Anaplasia in Pilocytic Astrocytoma Predicts
Aggressive Behavior
Fausto J. Rodriguez, MD,* Bernd W. Scheithauer, MD,*
Peter...
MATERIALS AND METHODS
Patients
A search was performed for PA with anaplastic
features accessioned in the Mayo Clinic Patho...
Postoperative treatment approaches to PA with anaplas-
tic features included radiation therapy in 13 (81%) and
chemotherap...
patients had received postoperative radiation therapy
before the time of developing anaplasia.
Histologic and Immunohistoc...
NF1-associated PA
NF1-association among PA with anaplastic features
study group was noted in 8 (24%) cases, 3 initially
pr...
(P = 0.01), not significantly different to those with grade
3 astrocytoma (P = 0.40), but better than grade 4 astro-
cytomas...
literature contains no firm histologic criteria for a
diagnosis of PA with anaplastic features. In Table 5 we
have summariz...
FIGURE 4. Neurofibromatosis type 1-associated PA with anaplastic features (case 34). Axial T1-weighted magnetic resonance
...
leptomeningeal dissemination and extended into the
musculature of the neck.
Previous studies of atypical and anaplastic fe...
study of adult PA by Stuer et al,32
defined criteria of
anaplastic transformation, including brisk mitotic activity
and pal...
TABLE 5. Literature Review: PA With Anaplastic Features With Histologic Documentation
Case Age/Sex Clinical Radiology Prio...
TABLE 5. (continued)
Case Age/Sex Clinical Radiology Prior Precursor Surgery Pathology Treatment Follow-up
proliferation,
...
with anaplastic features differ somewhat. Necrosis with-
out pseudopalisading is said to occur in approximately
10% of case...
prove useful for therapeutic stratification. Similarly, it
may shed light on the molecular mechanisms underlying
their gene...
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Anaplasia in Pilocytic Astrocytoma Predicts Aggressive Behavior

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Anaplasia in Pilocytic Astrocytoma Predicts Aggressive Behavior

  1. 1. Anaplasia in Pilocytic Astrocytoma Predicts Aggressive 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 rare event 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 approximately 2200 PA cases (1.7%). Tumors were included which demon- strated brisk mitotic activity [at least 4 mitoses/10 high power fields (400 Â )], in addition to hypercellularity and moderate- to-severe cytologic atypia, with or without necrosis. The tumors either had a PA precursor, coexistent (n = 14) (41%) or documented by previous biopsy (n = 10) (29%), or exhibited typical pilocytic features in an otherwise anaplastic astrocytoma (n = 10) (29%). Clinical features of neurofibromatosis type-1 were present in 24% and a history of radiation for PA precursor in 12%. Histologically, the anaplastic component was classified as pilocytic like (41%), small cell (32%), epithelioid (15%), or fibrillary (12%). Median MIB1 labeling index was 24.7% in the anaplastic component and 2.6% in the precursor, although overlapping values were present. Strong p53 staining (3+) was limited to areas with anaplasia (19%), with overlapping values for 1 and 2+ in areas without anaplasia. Median overall and progression-free survivals after diagnosis for the entire study group were 24 and 14 months, respectively. Overall and progression-free survivals were shorter in the setting of prior radiation for a PA precursor (P = 0.007, 0.028), increasing mitotic 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 necrosis paralleled 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 with decreased survival when compared with typical PA. Key Words: pilocytic astrocytoma, anaplasia, neurofibromatosis, prognosis, grading, glioma (Am J Surg Pathol 2010;34:147–160) Pilocytic astrocytoma (PA) is a World Health Organi- zation (WHO) grade I tumor typically affecting children and young adults. As the most common brain tumor of childhood, its estimated incidence in the United States is 0.87 per 100,000 individuals under 19 years of age11 The cerebellum is most often affected,22 but PA may occur along the entire neuraxis with a proclivity for certain sites (optic pathways, hypothalamus, basal gang- lia, brainstem, cerebral hemispheres, and spinal cord). In addition, PA is the most frequently occurring central nervous system tumor in association with neurofibroma- tosis type-1 (NF1). In this setting, PA tends to involve the optic pathways and typically has a particularly favorable prognosis,27 spontaneous involution occurring in some instances.24 The behavior of PA is generally favorable with 5 and 10-year overall survival rates greater than 95% after surgical intervention alone.8,14,22 Key prognostic factors include patient age and extent of resection.14,32 Progression and recurrence resulting in death occur in a small subset of cases despite typical histologic features.3,6,20 Pilomyxoid astrocytoma, a recently recog- nized PA variant, shows a predilection for the hypo thalamic region of young children, tends to undergo leptomeningeal dissemination, and is associated with a worse 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 the presence of anaplastic features are rare findings. Some authors even doubt the potential for anaplastic change in PA, proposing that PA are hamartomatous rather than neoplastic lesions.23 Published descriptions of anaplastic features in PA consist mainly of isolated case reports and small series.2,4,9,10,13,18–20,29–32,35–37 Many, but not all examples, have occurred in association with prior irradiation of a benign PA.2,4,9,19,29–31,35,36 Clinical behavior is often unpredictable: some patients do poorly, whereas others remain stable, even with disseminated leptomeningeal disease.1 This study evaluates our experi- ence of PA with anaplastic features, describes their histologic spectrum, and attempts to establish practical morphologic 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 Hopkins Medical Institutions, Baltimore, MD. Correspondence: Fausto J. Rodriguez, MD, Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 (e-mail: rodriguez.fausto@mayo.edu). ORIGINAL ARTICLE Am J Surg Pathol Volume 34, Number 2, February 2010 www.ajsp.com | 147
  2. 2. MATERIALS AND METHODS Patients A search was performed for PA with anaplastic features accessioned in the Mayo Clinic Pathology records between 1985 and 2008. Cases of PA with anaplastic features (n = 10) or with documented prior WHO grade I PA (n = 24) were included. Majority (30 cases) were identified among 1591 PA consults (1.8%). The remaining 4 tumors were obtained from 644 patients with PA, representing 0.6% of all PA operated at Mayo Clinic. Slides from original precursor lesions and from multiple surgical procedures were available for review in 11 cases (32%). Follow-up information was gathered from medical records, consultation letters, and online death registries. The study was approved by the Mayo Clinic Institutional Review Board. Pathology and Inclusion Criteria Cases were reviewed by 4 neuropathologists (P.C.B., C.G., F.J.R., and B.W.S.), with the exception of 6 consultation cases which were reviewed by 3. Tumors were included if they demonstrated brisk mitotic activity [at least 4 mitoses/10 high power fields (HPF) (Â 400)], in addition to hypercellularity and moderate-to-severe cyto- logic atypia, with or without necrosis. For case inclusion, anaplastic features were required to occupy at least one low-power field (20 Â). In addition some features typical of PA had to be present, in at least one low-power field (20 Â), including compact piloid astrocytes and/or micro- cystic zones, Rosenthal fibers, and eosinophilic granular bodies (Figs. 1A–C). High-grade astrocytomas arising after treatment for a PA, but lacking a distinct coexistent PA precursor or at least some histologic features typical of PA were excluded. Upon review of all available slides, the cases were included in the study if at least 3 neuropathologists agreed with the diagnosis of PA with anaplastic features. Histo- logic features were graded as previously described.26 In brief, nuclear atypia was graded on a 3-tiered scale based on chromatin and nuclear irregularities of nondegenera- tive type. Cellularity was rated as low, moderate, or high as previously described.26 Degree of invasiveness was classified as absent, partial, or diffuse based upon axonal density on neurofilament protein immunostains when available, in combination with the identification of entrapped neurons and/or axons on hematoxylin and eosin stain. Mitotic indices were calculated by counting the number of mitoses/10 HPF (400 Â) using an Olympus BH-2 microscope. We excluded optic pathway tumors in NF1-associated cases as elevated mitotic activity and hypercellularity are commonly seen in this group and are not associated with an adverse outcome.26 Immunohistochemistry Immunohistochemical stains used the Dual Link Envision+ (Dako) detection system and a DAKO Autostainer (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 the following antigens: glial fibrillary acidic protein (poly- clonal, 1:4000; Dako, Carpinteria, CA), neurofilament protein (clone 2F11, 1:75; Dako), p53 protein (clone DO7, 1:2000; Dako), INI-1-BAF47 (clone 25, 1:100; BD Transduction, BD Biosciences, San Jose, CA), and Ki–67 (clone MIB-1, monoclonal, 1:300; Dako). Whenever feasible, immunoreactivity for p53 protein was evaluated in both the anaplastic and benign-appearing tumor components. As previously reported,15 p53 protein stain was scored on the following semiquantitative scale: no staining (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 indices was performed using the Hamamatsu NanoZoomer Digital Pathology for scanning images and IHCScore software for computer-assisted analyses (Bacus Labora- tories, Lombard, IL). Statistics Patient and tumor characteristics were described using frequencies and percentages, or medians, ranges and interquartile ranges as appropriate. Overall and recurrence-free survivals were calculated from the best estimated time of development of anaplastic changes to time of death or recurrence (respectively). Overall and recurrence-free survivals were illustrated using Kaplan- Meier survival curves along with estimates and 95% confidence intervals (CI) for median survival. Survival and recurrence-free survivals were compared between clinicopathologic groups using Cox proportional hazards regression, adjusted for age, sex, and/or site of tumor. Hazard ratios and their 95% CI were estimated. If a precise date of recurrence was unknown, but the patient died within 3 years of the appearance of anaplastic features, the day of death was considered the recurrence date. Statistical analyses were performed using SAS version 9 software (SAS Institute Inc, Cary, NC). All two-sided P values 0.05 were considered statistically significant. RESULTS Clinical Features of PA With Anaplastic features Clinical features are summarized in Table 1. The patients included 13 females and 21 males. The median age at diagnosis of PA with anaplastic features was 35 years (range: 5 to 75 y). Six (18%) were pediatric cases (patients 18 y old). Fifty percent of tumors arose in the cerebellum, whereas 35% were supratentorial. Informa- tion regarding preoperative radiologic imaging was avai- lable in 24 cases (71%). Studies included magnetic resonance imaging in 14 (58%), computed tomography in 4 (17%), and unspecified methods in 6 (25%). Leptomeningeal dissemination was documented in only 1 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
  3. 3. Postoperative treatment approaches to PA with anaplas- tic features included radiation therapy in 13 (81%) and chemotherapy in 11 (69%), including temozolomide in 7 (44%). Two patients underwent Gliadel wafer (Eisai Corporation 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 10 cases (29%); the median time between original diagnosis and diagnosis of PA with anaplastic features was 14 years in this group (range: 4 mo 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, including Rosenthal fibers (A) and/or eosinophilic granular bodies (B). Perivascular pseudorosettes reminiscent of pilomyxoid morphology was a focal finding in a subset of cases (C). Some tumors were classified as ‘‘pilocytic like,’’ because of clear cut preservation of pilocytic features, but with brisk mitotic activity (arrows) (D). Example of a PA with an epithelioid/rhabdoid component. An atypical tripolar mitosis is present in the center of the field (E). PA with anaplastic features composed of oval hyperchromatic cells with high nuclear:cytoplasmic ratio resembling small cell astrocytoma (F). Eosinophilic granular bodies within an anaplastic small cell component were an occasional finding is some examples (G). A pattern of conventional fibrillary astrocytoma characterized the 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
  4. 4. patients had received postoperative radiation therapy before the time of developing anaplasia. Histologic and Immunohistochemical Features of PA With Anaplastic Features A total of 3 neuropathologists agreed with the diagnosis in all cases and 4 in 88% of cases. Histologic features are summarized in Table 2 and illustrated in Figures 1 and 2. The most common histologic pattern was ‘‘pilocytic like’’ (41%), that is featuring compact, bipolar cells with Rosenthal fibers, and/or microcysts with eosinophilic granular bodies, but with brisk mitotic activity and hypercellularity (Figs. 1D, G). The next most frequent pattern was that of a poorly differentiated, small cell process (32%) (Fig. 1F) which was glial fibrillary acidic protein immunoreactive (11 of 11 cases). Epithe- lioid or rhabdoid patterns were the third most frequent (15%) (Fig. 1E), followed by cytologic features of fibrillary astrocytoma in 12% (Fig. 1H and Fig. 2). Immunohistochemical stains for INI-1-BAF-47 per- formed in 3 (of 5) tumors with epithelioid/rhabdoid cytology showed preservation of nuclear immuno- reactivity (not shown). p53 overexpression (3+) was present in the anaplastic component in 4 (of 21) cases tested (19%), but not in the PA precursors. Median MIB1 labeling 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 noted in one brainstem and one cerebellar example each (Fig. 3). Both patients are well without evidence of disease, respectively 13 and 27 months after gross total resection alone. By comparison, in the rest of the group anaplastic features were multifocal or widespread. TABLE 1. Clinical and Demographic Features of Pilocytic Astrocytoma With Anaplastic Features N (%) Sex Female 13 (38) Male 21 (62) Tumor location Cerebellum 17 (50) Supratentorial 12 (35) Brainstem 2 (6) Spinal cord 2 (6) Tectum 1 (3) Extent of surgery GTR 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 treatmentw Observation 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 type Pilocytic 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) Atypia Moderate 12 (35) Severe 22 (65) Infiltration Absent 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 HPF Median (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) Necrosis Coagulative 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 component 0 3 (14) 1+ 8 (38) 2+ 6 (29) 3+ 4 (19) PA precursor 0 2 (25) 1+ 5 (63) 2+ 1 (13) 3+ 0 HPF indicates high power field; PA, pilocytic astrocytoma. Rodriguez et al Am J Surg Pathol Volume 34, Number 2, February 2010 150 | www.ajsp.com r 2010 Lippincott Williams Wilkins
  5. 5. NF1-associated PA NF1-association among PA with anaplastic features study group was noted in 8 (24%) cases, 3 initially presenting 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 the tumors received radiation therapy before the diagnosis of PA with anaplastic features. Median patient age in the entire NF1 patient group was 35 years (range: 11 to 59y). Follow up was available in 6 patients (75%); 3 developed recurrences at 2, 10, and 11 months and 2 patients died of disease, respectively 12 and 24 month postsurgery. Finally, 1 patient developed what appeared to be radiation necrosis on perfusion magnetic resonance imaging at 9 months and 2 patients are alive without evidence of disease at 1 and 13 years. The one patient alive without evidence of disease at 1 year received Avastin in combination with radiation therapy and camptothecin-11 after having undergone a gross total resection. After adjusting for age and site, no difference in recurrence-free (P = 0.83) or overall survival (P = 0.50) was noted between the NF1 group and patients with sporadically occurring tumors. Survival Analysis of PA With Anaplastic Features Survival data with clinical follow up was available in 28 patients (82%). Median overall and progression-free survivals 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 28 patients. Increasing patient age was inversely corre- lated with overall survival [hazard ratio (HR) = 1.03, P = 0.02]. There were no prognostic differences by tumor site (cerebellar vs. noncerebellar locations) (P0.05), but we chose to adjust for this parameter, given the recently identified biologic differences of PA from different sites.38 After adjusting for age and tumor site, the following variables were found to be associated with decreased overall and progression free-survivals, respectively: his- tory of prior radiation (P = 0.007, 0.028), history of a PA precursor (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 cytologic atypia were associated with decreased progression-free (P = 0.04 and 0.02, respectively), but not with overall survival. After adjusting for age and tumor site, there were no statistically significant associations (P0.05) with presence of NF1, tumor location, date of diagnosis (comparing patients treated before or after 2000), tumor cellularity, presence of atypical mitoses, endothelial pro- liferation, degree of parenchymal infiltration, microscopic leptomeningeal involvement, cytologic type of the malig- nant component, extent of resection, or the administration of postoperative temozolomide chemotherapy. Survival Analysis Comparing With Other Astrocytoma Subtypes To evaluate overall survival in the context of other astrocytoma subtypes, survival data was obtained from the historical cohort used to established St Anne-Mayo grading of astrocytomas, which was later used as the basis of the WHO grading of diffuse astrocytomas.12 That study included conventional PAs (n = 51), as well as grade 2 (n = 46), grade 3 (n = 51), and grade 4 (n = 188) diffusely infiltrative astrocytomas. The results of the survival analyses are summarized in Table 4 and illustrated in Figure 6. In brief, survival in our entire patient cohort (reference group) was worse than that associated with conventional PAs (HR = 0.11, P 0.0001) and better than grade 4 astrocytomas (HR = 3.20, P0.0001). It was, however, not statistically different from the survival of patients with grade 2 or grade 3 astrocytoma. When subdividing our current patient cohort according to the presence or absence of necrosis, survival in PA with anaplastic features without necrosis was: no different from that associated with St Anne-Mayo grade 2 astrocytomas (P = 0.44), better, but not significantly (P = 0.0943) than grade 3 astrocytoma patients, and significantly better than grade 4 astro- cytomas (P = 0.0004). Patients with necrosis-associated tumors had overall survivals worse than grade 2 astrocytomas TABLE 3. Neurofibromatosis type-1-associated Pilocytic Astrocytoma With Anaplastic Features Feature N (%) Sex Female 3 (38) Male 5 (62) Tumor location Cerebellum 4 (50) Supratentorial 4 (50) Extent of surgery GTR 2 (25) STR 2 (25) Indeterminate 4 (50) Historic precursor 3 (38) History of radiation 0 Postoperative treatment Radiation 5 (62) Chemotherapy 4 (50) Unknown 3 (38) Histologic type Pilocytic like 5 (62) Fibrillary astrocytoma 1 (13) Small cell astrocytoma 1 (13) Epithelioid/rhabdoid 1 (13) Necrosis Coagulative 3 (38) Pseudopalisading 0 Mitoses/10 HPF Median (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, subtotal resection. Am J Surg Pathol Volume 34, Number 2, February 2010 Anaplasia Changes in PA r 2010 Lippincott Williams Wilkins www.ajsp.com | 151
  6. 6. (P = 0.01), not significantly different to those with grade 3 astrocytoma (P = 0.40), but better than grade 4 astro- cytomas (P = 0.002). DISCUSSION PAs 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-differentiated biphasic component with Rosenthal fibers (A) and microcysts (B). High-grade astrocytoma component with increased cellularity and 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). Rodriguez et al Am J Surg Pathol Volume 34, Number 2, February 2010 152 | www.ajsp.com r 2010 Lippincott Williams Wilkins
  7. 7. literature contains no firm histologic criteria for a diagnosis of PA with anaplastic features. In Table 5 we have summarized the literature regarding cases of PA with anaplasia providing data regarding specific histolo- gic features. Reported examples lacking sufficient histo- logic descriptions of either a PA precursor25,40 or features of PA with anaplasia5,30,37 were excluded. In that some tumors, particularly in the older literature, were simply referred to as ‘‘cerebellar astrocytoma,’’ it is unclear whether they represented pilocytic or diffuse infiltrative astrocytomas. For example, Kepes et al18 reported the dramatic example of an infiltrating astrocytoma of the cerebellum with microcysts and anaplastic features in a 9-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 staining 400 Â). Am J Surg Pathol Volume 34, Number 2, February 2010 Anaplasia Changes in PA r 2010 Lippincott Williams Wilkins www.ajsp.com | 153
  8. 8. FIGURE 4. Neurofibromatosis type 1-associated PA with anaplastic features (case 34). Axial T1-weighted magnetic resonance imaging postcontrast preoperatively (A), immediately after the first resection demonstrating residual tumor (B) and 3 months after demonstrating rapid growth (C). Findings at the first resection included bipolar cells and Rosenthal fibers, but no malignant features (D) (hematoxylin and eosin staining). Recurrent tumor demonstrating a PA component (top) and a high-grade hypercellular component (bottom) (E) (hematoxylin and eosin staining). High power view of the malignant component demonstrates hyperchromatic cells with high nuclear:cytoplasmic ratios (F) (hematoxylin and eosin staining). MIB-1 labeling index was high (image matching H and E panel in E) (G). PA indicates pilocytic astrocytoma. Rodriguez et al Am J Surg Pathol Volume 34, Number 2, February 2010 154 | www.ajsp.com r 2010 Lippincott Williams Wilkins
  9. 9. leptomeningeal dissemination and extended into the musculature of the neck. Previous studies of atypical and anaplastic features in PA have been published.20,35 That of Tomlinson et al35 undertook a systematic study of various parameters in conventional PA and in 4 selected examples of PA with histologic malignancy. Whereas the latter exhibited malignant behavior and featured high-mitotic activity [multiple mitoses/HPF (400 Â) and palisading necrosis] attempts to identify clinically meaningful ‘‘atypical’’ PA based on low-level mitotic activity (1 mitosis per 10 250 Â microscopic fields) were unsuccessful. In a study of 36 pediatric PA by Krieger et al,20 4 were found to have developed anaplastic change upon recurrence. The frequency was somewhat high (11%), but diagnostic criteria 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 necrosis Necrosis 0.8 0.6 n=7 n=9 0.4 0.2 Survival B Survival 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=21 n=19 Years 0 2 4 6 8 10 12 14 Years Median NA days, 95% CI 758, NA Median 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 values from 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 Overall Survival 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 infiltrating astrocytomas 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) 0.12 Grade 3 astrocytoma 598 (498, 1004) 1.09 (0.64, 1.86) 0.75 Grade 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) 0.048 Diffusely infiltrating astrocytomas: Conventional PA NA* 0.27 (0.08, 0.97) 0.04 Grade 2 astrocytoma 1490 (1157, 1904) 1.59 (0.49, 5.13) 0.44 Grade 3 astrocytoma 598 (498, 1004) 2.71 (0.84, 8.70) 0.09 Grade 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) 0.048 Diffusely infiltrating astrocytomas: Conventional PA NA* 0.08 (0.04, 0.17) 0.0001 Grade 2 astrocytoma 1490 (1157, 1904) 0.46 (0.25, 0.83) 0.01 Grade 3 astrocytoma 598 (498, 1004) 0.78 (0.44, 1.38) 0.40 Grade 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. Am J Surg Pathol Volume 34, Number 2, February 2010 Anaplasia Changes in PA r 2010 Lippincott Williams Wilkins www.ajsp.com | 155
  10. 10. study of adult PA by Stuer et al,32 defined criteria of anaplastic transformation, including brisk mitotic activity and palisading necrosis. The changes, present in 14% of their cases, suggested that anaplastic transformation occurs more frequently in adults. This is in keeping with our findings that the median age at development of anaplasia in an unselected series was 35 years. An interesting finding of our study is that a history of radiation was present in only a minority of the cases (11%). This differs from the literature, in which the majority of PA with anaplastic features are associated with a history of irradiation of a PA precursor (Table 5). One possible explanation is that most tumors in our series were consultation derived and posed the challenge of diagnosing primary PA with anaplastic features. In any case, both the occurrence of a precursor PA at an earlier date and a history of prior irradiation, were associated with a less favorable prognosis. These findings suggest that tumors developing postradiation are biologically distinct from those developing anaplastic features spon- taneously in a PA precursor. It is still possible that some of these cases represent separate second primaries, although by only including in this setting tumors that had at least partial, coexistent typical pilocytic features, we attempted to minimize this possibility. This approach further explains the small number of postradiation PA with anaplastic features in our series compared with the literature. This study indicates that PA with anaplastic features is associated with decreased patient survival. We found it useful to compare our data with a large, published clinicopathologic study of pilocytic and diffusely infiltrative astrocytomas.12 Tumors in that published series12 were graded according to the St Anne-Mayo scheme, the criteria which were later adopted into the WHO.21 The approach was binary and included the presence or absence of nuclear atypia, 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 differing decades during which the patients were treated and the relatively smaller number of tumors studied in our current series. In addition, St Anne-Mayo and WHO grading schemes should not be equated. The current WHO classi- fication21 requires more than one mitosis for a diagnosis of anaplastic astrocytoma (WHO grade III), whereas a single mitosis was sufficient for a grade 3 designation in the St Anne-Mayo grade scheme. In a prior study we found that infiltrating astrocytomas with a solitary mitosis had a better prognosis than those with greater numbers of mitoses.16 This may have some confounding effects in our study, although astrocytomas with a solitary mitosis represent only a minority of grade 3 astrocytomas in the St Anne-Mayo scheme (approximately 24% in one study).16 These caveats aside, we found PA with anaplastic features without necrosis to behave closer to St Anne-Mayo grade 2 astro- cytoma, whereas the presence of necrosis in a mitotically active PA conferred a behavior analogous to that of grade 3 astrocytoma, 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, NA Grade 2 Median 1490 days, 95% CI 1157, 1904 Grade 3 Median 598 days, 95% CI 498, 1004 Grade 4 Median 260 days, 95% CI 242, 287 Anaplastic PA Median 716 days, 95% CI 513, 884 Microcystic/pilocytic Median NA days, 95% CI NA, NA Grade 2 Median 1490 days, 95% CI 1157, 1904 Grade 3 Median 598 days, 95% CI 498, 1004 Grade 4 Median 260 days, 95% CI 242, 287 Anaplastic PA, Median NA days, 95% CI 758, NA no necrosis Anaplastic PA Median 589 days, 95% CI 399, NA with necrosis 1.0 0.6 0.4 0.2 0.0 Survival B 0.8 1.0 0.6 0.4 0.2 0.0 Survival 0 2 4 6 8 10 12 14 Years 0 2 4 6 8 10 12 14 Years 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. Rodriguez et al Am J Surg Pathol Volume 34, Number 2, February 2010 156 | www.ajsp.com r 2010 Lippincott Williams Wilkins
  11. 11. 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)2 26/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 197819 52/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 5 mo 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’’ 8 mo previously; GTR STR Diffusely infiltrating high-grade astrocytoma, hypercellular, mitoses, endothelial proliferation, pseudopalisad- ing necrosis Expired 3 mo 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 4 mo after surgery; autopsy revealed high- grade astrocytoma with infiltration Am J Surg Pathol Volume 34, Number 2, February 2010 Anaplasia Changes in PA r 2010 Lippincott Williams Wilkins www.ajsp.com | 157
  12. 12. TABLE 5. (continued) Case Age/Sex Clinical Radiology Prior Precursor Surgery Pathology Treatment Follow-up proliferation, and pseudopalisad- ing necrosis, no PA features of cerebellum, brainstem, diencephalon, thalamus. Peritoneal metastases and pneumonia also present Ushio et al (1987)36 15/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 5 mo after, developed ataxia, speech disturbance; third surgery, additional radiation, chemotherapy; progression. Expired 17 mo 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 2 mo 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 Â field) Radiation (5400 rads) NED 6 mo 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 Â field). PA features present Steroid therapy Expired 2 mo 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 Â field, severe atypia, pseudopalisad- ing necrosis BCNU Tumor recurrence at 1 y, additional surgery. Stable 2 y after malignant transformation Wilson et al (1976)39 27/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. Rodriguez et al Am J Surg Pathol Volume 34, Number 2, February 2010 158 | www.ajsp.com r 2010 Lippincott Williams Wilkins
  13. 13. with anaplastic features differ somewhat. Necrosis with- out pseudopalisading is said to occur in approximately 10% of cases and to be of no prognostic significance in some studies,16 although it was associated with decreased event-free survival in a recent study.33 The same is true of only 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 a single low-power field (20 Â), is of prognostic significance, distinguishing PA with anaplastic features from conven- tional, WHO grade I PAs. We used this mitotic index cutoff because it was the lowest mitotic rate found in PA with anaplastic features in our files. As the survival of patients with PA showing increased mitotic activity but lacking necrosis is no worse as a group than that of patients with grade 2 infiltrating astrocytomas, with the caveats mentioned above, the designation of atypical PA may be appropriate. Further studies will be required to confirm our findings and formulate minimal criteria for the diagnosis. Our study included 2 cases in which anaplastic features of hypercellularity and increased mitotic activity were focal; these tumors did not behave in an aggressive manner. 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 not equate with the behavior of glioblastoma. We do not, therefore, apply the term glioblastoma or attribute a grade IV designation to pilocytic tumors with anaplastic features 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 optic pathways, because they represent a clinicopathologically unique niche in NF1 patients,38 often being associated with a favorable outcome, regardless of specific histologic features.26 Nonetheless, fully half of NF1-associated PA with anaplastic features in our series arose in the cerebellum. It is of note that early studies of NF1- associated gliomas found cerebellar tumors to behave less favorably.17,28 In that many such studies antedated current glioma and neurofibromatosis classification schemes, 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 lack of detailed clinical and therapeutic as well as follow-up data. This is often a problem in studies of rare tumors available only in large consultation services. Acquiring case numbers sufficient to arrive at solid, scientific generalizations is often impossible in single, even large, institutions. Nonetheless, we have studied the largest cohort to date of PA with anaplastic features patients. Our data suggest that such tumors behave in a more aggressive 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 between morphologic features and tumor behavior. Moreover, even ‘‘high-grade’’ PA with anaplastic features does not behave like glioblastoma. At best, PA with anaplastic features with the requisite mitotic index (4/10 HPF), as well as those featuring necrosis, may behave as a diffuse low-grade or anaplastic astrocytoma, respectively. In- creased recognition of low and high-grade lesions may TABLE 5. (continued) Case Age/Sex Clinical Radiology Prior Precursor Surgery Pathology Treatment Follow-up 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)10 41/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 6 mo; 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, magnetic resonance imaging; NA, not applicable; NED, no evidence of disease; PA, pilocytic astrocytoma STR, subtotal resection; R-CPA, right cerebellopontine angle. Am J Surg Pathol Volume 34, Number 2, February 2010 Anaplasia Changes in PA r 2010 Lippincott Williams Wilkins www.ajsp.com | 159
  14. 14. prove useful for therapeutic stratification. Similarly, it may shed light on the molecular mechanisms underlying their genesis. ACKNOWLEDGMENTS The 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, Steven Jones, Aaron Long, Takanori Hirose, Margie Cornwell, L. Resch, David Mirkin, Lawrence Bartusek, John Neal, Larry Tice, Nicolas Foreman, Charles Riedel, Stephanie Soofer, Teresa Hayes, and LT Smyth. REFERENCES 1. 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 malignant transformation 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 of childhood cerebellar astrocytoma. Report of two cases. J Neurosurg. 1972;37:470–474. 5. Blankenburg F, van Landeghem FK, Plotkin M, et al. Occurrence of a spinal anaplastic pilocytic astrocytoma and a supratentorial PNET in an adolescent. J Pediatr Hematol Oncol. 2007;29:832–835. 6. Bowers DC, Gargan L, Kapur P, et al. Study of the MIB-1 labeling index as a predictor of tumor progression in pilocytic astrocytomas in children and adolescents. J Clin Oncol. 2003;21:2968–2973. 7. Broniscer A, Baker SJ, West AN, et al. Clinical and molecular characteristics of malignant transformation of low-grade glioma in children. J Clin Oncol. 2007;25:682–689. 8. Brown PD, Buckner JC, O’Fallon JR, et al. Adult patients with supratentorial pilocytic astrocytomas: a prospective multicenter clinical trial. Int J Radiat Oncol Biol Phys. 2004;58:1153–1160. 9. Budka H. Partially resected and irradiated cerebellar astrocytoma of childhood: malignant evolution after 28 years. Acta Neurochir (Wien). 1975;32:139–146. 10. Casadei GP, Arrigoni GL, D’Angelo V, et al. Late malignant recurrence 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 of astrocytomas. A simple and reproducible method. Cancer. 1988; 62:2152–2165. 13. Dirks PB, Jay V, Becker LE, et al. Development of anaplastic changes in low-grade astrocytomas of childhood. Neurosurgery. 1994;34:68–78. 14. Forsyth PA, Shaw EG, Scheithauer BW, et al. Supratentorial pilocytic astrocytomas. A clinicopathologic, prognostic, and flow cytometric study of 51 patients. Cancer. 1993;72:1335–1342. 15. Giannini C, Hebrink D, Scheithauer BW, et al. Analysis of p53 mutation and expression in pleomorphic xanthoastrocytoma. Neurogenetics. 2001;3:159–162. 16. Giannini C, Scheithauer BW, Burger PC, et al. Cellular proliferation in 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 in associated cerebellar astrocytomas. Pathol Ann. 1985;20:331–358. 18. Kepes JJ, Lewis RC, Vergara GG. Cerebellar astrocytoma invading the 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. Malignant transformation in benign cerebellar astrocytoma. Case report. J Neurosurg. 1978;49:111–118. 20. Krieger MD, Gonzalez-Gomez I, Levy ML, et al. Recurrence patterns and anaplastic change in a long-term study of pilocytic astrocytomas. Pediatr Neurosurg. 1997;27:1–11. 21. Louis D, Ohgaki H, Wiestler O, et al. WHO Classification of Tumours of 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 undergo spontaneous malignant transformation: grounds for designation as hamartomas. Br J Ophthalmol. 2008;92:40–46. 24. Parsa CF, Hoyt CS, Lesser RL, et al. Spontaneous regression of optic gliomas: thirteen cases documented by serial neuroimaging. Arch Ophthalmol. 2001;119:516–529. 25. Ringertz N, Nordenstam H. Cerebellar astrocytoma. J Neuropathol Exp Neurol. 1951;10:343–367. 26. Rodriguez FJ, Perry A, Gutmann DH, et al. Gliomas in neurofibromatosis 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 with neurofibromatosis 1. J Child Neurol. 2002;17:630–637; discussion 646–651. 28. Rubinstein L, Russell D. Pathology of Tumours of the Nervous System. Baltimore: Williams Wilkins; 1989. 29. Schwartz AM, Ghatak NR. Malignant transformation of benign cerebellar astrocytoma. Cancer. 1990;65:333–336. 30. Scott RM, Ballantine HT Jr. Cerebellar astrocytoma: malignant recurrence after prolonged postoperative survival. Case report. J Neurosurg. 1973;39:777–779. 31. Steinberg GK, Shuer LM, Conley FK, et al. Evolution and outcome in malignant astroglial neoplasms of the cerebellum. J Neurosurg. 1985;62:9–17. 32. Stuer C, Vilz B, Majores M, et al. Frequent recurrence and progression in pilocytic astrocytoma in adults. Cancer. 2007;110: 2799–2808. 33. Tibbetts KM, Emnett RJ, Gao F, et al. Histopathologic predictors of pilocytic astrocytoma event-free survival. Acta Neuropathol. 2009;117:657–665. 34. Tihan T, Fisher PG, Kepner JL, et al. Pediatric astrocytomas with monomorphous 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 significance of atypia and histologic malignancy in pilocytic astrocytoma of the cerebellum: a clinicopathologic and flow cytometric study. J Child Neurol. 1994;9:301–310. 36. Ushio Y, Arita N, Yoshimine T, et al. Malignant recurrence of childhood cerebellar astrocytoma: case report. Neurosurgery. 1987;21:251–255. 37. Wallner KE, Gonzales MF, Edwards MS, et al. Treatment results of juvenile 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 underlie the unique pattern of optic glioma growth in neurofibromatosis type 1. Cancer Res. 2007;67:8588–8595. 39. Wilson WB, Feinsod M, Hoyt WF, et al. Malignant evolution of childhood chiasmal pilocytic astrocytoma. Neurology. 1976;26:322–325. 40. Wisoff HS, Llena JF. Glioblastoma multiforme of the cerebellum five decades after irradiation of a cerebellar tumor. J Neurooncol. 1989;7:339–344. Rodriguez et al Am J Surg Pathol Volume 34, Number 2, February 2010 160 | www.ajsp.com r 2010 Lippincott Williams Wilkins

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