Subventricular Zone Involvement Characterized by Diffusion Tensor Imaging in Glioblastoma

doi:10.1016/j.wneu.2017.06.075

World Neurosurgery

Volume 105, September 2017, Pages 697-701

https://doi.org/10.1016/j.wneu.2017.06.075 Get rights and content

Background

Glioblastomas have a poor prognosis, possibly because of a subpopulation of therapy-resistant stem cells within the heterogeneous glioblastoma. Because the subventricular zone is the main source of neural stem cells, we aimed at characterizing the subventricular zone using diffusion tensor imaging (DTI) to show subventricular zone involvement in glioblastoma.

Methods

We prospectively included 93 patients with primary glioblastomas who underwent preoperative DTI. The nonenhancing high fluid-attenuated inversion recovery (FLAIR) signal was used to describe the infiltrative tumor margin. We used a 5-mm margin surrounding the lateral ventricles to define the subventricular zone. The subventricular zone with high FLAIR was compared with the subventricular zone without high FLAIR, control high FLAIR outside the subventricular zone and control contralateral normal-appearing white matter. Normalized DTI parameters were calculated and compared between the different regions.

Results

The subventricular zone with high FLAIR showed increased isotropic p values compared with the subventricular zone without high FLAIR (t₁₂₆ = 3.9; P < 0.001) and control regions (t₁₇₉ = 1.9; P = 0.046). Anisotropic q and fractional anisotropy values were lower in regions with high FLAIR compared with the subventricular zone without high FLAIR (t₁₈₁ = 11.6, P < 0.001 and t₁₈₄ =12.4, P < 0.001, respectively).

Conclusion

DTI data showed that the subventricular zone is involved in glioblastoma with increased isotropic p values in the subventricular zone with high FLAIR, indicating tumor infiltration.

Introduction

Glioblastoma (GBM) is the most prevalent primary malignant brain tumor in adults.¹ It is associated with most years of life lost despite aggressive therapy consisting of maximal safe resection followed by radiotherapy and concomitant and/or adjuvant temozolomide chemotherapy.2, 3 GBMs are heterogeneous tumors for which local recurrence is unavoidable because of the locally invasive behavior of these tumors.⁴ This local recurrence might result from a subpopulation of neural stem cells within the heterogeneity of GBM that are relatively resistant to the current therapy.⁵

The subventricular zone (SVZ) harbors the largest population of neural stem cells in the brain.⁶ These stem cells were found to be astrocyte precursors that could generate multipotent neurospheres in vitro under the influence of epidermal growth factor and fibroblast growth factor.6, 7, 8, 9 In animals, these stem cells were capable of migrating away from the SVZ.6, 7 Furthermore, fully differentiated astrocytes are less susceptible to malignant transformation than are neural stem cells.¹⁰ Hence, neural stem cells from the SVZ have received increasing interest as the possible cell of origin in GBM.

Despite the importance of the SVZ in relation to tumor initiation and the local recurrence of GBM, only a few imaging studies have focused on the SVZ, mainly relying on conventional magnetic resonance imaging (MRI). However, it is known that conventional MRI does not show the local invasion of GBM that is present outside the contrast enhancement.¹¹ More advanced MRI methods, such as diffusion, better represent the biological behavior and could identify areas of tumor invasion.12, 13

We have previously histologically verified that diffusion tensor imaging (DTI) can show tumor infiltration and disruption of peritumoral white matter outside the contrast enhancement in GBM.¹¹ Because GBM has the tendency to infiltrate along white matter tracts, DTI can detect subtle white matter changes by decomposing the diffusivity into a pure isotropic component (p) and a directional anisotropic component (q).¹⁴ In our image-guided biopsy study we showed that infiltration by tumor cells can be identified by elevated isotropic p components because of vasogenic edema caused by the infiltrating cells, whereas disruption of white matter tracts causes a reduction in anisotropic q component.¹¹

The SVZ might thus play an important role in GBM initiation and local tumor recurrence, but its diffusion imaging characteristics have been unknown. We therefore aimed to characterize the SVZ using DTI to show involvement of the SVZ in GBM. We hypothesized that the presence of tumor cells within the SVZ leads to infiltration and disruption of white matter, with corresponding detectable alterations on DTI.

Section snippets

Patient Population

We prospectively recruited patients with a supratentorial primary GBM suitable for maximal resection surgery and a World Health Organization performance scale of 0–1 between 2010 and 2014. All patients underwent standard therapy consisting of maximal safe surgical resection, followed by concomitant chemoradiotherapy and adjuvant chemotherapy.³ All tumors that were not GBMs in the final pathology report were excluded. All patients underwent preoperative and postoperative MRI scans. The extent of

General Characteristics

Of the 115 initially enrolled patients, 93 met the inclusion criteria and were included in this study. The remaining 22 patients were excluded because histology showed a non-GBM tumor (n = 11), or because radiologic data were not accessible (n = 11). Patients in our cohort had a mean age of 57.6 years (range, 22–74 years) and 75% were males. General characteristics are summarized in Table 1.

Imaging Characteristics of the SVZ

One-way analysis of variance showed that all imaging parameters showed differences between the regions

Discussion

In this study, we characterized the SVZ in relation to GBM using DTI. Our DTI data were suggestive of tumor cells infiltrating the SVZ because isotropic p values were increased in the SVZ with high FLAIR.

Mean isotropic p values in the SVZ with high FLAIR in our study showed an increase of >10% compared with the SVZ without high FLAIR signal. We have previously shown that an increase in isotropic p of >10% corresponds to infiltration by tumor cells.¹¹ The anisotropic q values were not

Conclusions

This study is the first to characterize the SVZ in GBM using diffusion imaging. Because DTI-derived isotropic p values were increased in an area of the SVZ, suggestive of tumor infiltration, we propose that the SVZ is involved in GBM.

References (23)

F. Doetsch et al.
Subventricular zone astrocytes are neural stem cells in the adult mammalian brain
Cell
(1999)
F.G. Dhermain et al.
Advanced MRI and PET imaging for assessment of treatment response in patients with gliomas
Lancet Neurol
(2010)
L. Chen et al.
Increased subventricular zone radiation dose correlates with survival in glioblastoma patients after gross total resection
Int J Radiat Oncol Biol Phys
(2013)
F. Berger et al.
Development of gliomas: potential role of asymmetrical cell division of neural stem cells
Lancet Oncol
(2004)
Q.T. Ostrom et al.
CBTRUS Statistical Report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012
Neuro Oncol
(2015)
N.G. Burnet et al.
Years of life lost (YLL) from cancer is an important measure of population burden–and should be considered when allocating research funds
Br J Cancer
(2005)
R. Stupp et al.
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma
N Engl J Med
(2005)
A. Sottoriva et al.
Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics
Proc Natl Acad Sci U S A
(2013)
R. Galli et al.
Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma
Cancer Res
(2004)
N. Sanai et al.
Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration
Nature
(2004)

A. Alvarez-Buylla et al.

Neurogenesis in adult subventricular zone

J Neurosci

(2002)

Cited by (7)

Quantitative MRI demonstrates abnormalities of the third ventricle subventricular zone in neurofibromatosis type-1 and sporadic paediatric optic pathway glioma
2020, NeuroImage: Clinical
Citation Excerpt :
The subventricular zone of the brain is a germinal niche, mainly composed of neural stem cells, precursor cells and migrating neuroblasts, where neurogenesis continues throughout adulthood (Alvarez-Buylla and García-Verdugo, 2002; Lim and Alvarez-Buylla, 2016) (Fig. 1). Due to the self-renewing ability of these cells, the subventricular zone of the lateral ventricle has been explored, in-vivo and with clinical MRI, as a role-player in gliomagenesis (Piccirillo et al., 2015), cancer cell infiltration (van Dijken et al., 2017) and patient outcome (Lim et al., 2007) in high-grade gliomas. Previous studies have identified a contributing role of the subventricular zone of the third ventricle (TVZ) in NF1-associated OPGs, and animal model experiments indicate that stem cells distally migrate to the optic nerve; after which they differentiate (Ono et al., 1997; Tchoghandjian et al., 2009).
The subventricular zone of the third ventricle (TVZ) is a germinal stem cell niche, identified as the possible location of optic pathway glioma (OPG) cell origin. Paediatric OPGs are predominantly diagnosed as low-grade astrocytomas, which are either sporadic or are associated with neurofibromatosis type-1 (NF1). These tumours often cause a significant impairment to visual acuity (VA). Infiltrative/invasive tumour activity is associated with increased apparent diffusion coefficient (ADC) and cerebral blood flow (CBF). This study aimed to determine whether TVZ imaging features differed between sporadic-OPG, NF1-OPG and controls, and whether the ADC and CBF profile at the germinal stem cell niche (the TVZ) correlated with the primary outcome of VA.
ADC and CBF MRI data were acquired from 30 paediatric OPG patients (median age 6 years; range 8 months–17 years), along with VA measurements, during clinical surveillance of their tumour. Values for mean ADC and maximum CBF were measured at the TVZ, and normalized to normal-appearing grey matter. These values were compared between the two OPG groups and the healthy control subjects, and multivariate linear regression was used to test the linear association between these values and patient’s VA.
In the TVZ, normalized mean ADC was higher in NF1-associated OPG patients (N = 15), compared to both sporadic OPG patients (N = 15; p = 0.010) and healthy controls (N = 14; p < 0.001). In the same region, normalized maximum CBF was higher in sporadic OPG patients compared to both NF1-OPG patients (p = 0.016) and healthy controls (p < 0.001). In sporadic OPG patients only, normalized mean ADC in the TVZ was significantly correlated with visual acuity (R² = 0.41, p = 0.019). No significant correlations were found between TVZ CBF and ADC values and visual acuity in the NF1-associated OPG patients.
Quantitative MRI detects TVZ abnormalities in both sporadic and NF1-OPG patients, and identifies TVZ features that differentiate the two. TVZ features may be useful MRI markers of interest in future predictive studies involving sporadic OPG.
Multi-Modal Learning for Predicting the Genotype of Glioma
2023, IEEE Transactions on Medical Imaging
Structural connectome quantifies tumour invasion and predicts survival in glioblastoma patients
2023, Brain
Immunohistochemical Detection of Neural Stem Cells and Glioblastoma Stem Cells in the Subventricular Zone of Glioblastoma Patients
2021, Journal of Histochemistry and Cytochemistry
Magnetic Resonance Features of Lower-grade Gliomas in Prediction of the Reverse Phase Protein A
2021, Journal of Computer Assisted Tomography
Role and mechanism of neural stem cells of the subventricular zone in glioblastoma
2021, World Journal of Stem Cells

View all citing articles on Scopus

: Conflict of interest statement: This study was funded by a National Institute of Health Clinician Scientist Fellowship (S.P.), the Groningen University Fund (B.D.), the Marco Polo fund (B.D.), and grants from the Chang Gung Medical Foundation and Chang Gung Memorial Hospital, Keelung, Taiwan (J.Y.). The authors declare to have no conflicts of interest. This article presents independent research funded by the United Kingdom National Institute for Health Research. The views expressed are those of the author(s) and are not necessarily those of the United Kingdom National Health Service, the United Kingdom National Institute for Health Research, or the United Kingdom Department of Health.

View full text

Original ArticleSubventricular Zone Involvement Characterized by Diffusion Tensor Imaging in Glioblastoma

Background

Methods

Results

Conclusion

Introduction

Section snippets

Patient Population

General Characteristics

Imaging Characteristics of the SVZ

Discussion

Conclusions

Cell

Lancet Neurol

Int J Radiat Oncol Biol Phys

Lancet Oncol

CBTRUS Statistical Report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012

Neuro Oncol

Years of life lost (YLL) from cancer is an important measure of population burden–and should be considered when allocating research funds

Br J Cancer

Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma

N Engl J Med

Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics

Proc Natl Acad Sci U S A

Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma

Cancer Res

Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration

Nature

Neurogenesis in adult subventricular zone

J Neurosci

Original Article
Subventricular Zone Involvement Characterized by Diffusion Tensor Imaging in Glioblastoma