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Study of the MIB-1 Labeling Index as a Predictor of Tumor Progression in Pilocytic Astrocytomas in Children and Adolescents

Daniel C. Bowers, Lynn Gargan, Payal Kapur, Joan S. Reisch, Arlynn F. Mulne, Kenneth N. Shapiro, Roy D. Elterman, Naomi J. Winick, Linda R. Margraf

From the Departments of Pediatrics, Academic Computing Services, and Pathology, University of Texas Southwestern Medical Center at Dallas; and the Neuro-Oncology Program, Children’s Medical Center of Dallas, Dallas, TX.

Address reprint requests to Daniel Bowers, MD, MC 9063, Department of Pediatrics, University of Texas Southwestern Medical School at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75390-9063; email: daniel.bowers{at}utsouthwestern.edu.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: The pilocytic astrocytoma (PA) is the most common childhood brain tumor. This report examines the MIB-1 labeling index (LI) as a predictor of progression-free survival (PFS) among childhood PAs.

Patients and Methods: Consecutive PAs were examined to determine whether the MIB-1 LI was associated with tumor progression. Other variables evaluated included tumor location, use of adjuvant therapy, extent of resection, and age at diagnosis.

Results: One hundred forty-one children were identified (mean ± SD age, 7.6 ± 4.7 years; range, 0.43 to 18.56 years); 118 children had adequate tissue for MIB-1 immunohistochemistry. The 5-year PFS was 61.25%. By log-rank analysis, an MIB-1 LI of more than 2.0 was associated with shortened PFS (P = .035). Patients with PAs who underwent complete surgical resection, had tumors located in the cerebellum, and were treated with surgery only also had more prolonged PFS (P = .001 for all). Tumors in the optic pathways were associated with a shorter PFS (P = .001). Restricting the evaluation of MIB-1 LI to only incompletely resected tumors revealed an insignificant trend of MIB-1 LI of more than 2.0 having a shortened PFS. Multivariate analysis demonstrated completely resected tumors and tumors located in the cerebellum as less likely to progress (P = .001 and .019, respectively).

Conclusion: Children with PAs with an MIB-1 LI of more than 2.0 have a shortened PFS. PAs that are completely resected and are located in the cerebellum have a prolonged PFS. This initial study suggests that the MIB-1 LI identifies a more aggressive subset of PAs. Further work should focus on elucidating features of pilocytic astocytomas that will identify prospectively children at risk for progression.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
OF THE estimated 2,200 children younger than 18 years who are diagnosed with a CNS tumor in the United States annually, more than half will have a neoplasm of glial origin.^1,2 The most common glial neoplasm during childhood is the pilocytic astrocytoma (PA). There are several prognostic factors for PAs, including complete tumor resection, location in the cerebellum, and possibly coexisting neurofibromatosis type-1 (NF-1) and the child’s age at diagnosis of a PA.^3–8

MIB-1 is a monoclonal antibody that is immunoreactive with Ki-67, a nuclear antigen that is detectable only during the proliferative stages of the cell cycle and is a surrogate measure of the biologic processes that are present in phenotypically aggressive neoplasms.⁹ The MIB-1 labeling index (LI) is the fraction of tumor cells that are labeled by Ki-67. The prognostic importance of MIB-1 LI for progression-free survival (PFS) in pediatric low-grade gliomas has not been well described.

The purpose of this report is to evaluate an association between MIB-1 LI and PFS among children with PAs. This report also examines the importance of the MIB-1 LI in the context of other recognized potential factors associated with tumor progression. An elevated MIB-1 LI may identify a group of PAs that are at higher risk of tumor progression and would suggest that there is an as yet unreported biologic predisposition among PAs with an aggressive phenotype.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Population
Consecutive patients younger than 19 years with a diagnosis of a PA who were evaluated and treated by the Neuro-Oncology Program were included in this review. The Neuro-Oncology Program includes Children’s Medical Center of Dallas, the Zale-Lipshy University Hospital at University of Texas Southwestern Medical Center, and Medical City Dallas Hospital. This study was reviewed for human subject protection and confidentiality and was approved under the expedited review process by the institutional review board of University of Texas Southwestern Medical Center in accordance with standards of the National Institutes of Health. Demographic data, including the patient’s date of clinical presentation, age at diagnosis, sex, tumor location, postoperative and follow-up imaging findings, use of adjuvant therapy, date of last contact, and patient outcome were recorded. Data were censored as of March 2002. Tumor progression was defined as either an increase in tumor size, tumor recurrence, or worsening symptoms (eg, objective worsening of neurologic exam or increase in seizure activity).

Treatment
Surgery. The majority of patients had aggressive surgery as their primary and only therapy. Surgical outcomes were categorized as either complete resection (no evidence of residual tumor) or incomplete resection (residual tumor present) based on postoperative imaging studies performed from the first postoperative day until 3 months after surgery¹⁰ or by operating surgeon’s opinion.

Adjuvant therapy. As a result of the treating physician’s judgment, adjuvant therapy was occasionally prescribed for PAs that were located in unfavorable surgical locations (such as brainstem or optic pathway) or for the rare metastatic tumors. In general, chemotherapy was prescribed for prepubertal children and for tumors located in the cerebral hemispheres, thalamus, and optic pathways. In all instances, chemotherapy consisted of carboplatin with or without vincristine.^11,12 Radiation therapy was administered to older patients and for tumors located in the cerebellum and brainstem. Prescribed radiation therapy consisted of between 50 and 60 Gy administered to the tumor.

Pathology Review
Pathology slides all from resected tumor specimens were reviewed by two of the authors (P.K., L.R.M.) to confirm the diagnosis of a PA according to established criteria from the World Health Organization classification of brain tumors.¹³ When available, the pathology slides from patients who underwent a second tumor resection for recurrent or progressive tumors were reviewed and compared with the previous surgical specimen. A PA was defined as a relatively well-circumscribed and often cystic, biphasic astrocytic tumor with varying proportions of compacted bipolar cells with Rosenthal fibers and loose textured multipolar cells with microcysts and eosinophilic granular bodies.^13,14 Tumors that did not meet these criteria were not considered to be PAs and are not included in this report.

Immunohistochemistry
Immunohistochemistry with the MIB-1 monoclonal antibody against the Ki-67 antigen was performed using commercially available reagents and according to manufacturer’s recommendations. In brief, 4-µ thick sections of formalin-fixed, paraffin-embedded sections were dehydrated and dewaxed in graded alcohols, heated with steam in citrate buffer for 30 minutes, and treated with 3% H₂O₂ to block endogenous peroxidases. Sections were incubated with MIB-1 antibody (Dako Corporation, Carpenteria, CA), for 30 minutes at room temperature and processed using the Dako Envision Plus Staining System (Dako Corporation) with diaminobenzidine as the chromogen. Known positive and negative controls (tumor sections incubated in buffer alone) were processed with each batch of slides. Microscopic images were viewed with an Olympus BH-2 microscope (Olympus Optical Co Ltd, Tokyo, Japan) and the microscopic image was projected via a Sony DXC-107 color video camera (Sony Corp, Tokyo, Japan) onto a Sony DVM 1942Q color video monitor (Sony Corp) fitted with a 10 x 10 grid of equal squares. Nuclei showing obvious brownish staining were considered positive. Areas with the highest density of positively staining nuclei were identified by scanning the stained slides, and these so-called hot-spot areas were used for determining the MIB-1 index. The number of positive nuclei in 10 to 15 contiguous 200x fields (minimum of 1,000 nuclei) was quantified by one of two observers (L.R.M. or P.K.) without knowledge of the clinical or imaging findings for each case. The total number of nuclei in each field was determined using the method of Going.¹⁵ Nuclei of vessel endothelial cells and hematopoietic elements were not included in the counts. The percentage of reactive nuclei (MIB-LI) was calculated as the number of positive cells divided by the estimated number of total cells multiplied by 100.

Statistical Methods
The clinical data were expressed as means ± SD where appropriate. Clinical and histologic parameters were compared using t or ² test. Disease-free and overall survival were analyzed using the Kaplan-Meier method, and comparison of study groups was performed using the log-rank test. The Cox regression model was applied over both univariate and multivariate analysis, with the associated likelihood ratio test used for tests of trend differences. In multivariate analysis, a stepwise selection procedure was used. We calculated hazard ratios (HRs) for all the risk factors, and for each HR, the 95% confidence interval (CI) was determined. The statistical package SPSS version 10.0 and Advanced Statistics version 7.5 for Windows (SPSS Inc, Chicago, IL) were used to conduct statistical analysis. A P value of less than .05 was considered statistically significant, and all tests were two-tailed.

Using univariate and multivariate Cox regression analysis, six variables were examined for an association with tumor progression, including MIB-1 LI as both a continuous and categorical value ( 2.0), tumor location (optic pathways, thalamus/midbrain, brainstem, cerebellum, or cerebral hemispheres); age at diagnosis (both as a continuous variable and as categorical variables, including 0 to 4.9 years, 5.0 to 9.9 years, and 10.0 to 18.9 years); extent of tumor resection (complete resection v subtotal resection); and treatment (surgery alone v surgery and either chemotherapy or radiation therapy; Table 1).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

The mean age at diagnosis of the 141 patients with a PA was 7.6 years (SD, ± 4.7 years; range, 0.43 to 18.56 years). There were 78 male patients (55.3%). Seven patients (5%) had coexisting NF-1. Patient data, including tumor locations, are described in Table 1. Patients have been followed for a mean of 4.45 years (SD, 3.5 years) after biopsy confirmation of a PA. At the time of censoring of data, 53 patients had experienced tumor progression (Kaplan-Meier PFS at 5 years was 61.25%). The mean time to tumor progression was 1.3 years after diagnosis (SD, 1.9 years; Fig 1). Nine patients had died (overall survival rate, 93.8%). Seven patients died as a result of tumor progression, and two died of treatment-related complications.

View larger version (13K): [in this window] [in a new window]   Fig 1. Probability of progression-free and overall survival for 144 children with pilocytic astrocytomas.

View larger version (18K): [in this window] [in a new window]   Fig 2. Distribution of MIB-1 labeling index in pilocytic astrocytomas.

Prognostic Factors
By log-rank analysis, PAs with an MIB-1 LI of 2.0 had a shorter progression-free interval than tumors with an MIB-1 of less than 2.0 (P = .035; Fig 3). Among the 75 tumors that were incompletely resected and had sufficient tissue for immunohistochemistry, the 5-year PFS for children with an MIB-1 LI 2.0 was 33.3%, compared with 50.0% for tumors with an MIB-1 LI of less than 2.0. This difference, however, was not significant (P = .26; Fig 4). Tumors in the cerebellum had a prolonged PFS compared with tumors located elsewhere; tumors in the optic pathways had a shorter PFS than tumors in other locations (P = .001; Fig 5). Tumors that were treated with surgery only, had a prolonged PFS compared with tumors that received adjuvant therapy (P = .001; Fig 6). Tumors that were completely resected had a longer PFS than tumors that were incompletely resected (P = .001; Fig 7). Patient age at diagnosis (continuous and categorical) was not significantly associated with PFS (P = .431; Fig 8). Further analysis of statistical data by multivariate Cox regression analysis identified PAs that were completely resected as being less likely to progress than incompletely resected tumors (P = .001), and tumors that were located in the cerebellum were less likely to progress than tumors located in other locations (P = .019; Table 2). Other variables examined by multivariate Cox regression analysis were not associated with tumor progression.

View larger version (12K): [in this window] [in a new window]   Fig 3. Progression-free survival of 118 children with pilocytic astrocytomas according to MIB-1 labeling index (LI).

View larger version (14K): [in this window] [in a new window]   Fig 4. Progression-free survival of 75 children with incompletely resected pilocytic astrocytomas according to MIB-1 labeling index.

View larger version (18K): [in this window] [in a new window]   Fig 5. Progression-free survival of 132 children with pilocytic astrocytomas according to tumor location. Nine children had tumors that were in other locations. LI, labeling index.

View larger version (16K): [in this window] [in a new window]   Fig 6. Progression-free survival of 141 children with pilocytic astrocytomas according to whether patients received adjuvant therapy.

View larger version (13K): [in this window] [in a new window]   Fig 7. Progression-free survival of 141 children with pilocytic astrocytomas according to the extent of primary tumor resection.

View larger version (16K): [in this window] [in a new window]   Fig 8. Progression-free survival of 141 children with pilocytic astrocytomas according to patient age at diagnosis.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

An elevated MIB-1 LI is strongly associated with shortened PFS and overall survival with malignant gliomas, meningiomas, and ependymomas.^9,19–22 This report demonstrates that an MIB-1 LI of 2.0 is associated with an increased frequency of tumor progression among children with PAs. This is the first report of a biologic risk factor, rather than a clinical risk factor, as having prognostic importance for PAs. Whereas only 75 patients had incomplete resections, this study lacked sufficient statistical power to detect a difference in PFS among only incompletely resected tumors. However, we did observe an insignificant trend that PAs with an MIB-1 LI of 2.0 had a shortened PFS.

Few reports have examined an association of MIB-1 LI with PFS among low-grade gliomas during children. Dirven et al²³ examined the MIB-1 LI among 39 PAs in children and adults. Their study included 23 incompletely resected PAs and identified a lower mean MIB-1 LI among quiescent tumors compared with tumors that progressed. This difference was not statistically significant, likely a result of a small sample size.²³ Also, Fisher et al²⁴ reported that immunohistochemistry for the Ki-67 antigen was not statistically significant for overall survival (P = .3) and only of borderline statistical significance for PFS (P = .055) in a univariate analysis of 35 children with low-grade gliomas. Finally, the report by Giannini et al²⁵ of 131 children and adults with PAs reported that the MIB-1 was not associated with overall survival; the PFS was not reported. We propose two explanations for why these series did not identify the prognostic significance of MIB-1 LI in childhood PAs. First, the small number of patients reported in the above series lacked sufficient statistical power to identify the MIB-1 LI as prognostic for tumor progression. Second, tumor-related death is an uncommon occurrence among children with PAs (18% of patients in Giannini’s series of adults and children with PAs and 6.2% of children in our series); a much greater number of children with PAs would be required for sufficient statistical power to identify a difference in overall survival among children with PAs.

Understandably, there is a significant association between the location of a low-grade glioma and the ability to obtain a complete tumor resection. PAs in more peripheral locations, such as the cerebellum, are more likely to be completely resected than tumors located in other locations. Not surprisingly, both tumors in peripheral locations and a complete resection are associated with PFS. What is not known, however, is whether the good prognosis associated with these tumors is solely a result of their location, high frequency of complete tumor resection, or also the result of some intrinsic biologic predisposition of PAs in this location.

This report demonstrates a significant association between a complete tumor resection and reduced frequency of subsequent tumor progression by both log-rank and multivariate analysis.³ Not all reports, however, confirm that tumors that are completely resected have a more favorable prognosis. Gajjar et al,⁶ for example, reported no difference in the 4-year PFS between children whose tumors were completely resected versus those whose tumors were incompletely resected. We also identified an association between PAs located in the cerebellum and favorable prognosis by both log-rank and Cox regression multivariate analysis.^6,8,12 The MIB-1 LI was not correlated with tumor location, and likely these tumors have the same proliferative potential as tumors located elsewhere. Rather, we believe that the favorable prognosis for tumors located in favorable locations, such as the cerebellum, is most likely to be a result of their close association with complete tumor resection.

In this series, the addition of adjuvant therapy was not associated with an improvement in PFS. However, adjuvant therapy for newly diagnosed PAs was prescribed for only 40 (28.4%) of 141 patients. Clinical decisions to include adjuvant therapy were primarily based on treating physicians’ concerns over incomplete tumor resections, patient age, and tumor locations. Shaw et al²⁶ have also reported no improvement in overall survival among patients with PAs who received postsurgical adjuvant radiation therapy compared with those treated with surgery alone. In contrast, Pollack et al³ reported an improvement in 10-year PFS, but not overall survival, among children with low-grade gliomas who were treated with postsurgical adjuvant radiation therapy compared with those who did not receive adjuvant therapy.

In this series, patient age at the time of tumor diagnosis was not associated with PFS by either log-rank analysis or Cox regression multivariate analysis. Previous studies have reported younger children with low-grade gliomas as having a significantly worse PFS compared with older children.^6,12 This observation may be partially explained by our study’s restriction to only tumors with definitive histopathologic features of PA and exclusion of tumors resembling the recently described monomorphous pilomyxoid glioma.²⁷ Monomorphous pilomyxoid gliomas usually occur in young children and involve the hypothalamic/chiasmatic region. It is possible that these aggressive neoplasms may have been included in the previous studies reporting worse PFS in younger children with low-grade gliomas and may at least partially account for their worse prognosis.

For this study, tissue confirmation was required for the diagnosis of a pilocytic astrocytoma. At our institution and most others, optic pathway gliomas among children with NF-1 are usually not biopsied unless there are unusual features observed on magnetic resonance imaging, but are rather treated with chemotherapy or radiation therapy. Whereas only seven patients with neurofibromatosis at our institution underwent attempted tumor resection, underrepresentation of patients with NF-1 and a pilocytic astrocytoma limits this report’s ability to determine the impact of NF-1 on PFS. Reports of childhood low-grade gliomas generally identify NF-1 as a favorable prognostic factor.⁵ Janss et al⁴ reported a much more favorable prognosis among children younger than 5 years with NF-1 and optic pathway gliomas compared with children without NF-1. However, Packer et al¹² reported no difference in PFS between children with and without coexisting NF-1 and low-grade gliomas after treatment with carboplatin and vincristine.

In this series, several progressive tumors had a higher MIB-1 than the tumors from initial surgery. This observation differs from Dirven et al, ²³ who reported a lower MIB-1 LI in tumor samples from second operations in six patients. Only four patients from their series were PA at the initial surgery, and one of these patients underwent resection of stable residual tumor. Although we cannot exclude sampling differences of different specimens from the same tumor, we propose that the observed increase in MIB-1 LI found in progressive PAs may be a surrogate marker of an as yet unidentified proliferative cell signaling pathway found in the phenotypically aggressive PAs.

In summary, in this series of children with PAs, the mean MIB-1 LI was 1.61. An MIB-1 LI of 2.0 was associated with an increased frequency of subsequent tumor progression by log-rank analysis. However, there was not a statistically significant difference when the sample was restricted to only incompletely resected tumors because of small sample size. Also, this difference was not seen on Cox regression multivariate analysis, again likely because of relatively small sample size.

This study suggests that the MIB-1 LI may identify a subset of more clinically aggressive PAs. Future prospective studies should be statistically powered sufficiently to address the issue of the significance of MIB-1 LI among incompletely resected tumors. Also, we argue that there are as yet undetermined important proliferation-promoting factors that influence tumor progression in PAs. Further work should focus on prospectively elucidating other biologic features of PAs that will identify children at risk for tumor progression.

	NOTES

 
Supported in part by the Children’s Brain Tumor Foundation of the Southwest, the Children’s Medical Center Foundation, and the Children’s Cancer Fund of Dallas, Dallas, TX.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted January 2, 2003; accepted May 8, 2003.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bowers, D. C. Articles by Margraf, L. R. Search for Related Content PubMed PubMed Citation Articles by Bowers, D. C. Articles by Margraf, L. R. Social Bookmarking                            What's this?