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Clinical and Molecular Characteristics of Malignant Transformation of Low-Grade Glioma in Children

Alberto Broniscer, Suzanne J. Baker, Alina N. West, Melissa M. Fraser, Erika Proko, Mehmet Kocak, James Dalton, Gerard P. Zambetti, David W. Ellison, Larry E. Kun, Amar Gajjar, Richard J. Gilbertson, Christine E. Fuller

From the Departments of Oncology, Developmental Neurobiology, Biochemistry, Biostatistics, Radiological Sciences, and Pathology, St Jude Children's Research Hospital; Department of Interdisciplinary Sciences, University of Tennessee Health Sciences Center, Memphis, TN; and the Northern Institute for Cancer Research, University of Newcastle, Newcastle-upon-Tyne, United Kingdom

Address reprint requests to Alberto Broniscer, MD, Department of Oncology, St Jude Children's Research Hospital, Mail Stop 260, 332 North Lauderdale St, Memphis, TN 38105; e-mail: alberto.broniscer{at}stjude.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
PURPOSE: To analyze the clinical and molecular characteristics of malignant transformation (MT) of low-grade glioma (LGG) in children.

PATIENTS AND METHODS: The clinical, radiologic, and histologic characteristics of children treated at our institution who experienced MT of LGG were reviewed. Molecular alterations in these tumors were analyzed by fluorescent in situ hybridization, immunohistochemistry, and TP53 sequencing. Cumulative incidence estimate and risk factors for MT were determined for 65 patients with grade 2 astrocytoma treated at our institution during the study interval.

RESULTS: Eleven patients who experienced MT were identified (median age at diagnosis of LGG, 13.3 years). Initial diagnoses were grade 2 astrocytoma (n = 6) and other grade 1/2 gliomas (n = 5). The median latency of MT was 5.1 years. Histologic diagnoses after MT were glioblastoma (n = 7) and other high-grade gliomas (n = 4). The 15-year cumulative incidence estimate of MT among 65 patients with grade 2 astrocytoma was 6.7% ± 3.9%; no risk factor analyzed, including radiotherapy, was associated with MT. Tissue was available for molecular analysis in all patients, including nine with samples obtained before and after MT. TP53 overexpression was more common after MT. Deletions of RB1 and/or CDKN2A were observed in 71% of LGGs and in 90% of tumors after MT. PTEN pathway abnormalities occurred in 76% of patients. One of five oncogenes analyzed (PDGFRA) was amplified in one patient.

CONCLUSION: The molecular abnormalities that occur during MT of LGG in children are similar to those observed in primary and secondary glioblastoma in adults.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Gliomas are the most common group of CNS neoplasms in children and adults.¹ Whereas low-grade gliomas (LGGs) comprise the majority of these neoplasms in children, high-grade gliomas (HGGs), particularly glioblastoma (WHO grade 4), predominate in adults.¹ Glioblastoma in adults is classified as secondary or primary on the basis of progression from pre-existing LGGs and on distinct patterns of molecular abnormalities.² Unlike adults, little is known about the mechanisms of tumorigenesis of HGG in children.³ Although some molecular abnormalities encountered in HGG in children are reminiscent of secondary glioblastoma,⁴ these neoplasms rarely originate from pre-existing LGGs.^5-10

Although one study suggested an association between radiotherapy (RT) and malignant transformation (MT) of LGG in children,⁸ no information is available about cumulative incidence, risk factors, and molecular abnormalities associated with this event. We conducted extensive clinical and molecular analysis in the largest cohort to date of children who experienced MT of LGG to improve the understanding of this important phenomenon in pediatric gliomas.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Once institutional review board approval was obtained, we selected patients younger than age 22 years with HGG treated at our institution between January 1, 1985 and December 31, 2003 who experienced MT of LGG. Our criteria for MT were based on: consecutive histologic diagnosis of LGG and HGG in at least two distinct tumor samples obtained from the same patient at different time points; exclusion of second neoplasms by radiologic review; and compatible clinical history. Our radiologic criterion for MT was the presence of contiguous or overlapping sites of involvement of LGG and subsequent HGG. HGGs that arose in areas distinct from LGG were considered second neoplasms.¹¹ Central histologic review (C.E.F.) of all tumor samples at diagnosis of LGG and HGG confirmed MT. An independent histologic review was conducted by a second neuropathologist (D.W.E.) who was blinded in regards to sample identity and timing of collection. Clinical information and treatment data were ascertained from chart review. All available tumor samples were collected for molecular studies.

Immunohistochemistry and Fluorescent in Situ Hybridization Studies
These studies were performed on 5 µm-thick, formalin-fixed, paraffin-embedded tissue sections either as single samples or combined as tissue microarrays containing multiple 1-mm cores derived from the respective tumor blocks. Tissue sections used for molecular studies were adjacent to those used for central histologic review.

Immunohistochemical studies for the epidermal growth factor receptor (EGFR), other EGFR-family members (ERBB2, ERBB3, and ERBB4), TP53, phospho-AKT (pAKT) and phospho-S6 (pS6) were performed using standard techniques as previously reported.^4,12,13 Controls included a panel of healthy human tissues and tumor cells with previously characterized overexpression of each EGFR-family protein. For pAKT and pS6, brain tissue from Pten conditional knockout and healthy mice were used as positive and negative controls, respectively, for activation of the PTEN pathway.

Dual-color fluorescent in situ hybridization (FISH) analyses were conducted as previously described.¹⁴ Table 1 lists the bacterial artificial chromosome and P1 bacteriophage clones used to produce FISH probes. Probes were paired for dual-target hybridization as follows: EGFR/7q, 17p/ERBB2, PTEN/DMBT1, RB1/13q34, CDKN2A/9q, CDK4/12p, 4p/PDGFRA, 5p/PDGFRB, 1p/1q, and 19p/19q. Sections showing sufficient hybridization efficiency (signals in the majority of nuclei) were considered informative, and 100 to 200 intact, non-overlapping nuclei were scored for fluorescent signals by two independent reviewers. Thresholds indicating abnormalities/deletions were determined for each probe on the basis of counts from non-neoplastic control specimens (healthy brain from autopsy patients).

TP53 Sequencing
Polymerase chain reaction (PCR) amplification and subsequent high-throughput DNA sequencing was used to detect TP53 mutations. DNA was extracted from tumor specimens following standard procedures. PCR amplification of TP53 (exons 4-11) was adapted from methods designed for the Affymetrix human TP53 GeneChip probe array (Affymetrix, Santa Clara, CA). All primer sets but one (exon 5 reverse) differed from those used in the original Affymetrix protocol and are listed in Table 2. PCR amplification was performed using a 1:1 mixture of DNA (0.5 to 1 µg) and PCR mix (4x PCR buffer, 10 mmol/L MgCl₂; Applied Biosystems, Foster City, CA; 0.8 mmol/L dNTPs; GE Healthcare, Piscataway, NJ; 12.5 pmol human genomic TP53 primers, 5 to 10 U Amplitaq Gold; Applied Biosystems). Each exon was amplified by using the following cycling conditions: Taq polymerase activation at 94°C for 10 minutes, 35 cycles at 94°C for 1 minute, 60°C for 1 minute, 72°C for 1 minute, and final elongation at 72°C for 7 minutes. Exon 10 was cycled 40 times to increase yield. After amplification, DNA products were separated by 1% agarose gel electrophoresis and then purified by using ExoSAP-IT (USB, Cleveland, OH) according to the manufacturer's specifications. The Hartwell Center for Bioinformatics at St Jude (Memphis, TN) conducted high-throughput DNA sequencing from diluted PCR products. All generated sequences were compared with human TP53 genomic sequences (NCBI accession numbers U94788 and HSP53G) by using the Seqweb GCG Pretty program (Accelrys, San Diego, CA).

Statistical Analysis
The method of Kalbfleisch and Prentice was used to estimate the cumulative incidence of MT among patients with WHO grade 2 infiltrative astrocytoma (n = 65) who were treated at our institution during the study interval.¹⁵ For this analysis, we defined fibrillary astrocytomas, gemistocytic astrocytomas, and astrocytomas not otherwise specified as WHO grade 2 infiltrative astrocytomas. Inclusion criteria for these estimates were younger than 22 years and referral to us within 1 year of diagnosis of LGG. Exclusion criteria were MT before referral, brainstem tumors, and neurofibromatosis type 1. The latency of MT was defined as the interval between histologic diagnoses of LGG and HGG. Death of any cause was considered a competing event.

The exact log-rank test was used to compare the incidence of MT in patients with WHO grade 2 infiltrative astrocytoma (n = 65) on the basis of sex, race, tumor location, extent of resection, and use of RT or chemotherapy.¹⁶ Fisher's exact test was used to evaluate the association of molecular abnormalities. Clinical characteristics, treatment, and outcome of 65 patients with WHO grade 2 infiltrative astrocytoma are provided in Appendix Table A1 (online only).

	RESULTS

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Of 165 patients with HGG treated at our institution during the study interval, 11 patients met our criteria for MT of LGG (Table 3). Whereas both reviewers agreed on the diagnosis of MT in nine of 11 patients, a minor disagreement occurred in one patient where MT was confirmed by a third neuropathologist.¹⁷ No independent review was performed in one patient. The median age at diagnosis of LGG was 13.3 years.

Three patients (patients 6, 7, and 8 in Table 3) experienced treatment failure of LGG before the diagnosis of MT. Two patients (patients 6 and 7) received chemotherapy after surgery and local RT at the time of treatment failure. Another patient (patient 8) received RT after first surgery for LGG; he received chemotherapy and gene therapy with vector producer cells containing herpes simplex thymidine kinase and ganciclovir at subsequent treatment failures of LGG (Table 3).¹⁸

Characteristics of MT, Treatment, and Outcome
The median latency for the development of MT was 5.1 years (range, 1.6 to 13.4 years; Table 3). For five patients with available data, the median interval between RT and the diagnosis of MT was 3 years (range, 0.7 to 9.5 years). Seven (64%) of 11 patients developed glioblastoma at MT. An example of radiologic characteristics associated with MT is shown in Figure 1.

View larger version (29K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Contrast-enhanced axial T1-weighted brain magnetic resonance imaging images of (A) low-grade glioma of patient 1 and (B) corresponding image after malignant transformation.

Incidence and Risk Factors
Of 65 patients with WHO grade 2 infiltrative astrocytoma who met our inclusion criteria for cumulative incidence estimate, three experienced MT. Four patients (patients 2, 3, 4, and 11) were excluded from this analysis because they were referred to us after MT and one patient was excluded because of the diagnosis of pleomorphic xanthoastrocytoma (patient 5). The 10- and 15-year cumulative incidence of MT among these 65 patients were 3.8% ± 2.7% and 6.7% ± 3.9%, respectively. If only patients older than age 11 years (n = 22) at the time of diagnosis of WHO grade 2 infiltrative astrocytoma are included in this analysis, the 10- and 15-year cumulative incidence of MT were 4.8% ± 4.8% and 15.2% ± 11.3%, respectively. During the same period, 17 patients with ganglioglioma and 144 patients with JPA met our inclusion criteria for cumulative incidence estimate. Two (patients 7 and 10) of 17 patients with ganglioglioma and one (patient 6) of 144 patients with JPA experienced MT.

None of the potential risk factors analyzed in 65 patients with WHO grade 2 infiltrative astrocytoma, including use of RT (P = .54), tumor location (P = .37), extent of resection (P = .12), and use of chemotherapy (P = .11) were found to be statistically associated with increased incidence of MT.

Molecular Studies
Tumor tissue from all patients who experienced MT was available for molecular studies. Nine (82%) of 11 patients had tumor samples from both LGG and corresponding HGG available for molecular analysis (paired samples). The results of molecular studies are provided in Table 4. Table 5 summarizes the results of molecular studies in LGGs and HGGs. Six (67%) of nine paired samples contained at least one new molecular abnormality after MT.

Abnormalities of the retinoblastoma tumor-suppressor pathway (CDKN2A and/or RB1 deletion) were observed in five (71%) of seven LGGs, and in nine (90%) of 10 tumors after MT. RB1 and CDKN2A loss were mutually exclusive in 77% of patients, and RB1 loss was observed in combination with both hemizygous and homozygous deletions of CDKN2A.

All but one tumor showing loss of 1p had concomitant loss of 19q. There was no obvious relation of loss of 1p and 19q and histologic diagnosis.

Thirteen (76%) of 17 tumor samples analyzed showed evidence of PTEN pathway alteration (Table 4). Concomitant overexpression of pAKT and pS6 consistent with inactivation of PTEN was common (P = .015), although three tumors (two LGG and one HGG) showed combined overexpression of pAKT and pS6 without concomitant PTEN deletion. Therefore, a borderline statistical association was found between PTEN deletion and pAKT (P = .14) and pS6 (P = .085) overexpression suggesting that PTEN deletion alone does not identify all tumors in which PTEN pathway signaling is dysregulated. Representative examples of FISH evaluation of PTEN status and corresponding pAKT and pS6 immunohistochemical studies are shown in Figure 2.

View larger version (85K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Low-grade glioma showing absence of PTEN abnormalities by (A) fluorescent in situ hybridization and lack of expression of (B) phospho-AKT (pAKT) or (C) phospho-S6 (pS6) by immunohistochemistry. Glioblastoma showing deletion of PTEN relative to (D) control probe and overexpression of (E) pAKT and (F) pS6. Scale bar is 50 µm (magnification, x200) except for (A) and (D), in which magnification is x1000.

Control LGGs
Table 5 summarizes the results of molecular studies in LGGs who did not develop MT. One third of all control LGGs showed PTEN deletion. pAKT and pS6 overexpression occurred in 48% (16/33) and 76% (25/33) of all tumors, respectively. Whereas concordant overexpression of pAKT and pS6 was common among LGGs who did not develop MT (P = .04), we found no statistically significant association between PTEN deletion and pAKT (P = .13) or pS6 (P = .67) overexpression in these tumors.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Whereas half to more than 90% of adults with WHO grade 2 infiltrative astrocytoma experience MT,^20,21 we showed that the long-term risk of MT in histologically identical neoplasms in children is less than 10%. Although the cumulative incidence of MT among older children seemed to be higher than that for all patients, the small number of assessable patients and the large SEs of our estimates preclude any conclusions about differences in the occurrence of this phenomenon based on age. Of 65 patients with WHO grade 2 infiltrative astrocytoma in this study, 46 (71%) remained alive without tumor progression after a median follow-up of almost 11 years. Only two of 46 patients had not had follow-up within the past 2 years.

Whereas two of 17 patients with ganglioglioma experienced MT in this study, this phenomenon was observed in only three of 184 predominantly adult patients in a recent study.²² Another report described the occurrence of MT in one of 24 patients younger than age 21 years with ganglioglioma.²³ We did not draw any conclusions about MT in children with ganglioglioma because of the small number of assessable patients.

Unlike two previous studies that found an approximately 10% cumulative incidence of MT in children with JPA,^7,10 in our experience this event was exceedingly rare. Three of 36 patients (28 patients < 18 years of age) with JPA experienced MT in one of these previous studies⁷; however, no details were provided about the characteristics of MT. In a second study, Krieger et al¹⁰ reported four patients with JPA (age range at diagnosis of LGG, 15 months to 14 years) who experienced MT. Treatment after MT consisted of chemotherapy only (n = 2) and the combination of chemotherapy and RT (n = 1); one patient received no therapy after MT. All four patients remained alive at the time of publication (follow-up, 1 to 5 years). Their favorable outcome raises the question whether these tumors had truly undergone MT.

We acknowledge that the strict selection criteria for MT in this study and the lack of histologic confirmation at autopsy in patients who died of progressive LGG may have caused underestimation of the cumulative incidence of this phenomenon. In contrast, it is possible that the cumulative incidence of MT may have been overestimated by the inadequate representation of areas with more malignant characteristics at the time of diagnosis of LGG. However, the thorough and prolonged follow-up of our patients, combined with the radiologic and central histologic review of all instances of MT strengthened the reliability of our results.

None of the risk factors analyzed in this study demonstrated a statistically significant association with MT. The small number of assessable patients limited the power of our analysis to confirm or refute the previously proposed association between RT and MT of LGG in children.⁸

Whereas the molecular abnormalities associated with MT in adults have been extensively characterized,² limited molecular analyses have been previously described in only four patients younger than 22 years who experienced MT.^24-26 We were able to perform molecular studies in all tumor samples obtained after MT, and in nine tumor samples at the diagnosis of LGG and after MT. Our choice of molecular studies was based on abnormalities commonly seen in glioblastoma in adults.

TP53 overexpression was observed more frequently after than before MT in this study; however, this association did not reach statistical significance. As described previously,⁴ we found that TP53 overexpression did not strictly overlap with the presence of TP53 mutations. PTEN deletion was observed after MT in more than half of our patients, a rate similar to that described in both primary and secondary glioblastoma in adults and primary glioblastoma in children.^15,19,27 Unlike LGGs in adults,^28,29 we observed an unexpectedly high frequency of PTEN deletion in LGGs from patients who experienced MT as well as patients with LGG in the control group. Although deletions of chromosome 10q that encompass PTEN could target an alternative tumor-suppressor locus, the common combined overexpression of pAKT and pS6 observed in LGGs support dysregulation of the PTEN pathway. Future studies should analyze other molecular determinants of PTEN pathway regulation in LGG in children, particularly inactivating mutations of PTEN and activating mutations of PIK3CA. The latter have been reported in high-grade astrocytoma and would be predicted to cause coordinate increases in pAKT and pS6.^30,31 Combined loss of 1p and 19q was uncommon among our patients, particularly in those samples obtained after MT, and similar to the results of a recent pediatric study.³²

Although HGGs in children rarely originate from pre-existing LGGs, the molecular abnormalities found in pediatric de novo HGGs seem to be most reminiscent of secondary glioblastoma in adults.^4,33 Conversely, some of the genetic alterations observed in our patients after MT, including deletion of key genes in the retinoblastoma tumor-suppressor and PTEN pathways, overlap with those of both primary and secondary glioblastoma in adults.

Although this study revealed several key aspects of MT of LGG in children, our results were limited by the small number of affected patients. Therefore, larger series of children with MT of LGG are warranted to validate our findings.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
The authors indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Alberto Broniscer, Suzanne J. Baker, Larry E. Kun, Amar Gajjar, Richard J. Gilbertson, Christine E. Fuller

Financial support: Amar Gajjar

Administrative support: Amar Gajjar

Provision of study materials or patients: Alberto Broniscer, Larry E. Kun, Amar Gajjar

Collection and assembly of data: Alberto Broniscer, Suzanne J. Baker, Alina N. West, Melissa M. Fraser, Erika Proko, James Dalton, Gerard P. Zambetti, Amar Gajjar, Richard J. Gilbertson, Christine E. Fuller

Data analysis and interpretation: Alberto Broniscer, Suzanne J. Baker, Alina N. West, Melissa M. Fraser, Erika Proko, Mehmet Kocak, James Dalton, Gerard P. Zambetti, David W. Ellison, Amar Gajjar, Richard J. Gilbertson, Christine E. Fuller

Manuscript writing: Alberto Broniscer, Suzanne J. Baker, Alina N. West, Gerard P. Zambetti, Larry E. Kun, Amar Gajjar, Richard J. Gilbertson, Christine E. Fuller

Final approval of manuscript: Alberto Broniscer, Suzanne J. Baker, David W. Ellison, Larry E. Kun, Amar Gajjar, Richard J. Gilbertson, Christine E. Fuller

	Appendix

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	ACKNOWLEDGMENTS

 
We thank Pam Hays for her assistance with patient follow-up and Sharon Naron for her assistance with scientific editing.

	NOTES

 
Supported in part by National Institutes of Health grants (Cancer Center Support [CORE] Grant No. P30 CA21765 and Grant No. P01 CA096832 to S.J.B); Musicians Against Childhood Cancer; the Noyes Foundation; the Ryan McGhee Foundation; and by the American Lebanese Syrian Associated Charities (ALSAC).

Presented in part at the 12th International Symposium on Pediatric Neuro-Oncology, Nara, Japan, July 6-9, 2006.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
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Submitted March 29, 2006; accepted November 28, 2006.

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