anaplasia in pilocytic astrocytoma predicts aggressive behavior

Anaplasia in Pilocytic Astrocytoma PredictsAggressive Behavior

Fausto J. Rodriguez, MD,* Bernd W. Scheithauer, MD,*Peter C. Burger, MD,w Sarah Jenkins, MS,z

and Caterina Giannini, MD, PhD*

Abstract: The clinical significance of anaplastic features, a rareevent in pilocytic astrocytoma (PA), is not fully established.We reviewed 34 PA with anaplastic features (Male=21,

Female=13; median age 35 y, 5 to 75) among approximately2200 PA cases (1.7%). Tumors were included which demon-strated brisk mitotic activity [at least 4 mitoses/10 high power

fields (400� )], in addition to hypercellularity and moderate-to-severe cytologic atypia, with or without necrosis. The tumorseither had a PA precursor, coexistent (n=14) (41%) ordocumented by previous biopsy (n=10) (29%), or exhibited

typical pilocytic features in an otherwise anaplastic astrocytoma(n=10) (29%). Clinical features of neurofibromatosis type-1were present in 24% and a history of radiation for PA precursor

in 12%. Histologically, the anaplastic component was classifiedas pilocytic like (41%), small cell (32%), epithelioid (15%), orfibrillary (12%). Median MIB1 labeling index was 24.7% in

the anaplastic component and 2.6% in the precursor, althoughoverlapping values were present. Strong p53 staining (3+) waslimited to areas with anaplasia (19%), with overlapping values

for 1 and 2+ in areas without anaplasia. Median overall andprogression-free survivals after diagnosis for the entire studygroup were 24 and 14 months, respectively. Overall andprogression-free survivals were shorter in the setting of prior

radiation for a PA precursor (P=0.007, 0.028), increasingmitotic activity (P=0.03, 0.02), and presence of necrosis(P=0.02, 0.02), after adjusting for age and site. The biologic

behavior of PAs with high-mitotic rates and those with necrosisparalleled that of St Anne-Mayo grades 2 and 3 diffuse astro-cytomas, respectively. In summary, PA with anaplastic features

exhibits a spectrum of morphologies and is associated withdecreased survival when compared with typical PA.

Key Words: pilocytic astrocytoma, anaplasia, neurofibromatosis,prognosis, grading, glioma

(Am J Surg Pathol 2010;34:147–160)

P ilocytic astrocytoma (PA) is a World Health Organi-zation (WHO) grade I tumor typically affecting

children and young adults. As the most common braintumor of childhood, its estimated incidence in the UnitedStates is 0.87 per 100,000 individuals under 19 years ofage11 The cerebellum is most often affected,22 but PA mayoccur along the entire neuraxis with a proclivity forcertain sites (optic pathways, hypothalamus, basal gang-lia, brainstem, cerebral hemispheres, and spinal cord).In addition, PA is the most frequently occurring centralnervous system tumor in association with neurofibroma-tosis type-1 (NF1). In this setting, PA tends to involve theoptic pathways and typically has a particularly favorableprognosis,27 spontaneous involution occurring in someinstances.24

The behavior of PA is generally favorable with5 and 10-year overall survival rates greater than 95%after surgical intervention alone.8,14,22 Key prognosticfactors include patient age and extent of resection.14,32

Progression and recurrence resulting in death occur ina small subset of cases despite typical histologicfeatures.3,6,20 Pilomyxoid astrocytoma, a recently recog-nized PA variant, shows a predilection for the hypothalamic region of young children, tends to undergoleptomeningeal dissemination, and is associated with aworse prognosis.34

With diffusely infiltrating astrocytomas histo-logic progression to higher grade tumors is frequent,although to a lesser extent in the pediatric population.7,21

Conversely, histologic progression in PA as well as thepresence of anaplastic features are rare findings. Someauthors even doubt the potential for anaplastic change inPA, proposing that PA are hamartomatous rather thanneoplastic lesions.23 Published descriptions of anaplasticfeatures in PA consist mainly of isolated case reports andsmall series.2,4,9,10,13,18–20,29–32,35–37 Many, but not allexamples, have occurred in association with priorirradiation of a benign PA.2,4,9,19,29–31,35,36 Clinicalbehavior is often unpredictable: some patients do poorly,whereas others remain stable, even with disseminatedleptomeningeal disease.1 This study evaluates our experi-ence of PA with anaplastic features, describes theirhistologic spectrum, and attempts to establish practicalmorphologic definitions.Copyright r 2010 by Lippincott Williams & Wilkins

From the *Department of Laboratory Medicine and Pathology;zDivision of Biomedical Statistics and Informatics, Mayo Clinic,Rochester, MN; and wDepartment of Pathology, Johns HopkinsMedical Institutions, Baltimore, MD.

Correspondence: Fausto J. Rodriguez, MD, Department of LaboratoryMedicine and Pathology, Mayo Clinic, 200 First Street SW,Rochester, MN 55905 (e-mail: [email protected]).

ORIGINAL ARTICLE

Am J Surg Pathol � Volume 34, Number 2, February 2010 www.ajsp.com | 147

MATERIALS AND METHODS

PatientsA search was performed for PA with anaplastic

features accessioned in the Mayo Clinic Pathologyrecords between 1985 and 2008. Cases of PA withanaplastic features (n=10) or with documented priorWHO grade I PA (n=24) were included. Majority (30cases) were identified among 1591 PA consults (1.8%).The remaining 4 tumors were obtained from 644 patientswith PA, representing 0.6% of all PA operated at MayoClinic. Slides from original precursor lesions and frommultiple surgical procedures were available for review in11 cases (32%). Follow-up information was gatheredfrom medical records, consultation letters, and onlinedeath registries. The study was approved by the MayoClinic Institutional Review Board.

Pathology and Inclusion CriteriaCases were reviewed by 4 neuropathologists

(P.C.B., C.G., F.J.R., and B.W.S.), with the exceptionof 6 consultation cases which were reviewed by 3. Tumorswere included if they demonstrated brisk mitotic activity[at least 4 mitoses/10 high power fields (HPF) (� 400)], inaddition to hypercellularity and moderate-to-severe cyto-logic atypia, with or without necrosis. For case inclusion,anaplastic features were required to occupy at least onelow-power field (20�). In addition some features typicalof PA had to be present, in at least one low-power field(20�), including compact piloid astrocytes and/or micro-cystic zones, Rosenthal fibers, and eosinophilic granularbodies (Figs. 1A–C). High-grade astrocytomas arisingafter treatment for a PA, but lacking a distinct coexistentPA precursor or at least some histologic features typicalof PA were excluded.

Upon review of all available slides, the cases wereincluded in the study if at least 3 neuropathologists agreedwith the diagnosis of PA with anaplastic features. Histo-logic features were graded as previously described.26 Inbrief, nuclear atypia was graded on a 3-tiered scale basedon chromatin and nuclear irregularities of nondegenera-tive type. Cellularity was rated as low, moderate, or highas previously described.26 Degree of invasiveness wasclassified as absent, partial, or diffuse based upon axonaldensity on neurofilament protein immunostains whenavailable, in combination with the identification ofentrapped neurons and/or axons on hematoxylin andeosin stain. Mitotic indices were calculated by countingthe number of mitoses/10 HPF (400�) using an OlympusBH-2 microscope. We excluded optic pathway tumors inNF1-associated cases as elevated mitotic activity andhypercellularity are commonly seen in this group and arenot associated with an adverse outcome.26

ImmunohistochemistryImmunohistochemical stains used the Dual Link

Envision+ (Dako) detection system and a DAKOAutostainer (Dako North America, Inc, Carpinteria,CA). Antigen retrieval employed ethylenediaminetetra-

acetic acid and diaminobenzidine served as the chromo-gen. The various antibodies used were directed against thefollowing antigens: glial fibrillary acidic protein (poly-clonal, 1:4000; Dako, Carpinteria, CA), neurofilamentprotein (clone 2F11, 1:75; Dako), p53 protein (cloneDO7, 1:2000; Dako), INI-1-BAF47 (clone 25, 1:100; BDTransduction, BD Biosciences, San Jose, CA), and Ki–67(clone MIB-1, monoclonal, 1:300; Dako). Wheneverfeasible, immunoreactivity for p53 protein was evaluatedin both the anaplastic and benign-appearing tumorcomponents. As previously reported,15 p53 protein stainwas scored on the following semiquantitative scale: nostaining (0), strong focal staining of <10% of cells (1+),strong staining of 10% to 50% of cells or weak staining of>50% of cells (2+), and strong staining of >50% of cells(3+). Quantitative evaluation of MIB-1 labeling indiceswas performed using the Hamamatsu NanoZoomerDigital Pathology for scanning images and IHCScoresoftware for computer-assisted analyses (Bacus Labora-tories, Lombard, IL).

StatisticsPatient and tumor characteristics were described

using frequencies and percentages, or medians, rangesand interquartile ranges as appropriate. Overall andrecurrence-free survivals were calculated from the bestestimated time of development of anaplastic changes totime of death or recurrence (respectively). Overall andrecurrence-free survivals were illustrated using Kaplan-Meier survival curves along with estimates and 95%confidence intervals (CI) for median survival. Survivaland recurrence-free survivals were compared betweenclinicopathologic groups using Cox proportional hazardsregression, adjusted for age, sex, and/or site of tumor.Hazard ratios and their 95% CI were estimated. If aprecise date of recurrence was unknown, but the patientdied within 3 years of the appearance of anaplasticfeatures, the day of death was considered the recurrencedate. Statistical analyses were performed using SASversion 9 software (SAS Institute Inc, Cary, NC). Alltwo-sided P values <0.05 were considered statisticallysignificant.

RESULTS

Clinical Features of PA With Anaplastic featuresClinical features are summarized in Table 1. The

patients included 13 females and 21 males. The medianage at diagnosis of PA with anaplastic features was 35years (range: 5 to 75 y). Six (18%) were pediatric cases(patients <18 y old). Fifty percent of tumors arose in thecerebellum, whereas 35% were supratentorial. Informa-tion regarding preoperative radiologic imaging was avai-lable in 24 cases (71%). Studies included magneticresonance imaging in 14 (58%), computed tomographyin 4 (17%), and unspecified methods in 6 (25%).Leptomeningeal dissemination was documented in only1 instance. Information regarding postoperative treat-ment modalities was available in 16 patients (47%).

Rodriguez et al Am J Surg Pathol � Volume 34, Number 2, February 2010

148 | www.ajsp.com r 2010 Lippincott Williams & Wilkins

Postoperative treatment approaches to PA with anaplas-tic features included radiation therapy in 13 (81%) andchemotherapy in 11 (69%), including temozolomide in 7(44%). Two patients underwent Gliadel wafer (EisaiCorporation of North America) placement. In 3 cases

(19%) the patients were followed with observation alone.A PA precursor was documented at an earlier time in 10cases (29%); the median time between original diagnosisand diagnosis of PA with anaplastic features was 14 yearsin this group (range: 4mo to 40 y). Only 4 of these 10

FIGURE 1. The histologic spectrum of PA with anaplastic features. All cases had discernible PA features, at least focally, includingRosenthal fibers (A) and/or eosinophilic granular bodies (B). Perivascular pseudorosettes reminiscent of pilomyxoid morphologywas a focal finding in a subset of cases (C). Some tumors were classified as ‘‘pilocytic like,’’ because of clear cut preservation ofpilocytic features, but with brisk mitotic activity (arrows) (D). Example of a PA with an epithelioid/rhabdoid component. Anatypical tripolar mitosis is present in the center of the field (E). PA with anaplastic features composed of oval hyperchromatic cellswith high nuclear:cytoplasmic ratio resembling small cell astrocytoma (F). Eosinophilic granular bodies within an anaplastic smallcell component were an occasional finding is some examples (G). A pattern of conventional fibrillary astrocytoma characterizedthe anaplastic component in some cases (H). ‘‘Polar spongioblastoma like’’ change as a focal finding in one tumor (I)(hematoxylin and eosin staining). PA indicates pilocytic astrocytoma.

Am J Surg Pathol � Volume 34, Number 2, February 2010 Anaplasia Changes in PA

r 2010 Lippincott Williams & Wilkins www.ajsp.com | 149

patients had received postoperative radiation therapybefore the time of developing anaplasia.

Histologic and Immunohistochemical Featuresof PA With Anaplastic Features

A total of 3 neuropathologists agreed with thediagnosis in all cases and 4 in 88% of cases. Histologicfeatures are summarized in Table 2 and illustrated inFigures 1 and 2. The most common histologic patternwas ‘‘pilocytic like’’ (41%), that is featuring compact,bipolar cells with Rosenthal fibers, and/or microcystswith eosinophilic granular bodies, but with brisk mitoticactivity and hypercellularity (Figs. 1D, G). The next mostfrequent pattern was that of a poorly differentiated, smallcell process (32%) (Fig. 1F) which was glial fibrillaryacidic protein immunoreactive (11 of 11 cases). Epithe-lioid or rhabdoid patterns were the third most frequent(15%) (Fig. 1E), followed by cytologic features offibrillary astrocytoma in 12% (Fig. 1H and Fig. 2).Immunohistochemical stains for INI-1-BAF-47 per-formed in 3 (of 5) tumors with epithelioid/rhabdoidcytology showed preservation of nuclear immuno-reactivity (not shown). p53 overexpression (3+) waspresent in the anaplastic component in 4 (of 21) casestested (19%), but not in the PA precursors. Median MIB1labeling index was 24.7% (range: 4.44 to 62.5).

Focal anaplastic features in the form of hypercellu-larity and brisk mitotic activity (5 and 10 per 10 HPF,respectively) found in a single low-power field was notedin one brainstem and one cerebellar example each(Fig. 3). Both patients are well without evidence ofdisease, respectively 13 and 27 months after gross totalresection alone. By comparison, in the rest of the groupanaplastic features were multifocal or widespread.

TABLE 1. Clinical and Demographic Features of PilocyticAstrocytoma With Anaplastic Features

N (%)

SexFemale 13 (38)Male 21 (62)

Tumor locationCerebellum 17 (50)Supratentorial 12 (35)Brainstem 2 (6)Spinal cord 2 (6)Tectum 1 (3)

Extent of surgeryGTR 9 (26)STR 11 (32)Indeterminate 14 (41)

Historic precursor 10 (29)History of radiation 4 (12)History of NF1 8 (24)Radiographic features*Enhancement 20 (83)

Peripheral 3 (12)Heterogeneous 7 (24)NOS 10 (40)

Mass effect 3 (12)Partially cystic 8 (33)

Postoperative treatmentwObservation 3 (19)Radiation 13 (81)Chemotherapy 11 (69)

*Information available in 24 (71%) of patients.wInformation available in 16 (47%) of patients.GTR indicates gross total resection; NF1, neurofibromatosis type-1; NOS, not

otherwise specified; STR, subtotal resection.

TABLE 2. Pathologic Features of PA With Anaplastic Features(n = 34)

N (%)

Histologic typePilocytic like 14 (41)Fibrillary astrocytoma 4 (12)Small cell astrocytoma 11 (32)Epithelioid/rhabdoid change 5 (15)Polar spongioblastoma like (focal) 2 (6)

Rosenthal fibers 4 (12)Cellularity

Moderate 17 (50)Marked 17 (50)

AtypiaModerate 12 (35)Severe 22 (65)

InfiltrationAbsent 7 (21)Partial 18 (53)Diffuse 9 (26)

Leptomeningeal involvement 13 (38)Perivascular pseudorosettes 9 (26)Pilocytic features of precursor

Compact bipolar cells 34 (100)Rosenthal fibers 27 (79)Microcysts 19 (56)Eosinophilic granular bodies 33 (97)Biphasic pattern 7 (21)Calcification 11 (32)

Mitoses/10 HPFMedian (range)Anaplastic component 8 (4-37)PA precursor 0 (0-3)

Atypical mitoses 16 (47)Vascular changes

Glomeruloid 20 (59)Endothelial proliferation 9 (26)Thrombosis 17 (50)

NecrosisCoagulative 13 (38)Pseudopalisading 9 (26)

MIB-1 labeling index (n=23)Median (range)Anaplastic component 24.7 (4.44-62.5)PA precursor 2.6 (0.24-42.3)

p53 immunohistochemistry (n=21)Anaplastic component0 3 (14)1+ 8 (38)2+ 6 (29)3+ 4 (19)

PA precursor0 2 (25)1+ 5 (63)2+ 1 (13)3+ 0

HPF indicates high power field; PA, pilocytic astrocytoma.



NF1-associated PANF1-association among PA with anaplastic features

study group was noted in 8 (24%) cases, 3 initiallypresenting as PA and 5 PA with anaplastic features(Table 3). Imaging and pathologic features of a repre-sentative case are illustrated in Figure 4. None of thetumors received radiation therapy before the diagnosis ofPA with anaplastic features. Median patient age in theentire NF1 patient group was 35 years (range: 11 to 59 y).Follow up was available in 6 patients (75%); 3 developedrecurrences at 2, 10, and 11 months and 2 patients died ofdisease, respectively 12 and 24 month postsurgery. Finally,1 patient developed what appeared to be radiation necrosison perfusion magnetic resonance imaging at 9 months and2 patients are alive without evidence of disease at 1 and 13years. The one patient alive without evidence of disease at1 year received Avastin in combination with radiationtherapy and camptothecin-11 after having undergone agross total resection. After adjusting for age and site, nodifference in recurrence-free (P=0.83) or overall survival(P=0.50) was noted between the NF1 group and patientswith sporadically occurring tumors.

Survival Analysis of PA With Anaplastic FeaturesSurvival data with clinical follow up was available

in 28 patients (82%). Median overall and progression-freesurvivals for the entire group were 24 months (95% CI:17-29) and 14 months (95% CI: 11-29), respectively.Events included 19 deaths and 19 recurrences in 28patients. Increasing patient age was inversely corre-lated with overall survival [hazard ratio (HR)=1.03,P=0.02]. There were no prognostic differences by tumorsite (cerebellar vs. noncerebellar locations) (P>0.05), butwe chose to adjust for this parameter, given the recentlyidentified biologic differences of PA from different sites.38

After adjusting for age and tumor site, the followingvariables were found to be associated with decreasedoverall and progression free-survivals, respectively: his-tory of prior radiation (P=0.007, 0.028), history of a PAprecursor (P=0.02, 0.02), mitoses/10 HPF as a contin-uous variable (P=0.03, 0.02), and necrosis of any kind(P=0.02, 0.02) (Fig. 5). Adjusted for age and tumor site,greater than 5 mitoses/10 HPF and severe cytologicatypia were associated with decreased progression-free(P=0.04 and 0.02, respectively), but not with overallsurvival. After adjusting for age and tumor site, therewere no statistically significant associations (P>0.05)with presence of NF1, tumor location, date of diagnosis(comparing patients treated before or after 2000), tumorcellularity, presence of atypical mitoses, endothelial pro-liferation, degree of parenchymal infiltration, microscopicleptomeningeal involvement, cytologic type of the malig-nant component, extent of resection, or the administrationof postoperative temozolomide chemotherapy.

Survival Analysis Comparing With OtherAstrocytoma Subtypes

To evaluate overall survival in the context of otherastrocytoma subtypes, survival data was obtained fromthe historical cohort used to established St Anne-Mayograding of astrocytomas, which was later used as thebasis of the WHO grading of diffuse astrocytomas.12

That study included conventional PAs (n=51), as well asgrade 2 (n=46), grade 3 (n=51), and grade 4 (n=188)diffusely infiltrative astrocytomas. The results of thesurvival analyses are summarized in Table 4 andillustrated in Figure 6. In brief, survival in our entirepatient cohort (reference group) was worse than thatassociated with conventional PAs (HR=0.11, P<0.0001) and better than grade 4 astrocytomas (HR=3.20, P<0.0001). It was, however, not statisticallydifferent from the survival of patients with grade 2 orgrade 3 astrocytoma. When subdividing our currentpatient cohort according to the presence or absence ofnecrosis, survival in PA with anaplastic features withoutnecrosis was: no different from that associated withSt Anne-Mayo grade 2 astrocytomas (P=0.44), better, butnot significantly (P=0.0943) than grade 3 astrocytomapatients, and significantly better than grade 4 astro-cytomas (P=0.0004). Patients with necrosis-associatedtumors had overall survivals worse than grade 2 astrocytomas

TABLE 3. Neurofibromatosis type-1-associated PilocyticAstrocytoma With Anaplastic Features

Feature N (%)

SexFemale 3 (38)Male 5 (62)

Tumor locationCerebellum 4 (50)Supratentorial 4 (50)

Extent of surgeryGTR 2 (25)STR 2 (25)Indeterminate 4 (50)

Historic precursor 3 (38)History of radiation 0Postoperative treatmentRadiation 5 (62)Chemotherapy 4 (50)Unknown 3 (38)

Histologic typePilocytic like 5 (62)Fibrillary astrocytoma 1 (13)Small cell astrocytoma 1 (13)Epithelioid/rhabdoid 1 (13)

NecrosisCoagulative 3 (38)Pseudopalisading 0

Mitoses/10 HPFMedian (range) 8 (5-10)

MIB-1 labeling index (n=8)Median (range) 21.2 (4.4-50.1)

p53 immunohistochemistry (n=4)0 2 (50)1+ 1 (25)2+ 1 (25)3+

GTR indicates gross total resection; HPF, high power filed; STR, subtotalresection.



(P=0.01), not significantly different to those with grade3 astrocytoma (P=0.40), but better than grade 4 astro-cytomas (P=0.002).

DISCUSSIONPAs are low-grade tumors of an indolent nature

with little potential for malignant transformation. The

FIGURE 2. Pilocytic astrocytoma with anaplastic features (case 13): anaplastic astrocytoma with distinct well-differentiatedbiphasic component with Rosenthal fibers (A) and microcysts (B). High-grade astrocytoma component with increased cellularityand widespread infiltration of the cerebellum, including the molecular layer (C, D) as well as pseudopalisading necrosis(hematoxylin and eosin staining) (E) and marked pleomorphism with mitoses (F).



literature contains no firm histologic criteria for adiagnosis of PA with anaplastic features. In Table 5 wehave summarized the literature regarding cases of PAwith anaplasia providing data regarding specific histolo-gic features. Reported examples lacking sufficient histo-logic descriptions of either a PA precursor25,40 or featuresof PA with anaplasia5,30,37 were excluded. In that some

tumors, particularly in the older literature, were simplyreferred to as ‘‘cerebellar astrocytoma,’’ it is unclearwhether they represented pilocytic or diffuse infiltrativeastrocytomas. For example, Kepes et al18 reported thedramatic example of an infiltrating astrocytoma of thecerebellum with microcysts and anaplastic features in a9-year-old boy. The tumor had undergone widespread

FIGURE 3. Pilocytic astrocytoma with focal anaplastic change (case 32). Well differentiated piloid (A) and microcystic areas (B).A focal area was characterized by increased cellularity and brisk mitotic activity (arrows) (C) (hematoxylin and eosin staining400�).



FIGURE 4. Neurofibromatosis type 1-associated PA with anaplastic features (case 34). Axial T1-weighted magnetic resonanceimaging postcontrast preoperatively (A), immediately after the first resection demonstrating residual tumor (B) and 3 monthsafter demonstrating rapid growth (C). Findings at the first resection included bipolar cells and Rosenthal fibers, but no malignantfeatures (D) (hematoxylin and eosin staining). Recurrent tumor demonstrating a PA component (top) and a high-gradehypercellular component (bottom) (E) (hematoxylin and eosin staining). High power view of the malignant componentdemonstrates hyperchromatic cells with high nuclear:cytoplasmic ratios (F) (hematoxylin and eosin staining). MIB-1 labelingindex was high (image matching H and E panel in E) (G). PA indicates pilocytic astrocytoma.



leptomeningeal dissemination and extended into themusculature of the neck.

Previous studies of atypical and anaplastic featuresin PA have been published.20,35 That of Tomlinson et al35

undertook a systematic study of various parameters inconventional PA and in 4 selected examples of PA withhistologic malignancy. Whereas the latter exhibitedmalignant behavior and featured high-mitotic activity

[multiple mitoses/HPF (400�) and palisading necrosis]attempts to identify clinically meaningful ‘‘atypical’’ PAbased on low-level mitotic activity (<1 mitosis per 10250�microscopic fields) were unsuccessful. In a study of36 pediatric PA by Krieger et al,20 4 were found to havedeveloped anaplastic change upon recurrence. Thefrequency was somewhat high (11%), but diagnosticcriteria were not clearly defined. Conversely, the 44 case

1.0

0-5≥≥ 6 Median 647 days, 95% CI 396, 801

Median NA days, 95% CI 551, NAA No necrosisNecrosis

0.8

0.6

n=7

n=9

0.4

0.2

Su

rviv

al

B

Su

rviv

al

P=0.0758 P=0.0226

0.0

1.0

0.8

0.6

0.4

0.2

0.0

0 2 4 6 8 10 12 14

n=21n=19

Years0 2 4 6 8 10 12 14

Years

Median NA days, 95% CI 758, NAMedian 589 days, 95% CI 399, NA

FIGURE 5. Kaplan-Meier curves highlighting differences in overall survival for mitoses >5/10 HPF (A) and necrosis (B) (P valuesfrom Cox proportional hazards, adjusted for age and site).

TABLE 4. PA With Anaplastic Features Versus Historic Cohort of PA and Diffusely Infiltrating Astrocytomas: Comparisons of OverallSurvival by Cox Proportional Hazard Regression

Group

Median Overall

Survival in Days (95% CI) Reference Group

Hazard Ratio

(95% CI) P

PA with anaplastic features (whole group) 716 (513, 884) Diffusely infiltratingastrocytomas

0.77 (0.49, 1.24) 0.28

Diffusely infiltrating astrocytomas:Conventional PA NA* PA with anaplastic features

(whole group)0.11 (0.05, 0.23) <0.0001

Grade 2 astrocytoma 1490 (1157, 1904) 0.64 (0.37, 1.12) 0.12Grade 3 astrocytoma 598 (498, 1004) 1.09 (0.64, 1.86) 0.75Grade 4 astrocytoma 260 (242, 287) 3.20 (1.99, 5.16) <0.0001

PA with anaplastic features (without necrosis) NA* PA with anaplastic features(without necrosis)

— —

PA with anaplastic features (with necrosis) 589 (399, NAw) 3.47 (1.01, 11.94) 0.048Diffusely infiltrating astrocytomas:Conventional PA NA* 0.27 (0.08, 0.97) 0.04Grade 2 astrocytoma 1490 (1157, 1904) 1.59 (0.49, 5.13) 0.44Grade 3 astrocytoma 598 (498, 1004) 2.71 (0.84, 8.70) 0.09Grade 4 astrocytoma 260 (242, 287) 8.00 (2.55, 25.15) 0.0004

PA with anaplastic features (with necrosis) 589 (399, NAw) PA with anaplastic features(with necrosis)

— —

PA with anaplastic features (without necrosis) NA* 0.29 (0.08, 0.99) 0.048Diffusely infiltrating astrocytomas:Conventional PA NA* 0.08 (0.04, 0.17) <0.0001Grade 2 astrocytoma 1490 (1157, 1904) 0.46 (0.25, 0.83) 0.01Grade 3 astrocytoma 598 (498, 1004) 0.78 (0.44, 1.38) 0.40Grade 4 astrocytoma 260 (242, 287) 2.31 (1.38, 3.87) 0.002

*Median survival not applicable as it was not reached.wMedian survival reached, but not for the upper confidence limit.CI indicates confidence interval; NA, not applicable; PA, pilocytic astrocytoma.



study of adult PA by Stuer et al,32 defined criteria ofanaplastic transformation, including brisk mitotic activityand palisading necrosis. The changes, present in 14% oftheir cases, suggested that anaplastic transformationoccurs more frequently in adults. This is in keeping withour findings that the median age at development ofanaplasia in an unselected series was 35 years.

An interesting finding of our study is that a historyof radiation was present in only a minority of the cases(11%). This differs from the literature, in which themajority of PA with anaplastic features are associatedwith a history of irradiation of a PA precursor (Table 5).One possible explanation is that most tumors in our serieswere consultation derived and posed the challenge ofdiagnosing primary PA with anaplastic features. In anycase, both the occurrence of a precursor PA at an earlierdate and a history of prior irradiation, were associatedwith a less favorable prognosis. These findings suggestthat tumors developing postradiation are biologicallydistinct from those developing anaplastic features spon-taneously in a PA precursor. It is still possible that someof these cases represent separate second primaries,although by only including in this setting tumors thathad at least partial, coexistent typical pilocytic features,we attempted to minimize this possibility. This approachfurther explains the small number of postradiation PAwith anaplastic features in our series compared with theliterature.

This study indicates that PA with anaplastic features isassociated with decreased patient survival. We found it

useful to compare our data with a large, publishedclinicopathologic study of pilocytic and diffusely infiltrativeastrocytomas.12 Tumors in that published series12 weregraded according to the St Anne-Mayo scheme, the criteriawhich were later adopted into the WHO.21 The approachwas binary and included the presence or absence of nuclearatypia, mitotic activity, strictly defined endothelial prolifera-tion, and necrosis of any type. The results of these com-parisons should be viewed with caution, given the differingdecades during which the patients were treated and therelatively smaller number of tumors studied in our currentseries. In addition, St Anne-Mayo and WHO gradingschemes should not be equated. The current WHO classi-fication21 requires more than one mitosis for a diagnosis ofanaplastic astrocytoma (WHO grade III), whereas a singlemitosis was sufficient for a grade 3 designation in the StAnne-Mayo grade scheme. In a prior study we found thatinfiltrating astrocytomas with a solitary mitosis had a betterprognosis than those with greater numbers of mitoses.16

This may have some confounding effects in our study,although astrocytomas with a solitary mitosis represent onlya minority of grade 3 astrocytomas in the St Anne-Mayoscheme (approximately 24% in one study).16 These caveatsaside, we found PA with anaplastic features withoutnecrosis to behave closer to St Anne-Mayo grade 2 astro-cytoma, whereas the presence of necrosis in a mitoticallyactive PA conferred a behavior analogous to that of grade 3astrocytoma, but better than grade 4.

As compared with diffusely infiltrating astro-cytomas, the histologic characteristics indicative of PA

A

0.8

Microcystic/pilocytic Median NA days, 95% CI NA, NAGrade 2 Median 1490 days, 95% CI 1157, 1904Grade 3 Median 598 days, 95% CI 498, 1004Grade 4 Median 260 days, 95% CI 242, 287Anaplastic PA Median 716 days, 95% CI 513, 884

Microcystic/pilocytic Median NA days, 95% CI NA, NAGrade 2 Median 1490 days, 95% CI 1157, 1904Grade 3 Median 598 days, 95% CI 498, 1004Grade 4 Median 260 days, 95% CI 242, 287Anaplastic PA, Median NA days, 95% CI 758, NAno necrosisAnaplastic PA Median 589 days, 95% CI 399, NAwith necrosis

1.0

0.6

0.4

0.2

0.0

Su

rviv

al

B

0.8

1.0

0.6

0.4

0.2

0.0

Su

rviv

al

0 2 4 6 8 10 12 14Years

0 2 4 6 8 10 12 14Years

FIGURE 6. Kaplan-Meier curves comparing the overall survival of PA with anaplastic features (n = 28) to that of conventional PA(n = 51), as well as grade 2 (n = 46), grade 3 (n = 51), and grade 4 (n = 188) infiltrating astrocytoma obtained from a historic cohort(A). Panel B is further subdivided by the presence or absence of necrosis. PA indicates pilocytic astrocytoma.



TABLE 5. Literature Review: PA With Anaplastic Features With Histologic Documentation

Case Age/Sex Clinical Radiology Prior Precursor Surgery Pathology Treatment Follow-up

Alpers et al

(1982)226/Female Progressive

ataxia, hearing

loss on the left,

anorexia,

dysphagia

CT: cystic and

solid tumor

with tentorial

spread

STR of cerebellar

PA 21 y prior,

multiple

recurrences

STR Small cell

component

arising in PA

Radiation,

BCNU

chemotherapy

Undergoing

treatment

Bernell et al4

(1972; case 2)

33/Male Headaches,

ataxia,

dysmetria, loss

of equilibrium

Right posterior

fossa

abnormality

Treated at age 3

with radiation

for cerebellar

tumor; GTR of

recurrent

tumor at age 9

GTR, soft, poorly

demarcated

tumor

Fibrillary

astrocytoma

with increased

mitotic activity,

no pilocytic

component

described

NA Discharged home

postoperatively

Budka (1975)9 40/Female Progressive

headaches,

vertigo, and

vomiting

Pneumoencepha-

logram and

ventriculo-

gram-recurrent

tumor in right

cerebellum

PA at age 13;

STR followed

by radiation

Multiple cysts PA with areas

of increased

cellularity,

pleomorphic

giant cells, and

‘‘frequent

mitoses’’

NA Patient expired

2 d after

operation;

autopsy

revealed similar

findings to

biopsy

Kleinman et al

19781952/Female Right sided

tremor and

clumsiness,

speech

difficulties, and

gait ataxia

CT: hyperdense

lesion in the

right cerebellar

hemisphere

PA treated with

radiation at age

5 followed by

surgery

Biopsy only PA with brisk

mitotic rate,

hypercellular-

ity, and

necrosis

Observation Patient expired

one and half

months after

biopsy; autopsy

revealed

bronchopneu-

monia. The

residual tumor

was filling the

R-CPA,

foramen

Luschka,

fourth ventricle

and

compressing

the brainstem

Schwartz and

Ghatak

(1990)29

28/Male Headaches,

weakness,

ataxia,

dysmetria

CT, MRI: Right

cerebellar

hemisphere

mass with ring

enhancement

PA at age 4

treated with

radiation

STR-necrotic,

ill-defined

mass

High-grade

astrocytoma

with atypia,

mitotic activity,

palisading

necrosis; no

pilocytic

features

Irradiation Died 5mo after

treatment

Steinberg et al

198531 -case 1

11/Male NA Cerebellar tumor None STR PA with foci of

anaplasia

(hypercellu-

larity,

pleomorphism,

frequent

mitoses, and

hyperchromasia)

Radiation

5400 rads;

BCNU,

hydroxyurea,

5-FU,

misonidazole,

vincristine,

procarbazine

Stable 4.5 y after

presentation

Steinberg et al31

(1985;case 2)

50/Female NA Cerebellar tumor ‘‘Juvenile PA’’

8mo

previously;

GTR

STR Diffusely

infiltrating

high-grade

astrocytoma,

hypercellular,

mitoses,

endothelial

proliferation,

pseudopalisad-

ing necrosis

Expired 3mo

after malignant

transformation;

high-grade

astrocytoma at

autopsy

Steinberg et al31

(1985;case 3)

26/Female Headaches, left

leg numbness,

left dysmetria

CT: large

cerebellar cyst

with enhancing

nodule

PA treated with

4500 rads after

STR; second

resection 10 y

after

STR High-grade

astrocytoma

with

hypercellular-

ity, atypia,

mitotic figures,

endothelial

Radiation

1600 rads

Expired 4mo

after surgery;

autopsy

revealed high-

grade

astrocytoma

with infiltration



TABLE 5. (continued)


proliferation,

and

pseudopalisad-

ing necrosis, no

PA features

of cerebellum,

brainstem,

diencephalon,

thalamus.

Peritoneal

metastases and

pneumonia

also present

Ushio et al

(1987)3615/Male Asymptomatic CT: small

enhancing mass

in the right

cerebellar

hemisphere

PA treated with

surgery

irradiation

(5300 rads) 7 y

prior

STR of a soft,

invasive tumor

High-grade

astrocytoma

severe atypia,

mitoses,

pseudopalisad-

ing necrosis; no

PA features

Irradiation

(3550 rads) and

ACNU

chemotherapy

Progression 5mo

after,

developed

ataxia, speech

disturbance;

third surgery,

additional

radiation,

chemotherapy;

progression.

Expired 17mo

after second

resection.

Autopsy:

extensive

tumor

involving the

cerebellum and

lateral

ventricles, no

PA features

histologically

Tomlinson et al35

(1994; case 1)

16/Male Occipital

headache,

vomiting, gait

disturbance,

malaise

CT: cystic lesion

in left

cerebellar

hemisphere

NA GTR: cystic

lesion

PA with a

component

with atypia,

brisk mitotic

activity, and

pseudopalisad-

ing necrosis

Observation NED 5 y after

operation,

normal MRI

Tomlinson et al35

(1994; case 2)

18/Male 2mo history

of worsening

headache

MRI: 4 cm right

cerebellar

tumor with

edema,

heterogeneous

enhancement

NA GTR: well-

circumscribed

tumor

PA with a

malignant

component

with

infiltration,

brisk mitoses

(up to 5/250�

field)

Radiation

(5400 rads)

NED 6mo

postoperatively

Tomlinson et al35

(1994; case 3)

16/Female ‘‘Symptoms

suggestive

of recurrent

tumor’’

Ventriculogra-

phy:

hydrocephalus,

fourth ventricle

deformity

Typical PA STR,

irradiation

(5000 rads) 5 y

prior

STR: tumor

involving both

cerebellar

hemispheres

and vermis

Moderate-to-high

cellularity,

infiltration, 4

mitoses/250�

field). PA

features present

Steroid therapy Expired 2mo

after operation

Tomlinson et al35

(1994; case 4)

21/Female Increasing

headaches

Cystic tumor of

right

cerebellum

PA 10 y prior,

STR,

irradiation

6000 rads

STR Infiltrative

component

arising in

gradual

transition from

a PA, with 3

mitoses/250�

field, severe

atypia,

pseudopalisad-

ing necrosis

BCNU Tumor recurrence

at 1 y,

additional

surgery. Stable

2 y after

malignant

transformation

Wilson et al

(1976)3927/Female Behavioral

changes,

somnolence,

memory

problems

Angiogram,

pneumoence-

phalogram:

large vascular

mass in chiasm,

PA STR, at age 7;

5070 rads

STR Typical PA with

areas of

anaplasia,

increased

cellularity,

atypia, and

NA Developed left

middle cerebral

ischemia

postoperative

and expired

24 h later.



with anaplastic features differ somewhat. Necrosis with-out pseudopalisading is said to occur in approximately10% of cases and to be of no prognostic significance insome studies,16 although it was associated with decreasedevent-free survival in a recent study.33 The same is true ofonly occasional mitoses and microvascular prolifera-tion.16 Our study further focused upon all these para-meters, finding that mitotic activity exceeding 4/10 HPF,other than as a microscopic focal feature, defined as asingle low-power field (20�), is of prognostic significance,distinguishing PA with anaplastic features from conven-tional, WHO grade I PAs. We used this mitotic indexcutoff because it was the lowest mitotic rate found in PAwith anaplastic features in our files. As the survival ofpatients with PA showing increased mitotic activity butlacking necrosis is no worse as a group than that ofpatients with grade 2 infiltrating astrocytomas, with thecaveats mentioned above, the designation of atypical PAmay be appropriate. Further studies will be required toconfirm our findings and formulate minimal criteria forthe diagnosis.

Our study included 2 cases in which anaplasticfeatures of hypercellularity and increased mitotic activitywere focal; these tumors did not behave in an aggressivemanner. It is also of note that the presence of conven-tional or pseudopalisading necrosis, an important histo-logic component of PA with anaplastic features, does notequate with the behavior of glioblastoma. We do not,therefore, apply the term glioblastoma or attribute agrade IV designation to pilocytic tumors with anaplasticfeatures featuring necrosis.

With regards to NF1, 8 of our patients (22%)satisfied clinical criteria for the syndrome. As previously

noted, we purposely excluded tumors of the opticpathways, because they represent a clinicopathologicallyunique niche in NF1 patients,38 often being associatedwith a favorable outcome, regardless of specific histologicfeatures.26 Nonetheless, fully half of NF1-associated PAwith anaplastic features in our series arose in thecerebellum. It is of note that early studies of NF1-associated gliomas found cerebellar tumors to behave lessfavorably.17,28 In that many such studies antedatedcurrent glioma and neurofibromatosis classificationschemes, some of these early tumors may have repre-sented diffusely infiltrating astrocytomas or even ependy-momas in NF2.

The main limitation of our study is the frequent lackof detailed clinical and therapeutic as well as follow-updata. This is often a problem in studies of rare tumorsavailable only in large consultation services. Acquiringcase numbers sufficient to arrive at solid, scientificgeneralizations is often impossible in single, even large,institutions. Nonetheless, we have studied the largestcohort to date of PA with anaplastic features patients.Our data suggest that such tumors behave in a moreaggressive manner than conventional PA. Despite ex-hibiting morphologic features common to high-grade,diffuse, or infiltrative astrocytic tumors, PA with anaplas-tic features do not exhibit the same correlation betweenmorphologic features and tumor behavior. Moreover,even ‘‘high-grade’’ PA with anaplastic features does notbehave like glioblastoma. At best, PA with anaplasticfeatures with the requisite mitotic index (>4/10 HPF), aswell as those featuring necrosis, may behave as a diffuselow-grade or anaplastic astrocytoma, respectively. In-creased recognition of low and high-grade lesions may

TABLE 5. (continued)


inferior frontal

lobes

‘‘frequent

mitoses’’

Autopsy

showed a large

tumor

involving the

chiasm,

hypothalamus,

left globus

pallidus,

amygdala,

optic tract, and

geniculate body

Casadei et al

(1990)1041/Female Ataxia,

behavioral

changes,

irritability,

memory

disturbances

CT: enhancing

partially cystic

mass in the

right cerebellar

hemisphere

with a nodule

in the vermis

PA STR at age 6,

GTR at age 21;

no radiation

given

Yellow tissue

with

leptomeningeal

infiltration

PA component

with Rosenthal

fibers and

granular

bodies;

hypercellular

foci with

pleomorphism,

mitoses

(atypical), and

necrosis

Irradiation Recurrent

symptoms and

abnormal

imaging at

6mo; expired.

Extensive

residual tumor

with

leptomeningeal

spread

ACNU indicates nimustine hydrochloride; BCNU, bis-chloronitrusurea; CT, computed tomography; 5-Fu, 5-fluorouracil; GTR, gross total resection; MRI, magneticresonance imaging; NA, not applicable; NED, no evidence of disease; PA, pilocytic astrocytoma STR, subtotal resection; R-CPA, right cerebellopontine angle.



prove useful for therapeutic stratification. Similarly, itmay shed light on the molecular mechanisms underlyingtheir genesis.

ACKNOWLEDGMENTSThe authors thank the pathologists and clinicians

who contributed to this study, including Drs Paula Larson,Lawrence Lockett, Christopher Robinson, David George,Bolek Lach, Hannes Blondal, Susan Murakami, StevenJones, Aaron Long, Takanori Hirose, Margie Cornwell,L. Resch, David Mirkin, Lawrence Bartusek, John Neal,Larry Tice, Nicolas Foreman, Charles Riedel, StephanieSoofer, Teresa Hayes, and LT Smyth.

REFERENCES1. Abel TJ, Chowdhary A, Thapa M, et al. Spinal cord pilocytic

astrocytoma with leptomeningeal dissemination to the brain.Case report and review of the literature. J Neurosurg. 2006;105:508–514.

2. Alpers CE, Davis RL, Wilson CB. Persistence and late malignanttransformation of childhood cerebellar astrocytoma. Case report.J Neurosurg. 1982;57:548–551.

3. Austin EJ, Alvord EC Jr. Recurrences of cerebellar astrocytomas:a violation of Collins’ law. J Neurosurg. 1988;68:41–47.

4. Bernell WR, Kepes JJ, Seitz EP. Late malignant recurrence ofchildhood cerebellar astrocytoma. Report of two cases. J Neurosurg.1972;37:470–474.

5. Blankenburg F, van Landeghem FK, Plotkin M, et al. Occurrence ofa spinal anaplastic pilocytic astrocytoma and a supratentorial PNETin an adolescent. J Pediatr Hematol Oncol. 2007;29:832–835.

6. Bowers DC, Gargan L, Kapur P, et al. Study of the MIB-1 labelingindex as a predictor of tumor progression in pilocytic astrocytomasin children and adolescents. J Clin Oncol. 2003;21:2968–2973.

7. Broniscer A, Baker SJ, West AN, et al. Clinical and molecularcharacteristics of malignant transformation of low-grade glioma inchildren. J Clin Oncol. 2007;25:682–689.

8. Brown PD, Buckner JC, O’Fallon JR, et al. Adult patients withsupratentorial pilocytic astrocytomas: a prospective multicenterclinical trial. Int J Radiat Oncol Biol Phys. 2004;58:1153–1160.

9. Budka H. Partially resected and irradiated cerebellar astrocytoma ofchildhood: malignant evolution after 28 years. Acta Neurochir(Wien). 1975;32:139–146.

10. Casadei GP, Arrigoni GL, D’Angelo V, et al. Late malignantrecurrence of childhood cerebellar astrocytoma. Clin Neuropathol.1990;9:295–298.

11. CBTRUS. Primary Brain Tumors in the United States, 2000-2004.Hinsdale, IL: Central Brain Tumor Registry of the United States;2008.

12. Daumas-Duport C, Scheithauer B, O’Fallon J, et al. Grading ofastrocytomas. A simple and reproducible method. Cancer. 1988;62:2152–2165.

13. Dirks PB, Jay V, Becker LE, et al. Development of anaplasticchanges in low-grade astrocytomas of childhood. Neurosurgery.1994;34:68–78.

14. Forsyth PA, Shaw EG, Scheithauer BW, et al. Supratentorialpilocytic astrocytomas. A clinicopathologic, prognostic, and flowcytometric study of 51 patients. Cancer. 1993;72:1335–1342.

15. Giannini C, Hebrink D, Scheithauer BW, et al. Analysis of p53mutation and expression in pleomorphic xanthoastrocytoma.Neurogenetics. 2001;3:159–162.

16. Giannini C, Scheithauer BW, Burger PC, et al. Cellular proliferationin pilocytic and diffuse astrocytomas. J Neuropathol Exp Neurol.1999;58:46–53.

17. Ilgren E, Kinnier-Wilson L, Stiller C. Gliomas in neurofibromatosis:a series of 89 cases with evidence for enhanced malignancy inassociated cerebellar astrocytomas. Pathol Ann. 1985;20:331–358.

18. Kepes JJ, Lewis RC, Vergara GG. Cerebellar astrocytoma invadingthe musculature and soft tissues of the neck. Case report.J Neurosurg. 1980;52:414–418.

19. Kleinman GM, Schoene WC, Walshe TM III, et al. Malignanttransformation in benign cerebellar astrocytoma. Case report.J Neurosurg. 1978;49:111–118.

20. Krieger MD, Gonzalez-Gomez I, Levy ML, et al. Recurrencepatterns and anaplastic change in a long-term study of pilocyticastrocytomas. Pediatr Neurosurg. 1997;27:1–11.

21. Louis D, Ohgaki H, Wiestler O, et al. WHO Classification of Tumoursof the Central Nervous System. Lyon, France: IARC press; 2007.

22. Ohgaki H, Kleihues P. Population-based studies on incidence,survival rates, and genetic alterations in astrocytic and oligoden-droglial gliomas. J Neuropathol Exp Neurol. 2005;64:479–489.

23. Parsa CF, Givrad S. Juvenile pilocytic astrocytomas do not undergospontaneous malignant transformation: grounds for designation ashamartomas. Br J Ophthalmol. 2008;92:40–46.

24. Parsa CF, Hoyt CS, Lesser RL, et al. Spontaneous regression ofoptic gliomas: thirteen cases documented by serial neuroimaging.Arch Ophthalmol. 2001;119:516–529.

25. Ringertz N, Nordenstam H. Cerebellar astrocytoma. J NeuropatholExp Neurol. 1951;10:343–367.

26. Rodriguez FJ, Perry A, Gutmann DH, et al. Gliomas inneurofibromatosis type 1: a clinicopathologic study of 100 patients.J Neuropathol Exp Neurol. 2008;67:240–249.

27. Rosser T, Packer RJ. Intracranial neoplasms in children withneurofibromatosis 1. J Child Neurol. 2002;17:630–637; discussion646–651.

28. Rubinstein L, Russell D. Pathology of Tumours of the NervousSystem. Baltimore: Williams & Wilkins; 1989.

29. Schwartz AM, Ghatak NR. Malignant transformation of benigncerebellar astrocytoma. Cancer. 1990;65:333–336.

30. Scott RM, Ballantine HT Jr. Cerebellar astrocytoma: malignantrecurrence after prolonged postoperative survival. Case report.J Neurosurg. 1973;39:777–779.

31. Steinberg GK, Shuer LM, Conley FK, et al. Evolution and outcomein malignant astroglial neoplasms of the cerebellum. J Neurosurg.1985;62:9–17.

32. Stuer C, Vilz B, Majores M, et al. Frequent recurrence andprogression in pilocytic astrocytoma in adults. Cancer. 2007;110:2799–2808.

33. Tibbetts KM, Emnett RJ, Gao F, et al. Histopathologic predictorsof pilocytic astrocytoma event-free survival. Acta Neuropathol.2009;117:657–665.

34. Tihan T, Fisher PG, Kepner JL, et al. Pediatric astrocytomas withmonomorphous pilomyxoid features and a less favorable outcome.J Neuropathol Exp Neurol. 1999;58:1061–1068.

35. Tomlinson FH, Scheithauer BW, Hayostek CJ, et al. The significanceof atypia and histologic malignancy in pilocytic astrocytoma of thecerebellum: a clinicopathologic and flow cytometric study. J ChildNeurol. 1994;9:301–310.

36. Ushio Y, Arita N, Yoshimine T, et al. Malignant recurrence ofchildhood cerebellar astrocytoma: case report. Neurosurgery.1987;21:251–255.

37. Wallner KE, Gonzales MF, Edwards MS, et al. Treatment results ofjuvenile pilocytic astrocytoma. J Neurosurg. 1988;69:171–176.

38. Warrington NM, Woerner BM, Daginakatte GC, et al. Spatiotem-poral differences in CXCL12 expression and cyclic AMP underliethe unique pattern of optic glioma growth in neurofibromatosis type1. Cancer Res. 2007;67:8588–8595.

39. Wilson WB, Feinsod M, Hoyt WF, et al. Malignant evolution ofchildhood chiasmal pilocytic astrocytoma. Neurology. 1976;26:322–325.

40. Wisoff HS, Llena JF. Glioblastoma multiforme of the cerebellumfive decades after irradiation of a cerebellar tumor. J Neurooncol.1989;7:339–344.



anaplasia in pilocytic astrocytoma predicts aggressive behavior

Documents

pa cases

pilocytic astrocytoma

pa precursor p

anaplastic features

anaplastic astrocytoma

anaplastic component

typical pilocytic features

anaplastic change