DNA topoisomerase II-α and cyclin A immunoexpression in meningiomas and its prognostic significance. Arch Pathol Lab Med
Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia. Archives of pathology & laboratory medicine
(Impact Factor: 2.84).
09/2002; 126(9):1079-86. DOI: 10.1043/0003-9985(2002)126<1079:DTIACA>2.0.CO;2
Routine pathologic examination cannot distinctively predict the clinical course of meningiomas because even histologically benign tumors may recur after gross total resection. Therefore, numerous efforts have been made to evaluate the meningioma growth fraction and its prognostic value. However, a universally applicable proliferative marker for meningioma outcome is not yet a reality.
To investigate the prognostic utility of 3 proliferative markers, namely, Ki-67, DNA topoisomerase II-alpha (topoII), and cyclin A in a representative series of intracranial meningiomas.
Two hundred sixty-three adult patients with intracranial meningiomas (208 benign, 42 atypical, and 13 anaplastic) were studied retrospectively. Tumor specimens were immunohistochemically examined with antibodies to Ki-67 (MM-1), topoII, and cyclin A. A computerized color image analyzer was used to count immunostained nuclei.
The topoII and cyclin A scores exhibited a close correlation with Ki-67 immunostaining. Significant differences between the indices for all 3 markers were noted among the 3 grades of meningiomas. The scores for all 3 markers were significantly different between recurrent and nonrecurrent meningiomas, including benign tumors that were treated with gross total resection. Recurrence-free survival was significantly reduced for cases with a Ki-67 labeling index (LI) of 4.4% or greater, a topoII LI of 3.2% or greater, and a cyclin A LI of 3.1% or greater. Multivariate analysis revealed that the risk of recurrence for the entire meningioma cohort was significantly associated with tumor grade (hazard ratio = 2.7; P =.004), topoII LI of 3.2% or greater (hazard ratio = 5.5; P <.001), and a cyclin A LI of 3.1% or greater (hazard ratio = 2.4; P =.01).
There is a close correlation in the expression of these 3 proliferative markers in meningiomas, and all of the markers showed a significant association with tumor grade, recurrence rate, and recurrence-free survival. Consequently, in addition to Ki-67, immunoexpression of topoII and cyclin A is available for predicting meningioma recurrence. Moreover, the topoII and cyclin A staining scores were found to be more sensitive predictors for meningioma progression than Ki-67 and, therefore, either of these 2 markers may prove to be clinically informative and useful.
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ABSTRACT: Background: Complete surgical resection is the first-line therapy for meningiomas. However, tumor location and biological aggressiveness can make surgical cure impossible. Treatment options for these refractory meningiomas include further surgery, conventional external beam irradiation, stereotactic radiosurgery, and systemic therapies. In this paper, we discuss new and emerging systemic therapies when these "local" treatment options are not successful. Methods: We reviewed predictors of refractory meningiomas and novel systemic therapies in the treatment of refractory meningiomas. Results: Tumor location, atypical or malignant histologic subtypes, and staining for the Ki-67 protein (MIB-1 antibody) with a high labeling index are the best predictors of tumor recurrence. Novel systemic treatment options include angiogenesis inhibition, meningioma cell growth inhibition, blockade of growth factor effects, inhibition of intracellular secondary pathways, and gene therapies. Conclusions: MIB-1 labeling index staining is a good predictor for refractory meningiomas. Currently, the best-studied systemic treatment for patients with refractory meningiomas is hydroxyurea. Blockade of the growth hormone receptor by pegvisomant is promising because in vivo and in vitro studies have shown good results and the drug has a known side effect profile.
Available from: Andrey Korshunov
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ABSTRACT: Routine pathological examination cannot distinctively predict the clinical course of meningiomas because even histologically benign tumors may recur after gross total resection. Numerous efforts have been made for the evaluation of different immunohistochemical assays in meningioma prognosis. We investigated the prognostic significance of p16INK4a, p14ARF, p18INK4c, p21CIP1, p27KIP1 and p73 expression by immunohistochemical analysis of 271 meningiomas. All tumors were additionally stained for the proliferation markers Ki-67 and DNA topoisomerase II alpha (TopoIIalpha). Significant differences between the number of p16INK4a-, p18INK4c- and p21CIP1-positive cases were noted among the 3 grades of meningiomas. p16INK4a- and p21CIP-positive tumors were found to prevail among benign meningiomas, whereas p18INK4c immunostaining was closely associated to anaplastic meningiomas. The number of p16INK4a- and p21CIP-positive cases was significantly lower in the cohort of recurrent meningiomas. In contrast, p18INK4c-positive cases were clustered among recurrent meningiomas regardless of tumor grade. Immunoreactivity of p14ARF, p27KIP1 and p73 did not show any differences between meningiomas of various histology and clinical outcomes. Multivariate analysis revealed that only tumor grade and TopoIIalpha index are independent criteria for predicting meningioma recurrence. Thus, the immunohistochemical assessment of p16INK4a, p14ARF, p18INK4c, p21CIP1, p27KIP1 and p73 expression in meningiomas does not appear to provide prognostically useful information. Further studies are needed to identify more reliable prognostic markers and to address in more detail the role of cell cycle aberrations in these tumors.
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ABSTRACT: Aggressive surgical resection continues to be the mainstay of current meningioma management, with advances in microsurgical techniques facilitating the safety and effectiveness of this approach. Complete surgical removal of meningiomas provides the optimal opportunity for long-term remission. Advances in skull base surgical approaches have greatly improved patient outcomes for tumors in precarious locations once thought to be inoperable. For tumors that recur or are unresectable, stereotactic radiosurgery and conformal fractionated radiation therapy can provide safe, palliative treatment with favorable long-term outcomes. Additionally, advances in the understanding of molecular biologic and biochemical mechanisms underlying meningioma growth offer unique opportunities for potential treatment adjuncts for atypical and malignant tumors. This review discusses current understanding of meningioma pathology and accepted meningioma treatment paradigms. The technologic advances and experimental strategies for the future treatment of complex intracranial meningiomas are also discussed.
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