The prognostic role of Ki67, p53, Her2, and CyD1 immunohistochemical markers in recurrent parasagittal meningiomas
Keywords:parasagittal meningioma, parasagittal meningioma surgery, superior sagittal sinus, prolonged growth, recurrence, prognosis, risk factors, Ki67, p53, CyD1, Her2
Objective. Determine the role of Ki67, p53, Her2, and CyD1 immunohistochemical markers in predicting the recurrence of parasagittal meningiomas
Materials and Methods. The immunohistochemical (IHC) study was conducted in 26 parasagittal meningioma (PM) patients aged 36 to 72, who were treated in the Mechnikov Dnipropetrovsk Regional Clinical Hospital from 2000 to 2021 inclusive. 26 patients were divided into 2 equal groups with the most similar characteristics (patient’s gender, age, and meningioma malignancy as of the time of primary surgery) using the balancing method (pairwise selection). The study group consisted of 13 (50%) patients with detected postoperative PM recurrence/prolonged growth, while the control group included the remaining 13 (50%) patients with no PM recurrence. To evaluate prospects of further studies, the expression of the following markers by the tumor was analyzed: cell proliferation (Ki67), genome stability (p53 protein), dysfunction of epidermal growth factor signaling pathways (ERBB2 or Her-2/neu (Her2)), and cell cycle regulators (cyclin D1 (CyD1)).
Results. An association between the PM’s high proliferative activity and its recurrence was moderate (rs=0.44, р=0.025). Median Ki-67 in the study PM group (with recurrence) was three times higher than that in the control group (no recurrence) — 6.0% (4.0%; 9.0%) vs. 2.0% (0.5%; 4.5%) (p=0.029). In the case of Ki67 expression > 4.5%, the risk of PM recurrence/prolonged growth increased by 7.5 times (OR=7.5; 95% CI (1.3–43.0)) (area under the ROC curve, AUC=0.751 (95% CI, 0.544–0.898), p=0.011). The comparative and correlation analysis found no significant association between the p53 protein mutation and the PM recurrence (rs=0.23, р=0.254). Neither we found a significant association between the PM recurrence and the CyD1 expression (rs=0.29, р=0.147) or severity (rs=-0.08, р=0.696). The correlation between the Her2 expression in the PM cells and the PM recurrence was insignificant (rs=0.23, р=0.251). The primary PM malignancy (Grade II–III) increases the risk of unfavorable prognosis by 5.3 times (95% CI, 1.0–29.4) (AUC= 0.722) (95% CI, 0.513–0.878); p=0.016, sensitivity= 61.5%, specificity= 76.9%.
Conclusions. The following can be considered probable predictors of the PM recurrence after the primary surgery (within 20 years of follow-up): Ki67 proliferation index > 4.5% and grade II–III tumor malignancy. The comparative and correlation analysis found no statistically significant association between the tumor recurrence and the p53, Her2, and CyD1 immunohistochemical markers. However, the detected significant correlation between the p53, Her2, and CyD1 markers expression and the Ki67 proliferative index and tumor malignancy requires further research with a larger number of clinical observations.
1. Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2012-2016. Neuro Oncol. 2019 Nov 1;21(Suppl 5):v1-v100. [CrossRef] [PubMed] [PubMed Central]
3. Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, Ohgaki H, Wiestler OD, Kleihues P, Ellison DW. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016 Jun;131(6):803-20. [CrossRef] [PubMed]
4. Goldbrunner R, Minniti G, Preusser M, Jenkinson MD, Sallabanda K, Houdart E, von Deimling A, Stavrinou P, Lefranc F, Lund-Johansen M, Moyal EC, Brandsma D, Henriksson R, Soffietti R, Weller M. EANO guidelines for the diagnosis and treatment of meningiomas. Lancet Oncol. 2016 Sep;17(9):e383-91. [CrossRef] [PubMed]
5. Balik V, Kourilova P, Sulla I, Vrbkova J, Srovnal J, Hajduch M, Takizawa K. Recurrence of surgically treated parasagittal meningiomas: a meta-analysis of risk factors. Acta Neurochir (Wien). 2020 Sep;162(9):2165-2176. [CrossRef] [PubMed]
7. Marciscano AE, Stemmer-Rachamimov AO, Niemierko A, Larvie M, Curry WT, Barker FG 2nd, Martuza RL, McGuone D, Oh KS, Loeffler JS, Shih HA. Benign meningiomas (WHO Grade I) with atypical histological features: correlation of histopathological features with clinical outcomes. J Neurosurg. 2016 Jan;124(1):106-14. [CrossRef] [PubMed]
8. von Spreckelsen N, Kesseler C, Brokinkel B, Goldbrunner R, Perry A, Mawrin C. Molecular neuropathology of brain-invasive meningiomas. Brain Pathol. 2022 Mar;32(2):e13048. [CrossRef] [PubMed] [PubMed Central]
10. Amano T, Nakamizo A, Murata H, Miyamatsu Y, Mugita F, Yamashita K, Noguchi T, Nagata S. Preoperative Prediction of Intracranial Meningioma Grade Using Conventional CT and MRI. Cureus. 2022 Jan 25;14(1):e21610. [CrossRef] [PubMed] [PubMed Central]
12. Behzadmehr R, Behzadmehr R. Are the clinical manifestations of CT scan and location associated with World Health Organization histopathological grades of meningioma?: A retrospective study. Ann Med Surg (Lond). 2021 Apr 30;66:102365. [CrossRef] [PubMed] [PubMed Central]
13. Cucu AI, Turliuc MD, Costea CF, Dascălu CG, Dumitrescu GF, Sava A, Turliuc Ş, Scripcariu DV, Poeată I. Tumor recurrence in parasagittal and falcine atypical meningiomas invading the superior sagittal sinus. Rom J Morphol Embryol. 2020 Apr-Jun;61(2):385-395. [CrossRef] [PubMed] [PubMed Central]
14. Escribano Mesa JA, Alonso Morillejo E, Parrón Carreño T, Huete Allut A, Narro Donate JM, Méndez Román P, Contreras Jiménez A, Pedrero García F, Masegosa González J. Risk of Recurrence in Operated Parasagittal Meningiomas: A Logistic Binary Regression Model. World Neurosurg. 2018 Feb;110:e112-e118. [CrossRef] [PubMed]
15. Perepelytsia V, Sirko A. Prognostic Factors for Parasagital Meningiomas Recurrence. Ukrainian Scientific Medical Youth Journal. 2023 Mar; 1(136):68-83. [CrossRef]
16. Trosh RM, Shamaev MI, Onishchenko PM, Malysheva TA, Fedirko VO. [The peculiarities of topography and microsurgical anatomy of the petroclival meningiomas with sub- supratentorial growth]. Ukrainian Neurosurgical Journal. 2004;(1):39-43. Ukrainian.
17. de Carvalho GTC, da Silva-Martins WC, de Magalhães KCSF, Nunes CB, Soares AN, Tafuri LSA, Simões RT. Recurrence/Regrowth in Grade I Meningioma: How to Predict? Front Oncol. 2020 Aug 4;10:1144. [CrossRef] [PubMed] [PubMed Central]
19. Abtahi S, Hakimrabet S, Malekzadeh M, Deghanian AR, Ghaderi A. Investigating the Levels of Soluble Extracellular Domain of HER2 Protein in the Sera of Meningioma Patients. Turk Neurosurg. 2019;29(1):9-13. [CrossRef] [PubMed]
20. Wang S, Liu X, Wang W, Tu Y, Wang C, Mei J, Xiong J. The Effects of Silencing the Her2 Gene on Proliferation and Angiogenesis of Meningioma Cells in vivo and in vitro. Ann Clin Lab Sci. 2018 Sep;48(5):580-586. [PubMed]
21 Lee SH, Lee EH, Sung KS, Kim DC, Kim YZ, Song YJ. Ki67 Index Is the Most Powerful Factor for Predicting the Recurrence in Atypical Meningioma : Retrospective Analysis of 99 Patients in Two Institutes. J Korean Neurosurg Soc. 2022 Jul;65(4):558-571. [CrossRef] [PubMed] [PubMed Central]
23. Liu N, Song SY, Jiang JB, Wang TJ, Yan CX. The prognostic role of Ki-67/MIB-1 in meningioma: A systematic review with meta-analysis. Medicine (Baltimore). 2020 Feb;99(9):e18644. [CrossRef] [PubMed] [PubMed Central]
24. Zozulya YA, Kvasha MS, Shamaev MI, Malysheva TA. [Pathogenetic approach to the treatment of hormone-dependent brain meningiomas]. Ukrainian Neurosurgical Journal. 2003;(2):33-42. Russian.
26. Cheng G, Zhang L, Lv W, Dong C, Wang Y, Zhang J. Overexpression of cyclin D1 in meningioma is associated with malignancy grade and causes abnormalities in apoptosis, invasion and cell cycle progression. Med Oncol. 2015 Jan;32(1):439. [CrossRef] [PubMed]
27. Abdelzaher E, El-Gendi SM, Yehya A, Gowil AG. Recurrence of benign meningiomas: predictive value of proliferative index, BCL2, p53, hormonal receptors and HER2 expression. Br J Neurosurg. 2011 Dec;25(6):707-13. [CrossRef] [PubMed]
29. Pećina-Šlaus N, Kafka A, Vladušić T, Tomas D, Logara M, Skoko J, Hrašćan R. Loss of p53 expression is accompanied by upregulation of beta-catenin in meningiomas: a concomitant reciprocal expression. Int J Exp Pathol. 2016 Apr;97(2):159-69. [CrossRef] [PubMed] [PubMed Central]
30. Trott G, Pereira-Lima JF, Leães CG, Ferreira NP, Barbosa-Coutinho LM, Oliveira MC. Abundant immunohistochemical expression of dopamine D2 receptor and p53 protein in meningiomas: follow-up, relation to gender, age, tumor grade, and recurrence. Braz J Med Biol Res. 2015 May;48(5):415-9. [CrossRef] [PubMed] [PubMed Central]
31. Ongaratti BR, Silva CB, Trott G, Haag T, Leães CG, Ferreira NP, Oliveira MC, Pereira-Lima JF. Expression of merlin, NDRG2, ERBB2, and c-MYC in meningiomas: relationship with tumor grade and recurrence. Braz J Med Biol Res. 2016;49(4):e5125. [CrossRef] [PubMed] [PubMed Central]
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