pleomorphic xanthoastrocytoma ( pxa ) , first described by kepes et al.14 ) , is a rare neoplasm that accounts for 1% of all astrocytic tumors .
pxas are supratentorial and involve the temporal lobe , so the most common presentation is seizure3,6,12 - 14 ) .
the histologic features of the tumor are marked cellular pleomorphism , variable lipidization and abundant reticulin .
features such as necrosis , nuclear atypia and mitotic figures are suggestive of a high grade tumor7,11,14,17,18,21 ) . despite this ,
pxas possess a relatively favorable prognosis with a 10-year survival of 70% , and are classified as grade ii in the world health organization ( who ) classification6,20 ) .
factors such as mitotic activity and surgical extent are known to be related to prognosis6 ) . however , the clinical course and prognostic factors are still unknown . here
we describe the clinicopathologic and radiologic features , treatment outcomes and prognostic factors of 22 patients with pxa in a single institution .
between january 2000 and march 2012 , 22 consecutive patients were pathologically diagnosed with pxa in our institute .
a comprehensive analysis was conducted on these patients with regard to the clinical , radiologic and pathologic features at diagnosis as well as treatments and outcomes .
all patients underwent diagnostic and serial follow - up computed tomography ( ct ) or magnetic resonance ( mr ) scans on a regular basis .
the images were evaluated with respect to the following factors : location , degree of enhancement , size , demarcation , presence of cystic degeneration , peritumoral edema , hemorrhage , calcification , leptomeningeal involvement and bone remodeling .
peritumoral edema was defined as a maximum extent of increased t2 signal intensity on the tumor margin .
peritumoral edema was classified20 ) as mild , < 1 cm ; moderate , > 1 cm ; severe , > 2 cm .
an atypical tumor site was defined as any location other than the supratentorial cortex area .
a diagnosis of pxa was established based on the pathologic features described in the who classification of tumors of the central nervous system .
the presence of necrosis , mitotic figures and ki-67 were carefully evaluated by two pathologists .
the objective of surgery in all patients was to achieve gross total resection ( gtr ) .
the extent of resection was defined as follows : gtr , no surgical or imaging evidence of residual disease ; near total resection , < 10% residual tumor found in the surgical report and post - operative imaging ; and subtotal resection ( str ) , < 50% residual tumor found in the surgical report and post - operative imaging .
we evaluated the relationship between disease progression and enhancement , peritumoral edema , tumor size , atypical site , ki-67 index , necrosis and gtr by univariate analysis .
one patient who died from postoperative complications ( brain edema ) was excluded from the statistical analysis of overall survival and prognostic factors .
local control was defined as the absence of any tumor regrowth or progression on neuroimaging studies .
survival and local control rates were calculated with reference to the date of surgery ( all patients underwent an operation as part of their initial treatment ) using the kaplan - meier product limit method .
survival curves were constructed with kaplan - meier estimates and compared with the use of log - rank test . for all statistical tests ,
symptoms at presentation were seizures ( n=14 ) , headache ( n=4 ) , neurologic deficits ( n=3 ) and dizziness ( n=1 ) . apart from one patient who had a cerebellar tumor , all other patients presented with tumors in the supratentorial hemispheres . the primary tumors at typical sites consisted of temporal lobe ( n=10 ) , frontal lobe ( n=4 ) and parietal lobe ( n=3 ) .
the primary tumors in atypical sites were in the corpus callosum ( 2 patients ) and lateral ventricle , thalamus , and cerebellum ( 1 patient each ) .
, there were 12 were strongly enhanced , 7 moderately , 2 little enhanced and 1 not enhanced ( fig .
fifteen tumors had clean margins in the brain parenchyma , but the remaining 7 did not .
there were 11 large tumors and 10 small tumors and its size varied from 1 cm to 7 cm .
levels of peritumoral edema differed , with 6 displaying no edema , 8 mild edema , 3 moderate edema and 5 severe edema .
calcification was found in 3 patients , leptomeningeal involvement in 12 patients , bone remodeling in 1 patient and intratumoral hemorrhage in 1 patient .
the tumor cells were pleomorphic , comprising spindle cells and giant cells with one large atypical nucleus and occasionally multiple nuclei ( fig .
the nuclei of the giant cells had variable morphology , size and chromatin patterns with occasional intranuclear inclusions .
some cells had small vesicles in their cytoplasm , creating a lipidized or xanthomatous appearance .
the tumor cells were positive for gfap in all cases . three ( 14% ) of the 22 patients were initially diagnosed as pxa with anaplastic features , and one patient 's tumor underwent malignant transformation .
initially , gtr was achieved in 14 patients , str in six patients and a biopsy in one case .
reasons for the incomplete tumor resection were difficult location in five patients and poor demarcation in two patients .
all seven patients who underwent str were irradiated conventionally or by gamma knife radiosurgery ( gkrs ) , and four of them underwent a second operation .
were available for 21 patients and follow - up ranged from 3 to 134 months ( median : 31.0 months ) . overall survival at 3 years was 84% with event - free survival of 59% ( fig .
3 ) . three patients ( 14% ) died following progression of the disease ; one at 3 months and two at 15 months . of the 21 patients , 7 ( 33% )
metastasis occurred in two patients : in one ( patient 2 ) the metastasis was in the intramedullary spinal cord with no evidence of csf seeding ( the spinal tumor was resected and the patient recovered ) , and in the other there was csf seeding ( patient 19 , who died of the disease ) .
three of the 14 patients who received gtr had recurrent tumors at a median follow - up time of 21 months , while 4 of the 7 patients receiving incomplete resection suffered recurrence at a median follow - up time of 5 months .
multimodal therapy was given for the recurrent tumors and 4 of the seven patients showed no evidence of disease .
radiotherapy was given to 10 patients ( the 7 recurrent tumors , 2 incomplete resections and the tumor with csf seeding ) and 5 of them recurred .
19 ) who was diagnosed with csf seeding underwent radiotherapy after gtr , but died from the disease .
6 ) who underwent gkrs after str was found to be stable after for 42 months .
however , peritumoral edema above moderate grade ( p=0.022 ) , atypical tumor location ( p<0.001 ) and large tumor size ( p=0.048 ) were correlated with recurrence .
ki-67 index , necrosis and gtr seemed to be related to recurrence rates , but their effects were not statistically significant .
high ki-67 value and necrosis were more frequent in tumors at atypical sites ( table 5 ) .
symptoms at presentation were seizures ( n=14 ) , headache ( n=4 ) , neurologic deficits ( n=3 ) and dizziness ( n=1 ) . apart from one patient who had a cerebellar tumor , all other patients presented with tumors in the supratentorial hemispheres . the primary tumors at typical sites consisted of temporal lobe ( n=10 ) , frontal lobe ( n=4 ) and parietal lobe ( n=3 ) .
the primary tumors in atypical sites were in the corpus callosum ( 2 patients ) and lateral ventricle , thalamus , and cerebellum ( 1 patient each ) .
, there were 12 were strongly enhanced , 7 moderately , 2 little enhanced and 1 not enhanced ( fig .
fifteen tumors had clean margins in the brain parenchyma , but the remaining 7 did not .
there were 11 large tumors and 10 small tumors and its size varied from 1 cm to 7 cm .
levels of peritumoral edema differed , with 6 displaying no edema , 8 mild edema , 3 moderate edema and 5 severe edema .
calcification was found in 3 patients , leptomeningeal involvement in 12 patients , bone remodeling in 1 patient and intratumoral hemorrhage in 1 patient .
the tumor cells were pleomorphic , comprising spindle cells and giant cells with one large atypical nucleus and occasionally multiple nuclei ( fig .
the nuclei of the giant cells had variable morphology , size and chromatin patterns with occasional intranuclear inclusions .
some cells had small vesicles in their cytoplasm , creating a lipidized or xanthomatous appearance .
three ( 14% ) of the 22 patients were initially diagnosed as pxa with anaplastic features , and one patient 's tumor underwent malignant transformation .
initially , gtr was achieved in 14 patients , str in six patients and a biopsy in one case .
reasons for the incomplete tumor resection were difficult location in five patients and poor demarcation in two patients .
all seven patients who underwent str were irradiated conventionally or by gamma knife radiosurgery ( gkrs ) , and four of them underwent a second operation .
follow - up data were available for 21 patients and follow - up ranged from 3 to 134 months ( median : 31.0 months ) .
overall survival at 3 years was 84% with event - free survival of 59% ( fig .
3 ) . three patients ( 14% ) died following progression of the disease ; one at 3 months and two at 15 months . of the 21 patients , 7 ( 33% )
metastasis occurred in two patients : in one ( patient 2 ) the metastasis was in the intramedullary spinal cord with no evidence of csf seeding ( the spinal tumor was resected and the patient recovered ) , and in the other there was csf seeding ( patient 19 , who died of the disease ) .
three of the 14 patients who received gtr had recurrent tumors at a median follow - up time of 21 months , while 4 of the 7 patients receiving incomplete resection suffered recurrence at a median follow - up time of 5 months .
multimodal therapy was given for the recurrent tumors and 4 of the seven patients showed no evidence of disease .
radiotherapy was given to 10 patients ( the 7 recurrent tumors , 2 incomplete resections and the tumor with csf seeding ) and 5 of them recurred .
19 ) who was diagnosed with csf seeding underwent radiotherapy after gtr , but died from the disease .
the patient ( no . 6 ) who underwent gkrs after str was found to be stable after for 42 months .
however , peritumoral edema above moderate grade ( p=0.022 ) , atypical tumor location ( p<0.001 ) and large tumor size ( p=0.048 ) were correlated with recurrence .
ki-67 index , necrosis and gtr seemed to be related to recurrence rates , but their effects were not statistically significant .
high ki-67 value and necrosis were more frequent in tumors at atypical sites ( table 5 ) .
pxa is a low - grade glioma ( lgg ) and overall survival is similar to other lgg .
however , radiologic and pathologic findings of pxa suggest high - grade tumor . and some pxas show rapid progression unlike other lgg5,8,23,35 ) .
the most common tumor location is the temporal lobe , followed by the frontal , parietal and occipital lobes .
five tumors were located in an atypical site ; two in the corpus callosum , one in the thalamus , one in the cerebellum and one in the lateral ventricle .
hamlat et al.8 ) noted that the clinicopathologic features of cerebellar pxa show some differences from pxa located in the cerebral hemispheres .
gtr was difficult to achieve at atypical sites and pathologic markers , including mitoses and necrosis , seemed to be related to poor prognosis ( table 5 ) .
however , some studies reported that peritumoral edema is related with poor prognosis in high - grade gliomas9,27,29 ) . sheping et al
. found that peritumoral edema was a sign of tumor infiltration but was not a prognostic factor36 ) .
however , tien et al.33 ) concluded that it may point to a poor prognosis .
however , it is known that large tumor volume is a negative prognostic factor in lgg1,26,30 ) .
berger et al.1 ) suggested that the biology is different between small and large tumors .
smith et al.30 ) suggested that large tumors at presentation may grow faster than small tumors . out of eleven patients with large tumors ,
gtr was not achieved in 6 patients ( p=0.063 ) and 5 patients ( p=0.149 ) showed high ki-67 index .
five patients ( p=0.035 ) with tumor necrosis were shown to be all large tumors .
surgical extent and biological difference of large tumors may influence the recurrence rate . in our study ,
the cells in pxa are pleomorphic and often large , somewhat bipolar , with glassy cytoplasms and dark , lobulated nuclei reminiscent of malignant fibrous histiocytoma . however , the presence of gfap identified the tumors as variants of astrocytomas12 ) .
mitotic index was the most significant predictor of recurrence and survival in a multivariate analysis performed by giannini et al.6 ) .
they classified mitotic indices into three groups : 0 , < 5 , and > 5 mitoses per 10 high - power fields and suggested that the poor outcome group with > 5 mitoses should be referred to as pxa with anaplastic features , although this remains controversial6,10 ) . in our study , mitoses were seen in 12 patients , and most of those had mitotic indices of < 2 .
just 4 patients were diagnosed as suffering from pxas with anaplastic features and their outcomes were diverse .
two of 3 patients suffering from pxas with anaplastic features initially suffered rapid disease progression .
however , the remaining patient and a patient with a tumor that became malignant remained free from recurrence .
necrosis was present in 5 of our patients and was not correlated with disease progression .
usually the ki-67 index in pxas is very low ( 0 - 1%)4 ) . in our study
, six tumors were found to have ki-67 indices above 5% and of those , 4 ( 67% ) recurred ( p=0.064 ) .
11 showed no mitoses , a ki-67 index of less than 1% and no necrosis .
20 had malignant biopsy results including 6 mitoses and a ki-67 index of 12.6% with necrosis but was stable without adjuvant therapy for 21 months .
there is a previous report of a patient with no mitoses , necrosis , or endothelial proliferation whose disease progressed , with spinal metastasis and malignant transformation to glioblastoma23 ) . since the pathologic factors determining prognosis are not well understood , it is difficult to identify anaplastic pxas .
macaulay et al.21 ) reported no difference in overall survival between patients who had undergone gtr and those in which gtr was not achieved .
however , many studies such as those of pahapill et al.24 ) and giannini et al.6 ) found that gtr conferred a significant overall survival advantage .
giannini et al.6 ) reported that extent of resection was the single most significant predictor of recurrence - free survival in a multivariate analysis .
although gtr was not a significant factor in our study because of the small sample , it may promote disease control and is the recommended treatment for patients with pxa like other glioma .
the findings regarding the use of adjuvant therapy such as radiation or chemotherapy are controversial .
giannini et al.6 ) did not specifically address this question in their report , because only a small number of patients received adjuvant radiotherapy .
pahapill et al.24 ) noted that the survival curves for those receiving adjuvant radiotherapy were not significantly different from those who did not .
adjuvant therapy was not administered after gtr , even for pxas with anaplastic features ; in those cases the patients were followed up using mr .
radiotherapy seems to be ineffective , so far . however , koga et al.15 ) reported that stereotactic irradiation was helpful for disease control of pxa as shown in the case ( patient 6 ) of our study .
the trial of various radiation therapeutic modalities is needed for treating recurrent tumors when gtr is not achieved and metastasis occurs .
the frequency of recurrence of pxa has been reported to be 30% , and that of malignant transformation 10 - 20%16,23,34 ) . in our study ,
disease progression occurred in 7 patients ( 33% ) similar to other reports , and malignant transformation occurred in one patient ( 5% ) .
marton et al.22 ) noted that surgery is also the therapy of choice for recurrent tumors without malignant transformation and radiotherapy and chemotherapy did not seem to play a significant role .
fouladi et al.4 ) also noted that further surgery is recommended in the case of recurrent disease .
re - operation and gtr is the most important treatment for recurrent tumors ; adjuvant therapy can be administered provided pathological markers and clinical progression are taken into account .
the tumor morphology was a solid dominant , well - enhanced and well - demarcated cystic mass and was located in the left temporal lobe . a good prognosis was predicted as the patient showed low peritumoral edema and typical supratentorial cortical location on mr images , no mitoses , low ki-67 index and no necrosis on the biopsy .
adjuvant therapies can be administered to cases where recurrent tumors are shown to have metastasized or have aggressive extensions on mr images or new proliferative pathological markers are seen .
the most common tumor location is the temporal lobe , followed by the frontal , parietal and occipital lobes .
five tumors were located in an atypical site ; two in the corpus callosum , one in the thalamus , one in the cerebellum and one in the lateral ventricle .
hamlat et al.8 ) noted that the clinicopathologic features of cerebellar pxa show some differences from pxa located in the cerebral hemispheres .
gtr was difficult to achieve at atypical sites and pathologic markers , including mitoses and necrosis , seemed to be related to poor prognosis ( table 5 ) .
however , some studies reported that peritumoral edema is related with poor prognosis in high - grade gliomas9,27,29 ) . sheping et al
. found that peritumoral edema was a sign of tumor infiltration but was not a prognostic factor36 ) .
however , tien et al.33 ) concluded that it may point to a poor prognosis .
however , it is known that large tumor volume is a negative prognostic factor in lgg1,26,30 ) .
berger et al.1 ) suggested that the biology is different between small and large tumors .
smith et al.30 ) suggested that large tumors at presentation may grow faster than small tumors . out of eleven patients with large tumors ,
gtr was not achieved in 6 patients ( p=0.063 ) and 5 patients ( p=0.149 ) showed high ki-67 index .
five patients ( p=0.035 ) with tumor necrosis were shown to be all large tumors .
surgical extent and biological difference of large tumors may influence the recurrence rate . in our study , atypical site , peritumoral edema and tumor size significantly affected prognosis .
the cells in pxa are pleomorphic and often large , somewhat bipolar , with glassy cytoplasms and dark , lobulated nuclei reminiscent of malignant fibrous histiocytoma . however , the presence of gfap identified the tumors as variants of astrocytomas12 ) .
mitotic index was the most significant predictor of recurrence and survival in a multivariate analysis performed by giannini et al.6 ) .
they classified mitotic indices into three groups : 0 , < 5 , and > 5 mitoses per 10 high - power fields and suggested that the poor outcome group with > 5 mitoses should be referred to as pxa with anaplastic features , although this remains controversial6,10 ) . in our study , mitoses were seen in 12 patients , and most of those had mitotic indices of < 2 .
just 4 patients were diagnosed as suffering from pxas with anaplastic features and their outcomes were diverse .
two of 3 patients suffering from pxas with anaplastic features initially suffered rapid disease progression .
however , the remaining patient and a patient with a tumor that became malignant remained free from recurrence .
necrosis was present in 5 of our patients and was not correlated with disease progression .
usually the ki-67 index in pxas is very low ( 0 - 1%)4 ) . in our study ,
six tumors were found to have ki-67 indices above 5% and of those , 4 ( 67% ) recurred ( p=0.064 ) .
11 showed no mitoses , a ki-67 index of less than 1% and no necrosis .
20 had malignant biopsy results including 6 mitoses and a ki-67 index of 12.6% with necrosis but was stable without adjuvant therapy for 21 months .
there is a previous report of a patient with no mitoses , necrosis , or endothelial proliferation whose disease progressed , with spinal metastasis and malignant transformation to glioblastoma23 ) .
since the pathologic factors determining prognosis are not well understood , it is difficult to identify anaplastic pxas .
macaulay et al.21 ) reported no difference in overall survival between patients who had undergone gtr and those in which gtr was not achieved .
however , many studies such as those of pahapill et al.24 ) and giannini et al.6 ) found that gtr conferred a significant overall survival advantage .
giannini et al.6 ) reported that extent of resection was the single most significant predictor of recurrence - free survival in a multivariate analysis .
although gtr was not a significant factor in our study because of the small sample , it may promote disease control and is the recommended treatment for patients with pxa like other glioma .
the findings regarding the use of adjuvant therapy such as radiation or chemotherapy are controversial .
giannini et al.6 ) did not specifically address this question in their report , because only a small number of patients received adjuvant radiotherapy .
pahapill et al.24 ) noted that the survival curves for those receiving adjuvant radiotherapy were not significantly different from those who did not .
adjuvant therapy was not administered after gtr , even for pxas with anaplastic features ; in those cases the patients were followed up using mr .
however , koga et al.15 ) reported that stereotactic irradiation was helpful for disease control of pxa as shown in the case ( patient 6 ) of our study .
the trial of various radiation therapeutic modalities is needed for treating recurrent tumors when gtr is not achieved and metastasis occurs .
the frequency of recurrence of pxa has been reported to be 30% , and that of malignant transformation 10 - 20%16,23,34 ) . in our study ,
disease progression occurred in 7 patients ( 33% ) similar to other reports , and malignant transformation occurred in one patient ( 5% ) .
marton et al.22 ) noted that surgery is also the therapy of choice for recurrent tumors without malignant transformation and radiotherapy and chemotherapy did not seem to play a significant role .
fouladi et al.4 ) also noted that further surgery is recommended in the case of recurrent disease .
re - operation and gtr is the most important treatment for recurrent tumors ; adjuvant therapy can be administered provided pathological markers and clinical progression are taken into account .
the tumor morphology was a solid dominant , well - enhanced and well - demarcated cystic mass and was located in the left temporal lobe .
a good prognosis was predicted as the patient showed low peritumoral edema and typical supratentorial cortical location on mr images , no mitoses , low ki-67 index and no necrosis on the biopsy .
adjuvant therapies can be administered to cases where recurrent tumors are shown to have metastasized or have aggressive extensions on mr images or new proliferative pathological markers are seen .
peritumoral edema , atypical location and large tumor size were poor prognostic factors in our study .
although the difference between the effects of gtr and str on prognosis was not significant , we suggest that gtr is the treatment of choice for primary and recurrent tumors .
adjuvant radiotherapy , especially stereotactic irradiation can be an option for recurrent , residual or metastatic tumors .
 objectivepleomorphic xanthoastrocytoma ( pxa ) is a rare primary low - grade astrocytic tumor classified as who ii . 
 it is generally benign , but disease progression and malignant transformation have been reported . 
 prognostic factors for pxa and optimal therapies are not well known.methodsthe study period was january 2000 to march 2012 . 
 data on mr findings , histology , surgical extents and adjuvant therapies were reviewed in twenty - two patients diagnosed with pxa.resultsthe frequent symptoms of pxa included seizures , headaches and neurologic deficits . 
 tumors were most common in the temporal lobe followed by frontal , parietal and occipital lobes . 
 one patient who died from immediate post - operative complications was excluded from the statistical analysis . of the remaining 21 patients , 3 ( 14% ) died and 7 ( 33% ) showed disease progression . 
 atypical tumor location ( p<0.001 ) , peritumoral edema ( p=0.022 ) and large tumor size ( p=0.048 ) were correlated with disease progression , however , ki-67 index and necrosis were not statistically significant . 
 disease progression occurred in three ( 21% ) of 14 patients who underwent gtr , compared with 4 ( 57% ) of 7 patients who did not undergo gtr , however , it was not statistically significant . 
 ten patients received adjuvant radiotherapy and the tumors were controlled in 5 of these patients.conclusionthe prognosis for pxa is good ; in our patients overall survival was 84% , and event - free survival was 59% at 3 years . 
 atypical tumor location , peritumoral edema and large tumor size are significantly correlated with disease progression . 
 gtr may provide prolonged disease control , and adjuvant radiotherapy may be beneficial , but further study is needed . 
INTRODUCTION
MATERIALS AND METHODS
RESULTS
Clinical characteristics of the 22 patients
Radiological findings
Histopathological findings
Treatments and outcomes
Prognostic factors
DISCUSSION
Clinico-radiological findings
Histopathological review
Treatment
CONCLUSION