Skip to main content
NCBI home page
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 1995 Oct;59(4):413–419. doi: 10.1136/jnnp.59.4.413

Prognostic indicators in a range of astrocytic tumours: an immunohistochemical study with Ki-67 and p53 antibodies.

D W Ellison 1, P V Steart 1, A C Bateman 1, R M Pickering 1, J D Palmer 1, R O Weller 1
PMCID: PMC486079  PMID: 7561922

Abstract

The treatment and prognosis of patients with cerebral astrocytic tumours are currently guided by histopathological classification. This study evaluates immunohistochemistry using Ki-67, an antibody to a nuclear protein expressed in proliferating cells, and DO-7, an antibody to the product of the tumour suppressor gene p53, as prognostic indicators for these tumours. Immunohistochemistry with Ki-67 has been correlated with the behaviour of many different tumours, but its value as a prognostic indicator in astrocytic tumours is diminished by the conflicting results of previous studies. Immunohistochemistry with antibodies to the p53 protein has been used as a prognostic indicator in melanomas and some carcinomas, but the relation between prognosis and accumulation of this protein in astrocytic tumours has not been clarified. We have tested the hypothesis that survival is correlated with Ki-67 immunolabelling indices (LIs) and patterns of p53 immunolabelling in the cerebral astrocytic tumours of a large cohort of patients (n = 123) for whom clinical indices were well documented. Astrocytic tumours were divided into three histological types: fibrillary astrocytoma (n = 24), anaplastic astrocytoma (n = 31), and glioblastoma (n = 68). Histological type and patient age were independent predictors of survival. Median Ki-67 LIs differed significantly (P < 0.0001) between the types of astrocytic tumour, and tumours with a Ki-67 LI < 2% had a significantly (P < 0.0001) better prognosis. Ki-67 LI as a continuous variable carried a significant (P = 0.0043) unadjusted hazard to survival which was lost when adjusted for other variables, notably histological type. By contrast, no relation was found between survival and three categories of p53 labeling (p53-negative, p53 LI < 40%, and p53 LI > 60%). The results indicate that, whereas Ki-67 immunohistochemistry predicts survival in patients with astrocytic tumours, conventional histological appraisal remains the best guide to prognosis, and immunohistochemistry for p53 has no value in the assessment of these tumours.

Full text

PDF
413

Images in this article

415Image
on p.415
416Image
on p.416

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barbareschi M., Iuzzolino P., Pennella A., Allegranza A., Arrigoni G., Dalla Palma P., Doglioni C. p53 protein expression in central nervous system neoplasms. J Clin Pathol. 1992 Jul;45(7):583–586. doi: 10.1136/jcp.45.7.583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barnes D. M., Dublin E. A., Fisher C. J., Levison D. A., Millis R. R. Immunohistochemical detection of p53 protein in mammary carcinoma: an important new independent indicator of prognosis? Hum Pathol. 1993 May;24(5):469–476. doi: 10.1016/0046-8177(93)90158-d. [DOI] [PubMed] [Google Scholar]
  3. Brown D. C., Gatter K. C. Monoclonal antibody Ki-67: its use in histopathology. Histopathology. 1990 Dec;17(6):489–503. doi: 10.1111/j.1365-2559.1990.tb00788.x. [DOI] [PubMed] [Google Scholar]
  4. Burger P. C., Green S. B. Patient age, histologic features, and length of survival in patients with glioblastoma multiforme. Cancer. 1987 May 1;59(9):1617–1625. doi: 10.1002/1097-0142(19870501)59:9<1617::aid-cncr2820590916>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  5. Burger P. C., Vogel F. S., Green S. B., Strike T. A. Glioblastoma multiforme and anaplastic astrocytoma. Pathologic criteria and prognostic implications. Cancer. 1985 Sep 1;56(5):1106–1111. doi: 10.1002/1097-0142(19850901)56:5<1106::aid-cncr2820560525>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  6. Cattoretti G., Becker M. H., Key G., Duchrow M., Schlüter C., Galle J., Gerdes J. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992 Dec;168(4):357–363. doi: 10.1002/path.1711680404. [DOI] [PubMed] [Google Scholar]
  7. Chozick B. S., Pezzullo J. C., Epstein M. H., Finch P. W. Prognostic implications of p53 overexpression in supratentorial astrocytic tumors. Neurosurgery. 1994 Nov;35(5):831–838. doi: 10.1227/00006123-199411000-00005. [DOI] [PubMed] [Google Scholar]
  8. Clarke A. R., Purdie C. A., Harrison D. J., Morris R. G., Bird C. C., Hooper M. L., Wyllie A. H. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature. 1993 Apr 29;362(6423):849–852. doi: 10.1038/362849a0. [DOI] [PubMed] [Google Scholar]
  9. Cohadon F., Aouad N., Rougier A., Vital C., Rivel J., Dartigues J. F. Histologic and non-histologic factors correlated with survival time in supratentorial astrocytic tumors. J Neurooncol. 1985;3(2):105–111. doi: 10.1007/BF02228885. [DOI] [PubMed] [Google Scholar]
  10. Donehower L. A., Harvey M., Slagle B. L., McArthur M. J., Montgomery C. A., Jr, Butel J. S., Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992 Mar 19;356(6366):215–221. doi: 10.1038/356215a0. [DOI] [PubMed] [Google Scholar]
  11. Ellison D. W., Gatter K. C., Steart P. V., Lane D. P., Weller R. O. Expression of the p53 protein in a spectrum of astrocytic tumours. J Pathol. 1992 Dec;168(4):383–386. doi: 10.1002/path.1711680408. [DOI] [PubMed] [Google Scholar]
  12. Ellison D. W., Weller R. O. Forecasting the prognosis of a patient with a tumour. Neuropathol Appl Neurobiol. 1992 Dec;18(6):626–627. doi: 10.1111/j.1365-2990.1992.tb00834.x. [DOI] [PubMed] [Google Scholar]
  13. Fields S., Jang S. K. Presence of a potent transcription activating sequence in the p53 protein. Science. 1990 Aug 31;249(4972):1046–1049. doi: 10.1126/science.2144363. [DOI] [PubMed] [Google Scholar]
  14. Gerdes J., Li L., Schlueter C., Duchrow M., Wohlenberg C., Gerlach C., Stahmer I., Kloth S., Brandt E., Flad H. D. Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. Am J Pathol. 1991 Apr;138(4):867–873. [PMC free article] [PubMed] [Google Scholar]
  15. Haapasalo H., Isola J., Sallinen P., Kalimo H., Helin H., Rantala I. Aberrant p53 expression in astrocytic neoplasms of the brain: association with proliferation. Am J Pathol. 1993 May;142(5):1347–1351. [PMC free article] [PubMed] [Google Scholar]
  16. Jaros E., Perry R. H., Adam L., Kelly P. J., Crawford P. J., Kalbag R. M., Mendelow A. D., Sengupta R. P., Pearson A. D. Prognostic implications of p53 protein, epidermal growth factor receptor, and Ki-67 labelling in brain tumours. Br J Cancer. 1992 Aug;66(2):373–385. doi: 10.1038/bjc.1992.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Karamitopoulou E., Perentes E., Diamantis I. p53 protein expression in central nervous system tumors: an immunohistochemical study with CM1 polyvalent and DO-7 monoclonal antibodies. Acta Neuropathol. 1993;85(6):611–616. doi: 10.1007/BF00334670. [DOI] [PubMed] [Google Scholar]
  18. Kern S. E., Pietenpol J. A., Thiagalingam S., Seymour A., Kinzler K. W., Vogelstein B. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science. 1992 May 8;256(5058):827–830. doi: 10.1126/science.1589764. [DOI] [PubMed] [Google Scholar]
  19. Kim T. S., Halliday A. L., Hedley-Whyte E. T., Convery K. Correlates of survival and the Daumas-Duport grading system for astrocytomas. J Neurosurg. 1991 Jan;74(1):27–37. doi: 10.3171/jns.1991.74.1.0027. [DOI] [PubMed] [Google Scholar]
  20. Lane D. P. Cancer. p53, guardian of the genome. Nature. 1992 Jul 2;358(6381):15–16. doi: 10.1038/358015a0. [DOI] [PubMed] [Google Scholar]
  21. Lane D. P. The regulation of p53 function: Steiner Award Lecture. Int J Cancer. 1994 Jun 1;57(5):623–627. doi: 10.1002/ijc.2910570502. [DOI] [PubMed] [Google Scholar]
  22. Louis D. N., Edgerton S., Thor A. D., Hedley-Whyte E. T. Proliferating cell nuclear antigen and Ki-67 immunohistochemistry in brain tumors: a comparative study. Acta Neuropathol. 1991;81(6):675–679. doi: 10.1007/BF00296379. [DOI] [PubMed] [Google Scholar]
  23. Louis D. N. The p53 gene and protein in human brain tumors. J Neuropathol Exp Neurol. 1994 Jan;53(1):11–21. doi: 10.1097/00005072-199401000-00002. [DOI] [PubMed] [Google Scholar]
  24. Louis D. N., von Deimling A., Chung R. Y., Rubio M. P., Whaley J. M., Eibl R. H., Ohgaki H., Wiestler O. D., Thor A. D., Seizinger B. R. Comparative study of p53 gene and protein alterations in human astrocytic tumors. J Neuropathol Exp Neurol. 1993 Jan;52(1):31–38. doi: 10.1097/00005072-199301000-00005. [DOI] [PubMed] [Google Scholar]
  25. Marx J. How p53 suppresses cell growth. Science. 1993 Dec 10;262(5140):1644–1645. doi: 10.1126/science.8259506. [DOI] [PubMed] [Google Scholar]
  26. McGregor J. M., Yu C. C., Dublin E. A., Barnes D. M., Levison D. A., MacDonald D. M. p53 immunoreactivity in human malignant melanoma and dysplastic naevi. Br J Dermatol. 1993 Jun;128(6):606–611. doi: 10.1111/j.1365-2133.1993.tb00253.x. [DOI] [PubMed] [Google Scholar]
  27. Momand J., Zambetti G. P., Olson D. C., George D., Levine A. J. The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell. 1992 Jun 26;69(7):1237–1245. doi: 10.1016/0092-8674(92)90644-r. [DOI] [PubMed] [Google Scholar]
  28. Morimura T., Kitz K., Budka H. In situ analysis of cell kinetics in human brain tumors. A comparative immunocytochemical study of S phase cells by a new in vitro bromodeoxyuridine-labeling technique, and of proliferating pool cells by monoclonal antibody Ki-67. Acta Neuropathol. 1989;77(3):276–282. doi: 10.1007/BF00687579. [DOI] [PubMed] [Google Scholar]
  29. Onda K., Davis R. L., Wilson C. B., Hoshino T. Regional differences in bromodeoxyuridine uptake, expression of Ki-67 protein, and nucleolar organizer region counts in glioblastoma multiforme. Acta Neuropathol. 1994;87(6):586–593. doi: 10.1007/BF00293319. [DOI] [PubMed] [Google Scholar]
  30. Prives C. Doing the right thing: feedback control and p53. Curr Opin Cell Biol. 1993 Apr;5(2):214–218. doi: 10.1016/0955-0674(93)90105-y. [DOI] [PubMed] [Google Scholar]
  31. Quinlan D. C., Davidson A. G., Summers C. L., Warden H. E., Doshi H. M. Accumulation of p53 protein correlates with a poor prognosis in human lung cancer. Cancer Res. 1992 Sep 1;52(17):4828–4831. [PubMed] [Google Scholar]
  32. Raghavan R., Steart P. V., Weller R. O. Cell proliferation patterns in the diagnosis of astrocytomas, anaplastic astrocytomas and glioblastoma multiforme: a Ki-67 study. Neuropathol Appl Neurobiol. 1990 Apr;16(2):123–133. doi: 10.1111/j.1365-2990.1990.tb00941.x. [DOI] [PubMed] [Google Scholar]
  33. Reifenberger G., Liu L., Ichimura K., Schmidt E. E., Collins V. P. Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. Cancer Res. 1993 Jun 15;53(12):2736–2739. [PubMed] [Google Scholar]
  34. Rubio M. P., von Deimling A., Yandell D. W., Wiestler O. D., Gusella J. F., Louis D. N. Accumulation of wild type p53 protein in human astrocytomas. Cancer Res. 1993 Aug 1;53(15):3465–3467. [PubMed] [Google Scholar]
  35. Thomas D. J., Robinson M., King P., Hasan T., Charlton R., Martin J., Carr T. W., Neal D. E. p53 expression and clinical outcome in prostate cancer. Br J Urol. 1993 Nov;72(5 Pt 2):778–781. doi: 10.1111/j.1464-410x.1993.tb16267.x. [DOI] [PubMed] [Google Scholar]
  36. VandenBerg S. R. Current diagnostic concepts of astrocytic tumors. J Neuropathol Exp Neurol. 1992 Nov;51(6):644–657. doi: 10.1097/00005072-199211000-00008. [DOI] [PubMed] [Google Scholar]
  37. Vogelstein B., Kinzler K. W. p53 function and dysfunction. Cell. 1992 Aug 21;70(4):523–526. doi: 10.1016/0092-8674(92)90421-8. [DOI] [PubMed] [Google Scholar]
  38. Wu X., Bayle J. H., Olson D., Levine A. J. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993 Jul;7(7A):1126–1132. doi: 10.1101/gad.7.7a.1126. [DOI] [PubMed] [Google Scholar]
  39. Zuber P., Hamou M. F., de Tribolet N. Identification of proliferating cells in human gliomas using the monoclonal antibody Ki-67. Neurosurgery. 1988 Feb;22(2):364–368. doi: 10.1227/00006123-198802000-00015. [DOI] [PubMed] [Google Scholar]
  40. von Deimling A., Bender B., Jahnke R., Waha A., Kraus J., Albrecht S., Wellenreuther R., Fassbender F., Nagel J., Menon A. G. Loci associated with malignant progression in astrocytomas: a candidate on chromosome 19q. Cancer Res. 1994 Mar 15;54(6):1397–1401. [PubMed] [Google Scholar]
  41. von Deimling A., von Ammon K., Schoenfeld D., Wiestler O. D., Seizinger B. R., Louis D. N. Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Pathol. 1993 Jan;3(1):19–26. doi: 10.1111/j.1750-3639.1993.tb00721.x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES