Top

Published in:

01-12-2021 | Glioma | Research article

Clinicopathologic analysis of microscopic tumor extension in glioma for external beam radiotherapy planning

Authors: Shulun Nie, Yufang Zhu, Jia Yang, Tao Xin, Song Xue, Jujie Sun, Dianbin Mu, Zhaoqiu Chen, Pengpeng Sun, Jinming Yu, Man Hu

Published in: BMC Medicine | Issue 1/2021

Abstract

Background

There is no consensus regarding the clinical target volume (CTV) margins in radiotherapy for glioma. In this study, we aimed to perform a complete macropathologic analysis examining microscopic tumor extension (ME) to more accurately define the CTV in glioma.

Methods

Thirty-eight supra-total resection specimens of glioma patients were examined on histologic sections. The ME distance, defined as the maximum linear distance from the tumor border to the invasive tumor cells, was measured at each section. We defined the CTV based on the relationships between ME distance and clinicopathologic features.

Results

Between February 2016 and July 2020, a total of 814 slides were examined, corresponding to 162 slides for low-grade glioma (LGG) and 652 slides for high-grade glioma (HGG). The ME value was 0.69 ± 0.43 cm for LGG and 1.29 ± 0.54 cm for HGG (P < 0.001). After multivariate analysis, tumor grade, O⁶-methylguanine-DNA-methyltransferase promoter methylated status (MGMT_m), isocitrate dehydrogenase wild-type status (IDH_wt), and 1p/19q non-co-deleted status (non-codel) were positively correlated with ME distance (all P < 0.05). We defined the CTV of glioma based on tumor grade. To take into account approximately 95% of the ME, a margin of 1.00 cm, 1.50 cm, and 2.00 cm were chosen for grade II, grade III, and grade IV glioma, respectively. Paired analysis of molecularly defined patients confirmed that tumors that had all three molecular alterations (i.e., MGMT_m/IDH_wt/non-codel) were the most aggressive subgroups (all P < 0.05). For these patients, the margin could be up to 1.50 cm, 2.00 cm, and 2.50 cm for grade II, grade III, and grade IV glioma, respectively, to cover the subclinical lesions in 95% of cases.

Conclusions

The ME was different between the grades of gliomas. It may be reasonable to recommend 1.00 cm, 1.50 cm, and 2.00 cm CTV margins for grade II, grade III, and grade IV glioma, respectively. Considering the highly aggressive nature of MGMT_m/IDH_wt/non-codel tumors, for these patients, the margin could be further expanded by 0.5 cm. These recommendations would encompass microscopic disease extension in 95% of cases.

Trial registration

The trial was registered with Chinese Clinical Trial Registry (ChiCTR2100049376).

Available only for authorised users

Kruchko C, Ostrom QT, Gittleman H, Barnholtz-Sloan JS. The CBTRUS story: providing accurate population-based statistics on brain and other central nervous system tumors for everyone. Neuro Oncol. 2018; 20(3):295-298. https://doi.org/10.1093/neuonc/noy006.

Niyazi M, Brada M, Chalmers AJ, Combs SE, Erridge SC, Fiorentino A, Grosu AL, Lagerwaard FJ, Minniti G, Mirimanoff RO, Ricardi U, Short SC, Weber DC, Belka C ESTRO-ACROP guideline “target delineation of glioblastomas”. Radiother Oncol. 2016; 118(1):35-42. https://doi.org/10.1016/j.radonc.2015.12.003.

Stupp R, Hegi ME, Gorlia T, Erridge SC, Perry J, Hong YK, Aldape KD, Lhermitte B, Pietsch T, Grujicic D, Steinbach JP, Wick W, Tarnawski R, Nam DH, Hau P, Weyerbrock A, Taphoorn MJ, Shen CC, Rao N, Thurzo L, Herrlinger U, Gupta T, Kortmann RD, Adamska K, McBain C, Brandes AA, Tonn JC, Schnell O, Wiegel T, Kim CY, Nabors LB, Reardon DA, van den Bent M, Hicking C, Markivskyy A, Picard M, Weller M, European Organisation for Research and Treatment of Cancer (EORTC)., Canadian Brain Tumor Consortium., CENTRIC study team. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2014; 15(10):1100-1108. https://doi.org/10.1016/s1470-2045(14)70379-1.

Chang EL, Akyurek S, Avalos T, Rebueno N, Spicer C, Garcia J, Famiglietti R, Allen PK, Chao KSC, Mahajan A, Woo SY, Maor MH Evaluation of peritumoral edema in the delineation of radiotherapy clinical target volumes for glioblastoma. Int J Radiat Oncol Biol Phys. 2007; 68(1):144-150. https://doi.org/10.1016/j.ijrobp.2006.12.009.

Aydin H, Sillenberg I, von Lieven H. Patterns of failure following CT-based 3-D irradiation for malignant glioma. Strahlenther Onkol. 2001; 177(8):424-431. https://doi.org/10.1007/pl00002424.

Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014; 370(8):709-722. https://doi.org/10.1056/NEJMoa1308345.

Yamahara T, Numa Y, Oishi T, Kawaguchi T, Seno T, Asai A, Kawamoto K. Morphological and flow cytometric analysis of cell infiltration in glioblastoma: a comparison of autopsy brain and neuroimaging. Brain Tumor Pathol. 2010; 27(2):81-87. https://doi.org/10.1007/s10014-010-0275-7.

Eidel O, Burth S, Neumann JO, Kieslich PJ, Sahm F, Jungk C, Kickingereder P, Bickelhaupt S, Mundiyanapurath S, Bäumer P, Wick W, Schlemmer HP, Kiening K, Unterberg A, Bendszus M, Radbruch A Tumor infiltration in enhancing and non-enhancing parts of glioblastoma: a correlation with histopathology. PLoS One. 2017; 12(1):e0169292. https://doi.org/10.1371/journal.pone.0169292.

National Comprehensive Cancer Network. (NCCN) Clinical Practice Guidelines in Oncology. Central Nervous System Cancers, Version 1. 2021. https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed 4 Jun 2021. In.

10.

Mangiola A, de Bonis P, Maira G, Balducci M, Sica G, Lama G, Lauriola L, Anile C Invasive tumor cells and prognosis in a selected population of patients with glioblastoma multiforme. Cancer. 2008; 113(4):841-846. https://doi.org/10.1002/cncr.23624.

11.

Field A. Everything you never wanted to know about statistics. In: Discovering Statistics Using IBM SPSS Statistics: And Sex and Drugs and Rock ‘n’ Roll. Los Angeles, CA: Sage; 2013. p. 40–88.

12.

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; 131(6):803-820. https://doi.org/10.1007/s00401-016-1545-1.

13.

Nie S, Zhu Y, Yang J, Xin T, Xue S, Zhang X, Sun J, Mu D, Gao Y, Chen Z, Ding X, Yu J, Hu M Determining optimal clinical target volume margins in high-grade glioma based on microscopic tumor extension and magnetic resonance imaging. Radiat Oncol. 2021; 16(1):97. https://doi.org/10.1186/s13014-021-01819-0.

14.

Louis DN. Molecular pathology of malignant gliomas. Annu Rev Pathol. 2006; 1:97-117. https://doi.org/10.1146/annurev.pathol.1.110304.100043, 1.

15.

Xie WJ, Wu X, Xue RL, Lin XY, Kidd EA, Yan SM, Zhang YH, Zhai TT, Lu JY, Wu LL, Zhang H, Huang HH, Chen ZJ, Li DR, Xie LX More accurate definition of clinical target volume based on the measurement of microscopic extensions of the primary tumor toward the uterus body in international federation of gynecology and obstetrics Ib-IIa squamous cell carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 2015; 91(1):206-212. https://doi.org/10.1016/j.ijrobp.2014.09.009.

16.

Nguyen BT, Deb S, Fox S, Hill P, Collins M, Chua BH. A prospective pathologic study to define the clinical target volume for partial breast radiation therapy in women with early breast cancer. Int J Radiat Oncol Biol Phys. 2012; 84(5):1116-1122. https://doi.org/10.1016/j.ijrobp.2012.02.038.

17.

Wang W, Feng X, Zhang T, Jin J, Wang S, Liu Y, Song Y, Liu X, Yu Z, LI Y. Prospective evaluation of microscopic extension using whole-mount preparation in patients with hepatocellular carcinoma: Definition of clinical target volume for radiotherapy. Radiat Oncol. 2010; 5:73. https://doi.org/10.1186/1748-717x-5-73, 1.

18.

Nixon IJ, Ganly I, Patel S, Palmer FL, Whitcher MM, Tuttle RM, Shaha AR, Shah JP The impact of microscopic extrathyroid extension on outcome in patients with clinical T1 and T2 well-differentiated thyroid cancer. Surgery. 2011; 150(6):1242-1249. https://doi.org/10.1016/j.surg.2011.09.007.

19.

Meynard C, Mansuet-Lupo A, Giraud N, Boulle G, Imbault P, Guénégou-Arnoux A, Bobbio A, Durdux C, Damotte D, Giraud P Size and predictive factors of microscopic tumor extension in locally advanced non-small cell lung cancer. Pract Radiat Oncol. 2021; https://doi.org/10.1016/j.prro.2021.05.006.

20.

Whitfield GA, Kennedy SR, Djoukhadar IK, Jackson A. Imaging and target volume delineation in glioma. Clin Oncol (R Coll Radiol). 2014; 26(7):364-376. https://doi.org/10.1016/j.clon.2014.04.026.

21.

Castellano A, Bailo M, Cicone F, Carideo L, Quartuccio N, Mortini P, et al. Advanced imaging techniques for radiotherapy planning of gliomas. Cancers (Basel). 2021; 13(5). https://doi.org/10.3390/cancers13051063.

22.

Mair DB, Ames HM, Li R. Mechanisms of invasion and motility of high-grade gliomas in the brain. Mol Biol Cell. 2018; 29(21):2509-2515. https://doi.org/10.1091/mbc.E18-02-0123.

23.

Wank M, Schilling D, Schmid TE, Meyer B, Gempt J, Barz M, et al. Human glioma migration and infiltration properties as a target for personalized radiation medicine. Cancers (Basel). 2018; 10(11). https://doi.org/10.3390/cancers10110456.

24.

Brandes AA, Tosoni A, Franceschi E, Sotti G, Frezza G, Amistà P, Morandi L, Spagnolli F, Ermani M Recurrence pattern after temozolomide concomitant with and adjuvant to radiotherapy in newly diagnosed patients with glioblastoma: correlation With MGMT promoter methylation status. J Clin Oncol. 2009; 27(8):1275-1279. https://doi.org/10.1200/jco.2008.19.4969.

25.

Minniti G, Amelio D, Amichetti M, Salvati M, Muni R, Bozzao A, Lanzetta G, Scarpino S, Arcella A, Enrici RM. Patterns of failure and comparison of different target volume delineations in patients with glioblastoma treated with conformal radiotherapy plus concomitant and adjuvant temozolomide. Radiother Oncol. 2010; 97(3):377-381. /https://doi.org/10.1016/j.radonc.2010.08.020.

26.

Choi SH, Kim JW, Chang JS, Cho JH, Kim SH, Chang JH, Suh CO Impact of including peritumoral edema in radiotherapy target volume on patterns of failure in glioblastoma following temozolomide-based chemoradiotherapy. Sci Rep. 2017; 7:42148. https://doi.org/10.1038/srep42148.

27.

Liang HT, Chen WY, Lai SF, Su MY, You SL, Chen LH, et al. The extent of edema and tumor synchronous invasion into the subventricular zone and corpus callosum classify outcomes and radiotherapy strategies of glioblastomas. Radiother Oncol. 2017; 125(2):248-257. https://doi.org/10.1016/j.radonc.2017.09.024.

28.

Cuddapah VA, Robel S, Watkins S, Sontheimer H. A neurocentric perspective on glioma invasion. Nat Rev Neurosci. 2014; 15(7):455-465. https://doi.org/10.1038/nrn3765.

29.

Sharifi G, Pajavand AM, Nateghinia S, Meybodi TE, Hasooni H. Glioma migration through the corpus callosum and the brainstem detected by diffusion and magnetic resonance imaging: initial findings. Front Hum Neurosci. 2019; 13:472. https://doi.org/10.3389/fnhum.2019.00472.

30.

D'Souza S, Ormond DR, Costabile J, Thompson JA. Fiber-tract localized diffusion coefficients highlight patterns of white matter disruption induced by proximity to glioma. PLoS One. 2019; 14(11):e0225323. https://doi.org/10.1371/journal.pone.0225323.

31.

Wang X, Zhou C, Wang L, Wang Y, Jiang T. Motor cortex gliomas induces microstructural changes of large fiber tracts revealed by TBSS. Sci Rep. 2020; 10(1):16900. https://doi.org/10.1038/s41598-020-73746-1.

32.

Unkelbach J, Menze BH, Konukoglu E, Dittmann F, Le M, Ayache N, et al. Radiotherapy planning for glioblastoma based on a tumor growth model: improving target volume delineation. Phys Med Biol. 2014; 59(3):747-770. https://doi.org/10.1088/0031-9155/59/3/747.

Title: Clinicopathologic analysis of microscopic tumor extension in glioma for external beam radiotherapy planning
Authors: Shulun Nie
Yufang Zhu
Jia Yang
Tao Xin
Song Xue
Jujie Sun
Dianbin Mu
Zhaoqiu Chen
Pengpeng Sun
Jinming Yu
Man Hu
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Glioma
Glioma
Radiotherapy
Glioma
Published in: BMC Medicine / Issue 1/2021
Electronic ISSN: 1741-7015
DOI: https://doi.org/10.1186/s12916-021-02143-w

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Clinicopathologic analysis of microscopic tumor extension in glioma for external beam radiotherapy planning

Abstract

Background

Methods

Results

Conclusions

Trial registration

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2021

Evaluation of glycemic traits in susceptibility to COVID-19 risk: a Mendelian randomization study

EPHA7 mutation as a predictive biomarker for immune checkpoint inhibitors in multiple cancers

Paediatric rotavirus vaccination, coeliac disease and type 1 diabetes in children: a population-based cohort study

Following the science? Comparison of methodological and reporting quality of covid-19 and other research from the first wave of the pandemic

Renin-angiotensin system blockers and COVID-19

Homocysteine, B vitamins, and cardiovascular disease: a Mendelian randomization study