Techniques to assess the proliferative potential of brain tumors

SummaryAssessment of brain tumor proliferative potential provides important prognostic information that supplements standard histopathologic grading. Many laboratories rely on mitotic figures to quantify the proliferative potential of brain tumors, but this conventional cellular proliferative index is subject to inter-observer variability and not consistently predictive for low-and high-grade tumors. Recent advancements in technology have made it possible to use proliferative indices as a standard supplement in pathology laboratories. Non-invasive tumor tissue measurements of cell proliferation can be performed using– bromodeoxyuridine labeling index (BrdU LI), flow cytometry (FCM), MIB-1 antibody to the Ki-67 antigen (MIB-1), proliferating cell nuclear antigen (PCNA), and argyrophilic nucleolar organizing regions (AgNOR). Each of these assays has been described in the literature with respect to its ability to predict tumor grade or outcome. At the present time MIB-1 and AgNOR are the simplest and most reliable of these techniques. In addition, advances in our understanding of the genetic alterations associated with proliferation promise to provide more specific markers of proliferative potential. Beyond the pathology laboratory, radiographic studies such as positron emission tomography (PET), single photon emission computed tomography (SPECT), and most recently magnetic resonance spectroscopy (MRS) have been used as follow-up measures, assessing response to treatment and tumor recurrence, rather than as predictors of response to treatment. These radiographic tools, however, have the potential to provide an assessment of tumor proliferation without the need for invasive measures. In this article, we present a review of the current techniques utilized to understand the proliferative potential of brain tumors.

[1]  Y. Iwadate,et al.  Glucose and methionine uptake and proliferative activity in meningiomas. , 1999, Neurological research.

[2]  S. Nakasu,et al.  Meningioma: proliferating potential and clinicoradiological features. , 1995, Neurosurgery.

[3]  K. Plate,et al.  Proliferative potential of human brain tumours as assessed by nucleolar organizer regions (AgNORs) and Ki67-immunoreactivity , 2005, Acta Neurochirurgica.

[4]  O. Olopade,et al.  Detection of CDKN2 deletions in tumor cell lines and primary glioma by interphase fluorescence in situ hybridization. , 1995, Cancer research.

[5]  T. Hoshino A commentary on the biology and growth kinetics of low-grade and high-grade gliomas. , 1984, Journal of neurosurgery.

[6]  T. Nishizaki,et al.  Silver colloid staining technique for analysis of glioma malignancy. , 1990, Journal of neurosurgery.

[7]  D. Louis,et al.  MTS1/CDKN2 gene mutations are rare in primary human astrocytomas with allelic loss of chromosome 9p. , 1994, Human molecular genetics.

[8]  R. Wood,et al.  Proliferating cell nuclear antigen is required for DNA excision repair , 1992, Cell.

[9]  R A Brooks,et al.  Glucose utilization of cerebral gliomas measured by [18F] fluorodeoxyglucose and positron emission tomography , 1982, Neurology.

[10]  A. Boon,et al.  Value of AgNOR method in predicting recurrence of meningioma. , 1989, Journal of clinical pathology.

[11]  R. Jenkins,et al.  Genetic alterations in adult diffuse glioma: occurrence, significance, and prognostic implications. , 2000, Frontiers in bioscience : a journal and virtual library.

[12]  M. Koike,et al.  Correlation between bromodeoxyuridine‐labeling indices and patient prognosis in cerebral astrocytic tumors of adults , 1991, Cancer.

[13]  D. F. Brown,et al.  Correlation of bcl-2, p53, and MIB-1 expression with ependymoma grade and subtype. , 1998, Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc.

[14]  P. Caillet-Fauquet,et al.  Viruses and the cell cycle. , 1997, Progress in cell cycle research.

[15]  S. Kosuda,et al.  Prediction of survival in patients with suspected recurrent cerebral tumors by quantitative thallium-201 single photon emission computed tomography. , 1994, International journal of radiation oncology, biology, physics.

[16]  D. Ancri,et al.  Diagnosis of cerebral metastases by thallium 201. , 1980, The British journal of radiology.

[17]  W P Dillon,et al.  Preoperative proton MR spectroscopic imaging of brain tumors: correlation with histopathologic analysis of resection specimens. , 2001, AJNR. American journal of neuroradiology.

[18]  S. Coons,et al.  Prognostic significance of flow cytometry deoxyribonucleic acid analysis of human astrocytomas. , 1994, Neurosurgery.

[19]  H Stein,et al.  Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. , 1984, Journal of immunology.

[20]  K. Judy,et al.  The application of 5-bromodeoxyuridine in the management of CNS tumors , 2005, Journal of Neuro-Oncology.

[21]  J. Lafuente,et al.  Biologic parameters that correlate with the prognosis of human gliomas , 2000, Neuropathology : official journal of the Japanese Society of Neuropathology.

[22]  H. Budka,et al.  Immunostaining for proliferating cell nuclear antigen: its role in determination of proliferation in routinely processed human brain tumor specimens , 2004, Acta Neuropathologica.

[23]  P. Smith,et al.  Correlation between DNA flow cytometric and nucleolar organizer region data in non‐Hodgkin's lymphomas , 1988, The Journal of pathology.

[24]  R. Perry,et al.  Prognostic implications of p53 protein, epidermal growth factor receptor, and Ki-67 labelling in brain tumours. , 1992, British Journal of Cancer.

[25]  D. Louis,et al.  CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. , 1996, Cancer research.

[26]  K. Sasaki,et al.  Clinical evaluation of DNA index in human brain tumors , 1993, Journal of Neuro-Oncology.

[27]  J. Kuratsu,et al.  Prognostic significance of the MIB-1 labeling index for patient with craniopharyngioma. , 1999, International journal of molecular medicine.

[28]  P. Kleihues,et al.  The Use of the Monoclonal Antibody Ki-67 in the Identification of Proliferating Cells: Application to Surgical Neuropathology , 1986, The American journal of surgical pathology.

[29]  K. Kunishio,et al.  Malignant astrocytomas with homozygous CDKN2/p16 gene deletions have higher Ki-67 proliferation indices. , 1996, Journal of neuropathology and experimental neurology.

[30]  J. Koudstaal,et al.  The proliferative potential of the pilocytic astrocytoma: The relation between MIB-1 labeling and clinical and neuro-radiological follow-up , 1998, Journal of Neuro-Oncology.

[31]  Charles B. Wilson,et al.  PROGNOSTIC SIGNIFICANCE OF PROLIFERATIVE POTENTIAL OF INTRACRANIAL GLIOMAS MEASURED BY BROMODEOXYURIDINE LABELING: 233 , 1990 .

[32]  M. Prados,et al.  Prognostic implications of the bromodeoxyuridine labeling index of human gliomas. , 1989, Journal of neurosurgery.

[33]  G. Chiro Positron emission tomography using [18F] fluorodeoxyglucose in brain tumors. A powerful diagnostic and prognostic tool. , 1987 .

[34]  A. Chiò,et al.  Proliferating Cell Nuclear Antigen (PCNA) in Low-Grade Astrocytomas: Its Prognostic Significance , 1994, Tumori.

[35]  D. Ross,et al.  A comparison of the predictive power for survival in gliomas provided by MIB-1, bromodeoxyuridine and proliferating cell nuclear antigen with histopathologic and clinical parameters. , 1997, Journal of neuropathology and experimental neurology.

[36]  M. Strawderman,et al.  MIB-1 Proliferation Index Predicts Survival among Patients with Grade II Astrocytoma , 1998, Journal of neuropathology and experimental neurology.

[37]  J. Celis,et al.  Cell cycle-dependent variations in the distribution of the nuclear protein cyclin proliferating cell nuclear antigen in cultured cells: subdivision of S phase. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[38]  G. Landberg,et al.  Antibodies to proliferating cell nuclear antigen as S-phase probes in flow cytometric cell cycle analysis. , 1991, Cancer research.

[39]  R. Davis,et al.  Proliferative potential of human meningiomas of the brain: A cell kinetics study with bromodeoxyuridine , 1986, Cancer.

[40]  C. James,et al.  PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. , 2001, Journal of the National Cancer Institute.

[41]  V. Armbrustmacher,et al.  Grading of oligodendrogliomas , 1983, Cancer.

[42]  C. Degueldre,et al.  Preoperative evaluation of 54 gliomas by PET with fluorine-18-fluorodeoxyglucose and/or carbon-11-methionine. , 1998, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[43]  S. Tsunoda,et al.  Retinoblastoma protein expression and MIB‐1 correlate with survival of patients with malignant astrocytoma , 1997, Cancer.

[44]  K. Hess,et al.  Prognostic significance of bromodeoxyuridine labeling in primary and recurrent glioblastoma multiforme. , 1994, Neurosurgery.

[45]  J. Herman,et al.  5′ CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers , 1995, Nature Medicine.

[46]  I. Taylor,et al.  Clinical and biological significance of aneuploidy in human tumours. , 1984, Journal of clinical pathology.

[47]  T. Shiraishi,et al.  Nucleolar organizer regions in various human brain tumors. , 1991, Journal of neurosurgery.

[48]  J. Sarasa,et al.  Study of the DNA content by flow cytometry and proliferation in 281 brain tumors. , 1997, Oncology.

[49]  G. di Chiro,et al.  Glucose utilization by intracranial meningiomas as an index of tumor aggressivity and probability of recurrence: a PET study. , 1987, Radiology.

[50]  R. Dodd Hepatitis C virus, antibodies, and infectivity. Paradox, pragmatism, and policy. , 1992, American journal of clinical pathology.

[51]  Takuji Tanaka,et al.  Nucleolar Organizer Regions in Hepatocarcinogenesis Induced by N‐2‐Fluorenylacetamide in Rats: Comparison with Bromodeoxyuridine Immunohistochemistry , 1989, Japanese journal of cancer research : Gann.

[52]  J Hennig,et al.  Human brain tumors: assessment with in vivo proton MR spectroscopy. , 1993, Radiology.

[53]  R. Selker,et al.  Correlation of thallium-201 single photon emission computed tomography and survival after treatment failure in patients with glioblastoma multiforme. , 1994, Neurosurgery.

[54]  H. Korf,et al.  Prognostic implication of histopathological, immunohistochemical and clinical features of oligodendrogliomas: a study of 89 cases , 1998, Acta Neuropathologica.

[55]  A. Stansfeld,et al.  A comparison of nucleolar organizer region staining and Ki‐67 immunostaining in non‐Hodgkin's lymphoma , 1988, Histopathology.

[56]  J. Isola,et al.  Comparison of three quantitation methods for PCNA immunostaining: Applicability and relation to survival in 83 astrocytic neoplasms , 1993, The Journal of pathology.

[57]  R. Davis,et al.  Prognostic implications of the proliferative potential of low-grade astrocytomas. , 1988, Journal of neurosurgery.

[58]  D. A. Black,et al.  Controlled silver-staining of nucleolus organizer regions with a protective colloidal developer: a 1-step method , 1980, Experientia.

[59]  J. Olson,et al.  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. , 1995, Cancer research.

[60]  R. Martuza,et al.  TP53 Gene Mutations and 17p Deletions in Human Astrocytomas , 1991, Genes, chromosomes & cancer.

[61]  Takuji Tanaka,et al.  Rapid detection of proliferating potential in human brain tumors by nucleolar organizer region staining on squash preparations , 2005, Journal of Cancer Research and Clinical Oncology.

[62]  D. Louis,et al.  The retinoblastoma gene is involved in malignant progression of astrocytomas , 1994, Annals of neurology.

[63]  R. Bravo,et al.  Cyclin/PCNA is the auxiliary protein of DNA polymerase-δ , 1987, Nature.

[64]  R. Kiss,et al.  Relationship between proliferative activity and ploidy level in a series of 530 human brain tumors, including astrocytomas, meningiomas, schwannomas, and metastases. , 1993, Human pathology.

[65]  P. Black,et al.  Dual-isotope single-photon emission computerized tomography scanning in patients with glioblastoma multiforme: association with patient survival and histopathological characteristics of tumor after high-dose radiotherapy. , 1998, Journal of neurosurgery.

[66]  A Riccardi,et al.  Cell kinetics in human malignancies studied with in vivo administration of bromodeoxyuridine and flow cytometry. , 1988, Cancer research.

[67]  M. Berger,et al.  Detection of proliferating cell nuclear antigen in gliomas and adjacent resection margins. , 1993, Neurosurgery.

[68]  B. Scheithauer,et al.  Localization of common deletion regions on 1p and 19q in human gliomas and their association with histological subtype , 1999, Oncogene.

[69]  R. Zarbo,et al.  Clinical application of morphologic and immunocytochemical assessments of cell proliferation. , 1992, American journal of clinical pathology.

[70]  Charles B. Wilson,et al.  Proliferative potential and prognostic evaluation of low-grade astrocytomas , 2005, Journal of Neuro-Oncology.

[71]  G. Reifenberger,et al.  CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. , 1994, Cancer research.

[72]  L. Recht,et al.  Ki-67 (clone MIB-1) proliferation index in recurrent glial neoplasms: no prognostic significance. , 1998, Surgical neurology.

[73]  V P Collins,et al.  Human glioblastomas with no alterations of the CDKN2A (p16INK4A, MTS1) and CDK4 genes have frequent mutations of the retinoblastoma gene. , 1996, Oncogene.

[74]  B. Scheithauer,et al.  Prognostic factors in gliomas. A multivariate analysis of clinical, pathologic, flow cytometric, cytogenetic, and molecular markers , 1994, Cancer.

[75]  S. Coons,et al.  Prognostic significance of flow cytometry deoxyribonucleic acid analysis of human oligodendrogliomas. , 1994, Neurosurgery.

[76]  J. Frahm,et al.  Localized proton NMR spectroscopy of brain tumors using short-echo time STEAM sequences. , 1991, Journal of computer assisted tomography.

[77]  D. Louis,et al.  Proliferating cell nuclear antigen and Ki-67 immunohistochemistry in brain tumors: A comparative study , 2004, Acta Neuropathologica.

[78]  M. Prados,et al.  Prognostic significance of the proliferative potential of intracranial gliomas measured by bromodeoxyuridine labeling , 1993, International journal of cancer.

[79]  T. Montine,et al.  Prognostic significance of Ki-67 proliferation index in supratentorial fibrillary astrocytic neoplasms. , 1994, Neurosurgery.

[80]  S. Goldman,et al.  Prognostic value positron emission tomography with [18F]fluoro-2-deoxy-D-glucose in the low-grade glioma. , 1996, Neurosurgery.

[81]  K. Endo,et al.  Clinical evaluation of thallium-201 SPECT in supratentorial gliomas: relationship to histologic grade, prognosis and proliferative activities. , 1993, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[82]  M. Reivich,et al.  THE [14C]DEOXYGLUCOSE METHOD FOR THE MEASUREMENT OF LOCAL CEREBRAL GLUCOSE UTILIZATION: THEORY, PROCEDURE, AND NORMAL VALUES IN THE CONSCIOUS AND ANESTHETIZED ALBINO RAT 1 , 1977, Journal of neurochemistry.

[83]  J. Mazziotta,et al.  Thallium-201 SPECT and positron emission tomography equal predictors of glioma grade and recurrence. , 1994, Neurological research.

[84]  M. Prados,et al.  Meningiomas: clinical implications of a high proliferative potential determined by bromodeoxyuridine labeling. , 1992, Neurosurgery.

[85]  Kevin Ryan,et al.  The alternative product from the human CDKN2A locus, p14ARF, participates in a regulatory feedback loop with p53 and MDM2 , 1998, The EMBO journal.

[86]  S. Coons,et al.  The prognostic significance of Ki-67 labeling indices for oligodendrogliomas. , 1997, Neurosurgery.

[87]  J. Bederson,et al.  Bromodeoxyuridine labeling study of intracranial meningiomas: proliferative potential and recurrence , 2004, Acta Neuropathologica.

[88]  C. James,et al.  Amplification of the Platelet‐Derived Growth Factor Receptor‐A (PDGFRA) Gene Occurs in Oligodendrogliomas with Grade IV Anaplastic Features , 2000, Journal of neuropathology and experimental neurology.

[89]  A. Ahyai Flow cytometric analysis of cellular DNA content in human astrocytomas and oligodendrogliomas , 2005, Neurosurgical Review.

[90]  G. Butti,et al.  Prognostic significance of nuclear DNA content in human neuroepithelial tumors , 1991, International journal of cancer.

[91]  K. Christov,et al.  Histological grading, DNA content, cell proliferation and survival of patients with astroglial tumors. , 1988, Cytometry.

[92]  M. Yamamoto,et al.  Growth rate of intracranial meningioma: tumor doubling time and proliferating cell nuclear antigen staining index. , 1995, Neurologia medico-chirurgica.

[93]  T. Visakorpi,et al.  Prognostication of astrocytoma patient survival by Ki‐67 (MIB‐1), PCNA, and S‐phase fraction using archival paraffin‐embedded samples , 1994, The Journal of pathology.

[94]  S. Maetani,et al.  Tl-201 SPECT Compared with Histopathologic Grade in the Prognostic Assessment of Cerebral Gliomas , 2001, Clinical nuclear medicine.

[95]  C. Wilson,et al.  Prediction of tumor doubling time in recurrent meningiomas. Cell kinetics studies with bromodeoxyuridine labeling. , 1986, Journal of neurosurgery.

[96]  Otto Warburn,et al.  THE METABOLISM OF TUMORS , 1931 .

[97]  H. Wakimoto,et al.  Prognostic significance of Ki‐67 labeling indices obtained using MIB‐1 monoclonal antibody in patients with supratentorial astrocytomas , 1996, Cancer.

[98]  J. Rüschoff,et al.  Cell proliferation assessment in oncology , 2004, Virchows Archiv.

[99]  R. Maciunas,et al.  Optimal cutoff levels of F-18 fluorodeoxyglucose uptake in the differentiation of low-grade from high-grade brain tumors with PET. , 1995, Radiology.

[100]  M. Hamou,et al.  Identification of proliferating cells in human gliomas using the monoclonal antibody Ki-67. , 1988, Neurosurgery.

[101]  M. Prados,et al.  Final report on the University of California‐San Francisco experience with bromodeoxyuridine labeling index as a prognostic factor for the survival of glioma patients , 1999, Cancer.

[102]  M. Prados,et al.  Bromodeoxyuridine labeling index in glioblastoma multiforme: relation to radiation response, age, and survival. , 1996, International journal of radiation oncology, biology, physics.

[103]  M. Weiner,et al.  What might be the impact on neurology of the analysis of brain metabolism by in vivo magnetic resonance spectroscopy? , 1994, Journal of Neurology.

[104]  B. Scheithauer,et al.  Analysis of proliferation markers and p53 expression in gliomas of astrocytic origin: relationships and prognostic value. , 1997, Journal of neurosurgery.

[105]  A. Órfão,et al.  Proportion of S-phase tumor cells measured by flow cytometry is an independent prognostic factor in meningioma tumors. , 1999, Cytometry.

[106]  A. Levine,et al.  Functions of the MDM2 oncoprotein , 1999, Cellular and Molecular Life Sciences CMLS.

[107]  A. Chiò,et al.  Proliferating cell nuclear antigen expression in brain tumors, and its prognostic role in ependymomas: an immunohistochemical study , 2004, Acta Neuropathologica.

[108]  S. Coons,et al.  Correlation of DNA content and histology in prognosis of astrocytomas. , 1988, American journal of clinical pathology.

[109]  G. Reifenberger,et al.  Amplification and overexpression of the MDM2 gene in a subset of human malignant gliomas without p53 mutations. , 1993, Cancer research.

[110]  J. Hodes,et al.  S‐phase fraction of human brain tumors in situ measured by uptake of bromodeoxyuridine , 1986, International journal of cancer.

[111]  C. L. White,et al.  Proliferative activity in craniopharyngiomas: clinicopathological correlations in adults and children. , 2000, Surgical neurology.

[112]  K. Kinzler,et al.  Deletion of p16 and p15 genes in brain tumors. , 1994, Cancer research.

[113]  A. Falini,et al.  Proton magnetic resonance spectroscopy and intracranial tumours: Clinical perspectives , 1996, Journal of Neurology.

[114]  G. Eide,et al.  Oligodendroglioma. Histologic Evaluation and Prognosis , 1986, Journal of neuropathology and experimental neurology.

[115]  S. DeArmond,et al.  Immunocytochemical demonstration of S-phase cells by anti-bromodeoxyuridine monoclonal antibody in human brain tumor tissues , 2004, Acta Neuropathologica.

[116]  R. Prayson,et al.  MIB-1 labeling indices in benign, aggressive, and malignant meningiomas: a study of 90 tumors. , 1998, Human pathology.

[117]  Mercer We Checking on the cell cycle. , 1998 .