Abstract
AIMS: To evaluate a possible association between clinical outcome in patients with glioblastoma and expression of some immunohistochemical variables and apoptosis. METHODS: 168 selected patients with cerebral glioblastomas were studied retrospectively. Tumour specimens were examined immunohistochemically with antibodies to proliferating cell nuclear antigen (PCNA), p53, bcl-2, and epidermal growth factor receptor (EGFR) to detect the intracellular receptor domain. Apoptosis was detected by in situ end labelling. Multivariate analysis was performed using the Cox proportional hazard model. RESULTS: On univariate analysis the PCNA labelling index, immunoexpression of EGFR, and the apoptotic index were significantly related to glioblastoma outcome. Survival time was reduced as PCNA labelling index increased and apoptotic index decreased (p = 0.0073 and p = 0.00031, respectively). Survival time in patients with EGFR positive tumours was found to be reduced (p = 0.00024). Multivariate analysis showed independent prognostic value for the EGFR positivity and apoptotic index only (p = 0.0053 and p = 0.0039, respectively). There was no association between clinical outcome of glioblastoma and p53 or bcl-2 immunostaining. CONCLUSIONS: EGFR immunoreactivity and apoptotic index were found to be useful for assessing prognosis of individual glioblastomas but it seems unlikely that p53 and bcl-2 immunohistochemistry will be of value in determining survival in such patients.
Full text
PDF






Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Ang L. C., Plewes M., Tan L., Begley H., Agranovich A., Shul D. Proliferating cell nuclear antigen expression in the survival of astrocytoma patients. Can J Neurol Sci. 1994 Nov;21(4):306–310. doi: 10.1017/s0317167100040877. [DOI] [PubMed] [Google Scholar]
- Apolinario R. M., van der Valk P., de Jong J. S., Deville W., van Ark-Otte J., Dingemans A. M., van Mourik J. C., Postmus P. E., Pinedo H. M., Giaccone G. Prognostic value of the expression of p53, bcl-2, and bax oncoproteins, and neovascularization in patients with radically resected non-small-cell lung cancer. J Clin Oncol. 1997 Jun;15(6):2456–2466. doi: 10.1200/JCO.1997.15.6.2456. [DOI] [PubMed] [Google Scholar]
- Baxendine-Jones J., Campbell I., Ellison D. p53 status has no prognostic significance in glioblastomas treated with radiotherapy. Clin Neuropathol. 1997 Nov-Dec;16(6):332–336. [PubMed] [Google Scholar]
- Berardo M. D., Elledge R. M., de Moor C., Clark G. M., Osborne C. K., Allred D. C. bcl-2 and apoptosis in lymph node positive breast carcinoma. Cancer. 1998 Apr 1;82(7):1296–1302. [PubMed] [Google Scholar]
- 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]
- Carroll R. S., Zhang J., Chauncey B. W., Chantziara K., Frosch M. P., Black P. M. Apoptosis in astrocytic neoplasms. Acta Neurochir (Wien) 1997;139(9):845–850. doi: 10.1007/BF01411402. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Cunningham J. M., Kimmel D. W., Scheithauer B. W., O'Fallon J. R., Novotny P. J., Jenkins R. B. Analysis of proliferation markers and p53 expression in gliomas of astrocytic origin: relationships and prognostic value. J Neurosurg. 1997 Jan;86(1):121–130. doi: 10.3171/jns.1997.86.1.0121. [DOI] [PubMed] [Google Scholar]
- Ehrmann J., Jr, Kolár Z., Vojtesek B., Kala M., Komenda S., Oulton A. Prognostic factors in astrocytomas: relationship of p53, MDM-2, BCL-2 and PCNA immunohistochemical expression to tumor grade and overall patient survival. Neoplasma. 1997;44(5):299–304. [PubMed] [Google Scholar]
- Ekstrand A. J., Longo N., Hamid M. L., Olson J. J., Liu L., Collins V. P., James C. D. Functional characterization of an EGF receptor with a truncated extracellular domain expressed in glioblastomas with EGFR gene amplification. Oncogene. 1994 Aug;9(8):2313–2320. [PubMed] [Google Scholar]
- Ellison D. W., Steart P. V., Gatter K. C., Weller R. O. Apoptosis in cerebral astrocytic tumours and its relationship to expression of the bcl-2 and p53 proteins. Neuropathol Appl Neurobiol. 1995 Aug;21(4):352–361. doi: 10.1111/j.1365-2990.1995.tb01070.x. [DOI] [PubMed] [Google Scholar]
- Ganju V., Jenkins R. B., O'Fallon J. R., Scheithauer B. W., Ransom D. T., Katzmann J. A., Kimmel D. W. Prognostic factors in gliomas. A multivariate analysis of clinical, pathologic, flow cytometric, cytogenetic, and molecular markers. Cancer. 1994 Aug 1;74(3):920–927. doi: 10.1002/1097-0142(19940801)74:3<920::aid-cncr2820740320>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
- Haas-Kogan D. A., Yount G., Haas M., Levi D., Kogan S. S., Hu L., Vidair C., Deen D. F., Dewey W. C., Israel M. A. p53-dependent G1 arrest and p53-independent apoptosis influence the radiobiologic response of glioblastoma. Int J Radiat Oncol Biol Phys. 1996 Aug 1;36(1):95–103. doi: 10.1016/s0360-3016(96)00244-1. [DOI] [PubMed] [Google Scholar]
- 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]
- Kaklamanis L., Savage A., Whitehouse R., Doussis-Anagnostopoulou I., Biddolph S., Tsiotos P., Mortensen N., Gatter K. C., Harris A. L. Bcl-2 protein expression: association with p53 and prognosis in colorectal cancer. Br J Cancer. 1998 Jun;77(11):1864–1869. doi: 10.1038/bjc.1998.310. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kaufmann A. M., Lichtner R. B., Schirrmacher V., Khazaie K. Induction of apoptosis by EGF receptor in rat mammary adenocarcinoma cells coincides with enhanced spontaneous tumour metastasis. Oncogene. 1996 Dec 5;13(11):2349–2358. [PubMed] [Google Scholar]
- Kokunai T., Sawa H., Tamaki N. Localization of apoptotic cells in situ of brain tumors. Noshuyo Byori. 1995 Mar;12(1):15–21. [PubMed] [Google Scholar]
- Komaki R., Fujii T., Perkins P., Ro J. Y., Allen P. K., Mason K. A., Mountain C. F., Milas L. Apoptosis and mitosis as prognostic factors in pathologically staged N1 nonsmall cell lung cancer. Int J Radiat Oncol Biol Phys. 1996 Oct 1;36(3):601–605. doi: 10.1016/s0360-3016(96)00351-3. [DOI] [PubMed] [Google Scholar]
- Kordek R., Hironishi M., Liberski P. P., Yanagihara R., Gajdusek D. C. Apoptosis in glial tumors as determined by in situ nonradioactive labeling of DNA breaks. Acta Neuropathol. 1996;91(1):112–116. doi: 10.1007/s004010050400. [DOI] [PubMed] [Google Scholar]
- Korkolopoulou P., Christodoulou P., Kouzelis K., Hadjiyannakis M., Priftis A., Stamoulis G., Seretis A., Thomas-Tsagli E. MDM2 and p53 expression in gliomas: a multivariate survival analysis including proliferation markers and epidermal growth factor receptor. Br J Cancer. 1997;75(9):1269–1278. doi: 10.1038/bjc.1997.216. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Krajewski S., Krajewska M., Ehrmann J., Sikorska M., Lach B., Chatten J., Reed J. C. Immunohistochemical analysis of Bcl-2, Bcl-X, Mcl-1, and Bax in tumors of central and peripheral nervous system origin. Am J Pathol. 1997 Mar;150(3):805–814. [PMC free article] [PubMed] [Google Scholar]
- Krishna M., Smith T. W., Recht L. D. Expression of bcl-2 in reactive and neoplastic astrocytes: lack of correlation with presence or degree of malignancy. J Neurosurg. 1995 Dec;83(6):1017–1022. doi: 10.3171/jns.1995.83.6.1017. [DOI] [PubMed] [Google Scholar]
- Matsuda H., Strebel F. R., Kaneko T., Stephens L. C., Danhauser L. L., Jenkins G. N., Toyota N., Bull J. M. Apoptosis and necrosis occurring during different stages of primary and metastatic tumor growth of a rat mammary adenocarcinoma. Anticancer Res. 1996 May-Jun;16(3A):1117–1121. [PubMed] [Google Scholar]
- Migheli A., Cavalla P., Marino S., Schiffer D. A study of apoptosis in normal and pathologic nervous tissue after in situ end-labeling of DNA strand breaks. J Neuropathol Exp Neurol. 1994 Nov;53(6):606–616. doi: 10.1097/00005072-199411000-00008. [DOI] [PubMed] [Google Scholar]
- Montine T. J., Vandersteenhoven J. J., Aguzzi A., Boyko O. B., Dodge R. K., Kerns B. J., Burger P. C. Prognostic significance of Ki-67 proliferation index in supratentorial fibrillary astrocytic neoplasms. Neurosurgery. 1994 Apr;34(4):674–679. doi: 10.1227/00006123-199404000-00016. [DOI] [PubMed] [Google Scholar]
- Nagane M., Coufal F., Lin H., Bögler O., Cavenee W. K., Huang H. J. A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. Cancer Res. 1996 Nov 1;56(21):5079–5086. [PubMed] [Google Scholar]
- Nakasu S., Nakajima M., Nakazawa T., Nakasu Y., Handa J. Alteration of bcl-2 and bax expression in embolized meningiomas. Brain Tumor Pathol. 1998;15(1):13–17. doi: 10.1007/BF02482095. [DOI] [PubMed] [Google Scholar]
- Nakasu S., Nakasu Y., Nioka H., Nakajima M., Handa J. bcl-2 protein expression in tumors of the central nervous system. Acta Neuropathol. 1994;88(6):520–526. doi: 10.1007/BF00296488. [DOI] [PubMed] [Google Scholar]
- Nakatsu S., Kondo S., Kondo Y., Yin D., Peterson J. W., Kaakaji R., Morimura T., Kikuchi H., Takeuchi J., Barnett G. H. Induction of apoptosis in multi-drug resistant (MDR) human glioblastoma cells by SN-38, a metabolite of the camptothecin derivative CPT-11. Cancer Chemother Pharmacol. 1997;39(5):417–423. doi: 10.1007/s002800050592. [DOI] [PubMed] [Google Scholar]
- Patsouris E., Davaki P., Kapranos N., Davaris P., Papageorgiou K. A study of apoptosis in brain tumors by in situ end-labeling method. Clin Neuropathol. 1996 Nov-Dec;15(6):337–341. [PubMed] [Google Scholar]
- Rainov N. G., Dobberstein K. U., Bahn H., Holzhausen H. J., Lautenschläger C., Heidecke V., Burkert W. Prognostic factors in malignant glioma: influence of the overexpression of oncogene and tumor-suppressor gene products on survival. J Neurooncol. 1997 Oct;35(1):13–28. doi: 10.1023/a:1005841520514. [DOI] [PubMed] [Google Scholar]
- Salcman M., Scholtz H., Kaplan R. S., Kulik S. Long-term survival in patients with malignant astrocytoma. Neurosurgery. 1994 Feb;34(2):213–220. doi: 10.1227/00006123-199402000-00002. [DOI] [PubMed] [Google Scholar]
- Sallinen P. K., Haapasalo H. K., Visakorpi T., Helén P. T., Rantala I. S., Isola J. J., Helin H. J. Prognostication of astrocytoma patient survival by Ki-67 (MIB-1), PCNA, and S-phase fraction using archival paraffin-embedded samples. J Pathol. 1994 Dec;174(4):275–282. doi: 10.1002/path.1711740407. [DOI] [PubMed] [Google Scholar]
- Savitz S. I., Rosenbaum D. M. Apoptosis in neurological disease. Neurosurgery. 1998 Mar;42(3):555–574. doi: 10.1097/00006123-199803000-00026. [DOI] [PubMed] [Google Scholar]
- Schiffer D., Cavalla P., Migheli A., Giordana M. T., Chiadò-Piat L. Bcl-2 distribution in neuroepithelial tumors: an immunohistochemical study. J Neurooncol. 1996 Feb;27(2):101–109. doi: 10.1007/BF00177472. [DOI] [PubMed] [Google Scholar]
- Schober R., Bilzer T., Waha A., Reifenberger G., Wechsler W., von Deimling A., Wiestler O. D., Westphal M., Kemshead J. T., Vega F. The epidermal growth factor receptor in glioblastoma: genomic amplification, protein expression, and patient survival data in a therapeutic trial. Clin Neuropathol. 1995 May-Jun;14(3):169–174. [PubMed] [Google Scholar]
- Soini Y., Niemelä A., Kamel D., Herva R., Bloigu R., Päkkö P., Vähäkangas K. p53 immunohistochemical positivity as a prognostic marker in intracranial tumours. APMIS. 1994 Oct;102(10):786–792. doi: 10.1111/j.1699-0463.1994.tb05235.x. [DOI] [PubMed] [Google Scholar]
- Stemmer-Rachamimov A. O., Louis D. N. Histopathologic and immunohistochemical prognostic factors in malignant gliomas. Curr Opin Oncol. 1997 May;9(3):230–234. doi: 10.1097/00001622-199709030-00003. [DOI] [PubMed] [Google Scholar]
- Tachibana O., Lampe J., Kleihues P., Ohgaki H. Preferential expression of Fas/APO1 (CD95) and apoptotic cell death in perinecrotic cells of glioblastoma multiforme. Acta Neuropathol. 1996 Nov;92(5):431–434. doi: 10.1007/s004010050542. [DOI] [PubMed] [Google Scholar]
- Theunissen P. H., Blaauw G. Proliferating cell nuclear antigen immunostaining and survival in cerebral astrocytoma. Histopathology. 1993 Jul;23(1):75–79. doi: 10.1111/j.1365-2559.1993.tb01186.x. [DOI] [PubMed] [Google Scholar]
- Waha A., Baumann A., Wolf H. K., Fimmers R., Neumann J., Kindermann D., Astrahantseff K., Blümcke I., von Deimling A., Schlegel U. Lack of prognostic relevance of alterations in the epidermal growth factor receptor-transforming growth factor-alpha pathway in human astrocytic gliomas. J Neurosurg. 1996 Oct;85(4):634–641. doi: 10.3171/jns.1996.85.4.0634. [DOI] [PubMed] [Google Scholar]
- Weiner H. L. The role of growth factor receptors in central nervous system development and neoplasia. Neurosurgery. 1995 Aug;37(2):179–194. doi: 10.1227/00006123-199508000-00001. [DOI] [PubMed] [Google Scholar]
- Yamasaki F., Tokunaga O., Sugimori H. Apoptotic index in ovarian carcinoma: correlation with clinicopathologic factors and prognosis. Gynecol Oncol. 1997 Sep;66(3):439–448. doi: 10.1006/gyno.1997.4783. [DOI] [PubMed] [Google Scholar]
- Zhang G. J., Kimijima I., Watanabe T., Kanno M., Sagara H., Furukawa Y., Tsuchiya A., Abe R. [Correlation between apoptotic index, bcl-2 protein expression and progression and prognosis in breast carcinoma]. Gan To Kagaku Ryoho. 1998 Apr;25 (Suppl 3):415–421. [PubMed] [Google Scholar]
- Zhu A., Shaeffer J., Leslie S., Kolm P., El-Mahdi A. M. Epidermal growth factor receptor: an independent predictor of survival in astrocytic tumors given definitive irradiation. Int J Radiat Oncol Biol Phys. 1996 Mar 1;34(4):809–815. doi: 10.1016/0360-3016(95)02184-1. [DOI] [PubMed] [Google Scholar]
- 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]