Top

Child's Nervous System

Published in:

01-03-2012 | Original Paper

Biologic tumor behavior in pilocytic astrocytomas

Authors: Muhittin Belirgen, Su Gulsun Berrak, Hilâl Ozdag, Suheyla Uyar Bozkurt, Emel Eksioglu-Demiralp, M. Memet Ozek

Published in: Child's Nervous System | Issue 3/2012

Abstract

Purpose

The aim is to describe the behavior of pilocytic astrocytoma (PAs) and its effects on patient prognosis by using flow cytometric, immunohistochemical and cytogenetic methods. We also aim to find out whether there is any difference between differently localized tumors by the above mentioned analyses.

Methods

We studied DNA index, expression of p53, p16, pRb, MMAC/PTEN1, VEGF, MIB-1 index and chromosomal anomalies which can be detected by array comparative genomic hybridization (CGH) technique. We analyzed the association of the results of these studies with clinical prognosis and tumor localization. We included 53 patients (18 cerebellar, 20 chiasmatic/hypothalamic and 15 hemispheric). Samples were studied from paraffin embedded tumors.

Results

We found that PAs are mostly diploid and ploidy pattern does not affect the prognosis. The expression of p53, p16, pRb, MMAC/PTEN1 and VEGF was not significantly different between different localizations and could not predict the prognosis. Frequently seen copy number aberrations (CNAs) are: amplification in 1p36.33, 2p11.2, 9p11.2, 9q12, 16p11.2, 19q13.12–q13.2, Xp22.2–p21.3, Xp11.3–p11.22, Xq11.1–q12, Xq13.1, Xq21.1–q21.31, Xq22.3, Xq26.3 and homozygous deletion in 2p11.2, 8p23.1, 16p12.3. Among them, 2p11.2 amp, 9p11.2 amp and 1p36.21 hom del were correlated with prognosis. Moreover, we found a significant correlation between 16p11.2 amp and tumor localization.

Conclusions

Differently localized PAs have different properties which make them behave with different biological aggressiveness. PAs demonstrate a significant amount of CNAs that can be detected by a high-resolution study. However, tumor suppressor genes p53, p16, pRb, MMAC/PTEN1 and expression patterns do not play a significant role in PAs.

Abdulrauf SI, Edvardsen K, Ho KL, Yang XY, Rock JP, Rosenblum ML (1998) Vascular endothelial growth factor expression and vascular density as prognostic markers of survival in patients with low-grade astrocytoma. J Neurosurg 88:513–520PubMedCrossRef

Auer RN, Rice GP, Hinton GG, Amacher AL, Gilbert JJ (1981) Cerebellar astrocytoma with benign histology and malignant clinical course. Case report. J Neurosurg 54:128–132PubMedCrossRef

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

Bayani J, Pandita A, Squire JA (2005) Molecular cytogenetic analysis in the study of brain tumors: findings and applications. Neurosurg Focus 19:E1PubMedCrossRef

Ben Arush MW, Linn S, Ben-Izhak O, Levy R, Nahum MP, Tsuk-Shina T, Guilbord JN, Elhasid R, Postovski S (1999) Prognostic significance of DNA ploidy in childhood astrocytomas. Pediatr Hematol Oncol 16:387–396PubMedCrossRef

Bowers DC, Gargan L, Kapur P, Reisch JS, Mulne AF, Shapiro KN, Elterman RD, Winick NJ, Margraf LR (2003) Study of the MIB-1 labeling index as a predictor of tumor progression in pilocytic astrocytomas in children and adolescents. J Clin Oncol 21:2968–2973PubMedCrossRef

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

Burger PC, Shibata T, Kleihues P (1986) The use of the monoclonal antibody Ki-67 in the identification of proliferating cells: application to surgical neuropathology. Am J Surg Pathol 10:611–617PubMedCrossRef

Burger PCSB (1994) Atlas of tumor pathology. Tumors of the central nervous system. Armed Forces Institute of Pathology, Washington, DC

10.

Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U S A 96:4240–4245PubMedCrossRef

11.

Chaudhry IH, O’Donovan DG, Brenchley PE, Reid H, Roberts IS (2001) Vascular endothelial growth factor expression correlates with tumour grade and vascularity in gliomas. Histopathology 39:409–415PubMedCrossRef

12.

Coe BP, Ylstra B, Carvalho B, Meijer GA, Macaulay C, Lam WL (2007) Resolving the resolution of array CGH. Genomics 89:647–653PubMedCrossRef

13.

Collins VP (1998) Gliomas. Cancer Surv 32:37–51PubMed

14.

Conn G, Bayne ML, Soderman DD, Kwok PW, Sullivan KA, Palisi TM, Hope DA, Thomas KA (1990) Amino acid and cDNA sequences of a vascular endothelial cell mitogen that is homologous to platelet-derived growth factor. Proc Natl Acad Sci U S A 87:2628–2632PubMedCrossRef

15.

Connolly DT, Heuvelman DM, Nelson R, Olander JV, Eppley BL, Delfino JJ, Siegel NR, Leimgruber RM, Feder J (1989) Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 84:1470–1478PubMedCrossRef

16.

Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100:387–390PubMedCrossRef

17.

Dirven CM, Mooij JJ, Molenaar WM (1997) Cerebellar pilocytic astrocytoma: a treatment protocol based upon analysis of 73 cases and a review of the literature. Childs Nerv Syst 13:17–23PubMedCrossRef

18.

Duerr EM, Rollbrocker B, Hayashi Y, Peters N, Meyer-Puttlitz B, Louis DN, Schramm J, Wiestler OD, Parsons R, Eng C, von Deimling A (1998) PTEN mutations in gliomas and glioneuronal tumors. Oncogene 16:2259–2264PubMedCrossRef

19.

Fernandez C, Figarella-Branger D, Girard N, Bouvier-Labit C, Gouvernet J, Paz Paredes A, Lena G (2003) Pilocytic astrocytomas in children: prognostic factors—a retrospective study of 80 cases. Neurosurgery 53:544–553, discussion 554–545PubMedCrossRef

20.

Forsyth PA, Shaw EG, Scheithauer BW, O’Fallon JR, Layton DD Jr, Katzmann JA (1993) Supratentorial pilocytic astrocytomas. A clinicopathologic, prognostic, and flow cytometric study of 51 patients. Cancer 72:1335–1342PubMedCrossRef

21.

Geradts J, Kratzke RA, Niehans GA, Lincoln CE (1995) Immunohistochemical detection of the cyclin-dependent kinase inhibitor 2/multiple tumor suppressor gene 1 (CDKN2/MTS1) product p16INK4A in archival human solid tumors: correlation with retinoblastoma protein expression. Cancer Res 55:6006–6011PubMed

22.

Giannini C, Scheithauer BW, Burger PC, Christensen MR, Wollan PC, Sebo TJ, Forsyth PA, Hayostek CJ (1999) Cellular proliferation in pilocytic and diffuse astrocytomas. J Neuropathol Exp Neurol 58:46–53PubMedCrossRef

23.

Gjerris F, Klinken L (1978) Long-term prognosis in children with benign cerebellar astrocytoma. J Neurosurg 49:179–184PubMedCrossRef

24.

Gospodarowicz D, Abraham JA, Schilling J (1989) Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci U S A 86:7311–7315PubMedCrossRef

25.

Gutmann DH, Aylsworth A, Carey JC, Korf B, Marks J, Pyeritz RE, Rubenstein A, Viskochil D (1997) The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA 278:51–57PubMedCrossRef

26.

He J, Olson JJ, James CD (1995) Lack of p16INK4 or retinoblastoma protein (pRb), or amplification-associated overexpression of cdk4 is observed in distinct subsets of malignant glial tumors and cell lines. Cancer Res 55:4833–4836PubMed

27.

Hedley DW, Friedlander ML, Taylor IW, Rugg CA, Musgrove EA (1983) Method for analysis of cellular DNA content of paraffin-embedded pathological material using flow cytometry. J Histochem Cytochem 31:1333–1335PubMedCrossRef

28.

Hilton DA, Penney M, Evans B, Sanders H, Love S (2002) Evaluation of molecular markers in low-grade diffuse astrocytomas: loss of p16 and retinoblastoma protein expression is associated with short survival. Am J Surg Pathol 26:472–478PubMedCrossRef

29.

Hsu DW, Louis DN, Efird JT, Hedley-Whyte ET (1997) Use of MIB-1 (Ki-67) immunoreactivity in differentiating grade II and grade III gliomas. J Neuropathol Exp Neurol 56:857–865PubMedCrossRef

30.

Idoate MA, Soria E, Lozano MD, Sola JJ, Panizo A, de Alava E, Manrique M, Pardo-Mindan FJ (2003) PTEN protein expression correlates with PTEN gene molecular changes but not with VEGF expression in astrocytomas. Diagn Mol Pathol 12:160–165PubMedCrossRef

31.

James CD, Olson JJ (1996) Molecular genetics and molecular biology advances in brain tumors. Curr Opin Oncol 8:188–195PubMedCrossRef

32.

James CD, Galanis E, Frederick L, Kimmel DW, Cunningham JM, Atherton-Skaff PJ, O’Fallon JR, Jenkins RB, Buckner JC, Hunter SB, Olson JJ, Scheithauer BW (1999) Tumor suppressor gene alterations in malignant gliomas: histopathological associations and prognostic evaluation. Int J Oncol 15:547–553PubMed

33.

Jane Fridlyand AMS, Pinkel D, Donna GA, Jain AN (2004) Hidden Markov models approach to the analysis of array CGH data. Journal of Multivariate Analysis 90:132–153CrossRef

34.

Szymas J, Wolf G, Petersen S, Schluens K, Nowak S, Petersen I (2000) Comparative genomic hybridization indicating two distinct subgroups of pilocytic astrocytomas. Neurosurg Focus 8:1–6CrossRef

35.

Jen J, Harper JW, Bigner SH, Bigner DD, Papadopoulos N, Markowitz S, Willson JK, Kinzler KW, Vogelstein B (1994) Deletion of p16 and p15 genes in brain tumors. Cancer Res 54:6353–6358PubMed

36.

Jones DT, Ichimura K, Liu L, Pearson DM, Plant K, Collins VP (2006) Genomic analysis of pilocytic astrocytomas at 0.97 Mb resolution shows an increasing tendency toward chromosomal copy number change with age. J Neuropathol Exp Neurol 65:1049–1058PubMedCrossRef

37.

Kilic T, Pamir MN, Kullu S, Eren F, Ozek MM, Black PM (2000) Expression of structural proteins and angiogenic factors in cerebrovascular anomalies. Neurosurgery 46:1179–1191, discussion 1191–1172PubMedCrossRef

38.

Kirla R, Salminen E, Huhtala S, Nuutinen J, Talve L, Haapasalo H, Kalimo H (2000) Prognostic value of the expression of tumor suppressor genes p53, p21, p16 and prb, and Ki-67 labelling in high grade astrocytomas treated with radiotherapy. J Neurooncol 46:71–80PubMedCrossRef

39.

Klein O, Grignon Y, Civit T, Pinelli C, Auque J, Marchal JC (2006) Childhood diencephalic pilocytic astrocytoma. A review of seven observations. Neurochirurgie 52:3–14PubMed

40.

Kleinman GM, Schoene WC, Walshe TM 3rd, Richardson EP Jr (1978) Malignant transformation in benign cerebellar astrocytoma. Case report. J Neurosurg 49:111–118PubMedCrossRef

41.

Lamy P, Andersen CL, Dyrskjot L, Torring N, Wiuf C (2007) A Hidden Markov Model to estimate population mixture and allelic copy-numbers in cancers using Affymetrix SNP arrays. BMC Bioinformatics 8:434PubMedCrossRef

42.

Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309PubMedCrossRef

43.

Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947PubMedCrossRef

44.

Li J, Perry A, James CD, Gutmann DH (2001) Cancer-related gene expression profiles in NF1-associated pilocytic astrocytomas. Neurology 56:885–890PubMed

45.

Lin Y, Huang C, Liu D (1997) Relationship between p16 and Rb protein expression in astrocytomas. Zhonghua Bing Li Xue Za Zhi 26:340–342PubMed

46.

Louis DN (1997) A molecular genetic model of astrocytoma histopathology. Brain Pathol 7:755–764PubMedCrossRef

47.

McCullough DC, Epstein F (1985) Optic pathway tumors. A review with proposals for clinical staging. Cancer 56:1789–1791PubMedCrossRef

48.

Newcomb EW, Cohen H, Lee SR, Bhalla SK, Bloom J, Hayes RL, Miller DC (1998) Survival of patients with glioblastoma multiforme is not influenced by altered expression of p16, p53, EGFR, MDM2 or Bcl-2 genes. Brain Pathol 8:655–667PubMedCrossRef

49.

Nishikawa R, Furnari FB, Lin H, Arap W, Berger MS, Cavenee WK, Su Huang HJ (1995) Loss of P16INK4 expression is frequent in high grade gliomas. Cancer Res 55:1941–1945PubMed

50.

Oostlander AE, Meijer GA, Ylstra B (2004) Microarray-based comparative genomic hybridization and its applications in human genetics. Clin Genet 66:488–495PubMedCrossRef

51.

Palma L, Guidetti B (1985) Cystic pilocytic astrocytomas of the cerebral hemispheres. Surgical experience with 51 cases and long-term results. J Neurosurg 62:811–815PubMedCrossRef

52.

Perilongo G, Carollo C, Salviati L, Murgia A, Pillon M, Basso G, Gardiman M, Laverda A (1997) Diencephalic syndrome and disseminated juvenile pilocytic astrocytomas of the hypothalamic-optic chiasm region. Cancer 80:142–146PubMedCrossRef

53.

Perry A, Nobori T, Ru N, Anderl K, Borell TJ, Mohapatra G, Feuerstein BG, Jenkins RB, Carson DA (1997) Detection of p16 gene deletions in gliomas: a comparison of fluorescence in situ hybridization (FISH) versus quantitative PCR. J Neuropathol Exp Neurol 56:999–1008PubMedCrossRef

54.

Pietsch T, Valter MM, Wolf HK, von Deimling A, Huang HJ, Cavenee WK, Wiestler OD (1997) Expression and distribution of vascular endothelial growth factor protein in human brain tumors. Acta Neuropathol (Berl) 93:109–117CrossRef

55.

Pollack IF, Claassen D, al-Shboul Q, Janosky JE, Deutsch M (1995) Low-grade gliomas of the cerebral hemispheres in children: an analysis of 71 cases. J Neurosurg 82:536–547PubMedCrossRef

56.

Puduvalli VK, Kyritsis AP, Hess KR, Bondy ML, Fuller GN, Kouraklis GP, Levin VA, Bruner JM (2000) Patterns of expression of Rb and p16 in astrocytic gliomas, and correlation with survival. Int J Oncol 17:963–969PubMed

57.

Ransom DT, Ritland SR, Kimmel DW, Moertel CA, Dahl RJ, Scheithauer BW, Kelly PJ, Jenkins RB (1992) Cytogenetic and loss of heterozygosity studies in ependymomas, pilocytic astrocytomas, and oligodendrogliomas. Genes Chromosomes Cancer 5:348–356PubMedCrossRef

58.

Roessler K, Bertalanffy A, Jezan H, Ba-Ssalamah A, Slavc I, Czech T, Budka H (2002) Proliferative activity as measured by MIB-1 labeling index and long-term outcome of cerebellar juvenile pilocytic astrocytomas. J Neurooncol 58:141–146PubMedCrossRef

59.

Sallinen PK, Haapasalo HK, Visakorpi T, Helen PT, Rantala IS, Isola JJ, Helin HJ (1994) Prognostication of astrocytoma patient survival by Ki-67 (MIB-1), PCNA, and S-phase fraction using archival paraffin-embedded samples. J Pathol 174:275–282PubMedCrossRef

60.

Sano T, Lin H, Chen X, Langford LA, Koul D, Bondy ML, Hess KR, Myers JN, Hong YK, Yung WK, Steck PA (1999) Differential expression of MMAC/PTEN in glioblastoma multiforme: relationship to localization and prognosis. Cancer Res 59:1820–1824PubMed

61.

Sanoudou D, Tingby O, Ferguson-Smith MA, Collins VP, Coleman N (2000) Analysis of pilocytic astrocytoma by comparative genomic hybridization. Br J Cancer 82:1218–1222PubMedCrossRef

62.

Schilling H, Sehu KW, Lee WR (1997) A histologic study (including DNA quantification and Ki-67 labeling index) in uveal melanomas after brachytherapy with ruthenium plaques. Invest Ophthalmol Vis Sci 38:2081–2092PubMed

63.

Shlomit R, Ayala AG, Michal D, Ninett A, Frida S, Boleslaw G, Gad B, Gideon R, Shlomi C (2000) Gains and losses of DNA sequences in childhood brain tumors analyzed by comparative genomic hybridization. Cancer Genet Cytogenet 121:67–72PubMedCrossRef

64.

Tamura M, Gu J, Tran H, Yamada KM (1999) PTEN gene and integrin signaling in cancer. J Natl Cancer Inst 91:1820–1828PubMedCrossRef

65.

Thiel G, Losanowa T, Kintzel D, Nisch G, Martin H, Vorpahl K, Witkowski R (1992) Karyotypes in 90 human gliomas. Cancer Genet Cytogenet 58:109–120PubMedCrossRef

66.

Tsuzuki T, Tsunoda S, Sakaki T, Konishi N, Hiasa Y, Nakamura M (1996) Alterations of retinoblastoma, p53, p16(CDKN2), and p15 genes in human astrocytomas. Cancer 78:287–293PubMedCrossRef

67.

Wemmert S, Romeike BF, Ketter R, Steudel WI, Zang KD, Urbschat S (2006) Intratumoral genetic heterogeneity in pilocytic astrocytomas revealed by CGH-analysis of microdissected tumor cells and FISH on tumor tissue sections. Int J Oncol 28:353–360PubMed

68.

Wen S, Stolarov J, Myers MP, Su JD, Wigler MH, Tonks NK, Durden DL (2001) PTEN controls tumor-induced angiogenesis. Proc Natl Acad Sci U S A 98:4622–4627PubMedCrossRef

69.

White FV, Anthony DC, Yunis EJ, Tarbell NJ, Scott RM, Schofield DE (1995) Nonrandom chromosomal gains in pilocytic astrocytomas of childhood. Hum Pathol 26:979–986PubMedCrossRef

70.

Wiltshire RN, Herndon JE 2nd, Lloyd A, Friedman HS, Bigner DD, Bigner SH, McLendon RE (2004) Comparative genomic hybridization analysis of astrocytomas: prognostic and diagnostic implications. J Mol Diagn 6:166–179PubMedCrossRef

71.

Yang Y, Shao N, Luo G, Li L, Nilsson-Ehle P, Xu N (2006) Relationship between PTEN gene expression and differentiation of human glioma. Scand J Clin Lab Invest 66:469–475PubMedCrossRef

72.

Youmans JR (1990) Neurological surgery. W: B: Saunders, Philadelphia

73.

Zattara-Cannoni H, Gambarelli D, Lena G, Dufour H, Choux M, Grisoli F, Vagner-Capodano AM (1998) Are juvenile pilocytic astrocytomas benign tumors? A cytogenetic study in 24 cases. Cancer Genet Cytogenet 104:157–160PubMedCrossRef

74.

Zhong XY, Sun YH, Chen YX (2003) Relationship of PTEN, Mdm2 and p53 expression in astrocytoma. Zhonghua Zhong Liu Za Zhi 25:478–481PubMed

75.

Zhu R, Kang S, Wu D (1997) Expression of p53, c-erbB1, c-myc and p16 gene proteins in human glioma. Zhonghua Bing Li Xue Za Zhi 26:343–345PubMed

Title: Biologic tumor behavior in pilocytic astrocytomas
Authors: Muhittin Belirgen
Su Gulsun Berrak
Hilâl Ozdag
Suheyla Uyar Bozkurt
Emel Eksioglu-Demiralp
M. Memet Ozek
Publication date: 01-03-2012
Publisher: Springer-Verlag
Published in: Child's Nervous System / Issue 3/2012
Print ISSN: 0256-7040
Electronic ISSN: 1433-0350
DOI: https://doi.org/10.1007/s00381-011-1676-6

ACC 2024 Congress

Springer Medicine

Biologic tumor behavior in pilocytic astrocytomas

Abstract

Purpose

Methods

Results

Conclusions

ACC 2024 Congress

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 3/2012

Intrauterine myelomeningocele repair Postnatal results and follow-up at 3.5 years of age — initial experience from a single reference service in Brazil

Deficient language acquisition in children with single suture craniosynostosis and deformational posterior plagiocephaly

Infarction following chiasmatic low grade glioma resection

Ventriculoperitoneal shunt malfunction from cerebrospinal fluid eosinophilia in children: case-based update

Early endoscopy-assisted treatment of multiple-suture craniosynostosis

Blinking—an unusual presentation of obstructive hydrocephalus relieved by endoscopic third ventriculostomy