Ki-67 Proliferative Activity in the Tumor Margins as a Robust Prognosis Factor in Glioblastoma Patients

Abstract

Introduction The infiltrative margin of glioblastomas (GBM) contains proliferative tumor cells difficult to estimate radiologically as they are included in the hyperintense signal of T2 sequences and they remain in the cavity margin after tumor resection. The amount of these cells could determine overall survival (OS) of these patients.

Material and Methods From October 2007 to January 2010, patients whose MRI were suggestive of newly diagnosed, resectable high-grade glioma were operated using fluorescence-guided surgery (FGS). Separate samples were selectively taken from nonfluorescent white matter areas just adjacent to the border of the pale fluorescence and staining was made for Ki-67. OS was analyzed with Kaplan–Meier and Cox regression. Multivariate analysis included the following prognosis variables: age, extent of resection (EOR), O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and performance status index.

Results Sample included 65 patients, comprising 37 men and 28 women, with a median Karnofsky Performance Score (KPS) of 80 (40–100) and mean age of 60 (34–78) years. Mean preoperative tumor volume was 35.8 mL. EOR was 100% in 52 patients (80%), with the lower EOR being 88%. For Ki-67, 39 patients had <5% and 26 had ≥5%. OS was 26.8 months (95% confidence interval [CI]: 18.9–28.2) for the Ki-67 low group versus 15.8 months (95% CI: 7.7–18.2) for the Ki-67 high group (p = 0.002).

Conclusion Proliferative activity in the normal-looking brain around the resection cavity measured with Ki-67 immunostaining is an important independent prognostic factor for GBM cases with complete resection of enhancing tumor. When complete resection is not reached, this factor is not relevant for prognosis.

Keywords

proliferative invasive tumor - Ki-67 prognosis factor - Glioma extent of resection

Publication History

Received: 05 August 2019

Accepted: 30 December 2019

Article published online:
01 December 2020

• References

• 1 Kelly PJ. Computed tomography and histologic limits in glial neoplasms: tumor types and selection for volumetric resection. Surg Neurol 1993; 39 (06) 458-465
• 2 Wilson CB. Glioblastoma: the past, the present, and the future. Clin Neurosurg 1992; 38: 32-48
• 3 Dalrymple SJ, Parisi JE, Roche PC, Ziesmer SC, Scheithauer BW, Kelly PJ. Changes in proliferating cell nuclear antigen expression in glioblastoma multiforme cells along a stereotactic biopsy trajectory. Neurosurgery 1994; 35 (06) 1036-1044 , discussion 1044–1045
• 4 Giese A, Bjerkvig R, Berens ME, Westphal M. Cost of migration: invasion of malignant gliomas and implications for treatment. J Clin Oncol 2003; 21 (08) 1624-1636
• 5 Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ. ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol 2006; 7 (05) 392-401
• 6 Díez Valle R, Hadjipanayis CG, Stummer W. Established and emerging uses of 5-ALA in the brain: an overview. J Neurooncol 2019; 141 (03) 487-494
• 7 Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ. Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: a prospective study in 52 consecutive patients. J Neurosurg 2000; 93 (06) 1003-1013
• 8 Idoate MA, Díez Valle R, Echeveste J, Tejada S. Pathological characterization of the glioblastoma border as shown during surgery using 5-aminolevulinic acid-induced fluorescence. Neuropathology 2011; 31 (06) 575-582
• 9 Díez Valle R, Tejada Solis S, Idoate Gastearena MA, García de Eulate R, Domínguez Echávarri P, Aristu Mendiroz J. Surgery guided by 5-aminolevulinic fluorescence in glioblastoma: volumetric analysis of extent of resection in single-center experience. J Neurooncol 2011; 102 (01) 105-113
• 10 Marko NF, Weil RJ, Schroeder JL, Lang FF, Suki D, Sawaya RE. Extent of resection of glioblastoma revisited: personalized survival modeling facilitates more accurate survival prediction and supports a maximum-safe-resection approach to surgery. J Clin Oncol 2014; 32 (08) 774-782
• 11 Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg 2011; 115 (01) 3-8
• 12 Lacroix M, Abi-Said D, Fourney DR. et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 2001; 95 (02) 190-198
• 13 Li YM, Suki D, Hess K, Sawaya R. The influence of maximum safe resection of glioblastoma on survival in 1229 patients: can we do better than gross-total resection?. J Neurosurg 2016; 124 (04) 977-988
• 14 Mangiola A, de Bonis P, Maira G. et al. Invasive tumor cells and prognosis in a selected population of patients with glioblastoma multiforme. Cancer 2008; 113 (04) 841-846
• 15 Arbizu J, Tejada S, Marti-Climent JM. et al. Quantitative volumetric analysis of gliomas with sequential MRI and ¹¹C-methionine PET assessment: patterns of integration in therapy planning. Eur J Nucl Med Mol Imaging 2012; 39 (05) 771-781
• 16 Pirotte BJ, Levivier M, Goldman S. et al. Positron emission tomography-guided volumetric resection of supratentorial high-grade gliomas: a survival analysis in 66 consecutive patients. Neurosurgery 2009; 64 (03) 471-481 , discussion 481
• 17 Suchorska B, Jansen NL, Linn J. et al; German Glioma Network. Biological tumor volume in 18FET-PET before radiochemotherapy correlates with survival in GBM. Neurology 2015; 84 (07) 710-719
• 18 Aldave G, Tejada S, Pay E. et al. Prognostic value of residual fluorescent tissue in glioblastoma patients after gross total resection in 5-aminolevulinic acid-guided surgery. Neurosurgery 2013; 72 (06) 915-920 , discussion 920–921
• 19 Albert FKMD, Forsting M, Sartor K, Adams HP, Kunze S. Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 1994; 34 (01) 45-60 , discussion 60–61
• 20 Piccirillo SG, Dietz S, Madhu B. et al. Fluorescence-guided surgical sampling of glioblastoma identifies phenotypically distinct tumour-initiating cell populations in the tumour mass and margin. Br J Cancer 2012; 107 (03) 462-468
• 21 Skjulsvik AJ, Mørk JN, Torp MO, Torp SH. Ki-67/MIB-1 immunostaining in a cohort of human gliomas. Int J Clin Exp Pathol 2014; 7 (12) 8905-8910
• 22 Kim DK, Hoyt J, Bacchi C. et al. Detection of proliferating cell nuclear antigen in gliomas and adjacent resection margins. Neurosurgery 1993; 33 (04) 619-625 , discussion 625–626