence interval [CI], 0.2e10.3; P ¼ 0.03) and presence of ePTE (HR, 15.23; 95% CI, 1.9e121.5; P ¼ 0.01) were prognostic factors for a poor PFS according to the univariate analysis. A detailed description of the univariate analysis is given in Table 3. For PXA with the absence of ePTE, the OS at 1, 2, 5, 7, and 10 years was 100%, 100%, 100%, 100% and 66.7%, respectively, and the PFS at 6 months and 1, 2, 3, and 6 years was all 100%. For PXA with the presence of ePTE, the OS at 1, 2, 5, 7, and 10 years was 100%, 83.3%, 69.4%, 23.1%, and 23.1%, and the PFS at 6 months and 1, 2, 3, and 5 years was 84.6%, 61.5%, 38.5%, 30.8%, and 20.5%. The differences in OS and PFS between PXA with an absence of ePTE and PXA with the presence of ePTE were statistically significant (P ¼ 0.02 and < 0.01, respectively; Figure 3C and D). We also compared the characteristics of sex, age, tumor location, tumor size, presence of calcification, presence of ePTE, EOR, and adjuvant treatment between the posttreatment silent PXA WHO grade II group and the recurrent PXA WHO grade II group. All parameters except ePTE showed no significant between group differences. In the recurrent PXA WHO grade II group, the presence of ePTE was 87.5%, whereas in the silent PXA WHO grade II group, it was 23.1%. This difference was statistically significant (P < 0.01). We then analyzed the value of advanced magnetic resonance and PET findings for predicting recurrence rate in PXA WHO grade II. In the recurrent PXA WHO grade II group, diffusion restriction on DWI was shown in 3 of 5 patients (60%), increasing perfusion on PWI was shown in 3 of 4 patients (75%), and hypermetabolism on PET was shown in 4 of 6 patients (66.7%). In the silent PXA WHO grade II group, 3 of 6 patients (50%) showed diffusion restriction on DWI, 3 of 5 patients (60%) showed increasing perfusion on PWI, and 4 of 5 patients (80%) showed hypermetabolism on PET. There were no significant differences in DWI, PWI, and PET findings between the silent and recurrent PXA WHO grade II groups (P ¼ 1.00, 1.00, and 1.00, respectively). A detailed description of the values is given in Table 4. For PXA WHO grade II with an absence of ePTE, the OS at 1, 2, 5, 7, and 10 years was 100%, 100%, 100%, 100%, and 66.7%, whereas for PXA WHO grade II with the presence of ePTE, the OS at 1, 2, 5, 7, and 10 years was 100%, 77.8%, 77.8%, 25.9%, and 25.9%. For PXA WHO grade II with an absence of ePTE, the PFS at 6 months and 1, 2, 3, and 5 years was all 100%, whereas for PXA WHO grade II with the presence
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Figure 1. Magnetic resonance imaging (MRI) findings of adult pleomorphic xanthoastrocytoma (PXA). (A, B) MRI of a 31-year-old male patient with a tumor located in the right temporal lobe. (A) The tumor was round and solid with a well-demarcated margin on T2-weighted imaging. There was no peritumoral edema (PTE) around the tumor. (B) The tumor showed high enhancement on gadolinium-enhanced T1-weighted imaging. This patient was diagnosed with PXA World Health Organization (WHO) grade II and did not experience recurrence during follow-up. (C, D) MRI of a 40-year-old female patient with a tumor located in the right frontal lobe. (C) The tumor was round, contained a cystic portion, and its margin was well demarcated on T2-weighted imaging. There was evident PTE around the tumor. (D) The
of ePTE, the PFS at 6 months and 1, 2, 3 and 5 years was 80%, 60%, 40%, 30%, and 30%. The differences in OS and PFS between PXA WHO grade II with absence of ePTE and PXA WHO grade II with presence of ePTE were statistically significant (P ¼ 0.02 and 0.03, respectively) (Figure 3E and F).
DISCUSSION PXA was first described by Kepes et al.1 and was originally added to the WHO classification of tumors in 1993.4 In 2007, the WHO classification classified PXA as a WHO grade II tumor and mentioned PXA “with anaplastic features.” PXA with anaplastic features showed variable levels of necrosis and/or 5 mitoses per HPF.14 However, in 2007, the WHO classifications of PXA and PXA with anaplastic features were both classified as grade II tumors. The latest updated 2016 WHO classification of the
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solid portion of the tumor showed high enhancement on gadolinium-enhanced T1-weighted imaging. This patient was diagnosed with PXA WHO grade II and experienced recurrence 15 months after surgery. (E, F) MRI of an 18-year-old female patient with a tumor located in the right medial temporal lobe. (E) The tumor was well delineated in T2-weighted imaging. High signal lesion around tumor (red arrow) and its thickness of high signal lesion about 3 mm. This case was considered to have absence of evident PTE. (F) The tumor showed enhancement on gadolinium-enhanced T1-weighted imaging. This patient was diagnosed with PXA WHO grade II and did not experience recurrence during the follow-up period.
tumors redefined anaplastic PXA as requiring 5 or more mitoses per 10 HPF and categorized it as a WHO grade III tumor.5 Clinical and Histologic Findings PXA is known to be a very rare low-grade glial neoplasm and usually occurs in a younger age group, so symptomatic control and long-term survival outcomes are the most important consideration in the management of PXA.6 PXA is known to have a predilection for locations in the temporal lobe and frequently produces seizures.3,15 In our series, the mean age of patients was 29.9 years, and the tumors did show a predilection for the temporal lobe (44%), with the most common presenting symptom being seizure (48%). Our study results are therefore consistent with those of previously reported studies. Although PXA usually occurs in young adults, the oldest patient in our series was 60 years old, and Jagtap et al.16 recently reported a 75-year-old patient
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Figure 2. Conventional and advanced magnetic resonance imaging findings in a 37-year-old female patient with anaplastic pleomorphic xanthoastrocytoma. (A) The tumor was located in the left frontal lobe and showed mixed low and high signal intensity on T2-weighted imaging. There was evident peritumoral edema around the tumor. (B) The tumor showed high
diagnosed as having PXA WHO grade II. PXA may therefore affect all ages. Twenty-one of 25 patients (84%) had PXA WHO grade II, and 4 of 25 patients (16%) had anaplastic PXA of WHO grade III. However, we could not find any significant survival differences between PXA WHO grade II and III, but we suspect that this might be because of insufficient PXA WHO grade III patient numbers; our study included only 4 patients with PXA WHO grade III. Although our study included patients with PXA WHO grade III, the recurrence and malignant transformation rates (44% and 36.4%, respectively) found in our study were high, especially considering that most patients had PXA WHO grade II. The histologic criteria of PXA include pleomorphic tumor cells with giant nuclei, xanthomatous cells, and abundant reticulin fiber deposition in the stroma. The presence of glial fibrillary acidic protein suggests an astrocytic origin. In anaplastic PXA, significant mitotic activity (5 mitoses per 10 HPF) should be observable. Necrosis and endothelial hyperplasia are known histologic characteristics of glioblastoma multiforme; however, necrosis and endothelial proliferation also can be seen in PXA. Pahapill et al.17 reported that necrosis of PXA was associated with poorer OS. Furthermore, Nasuha et al.18 reported that the typical histologic features, which include an absence of mitoses, necrosis, and endothelial proliferation, were generally considered to be the reason for the slow growth of PXA. However, Nakajima et al.19 reported a case of PXA WHO grade II that transformed to
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enhancement on gadolinium-enhanced T1-weighted imaging. (C) The tumor showed diffusion restriction on diffusion-weighted imaging. (D) The tumor showed hyperperfusion on a perfusion image. (E) Increased fluorodeoxyglucose uptake in the periphery of the tumor was identified on the fluorodeoxyglucose-positron emission tomography scan.
glioblastoma without mitosis, necrosis, or endothelial hyperplasia in the initial histology. The clinical impact of necrosis and endothelial hyperplasia in PXA is still under debate and should be included in future studies. Alterations in the B-RAF gene have been shown in low-grade glioma,20 and nearly 50%e60% of PXA tumors have been shown to harbor the BRAFV600E mutation.13,21 Radiologic Findings Regarding the imaging aspects of PXA, Lucato22 mentioned that the features of PXA are variable and the key is in the term PXA. Consistent with the term pleomorphic, the imaging features of PXAs are varied, which makes preoperative diagnosis difficult. Yu et al.23 reported magnetic resonance findings of 19 patients with PXA and found that 89.4% of tumors were located at the brain surface, whereas the other 10.6% were located in a deeper area. These investigators divided tumors into 3 morphologic subgroups, with 21% of tumors being cystic, 36.8% of tumors being mixed cystic-solid, and 42.1% being solid. Solid components of tumors were low signal intensity or isosignal intensity on T1-weighted imaging and slightly hyperintense on T2-weighted imaging, whereas 89.4% of tumors showed contrast enhancement. In our series, 80% of tumors were cortical tumors and 20% were located in deeper areas. The unusual locations were 2 (8%) in the cerebellum, 1 (4%) in the suprasellar area, 1 (4%) in the fourth ventricle, and 1 (4%) in the thalamus. We divided the tumor
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Figure 3. Kaplan-Meier survival analysis of adult pleomorphic xanthoastrocytoma. (A and B) Overall survival (OS) and progression-free survival (PFS) of patients with PXA WHO grade II or grade III. (C and D)
morphologic types into 4 subgroups: solid, solid with cyst, hemorrhagic, and solid with hemorrhage and cyst. The most common type of tumor was solid (n ¼12; 48%). On T1-weighted imaging, 96.3% of tumors showed low signal intensity or isosignal intensity, whereas on T2-weighted imaging, 96% of tumors showed high signal intensity. These MRI findings are consistent with previous reports. PTE can be seen in various brain tumors. The mechanism of PTE development in brain tumors is known to be vasogenic, but there are suggestions of a complex mechanism.24,25 PTE is considered one of the main characteristics of malignant glioma. Schoeneggera et al.26 reported that PTE is an independent factor for a poor prognosis in high-grade glioma. In an early report, Tien et al.27 speculated that PTE is related to the aggressive clinical behavior of PXA; however, these investigators experienced only 1 case of a tumor with PTE that was subject to recurrence. We defined edema extending further than 5 mm from the tumor margin to the outer edge as ePTE, and edema extending less than 5 mm from the tumor margin to the outer edge or the
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OS and PFS of patients with or without evident peritumoral edema (ePTE). (E and F) OS and PFS of PXA WHO grade II patients with or without ePTE.
absence of high signal intensity surrounding the tumor on T2-weighted images as absence of ePTE. In our study, 52% of tumors showed ePTE, with ePTE being a prognostic factor for poor PFS in the univariate analysis (HR, 15.23; 95% CI, 1.9e121.5; P ¼ 0.01). In the comparison between nonrecurrent (silent) and recurrent PXA WHO grade II, the percentage of tumors with ePTE was significantly higher in the recurrent PXA group (87.5% vs. 23.1%; P < 0.01). According to this result, we speculate that ePTE in PXA tumor might be associated with recurrence. The cause of PTE was extravasation of the fluid through flaws in the brain tumor microvasculature; however, some investigators have described the cause of PTE as complex and have suggested that vascular endothelial growth factor has a role.24,25 The role of the PTE area in PXA has not been clearly elucidated. In glioblastoma, glioblastoma stemlike or glioblastoma initiating cells (GICs) have been identified in the PTE area.28 These GICs have enhanced migratory and invasive capabilities compared with GICs from the tumor mass, which are the source of tumor recurrence.29,30 Although this evidence from patients with glioblastoma cannot be applied
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Table 3. Univariate Analysis of Prognostic Factors for Disease Progression of Adult Pleomorphic Xanthoastrocytoma Progression-Free Survival
Hazard Ratio
95% Confidence Interval
2.51
0.7e8.7
Silent Group (n [ 13)
Recurrence Group (n [ 8)
Male
7 (53.8)
1 (12.5)
Female
6 (46.2)
7 (87.5)
0.09
25.8
33.6
0.12
0.07
Variables P Value
Age (years) 30
Table 4. Comparison of the Characteristics of Posttreatment Silent Pleomorphic Xanthoastrocytoma (Grade II) and Recurrent Pleomorphic Xanthoastrocytoma (Grade II) Groups
0.14
Sex
Sex
Age (years) Mean
Male Female
Tumor location 6.04
0.7e48.0
0.08
Histology, World Health Organization grade II III
2.28
0.5e8.8
0.23
Size
Frontal
2 (15.4)
3 (37.5)
Temporal
8 (61.5)
1 (12.5)
Parietal
0
0
Occipital
1 (7.7)
1 (12.5)
0
2 (25)
Cerebellum
>40 mm
4.39
1.1e2.4
0.03
Location Cortical Deep
Gross total resection
0.5e8.3
0.26
0.1 1.68
13.3
0.62
Radiologic findings Calcification (þ)
0.49
0.0e4.0
0.50
0
1 (7.7)
0
0
1 (12.5)
<40
11 (84.6)
4 (50)
>40
2 (15.4)
4 (50)
Absent
11 (84.6)
8 (100)
Present
2 (15.4)
0
Tumor size (mm) 0.15
Calcification
Diffusion restriction
Absence 15.23
1.9e121.5
0.01
0.51
Diffusion restriction
1.14
0.2e5.8
0.87
Hyperperfusion
1.09
0.1e9.4
0.93
3/5 (60)
1.00
3/5 (60)
3/4 (75)
1.00
Brain positron emission tomography scan (11 of 21 patients) Hypermetabolism
4/5 (80)
4/6 (66.7)
1.00
Absent
10 (76.9)
1 (12.5)
Present
3 (23.1)
7 (87.5)
Gross total resection
11 (84.6)
7 (87.5)
Subtotal resection
2 (15.4)
1 (12.5)
1.00
2/13 (15.4)
1/8 (12.5)
1.00
56.4
48.0
0.61
Peritumoral edema
Positron emission tomography findings 3.58
3/6 (50)
Magnetic resonance imaging perfusion-weighted imaging (9 of 21 patients) Hyperperfusion
Advanced magnetic resonance imaging findings
Hypermetabolism
1 (7.7)
Fourth ventricle
Magnetic resonance imaging diffusion-weighted imaging (11 of 21 patients)
Peritumoral edema
Presence
Suprasellar
Thalamus 2.16
Extent of resection
Subtotal resection
P Value
0.3e32.3
0.25
Bold values indicate statistical significance.
<0.01
Extent of resection
directly to PXA, some factors associated with the PTE may affect the prognosis of PXA. The role of PTE in the recurrence of PXA has not been fully shown, and the mechanism and clinical impact of PTE in PXA require further research. DWI has been used extensively in the evaluation of brain tumors; it can help with evaluation of tumor grading and the differential diagnosis of tumors.31 High signal intensity on DWI and a low ADC value in the brain tumor reflect high cellularity. High cellularity among the glial neoplasms suggests high-grade tumor.32
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Adjuvant treatment Radiation therapy Follow-up period (months) Mean
Values are number (%) except where indicated otherwise. Rate of presence of peritumoral edema shows statistical significance.
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Perfusion MRI findings can indicate higher-grade tumor and can distinguish treatment effects from true tumor progression in glial neoplasms,33 although from the limited results of our study, it seems that DWI and PWI may not reflect the aggressiveness and histologic grade of PXA. However, this result should be cautiously interpreted because of the low number of patients with anaplastic PXA (4 patients); if the number of patients were higher, the result could be different. PXA is a rare and unique circumscribed astrocytic neoplasm, and as mentioned earlier, it showed variable clinical and radiologic findings. Brain PET studies have been widely used to evaluate brain tumors, and PET findings of glioma may provide an independent measure of the aggressiveness of a brain tumor and may play a supplementary role in pathologic grading.34 PET is an adjunct radiologic tool for brain tumor, and has been used with DWI and PWI to make differential diagnoses of brain tumors. However, in our study, PET findings were not able to differentiate the tumor grade (PXA grade II vs. anaplastic PXA) or predict aggressiveness, the ability of PET to predict the aggressive clinical behavior of other brain tumors could not be directly applied to patients with PXA. Future studies to evaluate the clinical predictive abilities of DWI, PWI, and PET are needed. Treatment and Prognosis of PXA In our study, 21 patients (84%) underwent GTR and 4 patients (16%) underwent STR. Seven patients also underwent postoperative adjuvant radiotherapy (RT). The standard treatment guidelines for PXA have not been established. In our institute, after GTR of PXA grade II, we do not routinely give further treatment such as RT and chemotherapy. However, in PXA WHO grade III, postoperative adjuvant RT is routinely given to patients, even although GTR is normally performed. In their SEER (Surveillance Epidemiology and End Results) analysis, Perkins et al.6 reported that the EOR is an independent prognostic factor for PXA. Giannini et al.15 reported that the EOR of PXA is a single factor associated with recurrence-free survival but not OS. However, some investigators3,10 have also reported that EOR was not associated with OS and PFS. In our study, EOR did not affect the OS and PFS of PXA. Thus, EOR remains an equivocal factor for OS and PFS in PXA. The effectiveness of RT and chemotherapy for PXA are still controversial, and the role of adjuvant RT is unclear. Macaulay et al.35 reported that postoperative RT may have a benefit for reducing the recurrence of PXA. However, several investigators have reported that adjuvant RT showed no benefit for the prognosis of PXA.3,10,11,35 Because of our high recurrence rate for PXA, we cannot help but consider adjuvant therapy. In our series, adjuvant RT was given to 7 patients: 4 with anaplastic PXA, 1 after GTR for PXA WHO grade II (diagnosed PXA with anaplastic features according to previous 2007 WHO classification), and 2 after STR for PXA WHO grade II. In our study, of the 3 patients with PXA grade II who received adjuvant RT, 1 experienced recurrence. In the patients with PXA WHO grade III who received RT, 3 of 4 experienced recurrence during the follow-up period.
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Chemotherapy for PXA has generally been considered ineffective.1,3,15 In our institute, we did not give chemotherapy as a primary adjuvant therapy, and we used chemotherapy only as a salvage therapy for recurrent disease. We only used temozolomide and the vascular endothelial growth factor inhibitor bevacizumab after recurrence. Cartmill et al.36 reported the benefit of vincristine and carboplatin chemotherapy for 1 case of recurrent PXA, and in a case report, Koga et al.37 reported that nimustine and temozolomide achieved long-term control of disseminated recurrent PXA. These 2 reports were case reports, and thus, their results should be interpreted cautiously. The efficacy of chemotherapy for PXA is still controversial; future study should include the effect of RT and chemotherapy for PXA. Giannini et al.15 investigated 71 patients with PXA and reported favorable outcomes of 81% 5-year OS and 72% 5-year recurrencefree survival. However, recurrence rates of 29%e33% and overall mortality of 15%e30% have been reported for PXA,3,9 and furthermore, PXA can undergo malignant transformation with reported progression rates ranging from 10% to 38%.3,38 A recent report by Oh et al. showed a PXA recurrence rate of 78% and a malignant transformation rate of 28%.10 In our series, 6 deaths (24%) occurred during the mean follow-up period of 51.4 months, and recurrence occurred in 11 patients (44%). The 10-year survival was 40.9% for PXA WHO grade II. The 5-year PFS of PXA grade II was 65.1%, and the 3-year PFS of PXA WHO grade III was 50%. These are higher recurrence rates than found in other low-grade gliomas. Previously, we considered PXA as an indolent tumor with a relatively good prognosis; however, over time, we have increasingly recognized that PXA has an unpredictable clinical behavior and higher recurrence and malignant transformation rates. Considering the high recurrence rate of PXA, close follow-up of patients with PXA and regular brain imaging are needed. Although subject to debate, the prognostic factors for PXA reported in the previous literature include age, mitotic index, necrosis on histology, EOR, and BRAF V600E mutation.2,13,39 Tumor size and ePTE were statistically significant factors for poor PFS according to the univariate analysis. Age, EOR, histologic grade, and adjuvant therapy were not found to be prognostic factors in our study. Limitations Because of the rarity of PXA, our study contains only 25 adult patients. The study was also retrospectively designed, which thus precludes a fully meaningful analysis, because it could possibly be subject to a selection bias. Moreover, only 4 patients with anaplastic PXA were enrolled, and the preoperative imaging and immunohistochemical studies were not uniform across patients. This low number of patients with anaplastic PXA is insufficient to elicit a meaningful analysis. We also included the 4 patients with anaplastic PXA in the risk factor analysis, in which they may have acted as possible confounding factors. However, in the comparison of the silent and recurrent PXA WHO grade II groups, we were able to identify that ePTE was a distinguishing factor for the recurrent group. In addition, this is a single-institutional series
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spanning a 14-year study period, and the variable length of the follow-up data means that it is difficult to show the definitive clinical characteristics of PXA and draw conclusions on the best treatment strategies and outcomes. This study is the first to review the details of radiologic findings and their association with the clinical outcomes of adult PXA in a single institute, so our results may become a cornerstone study for future meta-analysis or prospective studies. CONCLUSIONS PXA is a very rare glial neoplasm, and the clinical and radiologic features of PXA are not uniform. As with other gliomas, our study
REFERENCES 1. Kepes JJ, Rubinstein LJ, Eng LF. Pleomorphic xanthoastrocytoma: a distintive meningocerebral glioma of young subjects with relatively favorable prognosis. A study of 12 cases. Cancer. 1979;44: 1839-1852. 2. Ida CM, Rodriguez FJ, Burger PC, Caron AA, Jenkins SM, Spears GM, et al. Pleomorphic xanthoastrocytoma: natural history and long term follow-up. Brain Pathol. 2015;25:575-586. 3. Lim S, Kim JH, Kim SA, Park ES, Ra YS, Kim CJ. Prognostic factors and therapeutic outcomes in 22 patients with pleomorphic xanthoastrocytoma. J Korean Neurosurg Soc. 2013;53:281-287. 4. Kleihues P, Burger PC, Scheithauer BW. The new WHO classification of brain tumours. Brain Pathol. 1993;3:255-268. 5. Louis DN, Perry A, Reifenberger G, Deimling Av, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131:803-820. 6. Perkins SM, Mitra N, Fei W, Shinohara ET. Patterns of care and outcomes of patients with pleomorphic xanthoastrocytoma: a SEER analysis. J Neurooncol. 2012;110:99-104. 7. Vu TM, Liubinas SV, Gonzales M, Drummond KJ. Malignant potential of pleomorphic xanthoastrocytoma. J Clin Neurosci. 2012;19:12-20. 8. Weldon-Linne CM, Victor TA, Groothuis DR, Vick NA. Pleomorphic xanthoastrocytoma ultrastructural and immunohistochemical study of a case with a rapidly fatal outcome following surgery. Cancer. 1983;52:2055-2063. 9. Cervoni L, Salvati M, Santoro A, Celli P. Pleomorphic xanthoastrocytoma: some observations. Neurosurg Rev. 1996;19:13-16. 10. Oh T, Kaur G, Madden M, Bloch O, Parsa AT. Pleomorphic xanthoastrocytomas: institutional experience of 18 patients. J Clin Neurosci. 2014;21: 1767-1772. 11. Rutkowski MJ, Oh T, Niflioglu GG, Safaee M, Tihan T, Parsa AT. Pleomorphic xanthoastrocytoma with anaplastic features: retrospective case series. World Neurosurg. 2016;95:368-374.
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findings suggest that PXA is not a homogenous disease entity. Tumor size and PTE are possible prognostic factors of adult PXA, and PTE may be associated with recurrence in PXA WHO grade II. Subject to the limitations of the study, PTE in PXA was found to be associated with a poorer prognosis. DWI, PWI, and PET findings failed to predict the clinical behavior and histologic grade of PXA. PXA showed a high recurrence rate, and thus, close follow-up is needed. In the future, collaborative international study is needed to show the natural history of PXA and establish the standard treatment. Also, a study of molecular marker that can accurately predict the prognosis is needed.
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