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Published in: Diagnostic Pathology 1/2011

Open Access 01-12-2011 | Research

Evaluation of the proliferation markers Ki-67/MIB-1, mitosin, survivin, pHH3, and DNA topoisomerase IIα in human anaplastic astrocytomas - an immunohistochemical study

Authors: Andreas H Habberstad, Sasha Gulati, Sverre H Torp

Published in: Diagnostic Pathology | Issue 1/2011

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Abstract

Background

Histological malignancy grading of astrocytomas can be challenging despite criteria given by the World Health Organisation (WHO). Grading is fundamental for optimal prognostication and treatment, and additional biomarkers are needed to support the histopathological diagnosis. Estimation of proliferative activity has gained much enthusiasm, and the present study was designed to evaluate and compare novel immunohistochemical proliferative markers in human anaplastic astrocytomas.

Methods

Proliferative activity was determined in twenty-seven cases with antibodies reactive against the Ki-67 antigen, mitosin, survivin, pHH3, and DNA topoisomerase IIα, and they were mutually compared as well as related to mitotic activity.

Results

The markers correlated well with each other, but poorly with mitoses, probably because of small and squeezed tumour samples, in which identification of mitoses can be difficult. Positive association to overall survival was observed as well.

Conclusions

Our data show that these markers may assist significantly in the evaluation of proliferative activity in anaplastic astrocytomas and even have prognostic value.

Virtual Slides

The virtual slide(s) for this article can be found here: http://​www.​diagnosticpathol​ogy.​diagnomx.​eu/​vs/​2653263345404531​.
Appendix
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Literature
1.
go back to reference Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007, 114: 97-109. 10.1007/s00401-007-0243-4.PubMedCentralCrossRefPubMed Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007, 114: 97-109. 10.1007/s00401-007-0243-4.PubMedCentralCrossRefPubMed
2.
go back to reference Prayson RA: Cell proliferation and tumors of the central nervous system. Part 1: Evaluation of mitotic activity. J Neuropathol Exp Neurol. 2002, 61: 501-509.PubMed Prayson RA: Cell proliferation and tumors of the central nervous system. Part 1: Evaluation of mitotic activity. J Neuropathol Exp Neurol. 2002, 61: 501-509.PubMed
3.
go back to reference Johannessen A, Torp S: The clinical value of Ki-67/MIB-1 labeling index in human astrocytomas. Pathol Oncol Res. 2006, 12: 143-147. 10.1007/BF02893360.CrossRefPubMed Johannessen A, Torp S: The clinical value of Ki-67/MIB-1 labeling index in human astrocytomas. Pathol Oncol Res. 2006, 12: 143-147. 10.1007/BF02893360.CrossRefPubMed
4.
go back to reference Prayson RA: The utility of MIB-1/Ki-67 imunostaining in the evaluation of central nervous system neoplasms. Adv Anat Pathol. 2005, 12: 144-148. 10.1097/01.pap.0000163957.21409.52.CrossRefPubMed Prayson RA: The utility of MIB-1/Ki-67 imunostaining in the evaluation of central nervous system neoplasms. Adv Anat Pathol. 2005, 12: 144-148. 10.1097/01.pap.0000163957.21409.52.CrossRefPubMed
5.
go back to reference Colman H, Giannini C, Huang L, Gonzalez J, Hess K, Bruner J, Fuller G, Langford L, Pelloski C, Aaron J, et al.: Assessment and prognostic significance of mitotic index using the mitosis marker phospho-histone H3 in low and intermediate-grade infiltrating astrocytomas. Am J Surg Pathol. 2006, 30: 657-664. 10.1097/01.pas.0000202048.28203.25.CrossRefPubMed Colman H, Giannini C, Huang L, Gonzalez J, Hess K, Bruner J, Fuller G, Langford L, Pelloski C, Aaron J, et al.: Assessment and prognostic significance of mitotic index using the mitosis marker phospho-histone H3 in low and intermediate-grade infiltrating astrocytomas. Am J Surg Pathol. 2006, 30: 657-664. 10.1097/01.pas.0000202048.28203.25.CrossRefPubMed
6.
go back to reference Liu X, Chen N, Wang X, He Y, Chen X, Huang Y, Yin W, Zhou Q: Apoptosis and proliferation markers in diffusely infiltrating astrocytomas: profiling of 17 molecules. J Neuropathol Exp Neurol. 2006, 65: 905-913. 10.1097/01.jnen.0000235857.79502.c3.CrossRefPubMed Liu X, Chen N, Wang X, He Y, Chen X, Huang Y, Yin W, Zhou Q: Apoptosis and proliferation markers in diffusely infiltrating astrocytomas: profiling of 17 molecules. J Neuropathol Exp Neurol. 2006, 65: 905-913. 10.1097/01.jnen.0000235857.79502.c3.CrossRefPubMed
7.
go back to reference Uematsu M, Ohsawa I, Aokage T, Nishimaki K, Matsumoto K, Takahashi H, Asoh S, Teramoto A, Ohta S: Prognostic significance of the immunohistochemical index of survivin in glioma: a comparative study with the MIB-1 index. J Neurooncol. 2005, 72: 231-238. 10.1007/s11060-004-2353-3.CrossRefPubMed Uematsu M, Ohsawa I, Aokage T, Nishimaki K, Matsumoto K, Takahashi H, Asoh S, Teramoto A, Ohta S: Prognostic significance of the immunohistochemical index of survivin in glioma: a comparative study with the MIB-1 index. J Neurooncol. 2005, 72: 231-238. 10.1007/s11060-004-2353-3.CrossRefPubMed
8.
go back to reference Preusser M, Gelpi E, Matej R, Marosi C, Dieckmann K, Rossler K, Budka H, Hainfellner JA: No prognostic impact of survivin expression in glioblastoma. Acta Neuropathol. 2005, 109: 534-538. 10.1007/s00401-005-0992-x.CrossRefPubMed Preusser M, Gelpi E, Matej R, Marosi C, Dieckmann K, Rossler K, Budka H, Hainfellner JA: No prognostic impact of survivin expression in glioblastoma. Acta Neuropathol. 2005, 109: 534-538. 10.1007/s00401-005-0992-x.CrossRefPubMed
9.
go back to reference Taniguchi K, Wakabayashi T, Yoshida T, Mizuno M, Yoshikawa K, Kikuchi A, Nakashima N, Yoshida J: Immunohistochemical staining of DNA topoisomerase IIalpha in human gliomas. J Neurosurg. 1999, 91: 477-482. 10.3171/jns.1999.91.3.0477.CrossRefPubMed Taniguchi K, Wakabayashi T, Yoshida T, Mizuno M, Yoshikawa K, Kikuchi A, Nakashima N, Yoshida J: Immunohistochemical staining of DNA topoisomerase IIalpha in human gliomas. J Neurosurg. 1999, 91: 477-482. 10.3171/jns.1999.91.3.0477.CrossRefPubMed
10.
go back to reference Faria MH, Goncalves BP, do Patrocinio RM, de Moraes-Filho MO, Rabenhorst SH: Expression of Ki-67, topoisomerase IIalpha and c-MYC in astrocytic tumors: correlation with the histopathological grade and proliferative status. Neuropathology. 2006, 26: 519-527. 10.1111/j.1440-1789.2006.00724.x.CrossRefPubMed Faria MH, Goncalves BP, do Patrocinio RM, de Moraes-Filho MO, Rabenhorst SH: Expression of Ki-67, topoisomerase IIalpha and c-MYC in astrocytic tumors: correlation with the histopathological grade and proliferative status. Neuropathology. 2006, 26: 519-527. 10.1111/j.1440-1789.2006.00724.x.CrossRefPubMed
11.
go back to reference Bredel M, Piribauer M, Marosi C, Birner P, Gatterbauer B, Fischer I, Strobel T, Rossler K, Budka H, Hainfellner JA: High expression of DNA topoisomerase IIalpha and Ki-67 antigen is associated with prolonged survival in glioblastoma patients. Eur J Cancer. 2002, 38: 1343-1347. 10.1016/S0959-8049(02)00065-5.CrossRefPubMed Bredel M, Piribauer M, Marosi C, Birner P, Gatterbauer B, Fischer I, Strobel T, Rossler K, Budka H, Hainfellner JA: High expression of DNA topoisomerase IIalpha and Ki-67 antigen is associated with prolonged survival in glioblastoma patients. Eur J Cancer. 2002, 38: 1343-1347. 10.1016/S0959-8049(02)00065-5.CrossRefPubMed
12.
go back to reference Korkolopoulou P, Patsouris E, Konstantinidou AE, Christodoulou P, Thomas-Tsagli E, Kouzelis K, Angelidakis D, Rologis D, Davaris P: Mitosin and DNA topoisomerase IIalpha: two novel proliferation markers in the prognostication of diffuse astrocytoma patient survival. Appl Immunohistochem Mol Morphol. 2001, 9: 207-214. 10.1097/00022744-200109000-00003.PubMed Korkolopoulou P, Patsouris E, Konstantinidou AE, Christodoulou P, Thomas-Tsagli E, Kouzelis K, Angelidakis D, Rologis D, Davaris P: Mitosin and DNA topoisomerase IIalpha: two novel proliferation markers in the prognostication of diffuse astrocytoma patient survival. Appl Immunohistochem Mol Morphol. 2001, 9: 207-214. 10.1097/00022744-200109000-00003.PubMed
13.
go back to reference Juan G, Traganos F, James WM, Ray JM, Roberge M, Sauve DM, Anderson H, Darzynkiewicz Z: Histone H3 phosphorylation and expression of cyclins A and B1 measured in individual cells during their progression through G2 and mitosis. Cytometry. 1998, 32: 71-77. 10.1002/(SICI)1097-0320(19980601)32:2<71::AID-CYTO1>3.0.CO;2-H.CrossRefPubMed Juan G, Traganos F, James WM, Ray JM, Roberge M, Sauve DM, Anderson H, Darzynkiewicz Z: Histone H3 phosphorylation and expression of cyclins A and B1 measured in individual cells during their progression through G2 and mitosis. Cytometry. 1998, 32: 71-77. 10.1002/(SICI)1097-0320(19980601)32:2<71::AID-CYTO1>3.0.CO;2-H.CrossRefPubMed
14.
go back to reference Hendzel MJ, Wei Y, Mancini MA, Van Hooser A, Ranalli T, Brinkley BR, Bazett-Jones DP, Allis CD: Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma. 1997, 106: 348-360. 10.1007/s004120050256.CrossRefPubMed Hendzel MJ, Wei Y, Mancini MA, Van Hooser A, Ranalli T, Brinkley BR, Bazett-Jones DP, Allis CD: Mitosis-specific phosphorylation of histone H3 initiates primarily within pericentromeric heterochromatin during G2 and spreads in an ordered fashion coincident with mitotic chromosome condensation. Chromosoma. 1997, 106: 348-360. 10.1007/s004120050256.CrossRefPubMed
15.
go back to reference Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC: Control of apoptosis and mitotic spindle checkpoint by survivin. Nature. 1998, 396: 580-584. 10.1038/25141.CrossRefPubMed Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC: Control of apoptosis and mitotic spindle checkpoint by survivin. Nature. 1998, 396: 580-584. 10.1038/25141.CrossRefPubMed
16.
17.
go back to reference Shirai K, Suzuki Y, Oka K, Noda SE, Katoh H, Itoh J, Itoh H, Ishiuchi S, Sakurai H, Hasegawa M, Nakano T: Nuclear survivin expression predicts poorer prognosis in glioblastoma. J Neurooncol. 2009, 91: 353-358. 10.1007/s11060-008-9720-4.CrossRefPubMed Shirai K, Suzuki Y, Oka K, Noda SE, Katoh H, Itoh J, Itoh H, Ishiuchi S, Sakurai H, Hasegawa M, Nakano T: Nuclear survivin expression predicts poorer prognosis in glioblastoma. J Neurooncol. 2009, 91: 353-358. 10.1007/s11060-008-9720-4.CrossRefPubMed
18.
go back to reference Saito T, Arifin MT, Hama S, Kajiwara Y, Sugiyama K, Yamasaki F, Hidaka T, Arita K, Kurisu K: Survivin subcellular localization in high-grade astrocytomas: simultaneous expression in both nucleus and cytoplasm is negative prognostic marker. J Neurooncol. 2007, 82: 193-198. 10.1007/s11060-006-9267-1.CrossRefPubMed Saito T, Arifin MT, Hama S, Kajiwara Y, Sugiyama K, Yamasaki F, Hidaka T, Arita K, Kurisu K: Survivin subcellular localization in high-grade astrocytomas: simultaneous expression in both nucleus and cytoplasm is negative prognostic marker. J Neurooncol. 2007, 82: 193-198. 10.1007/s11060-006-9267-1.CrossRefPubMed
19.
go back to reference Li F, Yang J, Ramnath N, Javle MM, Tan D: Nuclear or cytoplasmic expression of survivin: what is the significance?. Int J Cancer. 2005, 114: 509-512. 10.1002/ijc.20768.PubMedCentralCrossRefPubMed Li F, Yang J, Ramnath N, Javle MM, Tan D: Nuclear or cytoplasmic expression of survivin: what is the significance?. Int J Cancer. 2005, 114: 509-512. 10.1002/ijc.20768.PubMedCentralCrossRefPubMed
20.
go back to reference Chakravarti A, Zhai GG, Zhang M, Malhotra R, Latham DE, Delaney MA, Robe P, Nestler U, Song Q, Loeffler J: Survivin enhances radiation resistance in primary human glioblastoma cells via caspase-independent mechanisms. Oncogene. 2004, 23: 7494-7506. 10.1038/sj.onc.1208049.CrossRefPubMed Chakravarti A, Zhai GG, Zhang M, Malhotra R, Latham DE, Delaney MA, Robe P, Nestler U, Song Q, Loeffler J: Survivin enhances radiation resistance in primary human glioblastoma cells via caspase-independent mechanisms. Oncogene. 2004, 23: 7494-7506. 10.1038/sj.onc.1208049.CrossRefPubMed
21.
go back to reference McLaughlin N, Annabi B, Bouzeghrane M, Temme A, Bahary JP, Moumdjian R, Beliveau R: The Survivin-mediated radioresistant phenotype of glioblastomas is regulated by RhoA and inhibited by the green tea polyphenol (-)-epigallocatechin-3-gallate. Brain Res. 2006, 1071: 1-9. 10.1016/j.brainres.2005.10.009.CrossRefPubMed McLaughlin N, Annabi B, Bouzeghrane M, Temme A, Bahary JP, Moumdjian R, Beliveau R: The Survivin-mediated radioresistant phenotype of glioblastomas is regulated by RhoA and inhibited by the green tea polyphenol (-)-epigallocatechin-3-gallate. Brain Res. 2006, 1071: 1-9. 10.1016/j.brainres.2005.10.009.CrossRefPubMed
23.
go back to reference Larsen AK, Skladanowski A, Bojanowski K: The roles of DNA topoisomerase II during the cell cycle. Prog Cell Cycle Res. 1996, 2: 229-239.CrossRefPubMed Larsen AK, Skladanowski A, Bojanowski K: The roles of DNA topoisomerase II during the cell cycle. Prog Cell Cycle Res. 1996, 2: 229-239.CrossRefPubMed
24.
go back to reference Ho DM, Hsu CY, Ting LT, Chiang H: MIB-1 and DNA topoisomerase II alpha could be helpful for predicting long-term survival of patients with glioblastoma. Am J Clin Pathol. 2003, 119: 715-722. 10.1309/UN4WV65UH94JEWUV.CrossRefPubMed Ho DM, Hsu CY, Ting LT, Chiang H: MIB-1 and DNA topoisomerase II alpha could be helpful for predicting long-term survival of patients with glioblastoma. Am J Clin Pathol. 2003, 119: 715-722. 10.1309/UN4WV65UH94JEWUV.CrossRefPubMed
25.
go back to reference Zhu X, Mancini MA, Chang KH, Liu CY, Chen CF, Shan B, Jones D, Yang-Feng TL, Lee WH: Characterization of a novel 350-kilodalton nuclear phosphoprotein that is specifically involved in mitotic-phase progression. Mol Cell Biol. 1995, 15: 5017-5029.PubMedCentralCrossRefPubMed Zhu X, Mancini MA, Chang KH, Liu CY, Chen CF, Shan B, Jones D, Yang-Feng TL, Lee WH: Characterization of a novel 350-kilodalton nuclear phosphoprotein that is specifically involved in mitotic-phase progression. Mol Cell Biol. 1995, 15: 5017-5029.PubMedCentralCrossRefPubMed
26.
go back to reference Varis A, Salmela AL, Kallio MJ: Cenp-F (mitosin) is more than a mitotic marker. Chromosoma. 2006, 115: 288-295. 10.1007/s00412-005-0046-0.CrossRefPubMed Varis A, Salmela AL, Kallio MJ: Cenp-F (mitosin) is more than a mitotic marker. Chromosoma. 2006, 115: 288-295. 10.1007/s00412-005-0046-0.CrossRefPubMed
27.
go back to reference Gulati S, Ytterhus B, Granli US, Gulati M, Lydersen S, Torp SH: Overexpression of c-erbB2 is a negative prognostic factor in anaplastic astrocytomas. Diagn Pathol. 2010, 5: 18-10.1186/1746-1596-5-18.PubMedCentralCrossRefPubMed Gulati S, Ytterhus B, Granli US, Gulati M, Lydersen S, Torp SH: Overexpression of c-erbB2 is a negative prognostic factor in anaplastic astrocytomas. Diagn Pathol. 2010, 5: 18-10.1186/1746-1596-5-18.PubMedCentralCrossRefPubMed
28.
go back to reference Giannini C, Scheithauer BW, Burger PC, Christensen MR, Wollan PC, Sebo TJ, Forsyth PA, Hayostek CJ: Cellular proliferation in pilocytic and diffuse astrocytomas. J Neuropathol Exp Neurol. 1999, 58: 46-53. 10.1097/00005072-199901000-00006.CrossRefPubMed Giannini C, Scheithauer BW, Burger PC, Christensen MR, Wollan PC, Sebo TJ, Forsyth PA, Hayostek CJ: Cellular proliferation in pilocytic and diffuse astrocytomas. J Neuropathol Exp Neurol. 1999, 58: 46-53. 10.1097/00005072-199901000-00006.CrossRefPubMed
29.
go back to reference Ladstein RG, Bachmann IM, Straume O, Akslen LA: Ki-67 expression is superior to mitotic count and novel proliferation markers PHH3, MCM4 and mitosin as a prognostic factor in thick cutaneous melanoma. BMC Cancer. 2010, 10: 140-10.1186/1471-2407-10-140.PubMedCentralCrossRefPubMed Ladstein RG, Bachmann IM, Straume O, Akslen LA: Ki-67 expression is superior to mitotic count and novel proliferation markers PHH3, MCM4 and mitosin as a prognostic factor in thick cutaneous melanoma. BMC Cancer. 2010, 10: 140-10.1186/1471-2407-10-140.PubMedCentralCrossRefPubMed
30.
go back to reference Ribalta T, McCutcheon IE, Aldape KD, Bruner JM, Fuller GN: The mitosis-specific antibody anti-phosphohistone-H3 (PHH3) facilitates rapid reliable grading of meningiomas according to WHO 2000 criteria. Am J Surg Pathol. 2004, 28: 1532-1536. 10.1097/01.pas.0000141389.06925.d5.CrossRefPubMed Ribalta T, McCutcheon IE, Aldape KD, Bruner JM, Fuller GN: The mitosis-specific antibody anti-phosphohistone-H3 (PHH3) facilitates rapid reliable grading of meningiomas according to WHO 2000 criteria. Am J Surg Pathol. 2004, 28: 1532-1536. 10.1097/01.pas.0000141389.06925.d5.CrossRefPubMed
31.
go back to reference McCormick D, Hall PA: The complexities of proliferating cell nuclear antigen. Histopathology. 1992, 21: 591-594. 10.1111/j.1365-2559.1992.tb00454.x.CrossRefPubMed McCormick D, Hall PA: The complexities of proliferating cell nuclear antigen. Histopathology. 1992, 21: 591-594. 10.1111/j.1365-2559.1992.tb00454.x.CrossRefPubMed
Metadata
Title
Evaluation of the proliferation markers Ki-67/MIB-1, mitosin, survivin, pHH3, and DNA topoisomerase IIα in human anaplastic astrocytomas - an immunohistochemical study
Authors
Andreas H Habberstad
Sasha Gulati
Sverre H Torp
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Diagnostic Pathology / Issue 1/2011
Electronic ISSN: 1746-1596
DOI
https://doi.org/10.1186/1746-1596-6-43

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